Conditions: Renal Impairment
Allocation: NA | Intervention model: PARALLEL
Enrollment: 23
Healthy volunteers: yes

Brief summary:
This study is a phase 1 non-randomized, open-label, single-dose, parallel-group study of PF 04965842 in subjects with severe renal impairment and subjects without renal impairment (Part 1) and in subjects with moderate renal impairment (Part 2).

Detailed description:
This is a Phase 1 non randomized, open label, single dose, parallel cohort, multisite study to investigate the effect of renal impairment on the pharmacokinetics, safety and tolerability of PF-04965842 after a single 200 mg oral dose. Subjects will be selected and categorized into normal renal function or renal impairment groups based on their estimated glomerular filtration rate. Part 1: A total of approximately16 subjects will be enrolled; approximately 8 subjects with severe renal impairment and approximately 8 with normal renal function. After statistical evaluation of results from Part 1, Part 2 may be conducted and approximately 8 subjects with moderate renal impairment will be enrolled. The total duration of participation from the Screening Visit to Day 4 will be a maximum of 31 days and from the Screening Visit to Follow-up Contact/Visit will be a maximum of 67 days.

Arms:
arm 1: PF 04965842 is an oral selevtive janus kinase (JAK) 1 inhibitor

Interventions: intervention 1: PF-04965842
Intervention descriptions: intervention 1: PF 04965842 is a janus kinase (JAK) 1 inhibitor that is currently being developed for the treatment of atopic dermatitis (AD).

Protocol document:
Prot_000.pdf: 
PF-04965842 
B7451021
Protocol Amendment #1, 30 July 2019
PFIZER CONFIDENTIAL
Page 1
A PHASE 1, NON-RANDOMIZED, OPEN-LABEL, SINGLE-DOSE STUDY TO 
EVALUATE THE PHARMACOKINETICS, SAFETY AND TOLERABILITY OF 
PF-04965842 IN SUBJECTS WITH RENAL IMPAIRMENT AND IN HEALTHY 
SUBJECTS WITH NORMAL RENAL FUNCTION
Investigational Product Number:
PF-04965842
Investigational Product Name:
Not Applicable (N/A)
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
2018-002865-20
Protocol Number:
B7451021
Phase:
1
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this information in 
confidence and not copy or disclose it to others (except where required by applicable law) or use it for 
unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer must be 
promptly notified.
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Document History
Document
Version 
Date
Summary of Changes and Rationale
Original protocol
30 July 2018
Not applicable (N/A)
Amendment #1
30 July 2019
Changes are being made in Amendment 1 due to the 
pharmacological activity of 2 of the  major circulating 
metabolites of PF-04965842. In order to take into 
account the effects of renal impairment on the 
pharmaconetics of the PF-04965842 as well as its 
active metabolites, the active moiety exposure will be 
determined as outlined in the protocol Amendment 1. 
Accordingly, the decision criterion for Part 2 of the 
study will be based on ratio of active moiety AUC 
values in severe renal impairment vs. normal renal 
function groups in Part 1. In Part 2, the study will 
enroll only subjects with moderate renal impairment, 
and the effects in mild renal impairment, if expected 
based on results in moderate group, will be estimated 
based on modeling of results from all the subjects in 
the study.
•
Updated Inclusion #4 & Exclusion # 9 per 
PACL dated 13 Aug 2018.
•
Rationale: required to be included in a 
future amendment per sponsor SOP.
•
Updated Exclusion #12 & 13 and Sections 4.2 
& 5.7 per PACL dated 07 Jan 2019.
•
Rationale: required to be included in a 
future amendment per sponsor SOP.
•
Removed footnote “a” from Table 3.
•
Rationale: subjects should have total bili, 
direct bili, and indirect bili performed at the 
same time as the reflex of direct/indirect 
bili.
•
Removed references to mild renal impairment 
subjects in protocol.
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
Rationale: not planned to be included in 
Part 2.

Added “active metabolites PF-06471658 and 
PF-07055087” where applicable.

Rationale:

Revised statistical method due to removal of 
mild subjects and inclusion of active 
metabolites PF-06471658 and PF-07055087.

Rationale:

Corrected spelling & administrative errors.

Rationale: identified during amendment # 
writing.


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Protocol Amendment #1, 30 July 2019
PFIZER CONFIDENTIAL
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................8
LIST OF FIGURES ...................................................................................................................8
APPENDICES ...........................................................................................................................8
PROTOCOL SUMMARY.........................................................................................................9
SCHEDULE OF ACTIVITIES................................................................................................14
1. INTRODUCTION ...............................................................................................................17
1.1. Mechanism of Action/Indication.............................................................................17
1.2. Background .............................................................................................................18
1.2.1. Overview of Disease State..........................................................................18
1.2.2. Rationale for Development of PF-04965842..............................................18
1.2.3. Previous Human Experience with PF-04965842........................................18
1.2.3.1. Summary of Safety Data from Completed Clinical Studies .....19
1.2.3.2. Summary of PF-04965842 Pharmacokinetics, Metabolism 
and In Vitro Enzymology..................................................................20
1.3. Rationale..................................................................................................................22
1.3.1. Study Rationale...........................................................................................22
1.3.2. Study Population Rationale ........................................................................23
1.3.3. Study Design Rationale ..............................................................................23
1.3.4. Dose Rationale............................................................................................24
................................24
1.4. Summary of Benefit Risk Assessment....................................................................25
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................25
3. STUDY DESIGN.................................................................................................................26
3.1. Study Overview.......................................................................................................26
4. SUBJECT ELIGIBILITY CRITERIA.................................................................................30
4.1. Inclusion Criteria.....................................................................................................30
4.1.1. All Subjects:................................................................................................30
4.1.2. Additional Inclusion Criteria for Healthy Subjects with Normal 
Renal Function (Cohort 1 only) .......................................................................31
4.1.3. Additional Inclusion Criteria for Subjects with Impaired Renal 
Function (Cohort 2 and Cohorts 3 & 4 [if applicable] only)............................32
4.2. Exclusion Criteria....................................................................................................32
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4.2.1. All Subjects.................................................................................................32
4.2.2. Additional Exclusion Criteria for Healthy Subjects with Normal
Renal Function (Cohort 1, only) ......................................................................35
4.2.3. Additional Exclusion Criteria for Subjects with Impaired Renal 
Function (Cohort 2 and Cohorts 3 & 4 [if applicable] only)............................36
4.3. Enrollment Criteria..................................................................................................36
4.4. Lifestyle Requirements ...........................................................................................36
4.4.1. Meals and Dietary Restrictions...................................................................36
4.4.2. Alcohol, Caffeine, and Tobacco .................................................................37
4.4.3. Activity .......................................................................................................37
4.4.4. Contraception..............................................................................................37
4.5. Sponsor’s Qualified Medical Personnel..................................................................38
5. STUDY TREATMENTS.....................................................................................................39
5.1. Allocation to Treatment ..........................................................................................39
5.2. Subject Compliance.................................................................................................39
5.3. Investigational Product Supplies.............................................................................39
5.3.1. Dosage Form and Packaging ......................................................................39
5.3.2. Preparation and Dispensing........................................................................39
5.4. Administration.........................................................................................................40
5.5. Investigational Product Storage ..............................................................................40
5.6. Investigational Product Accountability...................................................................41
5.6.1. Destruction of Investigational Product Supplies ........................................41
5.7. Concomitant Treatment(s).......................................................................................41
5.7.1. Subjects with Healthy Renal Function (Cohort 1 Only).............................42
5.7.2. Subjects with Impaired Renal Function (Cohort 2 and Cohorts 3 and 
4 [if applicable])...............................................................................................42
5.8. Rescue Medication ..................................................................................................42
6. STUDY PROCEDURES .....................................................................................................43
6.1. Proposed Chronology of Procedures.......................................................................43
6.2. Screening.................................................................................................................43
6.3. Study Period ............................................................................................................44
6.4. Follow-up ................................................................................................................44
6.5. Subject Withdrawal/Early Termination ..................................................................44


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7. ASSESSMENTS..................................................................................................................46
7.1. Safety.......................................................................................................................46
7.1.1. Laboratory Tests .........................................................................................46
7.1.1.1. Hepatitis Testing .......................................................................48
7.1.1.2. Tuberculosis Testing: ................................................................48
7.1.2. Pregnancy Testing ......................................................................................49
7.1.3. Physical Examinations................................................................................50
7.1.4. Blood Pressure and Pulse Rate ...................................................................50
7.1.5. Electrocardiogram.......................................................................................50
7.2. Pharmacokinetics ....................................................................................................51
7.2.1. Plasma for Analysis of PF-04965842 and Metabolites, PF-06471658, 
PF-07055087 and 
......................................................................51
 
......................................................................52
..................................................................................................52
..................................................................................52
.............................................................................................53
....................................................................................54
7.5. Blood Volume .........................................................................................................54
8. ADVERSE EVENT REPORTING......................................................................................54
8.1. Requirements...........................................................................................................54
8.1.1. Additional Details on Recording Adverse Events on the CRF...................55
8.1.2. Eliciting Adverse Event Information..........................................................55
8.1.3. Withdrawal From the Study Due to Adverse Events (see also Section 
6.5) ...................................................................................................................55
8.1.4. Time Period for Collecting AE/SAE Information......................................56
8.1.4.1. Reporting SAEs to Pfizer Safety...............................................56
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF .................56
8.1.5. Causality Assessment .................................................................................56
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................57
8.2. Definitions...............................................................................................................57
8.2.1. Adverse Events...........................................................................................57
8.2.2. Abnormal Test Findings .............................................................................58
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8.2.3. Serious Adverse Events ..............................................................................58
8.2.4. Hospitalization............................................................................................59
8.3. Severity Assessment................................................................................................60
8.4. Special Situations ....................................................................................................60
8.4.1. Potential Cases of Drug-Induced Liver Injury............................................60
8.4.2. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................62
8.4.2.1. Exposure During Pregnancy......................................................62
8.4.2.2. Exposure During Breastfeeding ................................................63
8.4.2.3. Occupational Exposure .............................................................63
8.4.3. Medication Errors .......................................................................................64
8.4.3.1. Medication Errors......................................................................64
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................65
9.1. Sample Size Determination.....................................................................................65
9.2. Efficacy Analysis ....................................................................................................65
9.3. Pharmacokinetic Analysis.......................................................................................66
9.3.1. Analysis Populations ..................................................................................66
9.3.2. Derivation of Pharmacokinetic Parameters Prior to Analysis ....................66
9.3.2.1. Plasma .......................................................................................66
.........................................................................................67
9.3.3. Statistical Methods......................................................................................67
9.4. Safety Analysis........................................................................................................68
9.5. Interim Analysis ......................................................................................................68
9.6. Data Monitoring Committee ...................................................................................68
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................69
11. DATA HANDLING AND RECORD KEEPING .............................................................69
11.1. Case Report Forms/Electronic Data Record .........................................................69
11.2. Record Retention...................................................................................................70
12. ETHICS..............................................................................................................................71
12.1. Institutional Review Board/Ethics Committee......................................................71
12.2. Ethical Conduct of the Study ................................................................................71
12.3. Subject Information and Consent..........................................................................71
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12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................72
13. DEFINITION OF END OF TRIAL...................................................................................72
13.1. End of Trial in the United States...........................................................................72
14. SPONSOR DISCONTINUATION CRITERIA ................................................................73
15. PUBLICATION OF STUDY RESULTS..........................................................................73
15.1. Communication of Results by Pfizer ....................................................................73
15.2. Publications by Investigators ................................................................................74
16. REFERENCES ..................................................................................................................75
LIST OF TABLES
Table 1.
Renal Function Categories by eGFR ranges.........................................................26
Table 2.
Criteria to Establish Stable Renal Function..........................................................30
Table 3.
Safety Laboratory Tests........................................................................................47
Table 4.
Width of 90% CIs for Different Estimated Effects of Test/Reference Ratio 
For PF-04965842..................................................................................................65
Table 5.
Plasma PK Parameters..........................................................................................66
LIST OF FIGURES
Figure 1.
B7451021 Study Design.......................................................................................28
APPENDICES
Appendix 1. Abbreviations......................................................................................................76


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Protocol Amendment #1, 30 July 2019
PFIZER CONFIDENTIAL
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PROTOCOL SUMMARY 
Background: PF-04965842 is a janus kinase (JAK) 1 inhibitor that is currently being 
developed for the treatment of atopic dermatitis (AD). Key cytokines implicated in the 
pathophysiology of AD including interleukin (IL)-4, IL-5, IL-13, IL-22, IL-31, and interferon 
(IFN)-, require JAK1 for signal transduction, suggesting that selective JAK1 inhibitors, that 
modulate the activity of these cytokines, represent a compelling approach to the treatment of
inflammatory skin diseases such as AD.3  PF-04965842 is being developed as an oral 
treatment for patients with moderate to severe AD based on its mechanism of action, and the 
clinical results obtained in Phase 1 and Phase 2 studies.  The clinical development program 
for PF-04965842 includes 5 completed clinical studies: three (3) Phase 1 studies in healthy 
subjects (B7451001, B7451004, and B7451008), one (1) Phase 2 study in subjects with 
psoriasis (B7451005) and 1 Phase 2 study in subjects with AD (B7451006).  A total of 
423 subjects received PF 04965842 or placebo in the 5 completed clinical studies with 
335 subjects having received at least 1 dose of PF 04965842 (n=61 in Study B7451001; 
n=12 in study B7451004; n=6 in study B7451008; n=45 in study B7451005; n=211 in Study 
B7451006).  PF-04965842 is generally safe and well tolerated.
Study Rationale: The primary purpose of this non-randomized, single-dose, open-label 
study is to characterize the effect of renal impairment on the plasma pharmacokinetics (PK) 
of PF-04965842 following administration of a single 200 mg oral dose.  The major clearance 
mechanism of PF-04965842 is oxidative metabolism mediated primarily by cytochrome
P2C19 (CYP2C19) and CYP2C9.  The renal clearance of PF-04965842 is low 
(<4%) indicating that the renal pathway plays a minimal role in PF-04965842 excretion.
Recent European Medicines Agency (EMA) guideline suggests that renal impairment studies 
be conducted in patients with decreased renal function for nearly all small molecules, even if 
the drug or its active metabolite is not primarily eliminated by the kidneys.6 Furthermore, 
evidence suggests that the PK of drugs that are not only excreted by the kidney can be 
affected by renal impairment through inhibition of pathways of hepatic and gut drug 
metabolism and transport.7  In response, the revised Food and Drug Administration (FDA) 
Draft Guidance on renal impairment studies recommends that a PK study be conducted in 
subjects with renal impairment when the drug is likely to be used in patients with impaired 
renal function.7 PF-04965842 is intended for chronic use in patients with atopic dermatitis 
who may have some degree of impaired renal function. Therefore, the present study is being 
conducted to evaluate whether renal impairment has an impact on PF-04965842 PK.  The 
purpose of this study is to characterize the effect of renal impairment on the plasma PK of 
PF-04965842.  Findings from this study will be used to develop dosing recommendations so 
that dose and/or dosing interval may be adjusted appropriately in the presence of renal 
disease.
This study is a phase 1 non-randomized, open-label, single-dose, parallel-group study of 
PF-04965842 in subjects with severe renal impairment and subjects without renal impairment 
(Part 1) and in subjects with moderate renal impairment (Part 2), matched for age, body 
weight and, to the extent possible, for gender.  The study will follow a staged approach as 
renal excretion is minor (<4%) for PF-04965842.  Therefore, it is proposed that effect of 
renal impairment on PK of PF-04965842 and its active metabolites PF-06471658 and 


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PF-07055087 be evaluated first in the renally impaired population most likely to be of impact
ie, subjects with severe renal impairment.  Further, the impact of renal impairment on 
expression of CYP enzymes, if any, is expected to be minimal and hence can be evaluated in 
the severely renally impaired population to estimate the degree of impact.  If the study results 
confirm that severe renal impairment does not alter PK to an extent that warrants dosage 
adjustment, no further study is warranted. If the results do not strongly support such a 
conclusion, Part 2 will be conducted in subjects with moderate renal impairment.
A single oral dose of 200 mg PF-04965842 will be used in this study as it is the highest dose 
being evaluated in the Phase 3 AD program. This dose selection also takes into account 
safety considerations for subjects with severe renal impairment in whom an increase in 
plasma concentration of PF-04965842 may be observed.  In study B7451001, single oral 
doses of PF-04965842 as high as 800 mg, and repeated doses as high as 400 mg once daily 
(QD) and 200 mg twice daily (BID) (up to 10 days) have been found to be safe and well 
tolerated.  Thus, based on the safety data of PF-04965842 and prior clinical experience, with 
the single oral dose of 200 mg, exposure increases up to 4-fold (to 800 mg single dose) if 
observed, are not likely to pose any safety risks.
Study Objectives and Endpoints: 
Primary Objective(s): 
Primary Endpoint(s): 
•
Part 1: To evaluate the effect of severe renal 
impairment on the pharmacokinetics of 
PF-04965842 and its active metabolites 
PF-06471658 and PF-07055087 following single 
oral dose administration.
•
Part 2 (if applicable): To evaluate the effect of 
moderate renal impairment on the 
pharmacokinetics of PF-04965842 and its active 
metabolites PF-06471658 and PF-07055087
following single oral dose administration.
Plasma PK parameters of PF-04965842 and its 
active metabolites PF-06471658 and PF-07055087: 
•
Cmax, AUCinf.
Secondary Objective(s): 
Secondary Endpoint(s): 
•
To evaluate the safety and tolerability of a single 
oral dose of PF-04965842 in subjects with renal 
impairment and in healthy subjects with normal 
renal function.
•
Assessment of treatment-emergent adverse 
events, clinical laboratory tests, vital signs, 
physical examinations, and 12-lead ECGs.
Tertiary/Exploratory Objective(s): 
Tertiary/Exploratory Endpoint(s): 
•
To compare additional plasma pharmacokinetic 
parameters of PF-04965842 following single oral 
administration in subjects with renal impairment 
and in healthy subjects without renal impairment.
•
 
•
To determine the plasma 
 PK of the 
major circulating metabolites of PF-04965842: 
PF-06471658, PF-07055087 
.
Plasma PF-04965842 PK parameters: 
•
AUClast, 
 
 
 
 
Plasma PK parameters of PF-06471658, 
PF-07055087 
:
•
 AUClast, 
 
 
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Study Design: This is a Phase 1 non-randomized, open-label, single-dose, parallel-cohort, 
multisite study to investigate the effect of severe renal impairment on the plasma 
pharmacokinetics of PF-04965842 after a single 200 mg oral dose.  Subjects will be selected 
and categorized into normal renal function or renal impairment groups based on their 
estimated glomerular filtration rate (eGFR).
Part 1: A total of approximately16 subjects will be enrolled in Part 1; approximately 
8 subjects with severe renal impairment (Cohort 2) and approximately 8 with normal renal 
function (Cohort).  The 8 subjects from the impaired group will be recruited first. The 
demographics will be pooled across study sites to determine an average value for age and 
weight. Subsequently, the healthy subjects will be recruited later such that each subject’s age 
is within ±10 years and weight is within ±15 kg of the mean of the pooled impaired groups.
Part 2: Based on whether the decision criterion to proceed to Part 2 is met, up to 8 subjects 
with moderate renal impairment will be enrolled. As in Part 1, renal impairment 
classification will be based on eGFR.  Healthy subjects will not be enrolled in Part 2. 
Following an overnight fast of at least 10 hours, subjects will be administered a single oral 
200 mg dose of PF-04965842 with approximately 240 mL (8 ounces) of ambient temperature 
water in the morning on Day 1.  No food will be allowed for at least 4 hours post-dose.  
Blood 
 samples will be collected from subjects to determine plasma 
 PK of 
PF-04965842 up to 72 hours post-dose on Day 4.  The eGFR value obtained on Day -1 will 
be used for PK analysis.  Subjects will be confined to the unit during the study until 
completion of PK sampling and safety assessments (as specified in the Schedule of 
Activities) on the morning of Day 4.  Physical examinations, single supine 12-lead 
electrocardiogram (ECG), vital sign measurements, and clinical laboratory tests will be 
conducted and adverse events (AEs) will be monitored throughout the study to assess safety.  
Subjects will have a follow-up contact to assess for AEs.
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Statistical Methods: For Part 1, a one-way analysis of variance (ANOVA) will be used to 
compare the natural log transformed area under the concentration time curve from time 0 to 
infinity (AUCinf), area under the concentration time curve from time 0 to the time of the last 
quantifiable concentration (AUClast) and maximum observed concentration (Cmax) of the
parent and active moiety for the renal impairment cohort (Test) to the normal renal function 
cohort (Reference).  Active moiety Cmax, AUClast, AUCinf values for each subject will be 
calculated as the sum of unbound exposures of PF-04965842 and its active metabolites 
PF-06471658 and PF-07055087, adjusted for the relative potencies of the metabolites. 
Estimates of the adjusted mean differences (Test-Reference) and corresponding 
90% confidenc intervals (CI) will be obtained from the model.  The adjusted mean 
differences and 90% CI for the differences will be exponentiated to provide estimates of the
ratio of adjusted geometric means (Test/Reference) and 90% CI for the ratios.  If Part 2 is 
conducted, the same ANOVA analysis will be performed. Test group in this case will be 
subjects with moderate renal impairment and the reference group will be healthy subjects 
with normal renal function from Part 1. Covariates such as weight and age may be included 
in the ANOVA only if the demographics of the moderate subjects are not within the criteria 
stated in the protocol (mean weight ±15 kg of healthy group, age ±10 years of healthy 
group).
 
 
 
 
 
 
 
 
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Pharmacokinetics: The PK concentration population will be defined as all subjects who 
received 1 dose of PF-04965842 and in whom at least 1 plasma concentration value is 
reported.  The plasma 
 (if analyzed) PK parameters for PF-04965842, its
3 metabolites and the active moiety will be summarized descriptively by renal function group.  
 
Box plots of mean, median and individual subject parameters will
be generated by renal function cohort for AUCinf, AUClast and Cmax.
Individual plasma 
 
 (if analyzed) concentrations for PF-04965842 and the  major circulating metabolites 
will be listed and summarized descriptively by nominal PK sampling time and renal function 
cohort.  Individual subject and summary profiles (means and medians) of the
concentration- time data for parent and metabolites will be plotted by cohort.  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.
Safety: AEs, electrocardiograms (ECGs), vital signs, 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, blood pressure (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.  Physical examination 
and neurological examination information, as applicable, collected during the course of the 
study will be considered source data and will not be required to be reported, unless otherwise 
noted. 
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SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the STUDY PROCEDURES and
ASSESSMENTS sections of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the schedule of activities table, in order to conduct 
evaluations or assessments required to protect the well-being of the subject.
Visit Identifier
Screening
-28a
Day -1
Day 1
Day 2
Day 3
Day 4 
Follow-up 
Contact 
S1
S2
29 - 36
Hours Post Dose
0
0.5
1
2
3
4
6
8
10
12
24
36
48
72
--
Informed consent
X
CRU confinement
X













X
Eligibility assessment 
(inclusion/exclusion criteria) 
X
X
eGFR assessmentb
X
X
X
Demographyc
X
Medical history 
X
Physical examinationd
X
X
X
Height and Weighte
X
X
X
Alcohol/tobacco & Breath alcohol 
test
X
X
Contraception Usef
X
X
X
X
Single, supine 12-lead ECG
X
X
X
X
Vital assessment (blood pressure & 
pulse rate)
X
X
X
Safety laboratory tests (blood & 
urine)g
X
X
X
X
X
HepBcAb, HepBsAb, HepBsAg, 
HCVAbh, HIV tests
X
QuantiFERON® - TB Gold Test or 
PPD skin testi
X
Serum or urine pregnancy test 
(WOCP only)j
X
X
X


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Visit Identifier
Screening
≤-28a
Day -1
Day 1
Day 2
Day 3
Day 4 
Follow-up 
Contact 
S1
S2
29 - 36
Hours Post Dose
0
0.5
1
2
3
4
6
8
10
12
24
36
48
72
--
Serum FSH in post-menopausal 
females amenorrheic ≥12 months 
only
X
 
 
IP administration
X
Plasma PK for PF-04965842 and 
metabolites
Xn
X
X
X
X
X
X
X
X
X
X
X
X
X
 
Urine drug test
X
X
Prior/concomitant treatments
X
X
X
→
→
→
→
→
→
→
→
→
→
→
→
→
→
X
Serious and non-serious adverse event 
monitoring
X
X
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
X
CRU discharge 
X
Abbreviations: →= ongoing/continuous event; CRU = clinical research unit; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; FSH = follicle-stimulating 
hormone; HepBcAb = hepatitis B core antibody; HepBsAb = hepatitis B surface antibody; HepBsAg = hepatitis B surface antigen; HCVAb = hepatitis C antibody; 
HCV RNA = hepatitis C virus ribonucleic acid; HIV = human immunodeficiency virus; IP = investigational product; MDRD = Modification of Diet in Renal Disease;
PE = physical examination; PK = pharmacokinetics; PPD = purified protein derivative; QFT-G = QuantiFERON®-TB Gold; SOP = standard operating procedure;
TB = tuberculosis; WOCP = women of childbearing potential.
a.
Screening will consist of two CRU outpatient visits (Screening Visit 1 and 2) -between 3 to 14 days apart, with the 1st screening visit occurring within 
28 days prior to IP administration (Day 1).  The 2nd screening visit is only to demonstrate stable renal function with eGFR ≤25% of the value obtained at 
Screening visit 1.  Other screening procedures completed during the first visit do not need to be repeated.  See Section 3.1 for outpatient visit screening 
schedule. 
b.
To confirm eligibility, subjects must have stable renal function defined as ≤25% difference between two measurements of eGFR obtained from the same 
laboratory, on two separate occasions separated by at least 72 hours but no more than 14 days apart, during the Screening period (visits S1 and S2).  The 
Day -1 eGFR values will be used for subject stratification and group assignment (provided stable renal function is still demonstrated).  The eGFR 
determination will utilize the 4-variable MDRD equation.
c.
Demographics will include race, age and gender.
d.
Full PE at Screening Visit 1 (S1); limited PE at all other time points.
e.
Height to be obtained at Screening Visit 1 (S1) only, weight to be obtained at Screening Visit 1 (S1), Screening Visit 2 (S2) and Day -1.
f.
Confirmation of appropriate contraception use, only.
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g.
Safety laboratory assessments include chemistry, hematology and urinalysis (and microscopy, if needed) and will be performed at Screening Visit 1 (only 
serum creatinine to be assessed on Screening Visit 2 also), on Day -1, post-dose on Day 1, Day 2 and on Day 4.  All the assessments must be collected 
following at least a 4 hour fast.
h.
HCV RNA reflex testing required only if HCVAb is positive. 
i.
A chest x-ray is required if a positive QFT-G or PPD, unless previously performed and documented within 12 weeks prior to screening.
j.
Serum pregnancy test must be performed at screening; Urine or serum pregnancy test can be performed on Day -1 and Day 4. 
 
n.
Predose.
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1. INTRODUCTION
1.1. Mechanism of Action/Indication
PF-04965842 is a JAK1 inhibitor that is currently being developed for the treatment of AD. 
The JAK family, including JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2), is a group of 
cytoplasmic tyrosine kinases that mediate signal transduction via interactions with Type 1 
and Type 2 cytokine receptors critical for leukocyte activation, proliferation, survival and 
function.  Cytokine receptors demonstrate restricted association with JAKs such that different 
receptors or receptor classes preferentially utilize a given JAK dimer or trimer combination 
to transduce their signal.  JAK1 pairs with JAK3 to mediate -common cytokine signaling 
and also with JAK2 or TYK2 to transmit the signals of additional cytokines important in 
inflammation and immune responses including IL-4, -5, -6, -13, -21, -31, IFN-, and IFN-.  
JAK2 homodimers are critical for the signaling of hematopoietic cytokines and hormones 
including erythropoietin (EPO), IL-3, granulocyte-macrophage colony-stimulating factor 
(GM-CSF) and prolactin. IL-12 and IL-23 are dependent on TYK2 and JAK2 for 
transmitting their signals. 
Following cytokine activation, receptor-associated JAKs are phosphorylated and in turn 
phosphorylate specific sites on the receptor intracellular domain.  Phosphorylation of specific 
sites on the intracellular domain of the receptor allows for the recruitment of signal 
transducers and activators of transcription (STATs) that can subsequently be phosphorylated 
by JAKs.1 Phosphorylated STAT molecules are released from the receptor, translocate to the 
nucleus where they bind to specific sites on the deoxyribonucleic acid (DNA) and regulate 
gene transcription.2
Key cytokines implicated in the pathophysiology of AD including IL-4, IL-5, IL-13, IL-22,
IL-31, and IFN-, require JAK1 for signal transduction, suggesting that selective JAK1 
inhibitors, that modulate the activity of these cytokines, represent a compelling approach to 
the treatment of inflammatory skin diseases such as AD.3
PF-04965842 is an orally bioavailable small molecule that selectively inhibits JAK1 by 
blocking the adenosine triphosphate (ATP) binding site.  PF-04965842 has a high degree of 
selectivity against other kinases: 28-fold selectivity over JAK2, >340-fold over JAK3 and 
43-fold over TYK2, as well as a good selectivity profile over the broader range of human 
kinases. The selective inhibition of JAK1 will lead to modulation of multiple cytokine 
pathways involved in the pathophysiology of AD, including IL-4, IL-5, IL-13, IL-31 and 
IFN-.  Data from a Phase 2b proof of concept (POC) study (B7451006) that evaluated 
subjects with moderated to severe AD have shown positive efficacy, as well as an acceptable 
safety profile, sufficient to support further clinical development in a larger Phase 3 program.


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1.2. Background 
1.2.1. Overview of Disease State
AD also known as atopic eczema, is a common, chronic, inflammatory skin disorder 
characterized by flaky skin lesions, intense pruritus, and a general deterioration in the quality
of life.  Over the past 50 years, AD has become more prevalent, especially in industrialized, 
temperate countries such as the United States (US).4,5  Earlier reports indicated that, in up to 
70% of cases, the disease greatly improves or resolves until late childhood, however more 
recent findings suggest that disease activity remains manifest for a prolonged period of time. 
There are a limited number of treatments available for AD.  Current treatments for AD 
include emollients, topical corticosteroids (eg, betamethasone, clobetasol, fluocinonide), 
topical calcineurin inhibitors (eg, pimecrolimus, tacrolimus), and coal tar preparations.
Crisaborole was approved as a topical treatment in December 2016 by the FDA for use 
in patients with mild to moderate AD. In addition, dupilumab, an injectable monoclonal 
antibody targettting IL-4 and IL-13 was recently approved for the treatment of AD.  
Additional treatments generally reserved for severe AD include phototherapy and systemic 
agents (eg, corticosteroids, ciclosporin, recombinant IFN-, mycophenolate mofetil, 
methotrexate [MTX], azathioprine, intravenous [IV] immunoglobulin).6
1.2.2. Rationale for Development of PF-04965842
PF-04965842 is being developed as an oral treatment for patients with moderate to severe 
AD based on its mechanism of action, and the clinical results obtained in Phase 1 and 
Phase 2 studies.  The clinical development program for PF-04965842 includes healthy 
subjects, subjects with psoriasis and subjects with AD. 
Additional information for this compound may be found in the single reference safety 
document (SRSD), which for this study is the Investigator’s Brochure (IB). A summary of 
the components relevant to this study are presented below.
1.2.3. Previous Human Experience with PF-04965842
PF-04965842 has been assessed in 5 completed clinical studies: three (3) Phase 1 studies in 
healthy subjects (B7451001, B7451004, and B7451008), one (1) Phase 2 study in subjects 
with psoriasis (B7451005) and 1 Phase 2 study in subjects with AD (B7451006).  A total of 
423 subjects received PF-04965842 or placebo in the 5 completed clinical studies with 
335 subjects having received at least 1 dose of PF-04965842 (n=61 in study B7451001; 
n=12 in study B7451004; n=6 in study B7451008; n=45 in study B7451005; n=211 in study 
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1.2.3.1. Summary of Safety Data from Completed Clinical Studies
Based on the clinical experience with PF-04965842 and its mechanism of action, the 
potential risks of treatment with JAK inhibitors include: (1) viral reactivation; (2) serious 
infection and opportunistic infections (3) malignancy and lymphoproliferative disorders; 
(4) decreased lymphocyte counts; (5) decreased neutrophil counts; (6) decreased platelets;
and (7) alterations in the lipid profile.
In the completed Phase 1 and 2 studies in healthy subjects, subjects with psoriasis and 
subjects with AD, PF-04965842 was generally safe and well tolerated.
In the completed Phase 1 studies in healthy subjects receiving single doses of PF-04965842 
up to 800 mg and multiple doses up to 200 mg BID or 400 mg QD, the most commonly 
reported AEs were diarrhea, nausea, vomiting, headache, acne, and dizziness.  Following 
single or multiple dose of PF-04965842, most reported treatment emergent AEs (TEAEs)
were mild or moderate in severity. In study B7451001, during the single-ascending dose 
phase, one (1) subject in the placebo group had maximum fridericia corrected QT interval
(QTcF) of 450 to <480 msec, and 1 subject in the PF-04965842 800 mg treatment group had 
maximum QTcF interval increase from baseline of 30 to <60 msec.  In the 
multiple-ascending dose phase, three (3) subjects (1 each in the placebo, PF-04965842 30 mg 
QD, and 100 mg QD treatment groups) had maximum QTcF interval of 450 to <480 msec,
and 2 subjects in the PF-04965842 200 mg BID treatment group had maximum QTcF 
interval increase from baseline of 30 to <60 msec. There were no clinically significant 
changes in ECG findings in the B7451004 and B7451008 studies.
In the completed Phase 2 study in subjects with moderate to severe psoriasis (B7451005), the 
most frequently reported AEs across the PF-04965842 treatment groups (200 mg BID, 
200 mg QD, and 400 mg QD) were nausea, followed by headache.  Other commonly 
reported AEs included neutropenia and neutrophil counts decreased, thrombocytopenia and 
platelet count decreased.  One (1) of the subjects in the 200 mg QD group with an AE 
categorized as infections and infestations was reported as having VIIth nerve paralysis 
(Bell’s palsy) and later developed herpes zoster (shingles). The incidences of normal and 
abnormal ECG recordings were similar across all treatment groups at each time point. None 
of the abnormal ECG recordings were determined to be clinically significant by the 
investigator.
In the completed 12-week Phase 2b study (B7451006) in subjects with AD, AEs and serious 
AEs (SAEs) were numerically higher in subjects receiving PF-04965842 (10, 30, 100, and 
200 mg QD) compared to placebo, but did not appear to increase with dose.  The most 
common AEs were in the infections and infestations, skin and subcutaneous tissue disorders 
and gastrointestinal disorders system organ class (SOC), and the majority of the AEs were
mild. The most commonly reported TEAE across all the treatment groups were dermatitis 
atopic (38 events), and viral upper respiratory tract infection (33 events).  The most 
frequently reported treatment-related TEAE was nausea.  There were 2 cases of non-serious 
herpes zoster, one (1) in the 10 mg group (not treatment-related), and 1 in the 30 mg group 
(treatment-related).  There were 2 subjects (doses of ≥100 mg QD) with treatment related 
SAEs reported, the SAEs were eczema herpeticum and pneumonia.  One (1) subject 


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randomized to the PF-04965842 10 mg group reported an SAE of malignant melanoma. 
Dose-dependent mean platelet count decreases from baseline were observed with a nadir at 
Week 4.  At Week 4 the mean platelet count and the 90% CI were within the normal 
reference range for both the 100 mg dose and 200 mg dose. In these treatment groups, the 
mean platelet count increased towards baseline after Week 4.  There were no clinically 
significant findings in vital signs or physical examinations. Most of the ECG results were 
normal.  The incidences of normal and abnormal ECG recordings were similar between 
PF-04965842 and placebo groups at each time point. 
1.2.3.2. Summary of PF-04965842 Pharmacokinetics, Metabolism and In Vitro 
Enzymology
1.2.3.2.1. Single and Multiple Dose Pharmacokinetics
PF-04965842 was absorbed rapidly following single oral solution/suspension doses of 3 mg 
to 200 mg with median time to maximum concentration (Tmax) observed less than 1 hour
(ranging from 0.55 to 0.77 hours), and more slowly at the higher doses with median Tmax of 
1.5 and 4.0 hours for the 400 mg and 800 mg doses, respectively (study B7451001).  
Following attainment of maximum concentration (Cmax), the disposition of PF-04965842 
generally showed a monophasic decline at the lower doses of 3 to 30 mg (mean terminal 
half-life [t½] of 1.9 to 2.5 hours) while a biphasic decline was observed at doses of 100 to 
800 mg with a mean t½ of 3.6 to 4.9 hours. Plasma PF-04965842 Cmax appeared to increase
proportionally across the entire dose range from 3 mg to 800 mg, while increases in AUCinf
were greater than proportional at doses of 400 and 800 mg. For the 2-fold doses increases 
between 200 to 400 mg and between 400 to 800 mg, the mean AUCinf values in Western 
subjects in this study appeared to increase approximately 3.5- and 2.7-fold, respectively. 
On Day 10 of multiple-dose administration, PF-04965842 was absorbed rapidly with median 
Tmax of about 1 hour or less (ranging from 0.50-1.05 hours) across the entire range of doses, 
from a total daily dose of 30 mg (30 mg QD) up to 400 mg (200 mg BID or 400 mg QD).  
Following attainment of Cmax, the disposition of PF-04965842 was consistent with that 
observed following single-dose administration, showing a biphasic decline following all but 
the lowest dose and a mean terminal t½ of about 2.8 to 5.0 hours.  Plasma Cmax and area under 
the concentration time curve from time 0 to time tau (AUCtau) both appeared to show a trend 
towards greater than proportional increases with increasing daily dose.  Geometric mean 
values for the observed accumulation ratio (Rac), that compares AUCtau for multiple-dose 
administration to AUCtau for single-dose administration, ranged from 1.3 to 1.5 for QD 
dosing and 1.3 to 2.3 for BID dosing.  Similar ratios for Cmax comparison (Rac, Cmax) ranged 
from 1.1 to 1.3 for QD dosing and from 1.3 to 2.8 for BID dosing.  These results showed that 
drug concentration accumulation after repeated oral QD or BID administration is less than 
about 1.5- and 2.3-fold, respectively; at doses up to 200 mg QD, the accumulation was 
minimal and generally consistent with the prediction from t½. 


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At a single 800-mg dose, the geometric mean Cmax was similar in Western and Japanese 
subjects. However, geometric mean AUCinf was 26% higher in Western subjects than that 
observed in Japanese subjects.  Geometric mean Cmax and AUCtau following multiple-dose 
administration of 200 mg BID were 17% and 56% higher, respectively, in the Western 
subjects than in Japanese subjects. 
The urinary recovery of PF-04965842 was low, with <4% of the dose recovered unchanged 
in urine across all doses and regimens in all cohorts in study B7451001.
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
1.2.3.2.2. Metabolism and In Vitro Enzymology
In vitro 
 metabolite profiling in 
, and human indicated that the primary 
clearance mechanism for PF-04965842 was CYP450-mediated oxidative metabolism.  In 
vitro human CYP450 phenotyping studies indicated that CYP2C19 (fraction metabolized 
[fm] ~0.5), CYP2C9 (fm ~0.3), CYP3A4 (fm ~0.1), and CYP2B6 (~0.1) were involved in 
the metabolism of PF-04965842.  
 
 
 
Of the major 
circulating species, PF-04965842 and its two metabolites PF-06471658 and PF-07055087 are 
pharmacologically active.
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1.3. Rationale
1.3.1. Study Rationale 
The primary purpose of this non-randomized, single-dose, open-label study is to characterize
the effect of renal impairment on the plasma PK of PF-04965842 following administration of 
a single 200 mg oral dose.  The major clearance mechanism of PF-04965842 is oxidative 
metabolism mediated primarily by CYP2C19 and CYP2C9.  As described in 
Section 1.2.3.2.1, the renal clearance of PF-04965842 is low (<4%) indicating that the renal 
pathway plays a minimal role in PF-04965842 excretion. 
EMA guideline suggests that renal impairment studies be conducted in patients with 
decreased renal function for nearly all small molecules, even if the drug or its active 
metabolite is not primarily eliminated by the kidneys.7 Furthermore, evidence suggests that 
the PK of drugs that are not only excreted by the kidney can be affected by renal impairment 
through inhibition of pathways of hepatic and gut drug metabolism and transport.8  In 
response, the revised FDA Draft Guidance on renal impairment studies recommends that a 
PK study be conducted in subjects with renal impairment when the drug is likely to be used 
in patients with impaired renal function.8 PF-04965842 is intended for chronic use in 
patients with atopic dermatitis who may have some degree of impaired renal function. 
Therefore, the present study is being conducted to evaluate whether renal impairment has an 
impact on PF-04965842 PK.
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The purpose of this study is to characterize the effect of renal impairment on the plasma 
PK of PF-04965842.  Findings from this study will be used to develop dosing 
recommendations so that dose and/or dosing interval may be adjusted appropriately in the 
presence of renal disease.
 
 
PF-04965842 is not teratogenic based on nonclinical studies. Both male and female subjects 
of childbearing potential, as well as female subjects who are of non-childbearing potential, 
will be enrolled given the availability of embro-fetal development (EFD) toxicity studies 
with PF-04965842.  In addition, the nonclinical data support no need for male contraception 
because PF-04965842 is not genotoxic.  The amount of PF-04965842 estimated to be 
available to a partner via drug in ejaculate is well below the developmental no observed 
adverse effect levels (NOAELs) in the definitive rat and rabbit EFD studies.  PF-04965842 
did not affect male fertility or spermatogenesis but did decrease female fertility. However
measures will be taken to limit the risk of pregnancy in female subjects (refer to Schedule of 
Activities, Section 4.4.4 and Section 7.1.2).
1.3.2. Study Population Rationale
In this study, eGFR will be used to define the renal impairment cohorts with the reference 
cohort being demographically matched subjects without renal impairment.
1.3.3. Study Design Rationale 
This study is a phase 1 non-randomized, open-label, single-dose, parallel-group study of 
PF-04965842 in subjects with severe renal impairment and subjects without renal impairment 
(Part 1) and in subjects with moderate renal impairment (Part 2), matched for age, body 
weight and, to the extent possible, for gender.  Details on age and body weight matching 
criteria are specified in Section 3.1. 
The study will follow a staged approach as renal excretion is minor (<4%) for PF-04965842.  
Therefore, it is proposed that effect of renal impairment on PK of PF-04965842 and its active 
metabolites PF-06471658 and PF-07055087 be evaluated first in the renally impaired 
population most likely to be of impact ie, subjects with severe renal impairment.  Further, the 
impact of renal impairment on expression of CYP enzymes, if any, is expected to be minimal 
and hence can be evaluated in the severely renally impaired population to estimate the degree 
of impact.  If the study results confirm that severe renal impairment does not alter PK to an 
extent that warrants dosage adjustment, no further study is warranted. If the results do not 
strongly support such a conclusion, Part 2 will be conducted in subjects with moderate renal 
impairment, based on the decision criterion outlined in Section 3.1.
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Since single dose PF-04965842 PK is predictive of multiple dose PF-04965842 PK, a 
single-dose study design will be followed for this study.  All subjects enrolled in this study 
will receive one single oral 200 mg dose of PF-04965842. To adequately characterize the 
elimination phase of the plasma PF-04965842 concentration-time profile in the cohorts with 
severe renal impairment, where the elimination half-life of PF-04965842 may be prolonged, 
PK samples will be collected serially for up to 72 hours post-dose. 
 
 
1.3.4. Dose Rationale
A single oral dose of 200 mg PF-04965842 will be used in this study as it is the highest dose 
being evaluated in the Phase 3 AD program. This dose selection also takes into account 
safety considerations for subjects with severe renal impairment in whom an increase in 
plasma concentration of PF-04965842 may be observed. In study B7451001, single oral 
doses of PF-04965842 as high as 800 mg, and repeated doses as high as 400 mg QD and 
200 mg BID (up to 10 days) have been found to be safe and well tolerated.  Thus, based on 
the safety data of PF-04965842 and prior clinical experience, with the single oral dose of 
200 mg, exposure increases up to 4-fold (to 800 mg single dose) if observed, are not likely to 
pose any safety risks. 
 
 
 
 
 
 
 
 
 
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1.4. Summary of Benefit Risk Assessment
This is a single-dose study to assess the PK of PF-04965842 in subjects with and without 
renal impairment. The 200 mg dose proposed for the current study is 4-fold lower than the 
highest single oral dose (800 mg) administered to healthy subjects, and was found to be well 
tolerated with an acceptable safety profile.  There is no known benefit for subjects 
participating in this trial.  The data from this study are envisioned to provide the basis for 
development of dosing recommendations for the target patient population, including those 
with renal impairment.  Based on the clinical safety profile of PF-04965842, the risk to 
subjects receiving a single 200 mg dose is deemed to be minimal. Appropriate risk 
evaluation and monitoring have been incorporated into this protocol.
2. STUDY OBJECTIVES AND ENDPOINTS
Primary Objective(s): 
Primary Endpoint(s): 
•
Part 1: To evaluate the effect of severe renal 
impairment on the pharmacokinetics of 
PF-04965842 and its active metabolites 
PF-06471658 and PF-07055087 following single 
oral dose administration.
•
Part 2 (if applicable): To evaluate the effect of 
moderate renal impairment on the 
pharmacokinetics of PF-04965842 and its active 
metabolites PF-06471658 and PF-07055087
following single oral dose administration.
Plasma PK parameters of PF-04965842 and its 
active metabolites PF-06471658 and PF-07055087: 
•
Cmax, AUCinf.
Secondary Objective(s): 
Secondary Endpoint(s): 
•
To evaluate the safety and tolerability of a single 
oral dose of PF-04965842 in subjects with renal
impairment and in healthy subjects with normal
renal function.
•
Assessment of treatment-emergent adverse 
events, clinical laboratory tests, vital signs, 
physical examination, and 12-lead ECGs.
Tertiary/Exploratory Objective(s): 
Tertiary/Exploratory Endpoint(s): 
•
To compare additional plasma pharmacokinetic 
parameters of PF-04965842 following single oral 
administration in subjects with renal impairment 
and in healthy subjects without renal impairment.
•
 
•
To determine the plasma 
 PK of the 
major circulating metabolites of PF-04965842: 
PF-06471658, PF-07055087 
.
Plasma PF-04965842 PK parameters: 
•
 AUClast, 
 
 
 
 
Plasma PK parameters of PF-06471658, 
PF-07055087 
:
•
 AUClast, 
 
 
 
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3. STUDY DESIGN
3.1. Study Overview
This is a Phase 1 non-randomized, open-label, single-dose, parallel-cohort, multisite study to 
investigate the effect of severe renal impairment on the plasma pharmacokinetics, safety and 
tolerability of PF-04965842 after a single 200 mg oral dose.  A staged approach, as outlined 
in detail below, will be followed in the study.
Subjects will be selected and categorized into normal renal function or renal impairment 
groups based on their eGFR as shown in Table 1.
Table 1.
Renal Function Categories by eGFR ranges
Cohort
Renal Impairmenta
Estimated eGFRb
(mL/min)
Number of Completer
Subjects
1
None (Normal)
≥90
6c
2
Severe Renal Impairment
<30 and not requiring 
dialysis
6
3
Moderate Renal 
Impairment
≥30 to <60
6
a.
Stages of renal impairment are based on Kidney Disease Outcomes Quality Initiative (KDOQI) Clinical 
Practice Guidelines for Chronic Kidney Disease (CKD).9
b.
Estimate of eGFR based on Modification of Diet in Renal Disease (MDRD) formula.  The Day -1 eGFR 
value will be used for group assignment.
•
Step 1: eGFR (mL/min/1.73m2) = 175 × (Scr, std)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African 
American) where Scr, std denotes serum creatinine measured with a standardized assay.
•
Step 2: Convert the MDRD-derived, body surface area (BSA)-adjusted eGFR obtained above to 
absolute eGFR (mL/min) for eligibility assessment using the following equation: 
•
eGFR (mL/min) = eGFR (mL/min/1.73m2) ×subject’s BSA where BSA is calculated as BSA 
= (Weight0.425 x Height0.725) x 0.007184.
c.
Additional subjects may be dosed to a maximum of 10 subjects to ensure mean age is ±10 years and mean 
body weight ±15 kg of this cohort is in line with pooled average assessed when ≥75% of subjects are dosed 
in cohort 2.
Part 1: A total of approximately16 subjects will be enrolled in Part 1; approximately 
8 subjects with severe renal impairment and approximately 8 with normal renal function.  
The 8 subjects from the impaired group will be recruited first.  The demographics will be 
pooled across study sites to determine an average value for age and weight. Subsequently, 
the healthy subjects will be recruited later such that each subject’s age is within ±10 years 
and weight is within ±15 kg of the mean of the pooled impaired groups. An attempt will be 
made to maintain a similar male/female ratio and racial make-up between groups. Care will 
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be taken when recruiting the healthy subjects such that the entire group is not younger and of 
lower body weight than the impaired subjects.  Approval from the sponsor must be obtained 
before proceeding with dosing healthy subjects with normal renal function (Cohort 1).
Subjects who withdraw from the normal and severe impairment groups for non-safety related 
reasons and who are considered to be non-evaluable with respect to the primary objective 
may be replaced at the discretion of the principal investigator (PI) and the sponsor to ensure 
6 completers.
Active moiety Cmax, AUClast, AUCinf values for each subject will be calculated as the sum of 
unbound exposures of PF-04965842 and its active metabolites PF-06471658 and 
PF-07055087, adjusted for the relative potencies of the metabolites.
Statistical Criteria to proceed to Part 2: After statistical evaluation of results from Part 1 (see 
Section 9.3.3), Part 2 will be conducted if the upper bound (UB) of the 90% CI for the active 
moiety AUCinf geometric mean ratio (GMR) for the severe renal impairment group 
(compared to the normal group as control) is 3.0.  If variability is unexpectedly higher than 
assumed, eg, if the UB of the GMR is substantially higher than 3 with a point estimate of the 
GMR close to 2, the data will be further evaluated to determine whether to proceed to Part 2.
If the above mentioned criterion is not met, the study will stop after Part 1.
The UB of 3.0 for the AUC GMR 90% CI corresponds to an estimated effect size of 2.0 for 
the AUC GMR, based on the PK variability observed in study B7451001.
Part 2: Based on whether the decision criterion to proceed to Part 2 is met, up to 8 subjects 
with moderate renal impairment will be enrolled. As in Part 1, renal impairment 
classification will be based on eGFR. Healthy subjects will not be enrolled in Part 2. 
As in Part 1, subjects who withdraw from the moderate impairment group for non-safety 
related reasons and who are considered to be non-evaluable with respect to the primary 
pharmacokinetic objective may be replaced at the discretion of the PI and the sponsor to 
ensure 6 completers.
For both Parts 1 and 2: All subjects will provide informed consent and undergo Screening 
evaluations to determine their eligibility.  Subject screening for participation in this study 
will consist of two clinical research unit (CRU) outpatient visits no later than 14 days apart 
(but at least 3 days apart), with the 1st screening visit occurring within 28 days prior to 
administration of IP.  Each subject will be admitted to the research unit on Day -1 (at least 
12 hours prior to the dosing of PF-04965842 on Day 1).  In addition to the assessments and 
sample collection set forth in the Schedule of Activities, an eGFR value will be obtained on 
Day -1 (using the MDRD equation) for group placement (provided stable renal function is 
still demonstrated).
Eligible subjects will be admitted to the CRU on Day -1 and will be confined in the CRU 
until Day 4. 


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On Day 1, subjects will receive a single 200-mg dose of PF-04965842 after a fast of at least 
10 hours. Serial blood samples at specified intervals (as per Schedule of Activities) will be 
collected for 72 hours post-dose for PK assessments, prior to discharge from the CRU on 
Day 4.  The total duration of participation from the Screening Visit to Day 4 will be a 
maximum of 31 days and from the Screening Visit to Follow-up Contact/Visit will be a 
maximum of 67 days.
Following an overnight fast of at least 10 hours, subjects will be administered a single oral 
200 mg dose of PF-04965842 with approximately 240 mL (8 ounces) of ambient temperature 
water in the morning on Day 1. No food will be allowed for at least 4 hours post-dose.
Blood 
 samples will be collected from subjects to determine plasma 
 PK of 
PF-04965842 up to 72 hours post-dose on Day 4. The eGFR value obtained on Day -1 will 
be used for PK analysis.  Subjects will be confined to the unit during the study until 
completion of PK sampling and safety assessments (as specified in the Schedule of 
Activities) on the morning of Day 4. Physical examinations, single supine 12-lead ECG, 
vital sign measurements, and clinical laboratory tests will be conducted and AEs will be 
monitored throughout the study to assess safety.  Subjects will have a follow-up contact to 
assess for AEs, concomitant medications, and appropriate contraception use.
PF-04965842 will be supplied by Pfizer as a 100 mg oral tablet formulation.
All procedures and their timelines follow the Schedule of Activities.  The overall study 
design is summarized below in Figure 1. 
Figure 1.
B7451021 Study Design
Screen
Day -1
Day 2
Day 4 
(D/C from CRU)
Day 1
(IP administration) 
Day 3
Follow-up via telephone contacta
(Day 29-36)
Inpatient stay at CRU
≤28 days
Abbreviations: AE = adverse event; CRU = clinical research unit; D/C = discharge; IP = investigational product.
a.
Follow-up telephone contact may occur; but an onsite visit should be performed for follow-up of abnormal 
laboratory tests and/or ongoing AEs.
Age/Weight/Gender Matching Criteria:
Part 1: Subjects with severe renal impairment will be enrolled first and their demographics 
will be pooled across study sites. Enrollment of age-, weight-, and gender-matched healthy 
subjects (normal group) will begin after the severe renal impairment subjects have completed 
the in-patient portion of the study. Demographics of the healthy subjects will be matched to 
the pooled demographics of the severe impairment group such that the mean body weight for 
CCI
CCI


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the healthy group is within ±15 kg of the mean body weight of the subjects with renal 
impairment and mean age is within ±10 years of the mean age of the subjects with renal 
impairment. In general, care should be taken when recruiting the healthy subjects such that
the entire group is as closely matched in age and body weight to the impairment subjects as 
possible.  An attempt will be made to maintain a similar male/female ratio and racial 
make-up between cohorts.
Part 2: Healthy subjects will not be enrolled in this part. Healthy subjects from Part 1 will
be used as the control group for the moderate impairment subjects. Statistical considerations 
to account for any differences in demographics are detailed in Section 9.3.3.
Calculation of eGFR:
The following equation from the MDRD study will be used to calculate eGFR (Scr, std denotes 
serum creatinine measured with a standardized assay for serum creatinine):
eGFR (mL/min/1.73m2) = 175 × (Scr, std)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if 
African American)
Note that the value of eGFR, which is directly obtained from the lab or calculated using the
equation above, is generally normalized to an average body size of 1.73 m2 for diagnosis, 
prognosis and treatment of renal disease.  In terms of clearance of renally filtrated drugs 
(including secreted drugs), renal elimination capacity is related to absolute glomerular 
filtration rate (GFR) in mL/min. To use the MDRD-derived, body surface area 
(BSA)-adjusted value of eGFR to obtain absolute GFR (mL/min) for renal disease 
classification or subject assignment into different renal disease groups, this value should be 
multiplied by the individual subject’s BSA (ie, measured BSA/1.73 m2). The BSA of an 
individual can be calculated by the following formula as described below:
BSA = (Weight0.425 x Height0.725) x 0.007184
In summary, GFR in mL/min calculated as below will be used for renal impairment group 
placement:  

Step 1: Obtain the MDRD-derived eGFR:

eGFR (mL/min/1.73m2) = 175 × (Scr, std)-1.154 × (Age)-0.203 × (0.742 if female) 
× (1.212 if African American) where Scr, std denotes serum creatinine measured 
with a standardized assay.

Step 2: Convert the MDRD-derived, BSA-adjusted eGFR obtained above to absolute 
GFR (mL/min) for eligibility assessment using the following equation: 

eGFR (mL/min) = eGFR (mL/min/1.73m2) ×subject’s BSA where BSA is 
calculated as BSA = (Weight0.425 x Height0.725) x 0.007184.


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CLCR will also be estimated from a spot serum creatinine measurement using the following 
Cockcroft-Gault (C-G) equation:
CLCR (mL/min) = [140 – age (years)] × total body weight (kg) × (0.85 for females)
72 × serum creatinine (mg/dL)
Note that eGFR calculated by the MDRD equation will be used for categorization of degrees 
of renal impairment.  Nevertheless, renal function will be estimated using both C-G and 
MDRD equations in this study.
Subject screening for participation in this study will consist of two CRU outpatient visits no 
later than 14 days apart (but at least 72 hours apart), with the 1st screening visit occurring 
within 28 days prior to IP dosing on Day 1.  All subjects must have stable renal function to 
enter the study.  Stable renal function is defined as 25% difference between 2 measurements 
of eGFR obtained, from the same laboratory, on 2 separate occasions during the Screening 
period that are at least 72 hours but no more than 14 days apart.  Each subject will be 
admitted to the research unit on Day -1.  The Day -1 eGFR value (calculated using the 
MDRD equation) will be used for subject stratification and group placement.  The CLCR
value will be recorded at the same time eGFR is determined.
Please see Table 2 below regarding demonstration of stable renal function:
Table 2.
Criteria to Establish Stable Renal Function
Renal function Measurement
eGFR (mL/min)
Criterion for stability
Screening 1
G1
Screening 2
G2
=(G2-G1)/G1
If 25%; stable
If >25%; not stable
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
4.1.1. All Subjects
Subjects in all cohorts must meet all of the following inclusion criteria to be eligible for 
enrollment in the study:
1. Male or female subjects who, at the time of screening, are between the ages of 
18 and 75 years, inclusive, at the Screening visit:


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
Female subjects of nonchildbearing 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;  
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. Breath alcohol test at Screening and Day -1 must be negative.
3. Body mass index (BMI) of 17.5 to 40.0 kg/m2; and a total body weight >50 kg 
(110 lb).  A BMI lower limit of 17.5 kg/m2 may be rounded up to 18.0 kg/m2; a BMI 
upper limit of 40.5 kg/m2 may be rounded down to 40.0 kg/m2 and will be 
acceptable for inclusion, and dated informed consent document indicating that the 
subject has been informed.
4. Evidence of a personally signed and dated informed consent document indicating 
that the subject has been informed of all pertinent aspects of the study. 
5. Subjects who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, and other study procedures.
4.1.2. Additional Inclusion Criteria for Healthy Subjects with Normal Renal Function
(Cohort 1 only)
1. No clinically relevant abnormalities identified by a detailed medical history, full 
physical examination, including BP and pulse rate measurement, 12-lead ECG and 
clinical laboratory tests.
2. Normal renal function (eGFR 90 mL/min) at Screening based on the MDRD
equation. 
3. Demographically comparable to the group of subjects with impaired renal function.

The mean body weight will be within 15 kg of the mean body weight of the 
severe renal impairment cohort (Cohort 2).

The mean age will be within 10 years of the mean age of the severe renal 
impairment cohort (Cohort 2).


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
Attempts will be made to ensure that the male-to-female distribution in Cohort 1 
is comparable to that in the severe renal impairment cohort (Cohort 2); cohorts 
cannot comprise entirely of any one gender.

Other demographic characteristics, such as race and ethnicity, matched as closely 
as possible to the renal impairment cohort.
4.1.3. Additional Inclusion Criteria for Subjects with Impaired Renal Function 
(Cohort 2 and Cohort 3 [if applicable] only)
1. Good general health commensurate with the population with chronic kidney disease
(renal impairment). “Health” is defined as no clinically relevant abnormalities 
identified by a detailed medical history, full physical examination, measurement of 
pulse rate and 12-lead ECG as well as clinical laboratory tests (except serum 
creatinine and eGFR). Hypertension, diabetes mellitus, hyperparathyroidism, 
ischemic heart disease and other common co-morbidities in this population are 
possible exemptions, as long as, in the opinion of the investigator, the subject is 
medically stable, is on a stable drug regimen and can abide by the meals and dietary 
restrictions outlined in protocol Section 4.4.
2. Meet the following eGFR criteria during the screening period based on the MDRD 
equation:  

Severe renal impairment: eGFR <30 mL/min, but not requiring hemodialysis. 

Moderate renal impairment (Part 2 only): eGFR ≥30 mL/min and <60 mL/min.
The eGFR values of obtained at the two screening visits should not be more than 25% 
different (Section 3.1). 
3. Any form of renal impairment except acute nephritic syndrome (subjects with history
of previous nephritic syndrome but in remission can be included).
4. Stable drug regimen (as defined in Section 5.7.2) for the management of individual 
subject’s 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.
4.2. Exclusion Criteria
4.2.1. All Subjects
Subjects in all cohorts presenting with any of the following characteristics/conditions will not 
be included in the study: 
1. Renal transplant recipients.
2. Urinary incontinenence without catheterization.


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3. Subjects with clinically significant infections within the past 3 months (for example, 
those requiring hospitalization, or as judged by the Investigator), evidence of any 
infection (including influenza) within the past 7 days prior to baseline, history of 
disseminated herpes simplex infection or recurrent (>1 episode) or disseminated 
herpes zoster.
4. Subjects with a personal or family history of hereditary immunodeficiency (eg, severe 
combined immunodeficiency disorder [SCID], Wiskott-Aldrich syndrome, X-linked 
agammaglobulinemia).
5. Subjects who have been vaccinated with live or attenuated vaccines within the 
6 weeks of dosing, or is to be vaccinated with these vaccines at any time during 
treatment or within 6 weeks following discontinuation of dosing.
6. Have evidence of active or latent or inadequately treated infection with 
Mycobacterium tuberculosis (TB) (see details in Section 7.1.1).
7. Subjects with a malignancy or with a history of malignancy, with the exception of 
adequately treated or excised non-metastatic basal cell or squamous cell cancer of the 
skin or cervical carcinoma in situ.
8. 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.
9. A positive urine drug test, for illicit drugs, at Screening and Day -1:

NOTE: repeat urine drug testing is not permitted in this study.

Renal impairment subjects may be eligible to participate after approval from 
sponsor if their drug screen is positive with a prescribed substance that is not 
expected to interfere with the PK of PF-04965842.
10. History of regular alcohol consumption exceeding 7 drinks/week for females or 
14 drinks/week for males (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 Screening.
11. History of or current positive results for human immunodeficiency virus (HIV), 
Hepatitis B surface antigen (HepBsAg), Hepatitis B core antibody (HepBcAb) (with 
negative hepatitis B surface antibody [HepBsAb]), Hepatitis C antibody (HCVAb).


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12. Use of potent, moderate, and select weak CYP2C19 inhibitors (eg, fluconazole, 
fluoxetine, fluvoxamine, ticlopidine omeprazole, voriconazole, cimetidine, 
esomeprazole, felbamate, isoniazid, ketoconazole, lansoprazole, and pantoprazole) or 
inducers (eg, rifampin, ritonavir, efavirenz, enzalutamide, phenytoin, and St. John's
Wort) within 14 days or 5 half-lives (whichever is longer) prior to Day 1.
13. Use of potent, moderate, and select weak CYP2C9 inhibitors (eg, amiodarone, 
felbamate, fluconazole, miconazole, piperine, diosmin, disulfiram, fluvastatin, 
fluvoxamine, voriconazole, efavirenz, isoniazid, metronidazole, paroxetine, and 
sulfamethoxazole) or inducers (eg, aprepitant, carbamazepine, enzalutamide, 
rifampin, ritonavir, nevirapine, phenobarbital, and St. John's Wort) within 14 days or 
5 half-lives (whichever is longer) prior to Day 1.
14. Use of prescription or nonprescription drugs and dietary supplements within 7 days or 
5 half-lives (whichever is longer) prior to Day 1.  As an exception, 
acetaminophen/paracetamol may be used at doses of 1 g/day.  Limited use of 
nonprescription medications that are not believed to affect subject safety or the 
overall results of the study may be permitted on a case-by-case basis following 
approval by the sponsor. 
Herbal supplements, hormonal methods of contraception (Section 5.7), and hormone 
replacement therapy must have been discontinued at least 28 days prior to the first
dose of IP. 
For subjects with renal impairment, concomitant medications (including herbal 
supplements) are only permitted following approval by the sponsor if they are 
considered necessary for the welfare of the study subjects (eg, standard therapy for 
underlying diseases), are not contraindicated with the study drug, and are unlikely to 
interfere with the PK of the study drug.  Limited use of nonprescription medications 
that are not believed to affect subject safety or the overall results of the study may be 
permitted on a case by case basis following approval by the sponsor. 
15. Use of immunosuppressant agents, eg, cyclosporine, tacrolimus, sirolimus, 
everolimus, mycophenolate mofetil, mycophenolate sodium.
16. 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 IP; male subjects with partners who are 
currently pregnant, pregnant female subjects, female subjects planning to become 
pregnant, breastfeeding female subjects.
17. Treatment with an investigational drug(s) within 30 days or 5 half-lives preceding the 
first dose of IP (whichever is longer).
18. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to the dose of IP.


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19. History of sensitivity to heparin or heparin-induced thrombocytopenia, only if heparin 
is used to flush intravenous catheters used during serial blood collections).
20. Unwilling or unable to comply with the Lifestyle Requirements outlined in 
Section 4.4.
21. Other acute acute or chronic medical or psychiatric condition including recent (within 
the past year) or active suicidal ideation or behavior or active suicidal ideation or 
behavior or laboratory abnormality that may increase the risk associated with study 
participation or IP administration or may interfere with the interpretation of study 
results and, in the judgment of the investigator, would make the subject inappropriate 
for entry into this study.
22. 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. 
4.2.2. Additional Exclusion Criteria for Healthy Subjects with Normal Renal Function
(Cohort 1, only)
1. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or 
allergic disease (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing).
2. Evidence or history of clinically significant dermatological condition including atopic 
dermatitis (or eg, contact dermatitis or psoriasis) or visible rash present during 
physical examination.
3. Screening supine BP 150 mm Hg (systolic) or 95 mm Hg (diastolic), following at 
least 5 minutes of supine rest.  If BP is 150 mm Hg (systolic) or 95 mm Hg
(diastolic), the BP should be repeated 2 more times and the average of the 3 BP 
values should be used to determine the subject’s eligibility.
4. Screening supine 12-lead ECG demonstrating a a time from Q wave to the end of the 
T wave corresponding to electrical systole (QT interval) corrected for heart rate 
(QTc)>450 msec or a time from Q wave to the end of the S wave corresponding to 
ventricle depolarization (QRS interval) >120 msec.  If QTc exceeds 450 msec, or 
QRS exceeds 120 msec, the ECG should be repeated 2 more times and the average of 
the 3 QTc or QRS values should be used to determine the subject’s eligibility.


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4.2.3. Additional Exclusion Criteria for Subjects with Impaired Renal Function 
(Cohort 2 and Cohort 3 [if applicable] only)
1. Subjects requiring hemodialysis and peritoneal dialysis. 
2. Subjects with other clinically significant disease that may affect the safety of the 
subject or that may affect the pharmacokinetics of PF-04965842 (including drug 
allergies, but excluding untreated, asymptomatic, seasonal allergies at time of 
dosing). Subjects with any significant hepatic, cardiac, or pulmonary disease or 
subjects who are clinically nephrotic. Hypertension, diabetes mellitus, 
hyperparathyroidism, ischemic heart disease, etc. is not cause for exclusion as long as 
the subject is medically stable and any drugs that are administered for these 
conditions are not expected to interfere with the PK of PF-04965842. 
3. Screening BP 180 mm Hg (systolic) or 110 mm Hg (diastolic), following at least 
5 minutes of supine rest.  If initial BP is 180 mm Hg (systolic) or 110 mm Hg 
(diastolic), the BP should be repeated two more times and the average of the 3 BP 
values should be used to determine the subject’s eligibility.
4. Screening supine 12-lead ECG demonstrating QTcF >470 msec or a QRS interval 
>120 msec.  If initial QTcF exceeds 470 msec, or QRS exceeds 120 msec, the ECG 
should be repeated two more times and the average of the three QTcF or QRS values 
should be used to determine the subject’s eligibility.
4.3. Enrollment Criteria 
This is a non-randomized, open-label, single-dose, parallel-cohort study.  Subjects will be 
enrolled into the study and assigned to the respective cohorts provided they have satisfied all 
subject eligibility criteria.
4.4. Lifestyle Requirements
The following guidelines are provided:
4.4.1. Meals and Dietary Restrictions

Subjects must abstain from all food and drink (except water) at least 4 hours prior to 
any safety laboratory evaluations and 10 hours prior to the collection of the predose 
PK sample. Water is permitted until 1 hour prior to investigational product 
administration.

Water may be consumed without restriction beginning 1 hour after dosing.  
Noncaffeinated drinks (except grapefruit or grapefruit-related citrus fruit juices-see 
below) may be consumed with meals and the evening snack.

Food may be consumed without restriction beginning 4 hours after dosing on Day 1. 
No restriction to breakfast on the other days provided other restrictions are followed.

Lunch will be provided approximately 4 hours after dosing.


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
Dinner will be provided approximately 9 to 10 hours after dosing.

An evening snack may be permitted.

Subjects will not be allowed to eat or drink grapefruit or grapefruit-related citrus 
fruits (eg, Seville oranges, pomelos) from 7 days prior to the first dose of IP until 
collection of the final PK blood sample.

While confined, 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.
4.4.2. Alcohol, Caffeine, and Tobacco

Subjects will abstain from alcohol for 24 hours prior to the single dose of IP on 
Day 1 (plus have a negative breath alcohol test on Day -1) and continue abstaining 
from alcohol until the collection of the final PK sample on Day 4.

Subjects will undergo a breath alcohol test at time points indicated in the Schedule of 
Activities.

Subjects will abstain from caffeine-containing products for 24 hours prior to the start 
of dosing until collection of the final PK sample on Day 4.

Subjects will abstain from the use of tobacco- or nicotine-containing products for 
24 hours prior to dosing and during confinement in the CRU.
4.4.3. Activity

Subjects will abstain from strenuous exercise (eg, heavy lifting, weight training, 
calisthenics, aerobics) for at least 48 hours prior to each blood collection for clinical 
laboratory tests.  Walking at a normal pace will be permitted.
4.4.4. Contraception
All fertile female subjects of childbearing potential who are, in the opinion of the 
investigator, sexually active and at risk for pregnancy with their partner(s) must agree to use 
a highly effective method of contraception consistently and correctly for the duration of the 
active treatment period and for at least 28 days after the last dose of IP.  Although the female 
subjects with tubal ligation are considered to be of childbearing potential, no highly effective 
contraception is required if bilateral tubal ligation was performed.
The investigator or his or her designee, in consultation with the subject, will confirm that the 
subject has selected an appropriate method of contraception for the individual subject and his 
or her partner(s) from the permitted list of contraception methods (see below) and will 
confirm that the subject has been instructed in its consistent and correct use.  At time points 
indicated in the Schedule of Activities, the investigator or designee will inform the subject of 
the need to use highly effective contraception consistently and correctly and document the 


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conversation and the subject’s affirmation in the subject’s chart (subjects need to affirm their 
consistent and correct use of at least 1 of the selected methods of contraception).  In addition, 
the investigator or designee will instruct the subject to call immediately if the selected 
contraception method is discontinued or if pregnancy is known or suspected in the subject or 
partner. 
Females of childbearing potential cannot use hormonal methods of contraception
(including oral and transdermal contraceptives, injectable progesterone, progestin 
subdermal implants, progesterone-releasing intrauterine devices [IUDs], vaginal ring, 
and postcoital contraceptive methods).
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) and 
include the following:
1. Correctly placed copper-containing IUD. 
2. Male sterilization with absence of sperm in the postvasectomy ejaculate.
3. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
Male condom or female condom used WITH a separate spermicide product (ie, foam, gel, 
film, cream, or suppository) is not considered as a highly effective method of contraception.
NOTE: Sexual abstinence, defined as completely and persistently refraining from all 
heterosexual intercourse (including during the entire period of risk associated with the study 
treatments) 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 study portal. 
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 IP 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 CRU, the contact number is not 


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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, IP 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 IP is PF-04965842, provided as 100 mg tablets.
5.1. Allocation to Treatment
The investigator’s knowledge of the treatment should not influence the decision to enroll a 
particular subject or affect the order in which subjects are enrolled.
The investigator will assign subject identification numbers sequentially to the subjects as 
they are screened for the study.  All subjects enrolled will receive the same study treatment. 
5.2. Subject Compliance
IP will be administered under the supervision of investigator site personnel.  The oral cavity 
of each subject will be examined following dosing to ensure the IP was taken.
5.3. Investigational Product Supplies
5.3.1. Dosage Form and Packaging
PF-04965842 100 mg tablets will be supplied to the CRU by Pfizer as 100 mg tablets in high 
density polyethylene (HDPE) bottles.  PF-04965842 will be presented to the subjects in 
individual dosing containers. 
5.3.2. Preparation and Dispensing
Within this protocol, preparation refers to the investigator site activities performed to make 
the IP ready for administration or dispensing to the subject/caregiver by qualified staff.  
Dispensing is defined as the provision of IP, concomitant treatments, and accompanying 
information by qualified staff member(s) to a healthcare provider, subject, or caregiver in 
accordance with this protocol.  Local health authority regulations or investigator site 
guidelines may use alternative terms for these activities. 
PF-04965842 tablets will be prepared at the CRU in the individual dosing containers by 
2 operators, one (1) of whom is an appropriately qualified and experienced member of the 
study staff (eg, physician, nurse, physician’s assistant, nurse practitioner, pharmacy 
assistant/technician, or pharmacist).  The tablets will be provided in unit dose containers and 
labeled in accordance with Pfizer regulations and the clinical site’s labeling requirements. 


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5.4. Administration
Following an overnight fast of at least 10 hours, subjects will receive a single oral 200 mg 
dose of PF-04965842 at approximately 0800 hours (±2 hours).  Investigator site personnel 
will administer IP to subjects with ambient temperature water of approximately 240 mL.  
Subjects will swallow the IP whole, and will not manipulate or chew the IP prior to 
swallowing.
In order to standardize the conditions on PK sampling days, all subjects will be required to 
refrain from lying down (except when required for ECG measurements), eating, and drinking 
beverages other than water during the first 4 hours after dosing.
5.5. Investigational Product Storage 
The investigator or an approved representative, eg, pharmacist, will ensure that all IPs are 
stored in a secured area with controlled access under required storage conditions and in 
accordance with applicable regulatory requirements.
IPs 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 IP 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 IP must be quarantined and not used until Pfizer provides 
permission to use the IP.  It will not be considered a protocol deviation if Pfizer approves the 
use of the IP after the temperature excursion. Use of the IP 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. 


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Receipt of materials, door opening and closing, and other routine handling operations where 
the products are briefly out of the temperature range described in the labeling are not 
considered excursions. 
5.6. Investigational Product Accountability
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the IP supplies.  All IPs (PF-04965842 oral tablets) will be accounted for 
using a drug accountability form/record.
5.6.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused IP (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.
5.7. Concomitant Treatment(s)
Subjects will abstain from all concomitant treatments, except for the treatment of AEs, as 
described in the Exclusion Criteria section (Section 4.2) of this protocol.  Limited use of 
nonprescription medications that are not believed to affect subject safety or the overall results 
of the study may be permitted on a case-by-case basis following approval by the sponsor.
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.
Treatments taken within 28 days before the first dose of IP will be documented as a prior 
treatment.  Treatments taken after the first dose of IP will be documented as concomitant 
treatments.
Females who are using hormonal contraception (oral or transdermal contraceptives, 
injectable progesterone, progestin subdermal implants, progesterone-releasing IUDs, vaginal 
ring, and postcoital contraceptive methods) or who take hormone replacement therapy are not 
eligible to participate in this study.  However, a female of childbearing potential using 
hormonal contraceptives or a postmenopausal female receiving hormone replacement therapy 
who is willing to discontinue hormone therapy 28 days prior to dosing of IP and agree to 
remain off hormonal contraceptives or hormone replacement therapy, respectively, for the 
duration of the study, may be eligible for study participation.  Depo-Provera® must be 
discontinued at least 6 months prior to the first dose of study treatment.
Subjects on the following medications, at the Screening Visit, are excluded from the study:

Use of potent, moderate, and select weak CYP2C19 inhibitors (eg, fluconazole, 
fluoxetine, fluvoxamine, ticlopidine omeprazole, voriconazole, cimetidine, 
esomeprazole, felbamate, isoniazid, ketoconazole, lansoprazole, and pantoprazole) or 
inducers (eg, rifampin, ritonavir, efavirenz, enzalutamide, phenytoin, and St. John's 
Wort) within 14 days or 5 half-lives (whichever is longer) prior to Day 1.


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
Use of potent, moderate, and select weak CYP2C9 inhibitors (eg, amiodarone,
felbamate, fluconazole, miconazole, piperine, diosmin, disulfiram, fluvastatin,
fluvoxamine, voriconazole, efavirenz, isoniazid, metronidazole, paroxetine, and
sulfamethoxazole) or inducers (eg, aprepitant, carbamazepine, enzalutamide,
rifampin, ritonavir, nevirapine, phenobarbital, and St. John's Wort) within 14 days or
5 half-lives (whichever is longer) prior to Day 1.
Note: the CYP2C19 & CYP2C9 inhibitor and inducer examples above are not
exhaustive, consult the sponsor if additional guidance is needed.

Use of immunosuppressant agents, eg, cyclosporine, tacrolimus, sirolimus,
everolimus, mycophenolate mofetil, mycophenolate sodium within 7 days or
5 half-lives (whichever is longer) prior to Day 1.
Herbal supplements must be discontinued at least 28 days prior to Day 1 and until the end of 
CRU stay on Day 4.
5.7.1. Subjects with Healthy Renal Function (Cohort 1 Only)
In general, subjects will abstain from all concomitant treatments (prescription or 
over-the-counter [OTC] medications) as described in the Exclusion Criteria section of the 
protocol, except for the treatment of AEs.  Of note, the following restrictions apply:

Acetaminophen/paracetamol may be used at doses of 1 g/day;

Limited use of nonprescription medications that are not believed to affect subject
safety or the overall results of the study may be permitted on a case-by-case basis
after approval by the sponsor.
5.7.2. Subjects with Impaired Renal Function (Cohort 2 and Cohort 3 [if applicable])
Subjects are permitted to be on stable doses of background medications (including herbal 
supplements) if they are considered necessary for the welfare of the study subjects 
(ie, standard therapy for the underlying disease), are not contraindicated with the study drug 
and are unlikely to interfere with the PK of the study drug. Whenever possible, attempts 
must be made to not alter the doses and regimens of the concomitant medications after Day 1 
and until the end of study on Day 4.

Allowed concomitant medications should be administered to renally impaired
subjects at least 2 hours prior to dosing or withheld to 4 hours after dosing on Day 1.
5.8. Rescue Medication 
There is no rescue therapy to reverse any AEs observed with administration of IP; standard 
medical supportive care must be provided to manage any AEs.


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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 7.1.5).
•
Vital Signs (BP and pulse rate): obtain after 12-lead ECG collection but prior to 
obtaining blood samples and prior to dosing (refer to Section 7.1.4).
•
If an intravenous catheter is placed for serial blood sample collections, ECGs and 
vital signs (BP 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 7.1.1.
•
Serial blood samples for plasma
 PK (refer to Section 7.2): follow 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.
6.2. Screening
Subjects will be screened within 28 days prior to administration of the IP 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 the Section 12.3.  If the time between screening and dosing 
exceeds 28 days as a result of unexpected delays (eg, delayed drug shipment), then subjects 
do not require rescreening if the Day -1 laboratory results meet the eligibility criteria.
 
  This criterion would also apply to 
subjects who screened for this study more than 28 days prior to dosing. 
Refer to the Schedule of Activities for the study procedures to be completed at the Screening 
visit. To prepare for study participation, subjects will be instructed on the information in 
Section 4.4 and Section 5.7.
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6.3. Study Period
Refer to the Schedule of Activities for the study procedures to be completed during the study.
 
6.4. Follow-up 
Refer to the Schedule of Activities for the study procedures to be completed at the follow up 
contact.
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 (see also
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 randomized 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, CRU 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:
•
Limited physical examination;
•
Supine BP and pulse rate measurements;
•
Single 12-lead ECG measurement;
•
Blood 
 specimens for safety laboratory;
•
Pregnancy test (female of childbearing potential only);
•
Blood sample for PK analysis.
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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.
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.
For both Parts 1 and 2, subjects who withdraw from the normal and impairment groups for 
non-safety related reasons and who are considered to be non-evaluable with respect to the 
primary objective may be replaced at the discretion of the PI and the sponsor to ensure 
6 completers.
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 IP or also from study procedures and/or posttreatment study follow-up, and 
entered on the appropriate case report form (CRF) page.  In the event that vital status 
(whether the 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.  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.


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


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Table 3.
Safety Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils 
(Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN/urea and creatinine
Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST, ALT
Total bilirubin
Indirect, direct bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Microscopya
QuantiFERON-TB Gold Test 
or PPDb
FSH b, c
Urine drug screening
β-hCGd
Hepatitis B core antibodyb
Hepatitis B surface antibodyb
Hepatitis B surface antigenb
Hepatitis C core antibody b, e
Human immunodeficiency 
virusb
Additional Tests 
(Needed for Hy’s Law)
AST, ALT (repeat)
Total bilirubin (repeat)
Albumin (repeat)
Alkaline phosphatase 
(repeat)
Direct bilirubin
Indirect bilirubin
Creatine kinase
GGT
PT/INR
Total bile acids
Acetaminophen drug 
and/or protein adduct 
levels
a.
Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase.
b.
Screening only.
c.
Only females who are amenorrheic for at least 12 consecutive months with no alternative pathological or 
physiological cause.
d.
Serum or urine β-hCG for female subjects of childbearing potential.
e.
HCV RNA is reflex testing and is required only if HCVAb is positive. 
For list of abbreviations refer to Appendix 1.
•
The minimum requirement for drug screening includes cocaine, tetrahydrocannabinol
(THC), opiates/opioids, benzodiazepines, and amphetamines.
Any remaining serum/plasma from samples collected for clinical safety laboratory 
measurements at baseline and at all times after dose administration may be retained and 
stored for the duration of the study. 
 
 
 
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Clinically significant abnormal laboratory findings at the final assessment should be followed 
to resolution or until determined by the investigator to be stabilized. Repeat tests may be 
indicated to establish this.
7.1.1.1. Hepatitis Testing
The HepBsAg, HepBcAb, HepBsAb, and HCVAb tests will be performed. The HCV RNA 
is reflex testing which is only required if HCVAb is positive.
Interpretation of Hepatitis B Testing Results:

HepBsAg negative and HepBcAb negative: Subject is eligible for the study;

HepBsAg positive and HepBcAb negative: Subject is excluded from study 
participation;

HepBsAg negative and HepBcAb positive and HepBsAb positive: Subject is eligible 
for study;

HepBsAg negative, HepBcAb positive and HepBsAb negative: Subject is excluded 
from study participation.
Interpretation of Hepatitis C Testing Results: 

HCVAb positive and HCV RNA positive: Subject is excluded from study 
participation;

HCVAb positive and HCV RNA negative: Renal impairment subject may be eligible 
to participate in the study if subject has been adequately treated for hepatitis C.
7.1.1.2. Tuberculosis Testing
The active or latent or inadequately treated infection with Mycobacterium TB is evidenced 
by any of the following:
a.
A positive QuantiFERON-TB Gold (QFT-G) In-Tube test or positive 
Mantoux/Purified Protein Derivative (PPD) tuberculin skin test. 
A negative QFT-G or Mantoux/PPD tuberculin skin test is required unless the subject 
has previously received a documented adequate course of therapy for either latent 
(9 months of isoniazid in a locale where rates of primary multi-drug TB resistance are 
<5% or an acceptable alternative regimen) or active (acceptable multi-drug regimen) 
TB infection.  If the current incidence rates of multi-drug resistant TB infection in the 
locale are unavailable, an adequate treatment regimen should be defined as the 
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b. Chest x-ray taken at Screening with changes suggestive of active TB infection as 
determined by a qualified radiologist.  A chest x-ray is required if a positive QFT-G 
or PPD, unless previously performed and documented within 12 weeks prior to 
screening.
c.
A history of either untreated or inadequately treated latent or active TB infection.
QFT-G In-Tube Test is the preferred testing method. 
A blood sample (approximately 3 mL) will be collected at Screening for QFT-G In-Tube 
testing. 
7.1.1.2.1. Purified Protein Derivative (PPD) Test
If the QFT-G In-Tube test cannot be performed, or if the results cannot be determined to be 
positive or negative, then subjects may be screened using the PPD Tuberculin Test (Mantoux 
method). 
Subjects must have the PPD test administered and evaluated by a health care professional 
48 to 72 hours later in order to be eligible for the study.  The test should be performed 
according to local standards with induration of <5 mm required for inclusion.
7.1.2. Pregnancy Testing
For female subjects of childbearing potential, a serum or urine pregnancy test, with 
sensitivity of at least 25 mIU/mL, will be performed as outlined in the Schedules of 
Activities.  A serum pregnancy test should be performed at screening.  An urine or serum 
pregnancy test can be performed on Day -1 and Day 4.
A negative pregnancy test result is required before the subject may receive the IP/study 
treatment.  Pregnancy tests will also be done whenever 1 menstrual cycle is missed during 
the active treatment period (or when potential pregnancy is otherwise suspected).  Pregnancy 
tests may also be repeated if requested by IRBs/ECs or if required by local regulations.
Urine pregnancy tests must be sensitive to at least 25 mIU/mL and will be conducted with the 
test kit provided by the sites, local laboratory, or central laboratory in accordance with 
instructions provided in its package insert.  Subjects who have missed a menstrual period or 
who show an indeterminate or positive result on the urine test may not further progress in the 
study until pregnancy is ruled out using further diagnostic testing (eg, a negative quantitative 
serum pregnancy test conducted at a certified laboratory).
In the case of a positive confirmed pregnancy, the subject will be withdrawn from 
administration of IP and from the study.


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7.1.3. Physical Examinations
Physical examinations may be conducted by a physician, trained physician's assistant, or 
nurse practitioner as acceptable according to local regulation.  A full physical examination 
will include head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, 
and gastrointestinal, musculoskeletal, and neurological systems.  The limited or abbreviated 
physical examination will be focused on general appearance, the respiratory and 
cardiovascular systems, and subject-reported symptoms.
For measuring 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. 
7.1.4. Blood Pressure and Pulse Rate
BP and pulse rate will be measured at times specified in the Schedule of Activities section of 
this protocol.  Additional collection times, or changes to collection times, of BP, and pulse 
rate will be permitted, as necessary, to ensure appropriate collection of safety data.
Supine BP will be measured with the subject’s arm supported at the level of the heart, and 
recorded to the nearest mm Hg after approximately 5 minutes of rest.  The same arm 
(preferably the dominant arm) will be used throughout the study. Subjects should be 
instructed not to speak during measurements.
The same properly sized and calibrated BP cuff will be used to measure BP each time.  The 
use of an automated device for measuring BP and pulse rate is acceptable; however, when 
done manually, pulse rate will be measured in the brachial/radial artery for at least 
30 seconds.  When the timing of these measurements coincides with a blood collection, BP 
and pulse rate should be obtained prior to the nominal time of the blood collection.
7.1.5. Electrocardiogram 
12-lead ECGs should be collected at times specified in the Schedule of Activities section of 
this protocol.
All scheduled ECGs should be performed after the subject has rested quietly for at least 
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.
To ensure safety of the subjects, a qualified individual at the investigator site will make 
comparisons to baseline measurements.  If the QTc interval is increased by 45 msec from 
the baseline, or an absolute QTc value is 500 msec for any scheduled ECG, then 
2 additional ECGs will be collected, approximately 2 to 4 minutes apart, to confirm the 
original measurement.  If either of the QTc values from these repeated ECGs remains above 
the threshold value (ie, is 45 msec from the baseline, or is 500 msec), then a single ECG 
must be repeated at least hourly until QTc values from 2 successive ECGs fall below the 
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If QTc values remain ≥500 msec (or ≥45 msec from the baseline) for greater than 4 hours (or 
sooner, at the discretion of the investigator), or QTc intervals get progressively longer, the 
subject should undergo continuous ECG monitoring.  A cardiologist should be consulted if 
QTc intervals do not return to less than 500 msec (or to <45 msec above the baseline) after 
8 hours of monitoring (or sooner, at the discretion of the investigator).
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality.  It is important that leads are placed in the 
same positions each time in order to achieve precise ECG recordings.  If a machine-read QTc 
value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTc values are in the 
acceptable range.
7.2. Pharmacokinetics
7.2.1. Plasma for Analysis of PF-04965842 and Metabolites, PF-06471658, PF-07055087 
and 
During all study periods, blood samples (10 mL) to provide approximately 5 mL of plasma
for PK analysis will be collected into appropriately labeled tubes containing dipotassium
ethylenediaminetetraacetic acid (K2EDTA) at times specified in the Schedule of Activities
section of the protocol. 
The actual times may change, but the number of samples will remain the same.  All efforts 
will be made to obtain the PK samples at the exact nominal time relative to dosing.  
However, samples obtained within 10% of the nominal time (eg, within 6 minutes of a 
60-minute sample) from 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[/DCT]).
Samples will be analyzed using a validated analytical method in compliance with Pfizer 
standard operating procedures (SOPs).
Details regarding the collection, processing, aliquoting, storage and shipping of PK samples 
will be provided in the lab manual.  The shipment addresses and assay lab contact 
information will be provided to the investigator site prior to initiation of the study.
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.
 
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7.5. Blood Volume
The total blood sampling volume for individual subjects in this study is approximately 
268 mL.  The actual collection times of blood sampling may change.  Additional blood 
samples may be taken for safety assessments at times specified by Pfizer, provided the total 
volume taken during the study does not exceed 550 mL during any period of 60 consecutive 
days.
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 AEs; and (3) exposure to the IP 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 IP 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 IP(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 IP
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).  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.
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. 


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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 IP), through and including a minimum of 
28 calendar days after the last administration of the IP.
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 IP 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 IP caused or contributed to an AE; generally the facts (evidence) or 
arguments to suggest a causal relationship should be provided.  If the investigator does not 
know whether or not the IP caused the event, then the event will be handled as “related to IP” 
for reporting purposes, as defined by the sponsor.  If the investigator's causality assessment is 
“unknown but not related” to IP, this should be clearly documented on study records. 


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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;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;


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
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
An SAE 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.
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.


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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 TB 
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);

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.


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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. 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 
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 lab 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.


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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. 
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.  
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 OTC 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. 


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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.
8.4.2. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the IP under study during pregnancy or breastfeeding and occupational exposure 
are reportable to Pfizer Safety within 24 hours of investigator awareness.
8.4.2.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an EDP occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the IP; or the female 
becomes or is found to be pregnant after discontinuing and/or being exposed to the 
IP;

An example of environmental exposure would be a case involving direct contact 
with a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant 
and has been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to the 
IP prior to or around the time of conception and/or is exposed during his partner’s 
pregnancy.
If a subject or subject’s partner becomes or is found to be pregnant during the subject’s 
treatment with the IP, the investigator must report this information to Pfizer Safety on the 
CT SAE Report Form and an EDP supplemental form, regardless of whether an SAE has 
occurred.  In addition, the investigator must submit information regarding environmental 
exposure to a Pfizer product in a pregnant woman (eg, a 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 


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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 IP. 
Additional information regarding the EDP may be requested by the sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the subject with the Pregnant Partner Release of Information Form 
to deliver to his partner.  The investigator must document in the source documents that the 
subject was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.4.2.2. 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.
8.4.2.3. 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.


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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.
8.4.3. Medication Errors 
Other exposures to the IP under study may occur in clinical trial settings, such as medication 
errors.
Safety Event
Recorded on the CRF 
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
Medication errors 
All (regardless of whether 
associated with an AE) 
Only if associated with an 
SAE 
8.4.3.1. Medication Errors
Medication errors may result from the administration or consumption of the IP 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 IP;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
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.


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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
Renal impairment subjects will be enrolled based on their eGFR (MDRD) on Day -1.
In Part 1, eight (8) subjects will be enrolled into each of the two renal function groups (severe 
impairment and normal) to ensure 6 completers.  If Part 2 is conducted, up to eight 
(8) subjects will be enrolled in the moderate renal impairment groups to ensure 6 completers.
This is an estimation study. The sample size is based on recommendation from the FDA
Guidance for Industry “Pharmacokinetics in Patients with Impaired Renal Function: Study 
Design, Data Analysis, and Impact on Dosing and Labeling”.10
A total sample size of 12 subjects (6 per group) in Part 1 or Part 2 will provide 90% CI for 
the difference between populations of 0.4074 on the natural logarithm scale for AUCinf with 
80% coverage probability.  The following table presents the width of 90% CIs for different 
estimated effects:
Table 4.
Width of 90% CIs for Different Estimated Effects of Test/Reference Ratio 
For PF-04965842
Estimated Effect
(100* Test/Reference) (%)*
AUC
90% CI
(%)
CI Width
(%)
80
(53.232, 120.228)
67.0
100
(66.540, 150.285)
83.7
120
(79.848, 180.342)
100.5
140
(93.156, 210.399)
117.2
160
(106.465, 240.456)
134.0
180
(119.773, 270.513)
150.7
200
(133.081, 300.569)
167.5
220
(146.389, 330.626)
184.2
240
(173.005, 390.740)
217.7
These estimates are based on an assumed standard deviation of 0.29 for lnAUCinf, as 
obtained from completed study B7451001.
To allow for subjects who fail to complete the study, eight (8) subjects per group will be 
recruited into the study to ensure that we will have at least 6 completers in each group.
9.2. Efficacy Analysis
Efficacy analysis is not applicable to this study. 


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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-04965842 and in whom at least 1 plasma concentration value is reported.
The PK parameter analysis population is defined as all subjects dosed who have at least 1 of 
the PK parameters of primary interest.
9.3.2. Derivation of Pharmacokinetic Parameters Prior to Analysis
9.3.2.1. Plasma 
The plasma PK parameters for PF-04965842 following single dose administration will be 
derived from the concentration time profiles as detailed in Table 5.  In addition, these plasma 
PK parameters (as data permit), 
, will 
be derived for the metabolites, PF-06471658, PF-07055087 and 
.  Actual PK 
sampling times will be used in the derivation of PK parameters.  In the case that actual PK 
sampling times are not available, nominal PK sampling time will be used in the derivation of 
PK parameters.
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.
AUCinf*
Area under the plasma concentration-time 
profile from time zero extrapolated to 
infinite time.
AUClast + (Clast*/kel), 
where Clast* is the predicted plasma 
concentration at the last quantifiable time point 
estimated from the log-linear regression 
analysis.
Cmax
Maximum plasma concentration.
Observed directly from data.
 
 
 
 
 
 
For list of abbreviations refer to Appendix 1.
*As data permit.
CCI
CCI
CCI


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Active moiety Cmax, AUClast, AUCinf values for each subject will be calculated as the sum of 
unbound exposures of PF-04965842 and its active metabolites PF-06471658 and 
PF-07055087, adjusted for the relative potencies of the metabolites.
 
 
 
 
 
 
 
9.3.3. Statistical Methods
For Part 1, a one-way analysis of variance (ANOVA) will be used to compare the natural log 
transformed AUCinf, AUClast and Cmax of the parent PF-04965842 as well as the active moiety
for the renal impairment cohort (Test) to the normal renal function cohort (Reference).  
Estimates of the adjusted mean differences (Test-Reference) and corresponding 90% CI will 
be obtained from the model.  The adjusted mean differences and 90% CI for the differences
will be exponentiated to provide estimates of the ratio of adjusted geometric means 
(Test/Reference) and 90% CI for the ratios.  If Part 2 is conducted, the same ANOVA 
analysis will be performed. Test group in this case will be subjects with moderate renal 
impairment and the reference group will be healthy subjects with normal renal function from 
Part 1. Covariates such as weight and age may be included in the ANOVA only if the 
demographics of the moderate subjects are not within the criteria stated in the protocol (mean 
weight ±15 kg of healthy group, age ±10 years of healthy group).
 
 
  
 
 
 
 
 
CCI
CCI


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The PK parameters for PF-04965842 and the 3 metabolites will be summarized descriptively
by renal function group.  
 
Box plots of mean, median and individual 
subject parameters will be generated by renal function cohort for AUCinf, AUClast and Cmax.
Individual plasma concentrations for PF-04965842 and the 3 metabolites will be listed and 
summarized descriptively by nominal PK sampling time and renal function cohort.  
Individual subject and summary profiles (means and medians) of the concentration- time data 
will be plotted by cohort.  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.
9.4. Safety Analysis
All subjects who receive the IP will be included in the safety analyses and listings.
•
AEs, ECGs, vital signs, 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. 
•
Physical examination and neurological examination information, as applicable,
collected during the course of the study will be considered source data and will not be 
required to be reported, unless otherwise noted.  Any untoward findings identified on 
physical exams conducted during the active collection period will be captured as an 
AE, if those findings meet the definition of an AE. Data collected at Screening that is 
used for inclusion/exclusion criteria, such as ECGs and vital signs will be considered 
source data, and will not be captured for inclusion into the study database, unless 
otherwise noted. Demographic data, medical history and laboratory data collected at 
Screening will be included in the study database.
9.5. Interim Analysis 
No formal interim analysis will be conducted for this study. However, as this is an 
open-label study, the sponsor may conduct unblinded reviews of the data during the course of 
the study for the purpose of safety assessment, facilitating dose-escalation decisions, 
facilitating PK/pharmacodynamics (PD) modeling, and/or supporting clinical development.
9.6. Data Monitoring Committee 
This study will not use a data monitoring committee (DMC).
CCI
CCI


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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.
For studies conducted at non-Pfizer investigator sites, 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.
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 shall ensure that the 
CRFs are securely stored at the study site in encrypted electronic and/or paper form and will 
be password protected or secured in a locked room to prevent access by unauthorized third 
parties.


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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. The
investigator must ensure that the records continue to be stored securely for so long as they are 
retained.
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 comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of subject personal data. Such 
measures will include omitting subject names or other directly identifiable data in any
reports, publications, or other disclosures, except where required by applicable laws. 
The personal data will be stored at the study site in encrypted electronic and/or paper form 
and will be password protected or secured in a locked room to ensure that only authorized 
study staff have access.  The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster.  In the event of a potential personal data breach, the study site shall be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, when study data are compiled for transfer to Pfizer and other authorized 
parties, subject names will be removed and will be replaced by a single, specific numerical 
code, based on a numbering system defined by Pfizer. All other identifiable data transferred 
to Pfizer or other authorized parties will be identified by this single, subject-specific code.  
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 the CSA and applicable privacy laws.


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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, the sharing of data relating to the study and possible risks associated 
with participation, including the risks associated with the processing of the subject’s personal 
data.  The investigator further must ensure that each study subject is fully informed about his 
or her right to access and correct his or her personal data and to withdraw consent for the 
processing of his or her personal data. 
The 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 IP 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 IP, 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 the United States 
Last subject last visit (LSLV) is defined as the date the investigator reviews the last subject’s 
final safety data and determines that no further evaluation is required for the subject to 
complete the trial.


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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 IP safety problems, or at the discretion of Pfizer.  In 
addition, Pfizer retains the right to discontinue development of PF-04965842 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 7 days.  As directed by Pfizer, all study materials must be collected and 
all CRFs completed to the greatest extent possible.
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.


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www.pfizer.com
Pfizer posts public disclosure synopses (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
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 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.
Murray PJ. The JAK-STAT signaling pathway: input and output integration. J Immunol 
2007; 78(5):2623-9.
2.
O'Sullivan LA, Liongue C, Lewis RS, et al. Cytokine receptor signaling through the 
Jak-Stat-Socs pathway in disease. Mol Immunol 2007; 44(10):2497-506.
3.
Auriemma M, Vianale G, Amerio P, et al. Cytokines and T cells in atopic dermatitis.
Eur Cytokine Netw 2012;24(1):37-44.
4.
Eichenfield LF, Ellis CN, Mancini AJ, et al. Atopic dermatitis: epidemiology and 
pathogenesis update. Semin Cutan Med Surg 2012;31:S3-5.
5.
Leicht S, Hanggi M. Atopic dermatitis. How to incorporate advances in management. 
Postgrad Med 2001;109(6):119-27.
6.
Slater NA, Morrell DS. Systemic therapy of childhood atopic dermatitis. Clin Dermatol 
2015;33(3):289-99.
7.
Guideline on the evaluation of the pharmacokinetics of medicinal products in patients 
with decreased renal function.  EMA Committee for Medicinal Products or Human use.  
20 Feb 2014.
8.
Huang, S.M., et al., When to conduct a renal impairment study during drug 
development: US Food and Drug Administration perspective. Clin Pharmacol Ther, 
2009. 86(5): p. 475-9.
9.
National Kidney Foundation. (2002) K/DOQI Clinical practice guidelines for chronic 
kidney disease: Evaluation, classification, and stratification. Am J Kidney Dis. 39(2 
Suppl 1):S1-266.
10.
Guidance for Industry: Pharmacokinetics in Patients with Impaired Renal Function —
Study Design, Data Analysis, and Impact on Dosing and g. FDA Guidance, March 
2010.


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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
AD
atopic dermatitis
ADME
absorption, distribution, metabolism and elimination
AE
adverse event
ALT
alanine aminotransferase
AML
acute myeloid leukemia
ANOVA
analysis of variance
AST
aspartate aminotransferase
ATP
adenosine triphosphate
AUC
area under the curve
AUCinf
area under the concentration time curve from time 0 to infinity
AUClast
area under the concentration time curve from time 0 to the time of 
the last quantifiable concentration
AUCτ
area under the curve over the dosing interval tau, where 
τ = 24 hours for QD dosing
AUCtau
area under the concentration time curve from time 0 to time tau
BBS
Biospecimen Banking System
BCS
biopharmaceutic classification system
BE
Bioequivalence
β-hCG
beta human chorionic gonadotropin
BID
twice a day
BMI
body mass index
BP
blood pressure
BSA
body surface area
BUN
blood urea nitrogen
C-G
Cockcroft-Gault
CI
confidence intervals
CK
creatine kinase
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CL/F
apparent clearance
CLCR
creatinine clearance
Cmax
maximum observed concentration
CO2
carbon dioxide (bicarbonate)
CRF
case report form
CRU
clinical research unit
CSA
clinical study agreement
CSF
cerebrospinal fluid
CCI
CCI


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Abbreviation
Term
CSR
clinical study report
CT
clinical trial
CTA
clinical trial application
CTCAE
Common Terminology Criteria for Adverse Events
CYP2C19
cytochrome P2C19
DCT
data collection tool
D/C
discharge
DDI
drug-drug interaction
DILI
drug-induced liver injury
DMC
data monitoring committee
DMID
dosage form material identification
DNA
deoxyribonucleic acid
DU
dispensable unit
EC
ethics committee
ECG
electrocardiogram
EDMC
external data monitoring committee 
EDP
exposure during pregnancy
EDR
extemporaneous dispensing record
EDTA
edetic acid (ethylenediaminetetraacetic acid)
eGFR
estimated glomerular filtration rate
EFD
embro-fetal development
EM
extensive metabolizer
EMA
European Medicines Agency
EOS
end of study
EPO
erythropoietin
ET
early termination
EU
European Union
EudraCT
European Clinical Trials Database
FDA
food and drug administration
fm
fraction metabolized
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GGT
gamma-glutamyl transferase
GMR
geometric mean ratio
GI
gastrointestinal
GM-CSF
granulocyte-macrophage colony-stimulating factor
HBsAb
hepatitis B surface antibody
HepBcAb
hepatitis B core antibody
HepBsAg 
hepatitis B surface antigen
HCVAb
hepatitis C antibody
HDPE
high density polyethylene
CCI


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Abbreviation
Term
Hh
hedgehog
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
IC50
half maximal inhibitory concentration
ICH
International Conference on Harmonisation
ID
identification
IFN
interferon
IL
interleukin
IND
investigational new drug application
INR
international normalized ratio
IP 
investigational product 
IRB
institutional review board
IRC
internal review committee
IRT
interactive response technology
IUD
intrauterine device
IV
intravenous
JAK
janus kinase
K2EDTA
dipotassium ethylenediaminetetraacetic acid
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
mRNA
messenger ribonucleic acid
MTX
methotrexate
N/A
not applicable
NOAEL
no observed adverse effect level
OTC
over-the-counter
PCD
primary completion date
PD
pharmacodynamic(s)
PE
physical examination
 
pH
potential of hydrogen
PI
principal investigator
PK
pharmacokinetic(s)
POC
proof of concept
PPD
purified protein derivative
PT
prothrombin time
QD
once daily
CCI
CCI
CCI
CCI


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Abbreviation
Term
QFT-G
QuantiFERON®-TB Gold
QT interval
time from electrocardiogram Q wave to the end of the T wave 
corresponding to electrical systole
QTc interval
QT interval corrected for heart rate
QTcF
fridericia corrected QT interval
QRS interval
a time from Q wave to the end of the S wave corresponding to 
ventricle depolarization 
qual
qualitative
Rac
accumulation ratio
RBC
red blood cell
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SCID
severe combined immunodeficiency disorder
Scr, std
serum creatinine measured with a standardized assay for serum 
creatinine
SOA
schedule of activities
SOC
system organ class
SOP
standard operating procedure
SRSD
single reference safety document
STATs
signal transducers and activators of transcription
t½
terminal half life
TB
tuberculosis
TBili
total bilirubin
TEAE
treatment emergent adverse events
THC
tetrahydrocannabinol
Tmax
time to reach maximum concentration
TYK
tyrosine kinase
UB
upper bound
ULN
upper limit of normal
US
United States
WBC
white blood cell
WOCP
women of childbearing potential
CCI
CCI

SAP_001.pdf: 
Protocol B7451021 (PF-04965842) Statistical Analysis Plan
Page 1 of 21
DMB02-GSOP-RF20 2.0 STATISTICAL ANALYSIS PLAN TEMPLATE FOR RENAL IMPAIRMENT 
STUDY (TWO STAGE DESIGN) 30-Jun-2015
PFIZER CONFIDENTIAL
TMF Doc ID: 98.03
Protocol B7451021
A PHASE 1, NON-RANDOMIZED, OPEN-LABEL, SINGLE-DOSE STUDY TO 
EVALUATE THE PHARMACOKINETICS, SAFETY AND TOLERABILITY OF 
PF-04965842 IN SUBJECTS WITH RENAL IMPAIRMENT AND IN HEALTHY 
SUBJECTS WITH NORMAL RENAL FUNCTION
Statistical Analysis Plan 
(SAP)
Version:
1.0
SAP Author: 
(
., Mumbai)
Date:
10-SEP-2018
PPD
PPD


Protocol B7451021 (PF-04965842) Statistical Analysis Plan
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DMB02-GSOP-RF20 2.0 STATISTICAL ANALYSIS PLAN TEMPLATE FOR RENAL IMPAIRMENT 
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PFIZER CONFIDENTIAL
TMF Doc ID: 98.03
Revision History
Version
Date
Author(s)
Summary of Changes/Comments
1.0
10 Sep 2018
Not Applicable
NOTE: Italicized text within this document has been taken verbatim from the Protocol.
PPD


Protocol B7451021 (PF-04965842) Statistical Analysis Plan
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DMB02-GSOP-RF20 2.0 STATISTICAL ANALYSIS PLAN TEMPLATE FOR RENAL IMPAIRMENT 
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PFIZER CONFIDENTIAL
TMF Doc ID: 98.03
TABLE OF CONTENTS 
LIST OF TABLES.....................................................................................................................4
LIST OF FIGURES ...................................................................................................................4
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................6
2. INTRODUCTION .................................................................................................................6
2.1. Study Design .............................................................................................................6
2.2. Study Objectives .......................................................................................................8
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING..................................9
4. HYPOTHESES AND DECISION RULES...........................................................................9
4.1. Statistical Hypotheses ...............................................................................................9
4.2. Statistical Decision Rules..........................................................................................9
5. ANALYSIS SETS .................................................................................................................9
5.1. Pharmacokinetic (PK) Analysis Set ..........................................................................9
5.1.1. Concentration Analysis Set...........................................................................9
5.1.2. Parameter Analysis Set.................................................................................9
5.2. Pharmacodynamic Analysis Set..............................................................................10
5.3. Safety Analysis Set..................................................................................................10
5.4. Other Analysis Sets .................................................................................................10
5.5. Treatment Misallocations........................................................................................10
5.6. Protocol Deviations.................................................................................................10
5.6.1. Deviations Assessed Prior to Allocation ....................................................10
5.6.2. Deviations Assessed Post-Allocation .........................................................10
6. ENDPOINTS AND COVARIATES ...................................................................................10
6.1. Efficacy Endpoint(s) ...............................................................................................10
6.2. Safety Endpoints .....................................................................................................10
6.3. Other Endpoints.......................................................................................................11
6.3.1. PK Endpoints..............................................................................................11
..............................................................................................12
6.4. Covariates................................................................................................................12
7. HANDLING OF MISSING VALUES ................................................................................12
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TMF Doc ID: 98.03
7.1. Concentrations Below the Limit of Quantification.................................................12
7.2. Deviations, Missing Concentrations and Anomalous Values .................................12
7.3. Pharmacokinetic Parameters ...................................................................................12
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........................13
8.1. Statistical Methods ..................................................................................................13
8.2. Statistical Analyses .................................................................................................13
8.3. Safety Analysis........................................................................................................16
8.3.1. Treatment and Disposition of Subjects.......................................................16
8.3.2. Demographic and Clinical Examination Data............................................16
8.3.3. Discontinuation(s).......................................................................................16
8.3.4. Adverse Events...........................................................................................16
8.3.5. Laboratory Data..........................................................................................16
8.3.6. Vital Signs Data..........................................................................................16
8.3.7. ECG Data....................................................................................................17
8.3.8. Physical Examination Data.........................................................................17
.....................................................................................17
...............................................................17
8.3.11. Concomitant Treatments...........................................................................17
8.3.12. Screening and Other Special Purpose Data ..............................................17
9. REFERENCES ....................................................................................................................19
10. APPENDICES ...................................................................................................................20
LIST OF TABLES
Table 1.
Cohort Assignment Based on estimated Glomerular Filtration Rate Ranges.........6
Table 2.
Noncompartmental PK Parameters.......................................................................11
Table 3.
PK Parameters to be Summarized Descriptively by Cohort.................................14
LIST OF FIGURES
Figure 1.
Study Design...........................................................................................................8
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TMF Doc ID: 98.03
APPENDICES
Appendix 1. SAS CODE FOR ANALYSES...........................................................................20


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PFIZER CONFIDENTIAL
TMF Doc ID: 98.03
1. AMENDMENTS FROM PREVIOUS VERSION(S) 
None.
2. INTRODUCTION
PF-04965842 is a janus kinase (JAK) 1 inhibitor that is currently being developed for the 
treatment of atopic dermatitis (AD). 
PF-04965842 is intended for chronic use in patients with atopic dermatitis who may have 
some degree of impaired renal function. Therefore, the present study is being conducted to 
evaluate whether renal impairment has an impact on PF-04965842 PK.
The purpose of this study is to characterize the effect of renal impairment on the plasma PK
of PF-0496482 following administration of a single 200 mg oral dose. Findings from this 
study will be used to develop dosing recommendations so that dose and/or dosing interval 
may be adjusted appropriately in the presence of renal disease.
1.1. Study Design
This is a Phase 1 non-randomized, open-label, single-dose, parallel-cohort, multisite study to 
investigate the effect of severe renal impairment on the plasma pharmacokinetics, safety and 
tolerability of PF-04965842 after a single 200 mg oral dose. A staged approach, as outlined 
in detail below, will be followed in the study.
Subjects will be selected and categorized into normal renal function or renal impairment 
groups based on their estimated glomerular filtration rate (eGFR) as shown in Table 1.
Table 1.
Cohort Assignment Based on estimated Glomerular Filtration Rate Ranges
Cohort
Renal Impairmenta
Estimated eGFRb
(mL/min)
Number of 
Completer
Subjects
1
None (Normal)
90
6c
2
Severe Renal Impairment
<30 and not requiring dialysis
6
3
Moderate Renal Impairment
30 to <60
6
4
Mild Renal Impairment
60 – 89
6
a.
Stages of renal impairment are based on Kidney Disease Outcomes Quality Initiative (KDOQI) Clinical Practice 
Guidelines for Chronic Kidney Disease (CKD).
b.
Estimate of eGFR based on Modification of Diet in Renal Disease (MDRD) formula. The Day -1 eGFR value will be 
used for group assignment.

Step 1: eGFR (mL/min/1.73 m2) = 175 × (Scr, std)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African 
American) where Scr, std denotes serum creatinine measured with a standardized assay.

Step 2: Convert the MDRD-derived, body surface area (BSA)-adjusted eGFR obtained above to absolute eGFR 


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(mL/min) for eligibility assessment using the following equation:
eGFR (mL/min) = eGFR (mL/min/1.73 m2) ×subject’s BSA;
where, BSA =(Weight0.425 x Height0.725) x 0.007184.
c.
Additional subjects may be dosed to a maximum of 10 subjects to ensure mean age is 10 years and mean body weight 
15 kg of this cohort is in line with pooled average assessed when >=75% of subjects are dosed in cohort 2.
Part 1: A total of approximately 16 subjects will be enrolled in Part 1; approximately
8 subjects with severe renal impairment and approximately 8 with normal renal function.  
The 8 subjects from the impaired group will be recruited first. The demographics will be
pooled across study sites to determine an average value for age and weight. Subsequently,
the healthy subjects will be recruited later such that each subject’s age is within ±10 years
and weight is within ±15 kg of the mean of the pooled impaired groups. An attempt will be
made to maintain a similar male/female ratio and racial make-up between groups. Care will
be taken when recruiting the healthy subjects such that the entire group is not younger and of
lower body weight than the impaired subjects.  Approval from the sponsor must be obtained
before proceeding with dosing healthy subjects with normal renal function (Cohort 1).
Subjects who withdraw from the normal and severe impairment groups for non-safety related
reasons and who are considered to be non-evaluable with respect to the primary objective
may be replaced at the discretion of the principal investigator (PI) and the sponsor to ensure
6 completers.
Statistical Criteria to proceed to Part 2: After statistical evaluation of results from Part 1, 
Part 2 will be conducted if the upper bound (UB) of the 90% CI for PF-04965842 AUCinf 
geometric mean ratio (GMR) for the severe renal impairment group (compared to the normal 
group as control) is ≥3.0. If variability is unexpectedly higher than assumed, eg, if the UB of 
the GMR is substantially higher than 3 with a point estimate of the GMR close to 2, the data 
will be further evaluated to determine whether to proceed to Part 2. If the above mentioned 
criterion is not met, the study will stop after Part 1.
Part 2: Based on whether the decision criterion to proceed to Part 2 is met, approximately 
8 subjects each with moderate and mild renal impairment will be enrolled. As in Part 1, 
renal impairment classification will be based on eGFR. Healthy subjects will not be enrolled 
in Part 2.
As in Part 1, subjects who withdraw from the moderate or mild impairment group for 
non-safety related reasons and who are considered to be non-evaluable with respect to the 
primary pharmacokinetic objective may be replaced at the discretion of the PI and the 
sponsor to ensure 6 completers.
CLCR will be estimated from a spot serum creatinine measurement using the following 
Cockcroft-Gault (C-G) equation:


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CLCR (mL/min) =
(mg/dL)
creatinine
serum
 x 
72
females)
for 
(0.85
 x 
(kg)
t 
body weigh
 x total
(years)]
Age
[140 
Note that eGFR calculated by the MDRD equation will be used for categorization of degrees 
of renal impairment. Nevertheless, renal function will be estimated using both C-G and 
MDRD equations in this study.
The overall study design for both Parts 1 and 2 is summarized in below Figure 1.
Figure 1.
Study Design
2.1. Study Objectives
Primary Objectives:

Part 1: To evaluate the effect of severe renal impairment on the pharmacokinetics of 
PF-04965842 following single oral dose administration.

Part 2 (if applicable): To evaluate the effect of moderate and mild renal impairment 
on the pharmacokinetics of PF-04965842 following single oral dose administration.
Secondary Objective:

To evaluate the safety and tolerability of a single oral dose of PF-04965842 in 
subjects with renal impairment and in healthy subjects with normal renal function.


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Tertiary/Exploratory Objectives:
•
To compare additional plasma pharmacokinetic parameters of PF-04965842 
following single oral administration in subjects with renal impairment and in healthy 
subjects without renal impairment.
•
 
•
To determine the plasma 
 PK of the major circulating metabolites of 
PF-04965842: PF-06471658, PF-07055087 
.
•
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING
No formal interim analysis will be conducted for this study. However, data will be reviewed 
after completion of Part 1 in order to determine whether Part 2 will proceed. Final analysis 
will follow the official database release.  As this will be an open, nonrandomized study, there 
is no formal unblinding.
4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
No hypotheses are required.
4.2. Statistical Decision Rules
No decision rules are required.
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-04965842 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.
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5.2. Pharmacodynamic Analysis Set
None.
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.
5.4. Other Analysis Sets
None.
5.5. Treatment Misallocations 
All analyses will be performed on an “as-treated” basis and will not include data from 
subjects who are allocated to a cohort but not treated.
5.6. Protocol Deviations
Subjects who experience events that may affect their PK profile (eg, lack of compliance with 
dosing) may be excluded from the PK analysis.  At the discretion of the pharmacokineticist a 
concentration value may also be excluded if the deviation in sampling time is of sufficient 
concern or if the concentration is anomalous for any other reason.
A full list of protocol deviations will be compiled and reviewed to identify major and minor 
deviations prior to database closure.
5.6.1. Deviations Assessed Prior to Allocation
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-Allocation
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 start of treatment or increasing in severity will be counted as 
treatment emergent.


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Events that occur in a non-treatment period (for example, Washout or Follow-up) will be 
counted as treatment emergent and attributed to the previous treatment 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 (blood pressure and pulse rate);
•
ECG results;
•
physical examination.
6.3. Other Endpoints
6.3.1. PK Endpoints
Blood 
 samples for PK analysis of PF-04965842 and  major circulating 
metabolites, PF-06471658, PF-07055087 and 
 will be taken according to the 
Schedule of Activities given in the protocol.
The following PK parameters will be calculated for PF-04965842 and for  major circulating 
metabolites, PF-06471658, PF-07055087 and 
(if possible) from the 
concentration-time data using standard non compartmental methods:
Table 2.
Noncompartmental PK Parameters
PK 
Parameter
Analysis 
Scale
PF-04965842
PF-06471658
PF-07055087
AUCinf
*
ln
A, D
D
D
AUClast
ln
A, D
D
D
Cmax
ln
A, D
D
D
Key:
A=analyzed using statistical model, D=displayed with descriptive statistics;
ln=natural-log transformed, R=raw (untransformed);
NA=not applicable;
*=if data permits.
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6.4. Covariates
Covariates such as weight and age may be included in the analysis of variance (ANOVA) if 
necessary, if the demographics of the mild and moderate cohort subjects are not within the 
criteria stated in the protocol (mean weight ± 15 kg of healthy group, age ± 10 years of 
healthy group).
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), concentrations below the limit of quantification 
(BLQ) will be set to zero.  (In listings BLQ values will be reported as “<LLQ”, where LLQ 
will be replaced with the value for the lower limit of quantification.)
7.2. Deviations, Missing Concentrations and Anomalous Values
In summary tables and plots of median profiles, statistics will be calculated having set 
concentrations to missing if 1 of the following cases is true:
1. A concentration has been collected as ND (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.)
In summary tables, statistics will be calculated by setting NC values to missing; and statistics 
will be presented for a particular renal function group with ≥3 evaluable measurements.  For 
statistical analyses (ie, analysis of variance), PK parameters coded as NC will also be set to 
missing; and analyses will not be performed for a particular parameter if more than 50% of 
the data are NC.
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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
Following Part 1, the effect of the severe renal impairment on PK parameters will be assessed 
by constructing 90% confidence intervals around the estimated difference between the severe 
renal impairment and the normal renal function using a one-way ANOVA model based on 
natural log transformed data.
Following Part 2 (if conducted), the same ANOVA analysis will be performed using data 
from the mild and moderate renal impairment groups. 
 
 
 
.
8.2. Statistical Analyses
For Part 1, a one-way analysis of variance (ANOVA) will be used to compare the natural log 
transformed AUCinf, AUClast and Cmax of PF-04965842 for the renal impairment cohort (Test) 
to the normal renal function cohort (Reference). Estimates of the adjusted mean differences 
(Test-Reference) and corresponding 90% CI will be obtained from the model. The adjusted 
mean differences and 90% CI for the differences will be exponentiated to provide estimates 
of the ratio of adjusted geometric means (Test/Reference) and 90% CI for the ratios. 
If Part 2 is conducted, the same ANOVA analysis will be performed. Test group in this case 
will be subjects with moderate or mild renal impairment and the reference group will be 
healthy subjects with normal renal function from Part 1. Covariates such as weight and age 
may be included in the ANOVA if necessary, if the demographics of the mild and moderate 
subjects are not within the criteria stated in the protocol (mean weight ±15 kg of healthy 
group, age ±10 years of healthy group).
 
 
 
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Residuals from the models will be examined for normality and the presence of outliers via 
visual inspection of plots of residuals vs predicted values and normal probability plots of 
residuals but these will not be included in the clinical study report. If there are major 
deviations from normality or outliers then the effect of these on the conclusions will be 
investigated through alternative transformations and/or analyses excluding outliers.  
Justification for any alternative to the planned analysis will be given in the report of the 
study.
The following PK parameters (as data permit) for PF-04964842 and metabolites, 
PF-06471658, PF-07055087 and
 
 will be summarized by renal function group:
Table 3.
PK Parameters to be Summarized Descriptively by Cohort
Parameter
Summary Statistics
AUClast, AUCinf
*, 
Cma , 
 
 
N, arithmetic mean, median, cv%, standard deviation, minimum, 
maximum, geometric mean and geometric cv%.
 
 
*: as data permit; #: PF-04965842 only.
 
Box and whisker plots for individual subject parameters (AUCinf, 
AUClast and Cmax) be presented by renal function cohort and overlaid with geometric means.
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Supporting data from the estimation of 
 AUCinf will be listed by analyte and 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-04965842 and metabolites PF-06471658, PF-07055087 and 
concentrations will include:
•
a listing of all plasma concentrations sorted by renal 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 plasma concentrations by renal 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 plasma concentrations time plots (on both linear and semi-log scales) against 
nominal time postdose by renal function cohort (all renal function cohorts on the 
same plot per scale, based on the summary of concentrations by renal function cohort
and time postdose).
•
mean plasma concentrations time plots (on both linear and semi-log scales) against 
nominal time postdose by renal function cohort (all renal function cohorts on the 
same plot per scale, based on the summary of concentrations by renal function cohort 
and time postdose).
•
individual plasma concentration time plots by renal function cohort (on both linear 
and semi-log scales) against actual time postdose (there will be separate spaghetti 
plots for each renal 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.
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8.3. Safety Analysis
A set of summary tables split by renal function cohort will be produced to evaluate any 
potential risk associated with the safety and toleration of administering PF-04965842.
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, as well as for safety (adverse events and 
laboratory data).  Frequency counts will be supplied for subject discontinuation(s) by renal
function cohort.
Data will be reported in accordance with the sponsor reporting standards.
8.3.2. Demographic and Clinical Examination Data
A break-down 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.
8.3.3. Discontinuation(s)
Subject discontinuations will be detailed and summarized by renal 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 renal
function cohort.
8.3.5. Laboratory Data
Laboratory data from each planned timepoint including screening will be listed and 
summarized in accordance with the sponsor reporting standards.
For laboratory parameters which are collected only at Screening for inclusion/exclusion 
criteria, data will not be captured for inclusion into the study database and therefore will not 
be listed or summarized.
8.3.6. Vital Signs Data
Vital sign data will include blood pressure and pulse rate. The baseline measurement is the 
last planned predose measurement.
For each planned timepoint, baseline values and change from baseline values within each 
renal function group will be summarized with descriptive statistics (using sponsor default 
standards).


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These data will be listed in accordance with the sponsor reporting standards.
8.3.7. ECG Data
The baseline measurement is the last planned predose measurement.
For each planned timepoint, summary of shift in normality status (normal\abnormal) from 
baseline will be provided using sponsor default standards.
These data will be listed in accordance with the sponsor reporting standards.
8.3.8. Physical Examination Data
The baseline measurement is the predose measurement.
For each planned timepoint, summary of shift in normality status (normal\abnormal) from 
baseline will be provided using sponsor default standards.
These data will be listed in accordance with the sponsor reporting standards.
 
 
8.3.11. Concomitant Treatments
All concomitant medication(s) as well as non-drug treatment(s) and physical examination 
data will be provided in the listings.
8.3.12. Screening and Other Special Purpose Data
Prior medication(s) and non-drug treatment(s), serum FSH concentrations, urine drug screen, 
serum or urine pregnancy test for all females of childbearing potential, alcohol/tobacco use, 
breath alcohol test, HepBcAb, HepBsAb, HepBsAg, HCVAb (HCV RNA reflex test in case 
of positive HCVAb test), HIV tests, QFT-G Test or PPD skin test (chest x-ray in case of 
positive QFT-G or PPD) will be assessed at Screening.
Data for prior medication(s) and non-drug treatment(s), urine drug screen, serum or urine 
pregnancy test for all females of childbearing potential and tobacco use will be collected and 
listed at Screening or Day -1. For rest of the parameters data will not be brought in-house, 
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and therefore will not be listed as they will be considered the sources data at sites per 
protocol.


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9. REFERENCES
1.
FDA Guidance for Industry – Pharmacokinetics in Patients with Impaired Renal 
Function - Study Design, Data Analysis, and Impact on Dosing and Labeling.  05/98


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10. APPENDICES
Appendix 1. SAS CODE FOR ANALYSES
For Part 1:
An example of the PROC MIXED code is provided below:
proc mixed data = tab.pk covtest alpha=0.1;
class group;
model l&var = group / S covb alpha=0.1 CL DDFM=KR;
repeated/type=un subject=subjid group=group R;
lsmeans group;
estimate 'Severe vs Normal'
group -1 1;
ods output lsmeans = lsmeans&var;
ods output solutionf = solution&var;
run;
/* Letter assignments for group within the estimate statement above are as follows;
A = Normal (Reference), B = Severe (Test);*/;
For Part 2:
An example of the PROC MIXED code is provided below:
proc mixed data = tab.pk covtest alpha=0.1;
class group;
model l&var = group / S covb alpha=0.1 CL DDFM=KR;
repeated/type=un subject=subjid group=group R;
lsmeans group;
estimate 'Mild vs Normal'
group -1 1 0;
estimate 'Moderate vs Normal'
group -1 0 1;


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ods output lsmeans = lsmeans&var;
ods output solutionf = solution&var;
run;
/* Letter assignments for group within the estimate statement above are as follows;
A = Normal (Reference), C = Moderate (Test), D = Mild (Test);*/;
Following Part 2:
An example of the PROC REG code is provided below:
proc reg data=tab.pk;
model l&var=clcr/clb alpha=0.1;
ods output ParameterEstimates = param&var;
ods output FitStatistics = fit&var;
ods output ANOVA = reg&var;
run;
Note: Similar code will be used for regression analysis with respect to eGFR.