Conditions: Atopic Dermatitis
Keywords: Phase 2 randomized double-blind placebo atopic dermatitis safety efficacy JAK janus kinase moderate severe
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 269
Healthy volunteers: no

Brief summary:
Study B7451006 is a Phase 2b POC study which is planned to assess four PF 04965842 once daily (QD) doses (10, 30, 100, 200 mg) relative to placebo over 12 weeks to characterize the efficacy and safety of PF 04965842 in subjects with moderate to severe AD. The objectives of the study are to demonstrate the efficacy of PF 04965842 by showing improvement in disease severity in patients with moderate to severe AD as measured by the Investigator's Global Assessment (IGA) and Eczema Area and Severity Index (EASI) scores, and safety to support further clinical development of PF 04965842.

Detailed description:

Arms:
arm 1: 10 mg of PF-04965842 QD arm 2: 30 mg of PF-04965842 QD arm 3: 100 mg of PF-04965842 QD arm 4: 200 mg of PF-04965842 QD arm 5: placebo QD

Interventions: intervention 1: PF-04965842 intervention 2: PF-04965842 intervention 3: PF-04965842 intervention 4: PF-04965842 intervention 5: Placebo
Intervention descriptions: intervention 1: 10 mg of PF-04965842 QD for 12 weeks intervention 2: 30 mg of PF-04965842 QD for 12 weeks intervention 3: 100 mg of PF-04965842 QD for 12 weeks intervention 4: 200 mg of PF-04965842 QD for 12 weeks intervention 5: Placebo QD for 12 weeks

Protocol document:
Prot_001.pdf: 
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CLINICAL PROTOCOL 
A PHASE 2BRANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL, MULTICENTER, DOSE-RANGING, STUDY TO EVALUATE THE 
EFFICACYAND SAFETYPROFILE OF PF-04965842IN SUBJECTS WITH 
MODERATE TO SEVERE ATOPIC DERMATITIS
Compound:
PF-04965842
Compound Name:
Not applicable (N/A)
United States (US) Investigational New 
Drug (IND) Number:
123554
European Clinical Trials Database 
(EudraCT) Number:
2015-005513-72
Protocol Number:
B7451006
Phase:
2B
 
 
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Document History
Document
Version Date
Summary of Changes 
Original protocol
22 December 2015
N/A
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................8
LIST OF FIGURES...................................................................................................................8
APPENDICES...........................................................................................................................9
PROTOCOL SUMMARY.......................................................................................................10
SCHEDULE OF ACTIVITIES................................................................................................17
1. INTRODUCTION...............................................................................................................22
1.1. Indication.................................................................................................................22
1.2. Mechanism of Action..............................................................................................22
1.3. Background and Rationale......................................................................................23
1.3.1. Drug Development and Rationale..............................................................23
1.3.2. Atopic Dermatitis........................................................................................23
1.3.3. Nonclinical Pharmacokinetics and Metabolism.........................................25
1.3.4. Biopharmaceutics Properties......................................................................25
1.4. Safety Data..............................................................................................................26
1.4.1. Non-Clinical Safety....................................................................................26
1.4.2. Clinical Experience.....................................................................................27
1.4.2.1. First-in-Human (B7451001) Data.............................................27
1.4.2.2. Bioavailability (BA) study Safety Data....................................28
1.4.2.3. B7451005 Study Safety Data....................................................29
1.5. Summary of PF-04965842 Pharmacokinetics.........................................................29
1.6. Summary of PF-04965842 Pharmacodynamics......................................................30
1.6.1. First-in-Human (B7451001) Data...............................................................30
1.6.2. B7451005 Study Data.................................................................................31
1.7.Summary of Benefits and Risks..............................................................................31
1.8. Rationale..................................................................................................................31
1.8.1. Study Rationale...........................................................................................31
1.8.2. Dose Selection Rationale............................................................................32
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................34
2.1. Primary Objectives..................................................................................................34
2.2. Secondary Objectives..............................................................................................34
2.3. Exploratory Objectives............................................................................................34
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2.4. Endpoints.................................................................................................................34
2.4.1. Primary Endpoints......................................................................................34
2.4.2. Secondary Endpoints..................................................................................34
2.4.2.1. Efficacy Endpoints....................................................................34
2.4.2.2. Safety Endpoints.......................................................................35
2.4.2.3. Patient-Reported Outcome (PRO) Endpoints...........................35
2.4.3. Exploratory Endpoints................................................................................36
3. STUDY DESIGN.................................................................................................................36
4. SUBJECT SELECTION......................................................................................................37
4.1. Inclusion Criteria.....................................................................................................37
4.2. Exclusion Criteria....................................................................................................38
4.3. Randomization Criteria...........................................................................................43
4.4. Lifestyle Guidelines................................................................................................43
4.4.1. Surgery........................................................................................................43
4.4.2. Contraception..............................................................................................43
4.5. Sponsor’s Qualified Medical Personnel..................................................................45
4.6. Rater Qualifications.................................................................................................45
5. STUDY TREATMENTS.....................................................................................................45
5.1. Allocation to Treatment..........................................................................................46
5.2. Breaking the Blind..................................................................................................46
5.3. Subject Compliance.................................................................................................46
5.4. Investigational Product Supplies.............................................................................47
5.4.1. Dosage Form(s) and Packaging..................................................................47
5.4.2. Preparation and Dispensing........................................................................47
5.5. Administration.........................................................................................................47
5.6. Investigational Product Storage..............................................................................48
5.7. Investigational Product Accountability...................................................................48
5.7.1. Destruction of Investigational Product Supplies........................................49
5.8. Concomitant Treatment(s).......................................................................................49
5.8.1. Permitted Concomitant Medications..........................................................49
5.8.2. Prohibited Medications and Treatments.....................................................50
5.8.3. Vaccinations...............................................................................................51
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6. STUDY PROCEDURES.....................................................................................................51
6.1. Visit1, Screening....................................................................................................52
6.2. Study Period............................................................................................................53
6.2.1. Visit 2, Day 1/Week 0................................................................................53
6.2.2. Visit 3, Day 8/Week 1 (1 day)..................................................................54
6.2.3. Visit 4, Day 15/Week 2 (1 day)................................................................55
6.2.4. Visit 5, Day 29/Week 4 (1 day)................................................................56
6.2.5. Visit 6, Day 43/Week 6 (1 day)................................................................56
6.2.6. Visit 7, Day 57/Week 8 (3 day)................................................................57
6.2.7. Visit 8, Day 85/Week 12 (3 day)..............................................................58
6.3. Follow-up Visits......................................................................................................59
6.3.1. Visit 9, Day 92/Week 13 (3 day)..............................................................59
6.3.2. Visit 10, Day 99/Week 14 (3 day)............................................................59
6.3.3. Visit 11, End of Study Visit, Day 113/Week 16 (3 day) or Early 
Termination Visit.............................................................................................60
6.4. Subject Withdrawal.................................................................................................61
7. ASSESSMENTS..................................................................................................................62
7.1. Pregnancy Testing...................................................................................................62
7.2. Banked Biospecimens.............................................................................................62
7.2.1. Markers of Drug Response.........................................................................62
7.2.2. Additional Research....................................................................................64
7.3. Safety Assessments.................................................................................................64
7.3.1. Vitals Signs.................................................................................................64
7.3.2. Medical History, Physical Exam, Height, and Weight...............................65
7.3.3. Chest X-Ray................................................................................................65
7.3.4. Electrocardiogram.......................................................................................65
7.3.5. QuantiFERON-TB Gold In-Tube Test and Mantoux/Purified 
Protein Derivative (PPD) Tuberculin Skin Test..............................................66
7.3.6. Special Safety Assessment.........................................................................66
7.4. Skin Type Assessment............................................................................................66
7.5. Clinical Laboratory Tests........................................................................................67
7.5.1. Blood Volume.............................................................................................67
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7.5.2. Laboratory Tests 
.........................................................................................67
7.5.2.1. Viral Surveillance......................................................................68
7.6. Efficacy Assessments 
..............................................................................................68
7.6.1. Investigator Global Assessment (IGA).......................................................68
7.6.2. Eczema Area and Severity Index (EASI) 
...................................................69
7.6.2.1. Body Surface Area – Efficacy (BSA Efficacy).........................71
7.6.3. Scoring Atopic Dermatitis (SCORAD) 
......................................................71
7.7. Patient-Reported Outcomes (PROs)........................................................................73
7.7.1. Pruritus Numeric Rating Scale (NRS)........................................................73
7.7.2. Patient Global Assessment (PtGA).............................................................73
7.7.3. Dermatology Life Quality Index (DLQI) ...................................................73
7.7.4. Patient-Oriented Eczema Measure (POEM)...............................................74
7.7.5. Hospital and Anxiety Depression Scale (HADS).......................................74
7.7.6. 
 .......74
7.8. Photography of Atopic Dermatitis Treated with Study Drug..................................74
7.9. Pharmacokinetics ....................................................................................................74
7.9.1. Plasma for Analysis of PF-04965842 
.........................................................74
7.9.2. Shipment of Pharmacokinetic Samples ......................................................75
7.10. Pharmacodynamics Markers .................................................................................75
7.10.1. Samples for IP-10 Analysis ......................................................................76
7.10.2. Samples for hs-CRP Analysis...................................................................76
7.10.3. Samples for Immunoglobulin E (IgE) Analysis .......................................76
7.10.4. Samples for FACS analysis (T cell, B cell, and NK cell subsets) 
............77
7.10.5. Samples for FACS Analysis: T-cell subtype profiling 
.............................77
7.10.6. Samples for IL-31 Analysis 
......................................................................77
7.10.7. Samples for CCL17 (TARC) Analysis 
.....................................................77
7.10.8. Serum for Exploratory Analysis 
...............................................................78
7.10.9. Cell-free Plasma for Exploratory Analysis...............................................78
7.10.10. Gene Expression Analysis 
......................................................................78
7.10.11. Shipment of Pharmacodynamic Samples ...............................................78
8. ADVERSE EVENT REPORTING......................................................................................78
8.1. Adverse Events........................................................................................................78
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8.2. Reporting Period.....................................................................................................79
8.3. Definition of an Adverse Event...............................................................................79
8.4. Medication Errors....................................................................................................80
8.5. Abnormal Test Findings..........................................................................................80
8.6. Serious Adverse Events...........................................................................................81
8.6.1. Protocol-Specified Serious Adverse Events...............................................81
8.6.2. Potential Cases of Drug-Induced Liver Injury............................................81
8.7. Hospitalization........................................................................................................82
8.8. Severity Assessment................................................................................................84
8.9. Causality Assessment..............................................................................................84
8.10. Exposure During Pregnancy..................................................................................84
8.11. Occupational Exposure.........................................................................................86
8.12. Withdrawal Due to Adverse Events (See Also the Section on Subject 
Withdrawal)...............................................................................................................86
8.13. Eliciting Adverse Event Information....................................................................86
8.14. Reporting Requirements........................................................................................86
8.14.1. Serious Adverse Event Reporting Requirements.....................................86
8.14.2. Nonserious Adverse Event Reporting Requirements...............................87
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities................87
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................87
9.1. Sample Size Determination.....................................................................................87
9.2. Efficacy Analysis....................................................................................................88
9.2.1. Analysis of the Primary Endpoint...............................................................88
9.2.2. Analysis of the Secondary Endpoints.........................................................88
9.2.3. Analysis of Other Endpoints.......................................................................89
9.3. Safety Analysis........................................................................................................89
9.4. Interim Analysis......................................................................................................90
9.5.PK/PD Unblinding Plan..........................................................................................90
9.6. Analysis of Pharmacokinetics Endpoints................................................................91
9.7. Data Monitoring Committee...................................................................................91
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................91
11. DATA HANDLING AND RECORD KEEPING.............................................................92
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11.1. Case Report Forms/Electronic Data Record.........................................................92
11.2. Record Retention...................................................................................................92
12. ETHICS..............................................................................................................................93
12.1. Institutional Review Board/Ethics Committee......................................................93
12.2. Ethical Conduct of the Study................................................................................93
12.3. Subject Information and Consent..........................................................................93
12.4. Subject Recruitment..............................................................................................94
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP...........................................................................................................................94
13. DEFINITION OF END OF TRIAL...................................................................................95
13.1. End of Trial in a Member State.............................................................................95
13.2. End of Trial in All Other Participating Countries.................................................95
14. SPONSOR DISCONTINUATION CRITERIA................................................................95
15. PUBLICATION OF STUDY RESULTS..........................................................................95
15.1. Communication of Results by Pfizer....................................................................95
15.2. Publications by Investigators................................................................................96
16. REFERENCES..................................................................................................................98
LIST OF TABLES
Table1. Predicted Geometric Mean PK Parameters following QD Dosing......................32
Table2.
Modeled Predicted Geometric Mean Percent Reduction in Pathways 
Signaling and Biomarkers.....................................................................................33
Table3.
Investigator Global Assessment (IGA) Score.......................................................69
Table4.
Clinical Sign Severity Scoring Criteria for the Eczema Area and Severity 
Index (EASI).........................................................................................................70
Table5.
Handprint Determination of Body Region Surface Area (BSA)..........................70
Table6.
Eczema Area and Severity Index (EASI) Area Score Criteria.............................71
Table7.
Eczema Area and Severity Index (EASI) Body Region Weighting.....................71
LIST OF FIGURES
Figure1. Study Design Schematic.......................................................................................36
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APPENDICES
Appendix 1. Abbreviations 
....................................................................................................100
Appendix 2. Diagnostic Criteria for Atopic Dermatitis.........................................................104
Appendix 3. Prohibited Concomitant Medications................................................................105
Appendix 4. Fitzpatrick Skin Type........................................................................................106
Appendix 5. Patient Global Assessment (PtGA) 
...................................................................107
Appendix 6. Pruritus Severity and Frequency 
.......................................................................108
Appendix 7. Dermatology Life Quality Index (DLQI)..........................................................109
Appendix 8. Patient-Oriented Eczema Measure (POEM) 
.....................................................110
Appendix 9. Hospital and Anxiety Depression Scale (HADS) .............................................111
Appendix 10.
 
..........................................................................................112
Appendix 11. Guidelines for Subject Safety Monitoring and Discontinuation 
.....................116
Appendix 11.1. Monitoring....................................................................................................116
Appendix 11.2. Discontinuation 
............................................................................................116
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PROTOCOL SUMMARY
Background and Rationale:
Atopic dermatitis (AD), also known as atopic eczema, is a common, chronic, inflammatory 
skin disorder characterized byflaky skin lesions, intense pruritus, and a general deterioration 
in the quality of life.  The lifetime prevalence of AD in children is 10-20% with 70% of cases 
occurring in children <5years of age.  Most cases (approximately 75%) improve by 
adulthood, while approximately 25% ofAD patients have symptoms throughout their life. 
There area limited number of treatments available for AD.  Current treatments for mild to 
moderate ADinclude emollients, topical corticosteroids (eg, betamethasone, clobetasol, 
fluocinonide), topical calcineurin inhibitors (eg, pimecrolimus, tacrolimus), and coal tar 
preparations.  Additional treatments generally reserved for severe AD include phototherapy 
(eg, ultravioletA light [UVA] with or without psoralen, ultravioletB light [UVB] 
narrowband or broadband) and systemic agents (eg,corticosteroids, cyclosporine, 
recombinant IFN-, mycophenolate mofetil, methotrexate[MTX], azathioprine, intravenous 
immunoglobulin).
15  Of the currently available therapies, none offers a cure; therefore, the 
main aims of existing treatments are to reduce the occurrence of acute flares, to increase the 
time between relapses to reduce pruritus and the resulting sleep disturbance.
9,13
Key cytokinesimplicated in the pathophysiology of ADincludingIL-4, IL-5, IL-13, IL-31, 
and IFN-, require janus kinase1(JAK1)for signal transduction, suggesting thatselective 
JAK1 inhibitors, that modulate the activity of these cytokines, represent a compelling 
approach to the treatment ofinflammatory skin diseases such as AD.
1
PF-04965842 is anorally bioavailable small molecule that selectively inhibits JAK1by 
blocking the adenosine triphosphate(ATP) binding site.  PF-04965842has a high degree of 
selectivity against other kinases in the human genome: 28-fold selectivity over JAK2, 
>340-fold over JAK3 and 43-fold over tyrosine kinase 2 (TYK2)as well as a goodselectivity 
profile over the broader range of human kinases. The selective inhibition of JAK1 will lead 
to modulation of multiple cytokine pathways involvedin the pathophysiology of AD, 
including IL-4, IL-5, IL-13, IL-31 and IFN.
Objectives and Endpoints:
Primary Objectives
The primary objective of this studyis to evaluate the efficacy of 4QD dose levels
(10, 30, 100, and 200mg) of PF-04965842 relative to placebo in adult subjectswith 
moderate to severe atopic dermatitis, using the Investigator’s Global Assessment 
(IGA).
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Secondary Objectives
To evaluate the effect of PF-0465842 on additional efficacy endpoints and patient 
reported outcomes over time in adult subjects with moderate to severe atopic 
dermatitis.
To evaluate the safety and tolerability of PF-0465842 over time in adult subjects with 
moderate to severe atopic dermatitis.


 
Endpoints
Primary Endpoints
Proportion of subjects achieving the IGA for clear (0) or almost clear (1) and 
2 points improvement from baseline at Week 12.  The baseline will be defined as the 
IGA score on Day 1 pre-dose.
Secondary Endpoints
Efficacy Endpoints
Baseline is defined as the score for each assessment on Day 1 pre-dose.
Key Secondary Efficacy Endpoint
Percent change from baseline in the eczema area and severity index (EASI) total 
score at Week 12. 
Secondary Efficacy Endpoints
Proportion of subjects achieving the IGA for clear (0) or almost clear (1) and 
2 points improvement from baseline at all scheduled time points except Week 12.
Percent change from baseline in the EASI total score at all scheduled time points 
except Week 12.
Proportion of subjects achieving 3 points improvement in the pruritus numerical 
rating scale (NRS) from baseline at all scheduled time points.
Percent change from baseline in the pruritus NRS from baseline at all scheduled time 
points.
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Proportion of subjects achieving 2 points improvement in the IGA from baseline at 
all scheduled time points. 
Proportion of subjects achieving a 50%, 75% and 90% improvement in the EASI 
Total score (EASI50, EASI75, EASI90) at all scheduled time points.
Change from baseline in affected body surface area (BSA) at all scheduled time 
points.
Change from baseline in SCORing atopic dermatitis (SCORAD) at all scheduled time 
points. 
Proportion of subjects achieving a 50% and 75% improvement in SCORAD 
(SCORAD50, SCORAD75) from baseline at all scheduled time points.
Safety Endpoints
Incidence of treatment-emergent adverse events.
Incidence of specific clinical laboratory abnormalities (anemia, neutropenia, 
thrombocytopenia, lymphopenia, lipid profile, liver function tests[LFTs]).
Patient-Reported Outcome (PRO) Endpoints
Baseline is defined as the score for each assessment on Day 1 pre-dose.
Change from baseline in Pruritus NRS score at all scheduled time points.
Proportion of subjects with patient global assessment (PtGA) of AD of clear (0) or 
almost clear (1) and 2 points improvement from baseline at all scheduled time 
points. 
Change from baseline in dermatology life quality index (DLQI) total score at all 
scheduled time points. 
Change from baseline in patient Oriented Eczema Measure (POEM) at all scheduled 
time points.
Change from baseline in the hospital and anxiety depression scale (HADS) at all 
scheduled time points. 

 
 
 
 
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

Study Design:
This Phase 2b, multi-center, randomized, double-blind, 5-arm, parallel group study will 
enroll a total of approximately 250 subjects (providing approximately 200 completers, 
40 subjects per treatment group).  The study will be conducted at approximately 60 sites.
Subjects who have chronic AD that has been present for at least 1 year (prior to screening 
visit) and affected BSA of10%, EASI12 and IGA3 at the screening and baseline visits
will be included in the study.  Subjects must also have a documented history of inadequate 
response to treatment with topical medications given for at least 4 weeks, or for whom 
topical treatments are otherwise medically inadvisable (eg, because of important side effects 
or safety risks) within 12 months of the first dose of study drug.  Subjects will be randomized 
to 1 of 4 treatment groups or placebo in the ratio of 1:1:1:1:1.  Investigators, subjects, and the 
sponsor study team will be blinded as to treatment group. 
Subjects will be screened within 35 days prior to the first dose of study drug to confirm that 
they meet the subject selection criteria for the study.  There will be a 12-week double-blind 
treatment period as well as a 4-week follow up period.
An interim analysis may be performed when a total of approximately 110 randomized 
subjects complete 6 weeks of study or discontinue prematurely from study in order to assess 
the percent change of EASI score from baseline as well as other efficacy and safety 
endpoints such as IGA response, pruritus NRS response and hematological parameters as 
appropriate.  Modifications to the design such as adjustments to the final sample size or 
termination of enrollment of subjects in a treatment arm or stopping a treatment arm may be 
made upon review of the data.  Unless a safety concern arises, no decisions to stop the trial 
will be made based on this interim analysis.  Please refer to Section 9.4for details.
Study Treatments:
PF-04965842 will be administered orally at one of the following 4 doses: 10, 30, 100, or 
200 mg administered QD for 12 weeks.  In addition, one cohort will receive 
PF-04965842-matching placebo. 
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Statistical Methods:
Sample Size Determination
The sample size is based on the primary efficacy endpoint, IGA response rate of clear or 
almost clear and 2points improvement at Week12.  For IGA response rate at Week12, a 
total of 250randomized subjects from the 5treatment groups (providing approximately 
200completers, 40completers per treatment group assuming 20% dropout rate) will provide 
approximately 95% power to detect a 33% difference between PF-04965842 and placebo 
assuming placebo response rate is approximately 10%, and significance level is 0.0125 
(Bonferroni adjusted with 4comparisons). 
Efficacy Analysis
Analysis of the Primary Endpoint 
When the 12 week treatment period is completed, the analysis of the primary endpoint will 
be conducted.  The primary endpoint is the proportion of IGA responders at Week12 and the 
corresponding primary analysis will be based on the normal approximation for the difference 
in binomial proportions (such as IGA response rates) to test the superiority of each dose of 
PF-04965842 to placebo at Week 12.  Subjects who receive at least one treatment and 
discontinue from the study before Week12will be considered non-responders for the 
primary endpoint (IGA) for all subsequent visits during the treatment phase until Week12.
Sensitivity analysis will be performed witha generalized linear mixed model if there are no 
convergence issues.  The modified intention-to-treat (mITT)population will be the subjects 
who receive at least one dose of randomized investigational product(PF-04965842or
placebo).  In addition, dose-response analysis using an E
maxmodel may be provided for the 
primary endpoint. 
Analysis of the Secondary Endpoints
The keysecondary endpoint is the percent change from baseline in EASI score at Week12.  
The estimates for treatment effect will be obtained by fitting the mixed-effect models 
repeated measures (MMRM) assumingmissing at random if there is no convergence issueto 
the percent change of EASI score from baseline score.  MMRM will also be employed for 
other continuous secondary endpoints.
In addition to the primary analysis based on the pairwise evaluation of the treatment effects, 
we will explore the modeling of dose-response relationship for the key secondary endpoint.
The binary secondary endpoints will beanalyzed using the same method specified for the 
primary endpoint.
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Analysis of Other Endpoints
Other continuous endpoints such as change from baseline in   
 PtGA, DLQI, POEM, 
and HADS over 12 weeks and change from baseline in the pruritus severity and frequency 
over time will be analyzed with the same method used for the continuous endpoints in 
Section 9.2.2.  For the binary endpoint such as proportion of subjects with PtGA of AD of 
clear (0) or almost clear (1) and 2 points improvement from baseline over 12 weeks, the 
same method used for the binary endpoint in Section 9.2.1will be employed.
Safety Analysis
All subjects who receive investigational product (safety population) will be included in the 
safety analyses.  All the safety data will be summarized descriptively through appropriate 
data tabulations, descriptive statistics, categorical summaries, and graphical presentations.  
Safety endpoints for the study include:
On-treatment adverse events (AEs) and serious adverse events (SAEs).
Withdrawals from active treatment due to AEs.
Serious infections, defined as any infection (viral, bacterial, and fungal) requiring 
hospitalization or parenteral antimicrobials. 
Safety laboratory tests (eg, anemia, neutropenia, thrombocytopenia, lymphopenia, 
lipid profile, LFTs).
Vital signs.
Electrocardiography (ECG) parameters if applicable.
Safety data will be reviewed and summarized on an ongoing basis during the study to 
evaluate the safety of subjects.  The safety endpoints will be listed and summarized in 
accordance with Pfizer Data Standards.  The safety analyses will be carried out in the safety 
population, detailed analyses will be described in the SAP.
Interim Analysis 
An interim analysis may be performed when approximately a total of 110 randomized 
subjects complete 6 weeks of study or discontinue prematurely from study in order to assess 
the percent change of EASI score from baseline as well as other efficacy and safety 
endpoints such as IGA response, NRS response and hematological parameters as appropriate.  
A non-binding futility analysis may be performed on the efficacy endpoints.  Modifications 
to the design such as adjustments to the final sample size or termination of enrollment of 
subjects in a treatment arm or stopping a treatment arm may be made upon review of the 
data.  Unless a safety concern arises, no decisions to stop the trial will be made based on this 
interim analysis.  An unblinded support team will perform the interim analysis.  The study 
team and investigators will remain blinded to the results of the interim analysis.
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Analysis of Pharmacokinetics Endpoints
Pharmacokinetic concentrations will be summarized and presented by treatment group with 
summary statistics and, where appropriate, non-compartmental PK parameters estimates will 
be provided.  A population PK model may bedeveloped for the purpose of estimating PK 
parameters.  Population PK data for PF-04965842 will be summarized through appropriate 
data tabulations, descriptive statistics, and graphical presentation and will be reported 
separately.  Data permitting, the relationship between exposure and clinical responses 
(efficacy and safety) during 12weeks of treatment in subjects with moderate to severe atopic 
dermatitis may be explored using either observed or modeled exposures.
Data Monitoring Committee 
This study will use an internal review committee (IRC)tomonitor the safety of the subjects 
throughout the study and tomake recommendations to the study team.  Composition of the 
IRCand processes under which the IRC operates will be documented in an IRCcharter.
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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 PROCEDURESand 
ASSESSMENTSsections 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 on the schedule of activities, in order to conduct 
evaluations or assessments requiredto protect the well-being of the subject.
Protocol Activity
Screening
Treatment Period
Follow-upPeriod
Visit Identifier
1
2
3
4
5
6
7
8
9
10
11
Visit Day/Week
Days -35to -1 Day 1/
W 0
Day 8/
W 1
Day 15/
W 2
Day 29/
W 4
Day 43/
W 6
Day 57/
W 8
Day 85/
W 12
Day 92/
W 13
Day 99/
W 14
Day 113/W 16 
ET/EOS
Visit Windowa
None
None
1Day based on Day 1 visit
3Daysbased on Day 1 
visit
3Day based on Day 1 visit
Enrollment Procedure
Informed Consent
X
Inclusion/Exclusion Criteria
X  
X
Demographics, Medical History, 
Atopic Dermatitis Disease Historyb
X
Medical Procedures
Complete Physical Examc
X  
X
X
X
Targeted Physical Examc
X  
X  
X  
X  
X
X  
X
Vital Signsd
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Weight
X  
X
X
Height
X
Chest X-ray
e
X
ECG (12 lead)
X  
X
X
X
Laboratory Assessments
BloodChemistryf
X  
X
X
X
X
X  
X
Urinalysis
X  
X
X
X
X
Hematology
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Serum FSH (WONCBP only)or 
Pregnancy Testg
X
Urine Pregnancy Test(conducted at 
study site)
h
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
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Protocol Activity
Screening
Treatment Period
Follow-upPeriod
Visit Identifier
1
2
3
4
5
6
7
8
9
10
11
Visit Day/Week
Days -35to -1 Day 1/
W 0
Day 8/
W 1
Day 15/
W 2
Day 29/
W 4
Day 43/
W 6
Day 57/
W 8
Day 85/
W 12
Day 92/
W 13
Day 99/
W 14
Day 113/W 16 
ET/EOS
Visit Windowa
None
None
1Day based on Day 1 visit
3Daysbased on Day 1 
visit
3Day based on Day 1 visit
HIVTesting (per local regulations)
i
X
HBsAg, HBcAb, and HCVAb 
(HepB reflex testing)
j
X
Tuberculosis testk
X
Viral Surveillance: EBV, CMV,
HSV1,HSV2,and VZV
X
X
X
X
Laboratory Pharmacodynamics
Total IgE
X
X  
X  
X  
X  
X
X
hsCRP
X
X  
X  
X  
X  
X
X
IP-10 (CXCL10)
X
X  
X  
X  
X  
X
X
IL-31 
X
X  
X  
X  
X  
X
X
CCL17 (TARC)
X
X  
X  
X  
X  
X
X
FACS-TBNK and T cell Subsets
X
X  
X  
X  
X  
X
X
Blood for mRNA exploratory 
analysis
X
X
X  
X
X
Serum for exploratory analysis
X
X
X  
X
X
Cell-free plasma for exploratory 
analysis
X
X
X  
X
X
Pharmacokinetic 
Pharmacokinetic Sampling (Pre-dose
only)
l
X  
X
X
Pharmacokinetic Samplingm
X
X
Trial Treatment
Impala Registration
X
Randomize Subjects in IWRS
X
Drug Dispensing
X  
X  
X  
X  
X  
X
Drug Accountability
X  
X  
X  
X  
X  
X
Investigational Treatment 
Administrationn
    X------------------------------------------------------------------------------X
Emollient and Sunscreen 
Dispensingo
X
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Protocol Activity
Screening
Treatment Period
Follow-up Period
Visit Identifier
1
2
3
4
5
6
7
8
9
10
11
Visit Day/Week
Days -35 to -1
Day 1/
W 0
Day 8/
W 1
Day 15/
W 2
Day 29/
W 4
Day 43/
W 6
Day 57/
W 8
Day 85/
W 12
Day 92/
W 13
Day 99/
W 14
Day 113/W 16 
ET/EOS
Visit Windowa
None
None
1 Day based on Day 1 visit
3 Days based on Day 1 
visit
3 Day based on Day 1 visit
Review Prior/concomitant 
Medications & Treatments
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Adverse Event Assessment
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Review Contraception Method
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Clinical Assessments
Fitzpatrick Skin Type Assessment
X
Investigator’s Global Assessment 
(IGA)
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
SCORing Atopic Dermatitis 
(SCORAD)
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Eczema Area and Severity Index 
(EASI)
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Body Surface Area (BSA)
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Photographyp
X 
X
X
X
Patient Reported Outcome
Pruritus Numerical Rating Scale 
(NRS)
q
X 
X   X 
X 
X 
X   
X   
X 
X
Patient Global Assessment (PtGA)
X 
X   X 
X 
X 
X   
X   
X 
X
Dermatology Life Quality Index 
(DLQI)
X 
X   X 
X 
X 
X   
X   
X 
X
Patient Oriented Eczema Measure 
(POEM)
X 
X   X 
X 
X 
X   
X   
X 
X
 
       
Hospital and Anxiety Depression 
Scale (HADS)
X 
X 
  
X 
X 
  
X 
X 
  
X 
X
Banked Biospecimens 
Prep D1 (DNA)
X
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Abbreviations: BSA =  body surface area; CCL17 = Chemokine ligand 17; CMV = Cytomegalovirus; CXCL-10 = C-X-C motif chemokine 10; 
DLQI = Dermatology Life Quality Index; DNA = Deoxyribonucleic acid; EASI = Eczema Area and Severity Index; EBV = Epstein-Barr virus; 
ECG = electrocardiogram; FACS = fluorescence-activated cell sorting; FSH = follicle stimulating hormone; HADS= Hospital and Anxiety Depression Scale
; 
HBsAg = hepatitis B surface antigen;  HBcAb = hepatitis B core antibody; HCVAb = hepatitis C antibody; Hep B = Hepatitis B; HIV = human 
immunodeficiency virus; hs-CRP = high-sensitivity C-reactive protein; HSV1 = herpes simplex virus type 1; HSV 2 = herpes simplex virus type 2;
IGA = Investigator Global Assessment; IgE = Immunoglobulin E; IL-31 = Interleukin-31;  IP10 = Interferon gamma-induced protein 10; IWRS = Interactive 
Web-based Response System; NRS = numerical rating scale; POEM= Patient Oriented Eczema Measure; 
 
PtGA =  Patient Global Assessment; RNA = Ribonucleic acid; SCORAD = SCORing Atopic Dermatitis; TBNK = T, B, and NK cell; 
TARC = thymus and activation regulated chemokine; VZV = varicella zoster virus; WONCBP = women of non-childbearing potential.
a.  Day relative to start of study treatment (Day 1).
b.  Atopic Dermatitis Disease History includes collection of details of AD: AD diagnosis, the use of topical treatments, systemic treatments and other treatments 
for AD. 
c.  Complete physical examinations consist of assessments of general appearance; skin; head, eyes, ears, nose and throat (HEENT); mouth, heart; lungs; breast 
(optional); abdomen; external genitalia (optional); extremities; neurologic function; and lymph nodes.  Targeted physical examinations should include skin, 
heart, lung, and abdomen and examination of body systems where there are symptom complaints by the subject.
d.  Vital Signs include sitting blood pressure, pulse, respiratory rates, and temperature measured after approximately 5 minutes of rest. 
e.  Chest X-ray or other appropriate diagnostic image (ie, CT or MRI) may be performed up to 12 weeks prior to Day 1.  Official reading must be located in the 
source documentation.
f.  Blood Chemistry consists of blood urea nitrogen (BUN), serum creatinine, creatine phosphokinase, glucose, Ca++, Na+, K+, Cl-, total CO2, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), total and direct bilirubin, alkaline phosphatase, uric acid, albumin, total protein, and lipid profile 
panel.  Lipid profile panel will include total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides.  A minimum of 
8-hour fasting is required for lipid profile evaluation at Day 1, W 6, W 12, and EOS.  Laboratory tests may be repeated once during the screening 
period; the last value will be used to determine eligibility. 
g.  Serum pregnancy testing at screening is required for women of childbearing potential.  Follicle stimulating hormone (FSH) test to be performed at Screening 
to confirm postmenopausal status in female subjects who have been amenorrheic for at least 12 consecutive months.
h.  Urine pregnancy test must be performed prior to dosing with the investigational product for female subjects of childbearing potential. 
i.  Subjects who are positive for HIV will be screen-failed. 
j. All subjects will be screened for HBsAg and HBcAb; subjects who are HBsAg positive will be screen-failed.  Subjects who are HBsAg negative but HBcAb 
positive will be reflex-tested for HBsAb and, if HBsAb positive, may enroll; if HBsAb negative, they will be screen-failed.  Subjects who are positive for 
HCVAb will be screen-failed.
k.  A documented TB test performed within 12 weeks prior to Day 1 is acceptable.  IGRA official reading and method, or test as per country specific guidelines, 
must be located in source documentation.  Subjects with a history of tuberculosis may not require TB testing as per the protocol Section 4.2. 
l.  Pharmacokinetic samples will be collected at the following visits prior to dosing at the study site on: Week 2, 4 and 8. 
m. On Week 6, PK samples will be collected at 2 hour (30 min) pre-dose, immediately prior to dosing, and 0.5 hour (15 min) post dose.  On Week 12, PK 
samples will be collected at 2 hour (30 min) pre-dose, immediately prior to dosing, and 1 hour (30 min), 2 hour (30 min) and 4 hour (30 min) post dose.
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n.  Subjects should take the medication from study Days 1 to 85.  Subjects will be encouraged to take the medication after breakfast whenever it is possible.  
However, at study visit days, subjects are to be instructed to refrain from dosing at home, and are to take the dose in the clinic.
o.  Non-medicated study emollient and sunscreen will be provided to subjects at the Screening visit and re-supplied during the study as applicable.  Subjects 
will start the study provided emollient 7 days prior to Day 1 through to the End of Study visit.
p.  For subjects at a selected study site(s), photographs of treatment-eligible atopic dermatitis will be obtained at Day 1 and Week 6.  Areas photographed 
should be recorded in study documents so that the same atopic dermatitis body region(s) will be photographed at Week 6.  Additional photographs may also 
be taken at Week 8 and/or Week 12 at the investigator’s discretion. 
q.  Pruritus Numerical Rating Scale (NRS) will be assessed daily from Day 1 to 15 and then at study site at every study visits.
r.
 
 
 
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1.INTRODUCTION
1.1.Indication
PF-04965842 is a Janus kinase 1 (JAK1) inhibitor that is currently being investigated in 
patients with Atopic Dermatitis (AD). 
1.2.Mechanism of Action
The Januskinase (JAK)family, including JAK1, JAK2, JAK3 and tyrosine kinase2 (TYK2), 
is a group of cytoplasmic tyrosine kinases that mediate signal transduction via interactions 
with Type1 and Type2 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 includinginterleukin (IL) -4, -5, -6, -13, 
-21, -31, interferon gamma(IFN), and interferonalfa(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.
11  
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.
12
Key cytokines implicated in the pathophysiology of ADincludingIL-4, IL-5, IL-13, IL-31, 
and IFN-, require JAK1 for signal transduction, suggesting thatselective JAK1 inhibitors, 
that modulate the activity of these cytokines, represent a compelling approach to the 
treatment ofinflammatory skin diseases such as AD.
1
PF-04965842 is anorally bioavailable small molecule that selectively inhibits JAK1by 
blocking the ATP binding site.  PF-04965842has a high degree of selectivity against other 
kinases in the human genome: 28-fold selectivity over JAK2, >340-fold over JAK3 and 
43-fold over TYK2 as well as a goodselectivity profile over the broader range of human 
kinases. The selective inhibition of JAK1 will lead to modulation of multiple cytokine 
pathways involvedin the pathophysiology of AD, including IL-4, IL-5, IL-13, IL-31 and 
IFN. 
The Phase1 study with the JAK1 selective inhibitor PF-04965842 in adult healthy volunteers
has demonstrated an acceptable pharmacokinetic (PK) and pharmacodynamic (PD) profile 
with no safety issues to date.  The PF-04965842 proof-of-concept (POC) study in patients 
with moderate to severe psoriasis (B7451005) was terminated early due toa clinical 
development strategy change.  Preliminary data showed that PF-04965842 appeared 
generally well tolerated in this 4week study.
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This study B7451006 is a Phase2b POC study which is planned to assess fourPF-04965842 
once daily (QD) doses (10, 30, 100, 200mg) relative to placebo over 12weeks to 
characterize the efficacy and safety of PF-04965842 in subjects with moderate tosevere AD.  
The objectives of the study are to demonstrate the efficacy of PF-04965842 by showing 
improvement in disease severityinpatients with moderate to severe ADas measured by the 
Investigator’s Global Assessment (IGA) and Eczema Area and Severity Index (EASI) scores, 
andsafetyto support further clinical development of PF-04965842.
Complete information for this compound may be found in the single reference safety 
document (SRSD), which for this study is the Investigator’s Brochure(IB).
1.3.Background and Rationale
1.3.1.Drug Development and Rationale
PF-04965842 is being developed for several indications.  The clinical development program 
for PF-04965842 includes healthy volunteers, patients with psoriasis, and under this protocol, 
patientswith AD.Information on clinicalsafety for all doses of PF-04965842from the 
completed studies isprovided in the current version of the IB.
1.3.2.Atopic Dermatitis 
Atopic dermatitis, also known as atopic eczema, is a common, chronic, inflammatory skin 
disorder characterized byflaky skin lesions, intense pruritus, and a general deterioration in 
the quality of life.  The lifetime prevalence of AD in children is 10-20% with 70% of cases 
occurring in children <5years of age.  Most cases (approximately 75%) improve by 
adulthood, while approximately 25% ofAD patients have symptoms throughout their life.  
The majority of studies conducted across multiple age groupssuggest a continued decrease in 
prevalence with older age.
5 Adult-onset AD does also occur, though it is less common.  The 
prevalence of ADin adults is estimated to be 10%.
14 Recentstudies have indicated that 
adults with ADare more likely to smoke cigarettes, drink alcohol, and have a sedentary 
lifestyle, potentially associated with increased comorbidities, such as asthma and 
cardiovascular disease.
8  
Although great strides have been made in understanding the causes, the complex 
pathophysiology of AD is still not completely understood.  However, it has been established 
that the pathophysiology of AD includes a defective skin barrier function, allergic responses, 
defective antimicrobial immune defense, and a genetic predisposition.  The predominant 
symptom of AD, pruritus and the resulting scratchingtypically sets off an amplification cycle 
of atopic skin inflammation.  Activation of T lymphocytes, dendritic cells, macrophages, 
keratinocytes, mast cells, and eosinophils results in a release of numerous pro-inflammatory 
cytokines and chemokines.  This amplification cycle sustains the inflammatory responses 
characteristic of the ADlesions.
7
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Acute ADlesions havebeen associated with theType 2 helper T cell (TH2)phenotype, 
showing dominance of IL-4, -5, -13, and -31secretion.
7,3,1  Recent research showed that a 
small increase of Type1 helper Tcell (T
H1)-associated genes has been also detected in acute 
phase.
6 While IL-4-producing TH2cells may drive the development of atopic skin lesions, 
chroniclesions show either the coexistence of both IL-4-producing TH2 and IFN--producing 
TH1cells or T
H1dominance.
7  This coexistence of TH2 and TH1 responses or TH1 dominance 
is more likely to be the underlying immunopathology in adult patients who have had AD
chronically or intermittently since childhood.  Recent evidence supports IL-31’srole in 
pruritus and inflammation in AD.
3,1
Atopic dermatitis can be categorized into extrinsic and intrinsic types.  The extrinsic or 
allergic AD is characterized by high total serum immunoglobulin E(IgE)levels, and the 
presence of specific IgE for environmental and food allergens.  While the extrinsicADis the 
classical type and hashigher prevalence, the incidence of intrinsic AD is approximately 20% 
and is associated with female predominance.
16 The clinical features of intrinsic AD include 
relative late onset, milder severity, and Dennie-Morgan folds, but no ichthyosis vulgarisor 
palmar hyperlinearity observed in the extrinsic AD.  Compared to the extrinsic AD, the 
intrinsic type is immunologically characterized by the lower expression of IL-4, IL-5 and 
IL-13, and the higher expression of IFN. 
There area limited number of treatments available for AD.  Current treatments for mild to 
moderate ADinclude emollients, topical corticosteroids (eg, betamethasone, clobetasol, 
fluocinonide), topical calcineurin inhibitors (eg, pimecrolimus, tacrolimus), and coal tar 
preparations.  Additional treatments generally reserved for severe AD include phototherapy 
(eg, ultraviolet A light [UVA] with or without psoralen, ultravioletB light [UVB] 
narrowband or broadband) and systemic agents (eg,corticosteroids, cyclosporine, 
recombinant IFN-, mycophenolate mofetil, methotrexate[MTX], azathioprine, intravenous 
immunoglobulin.
15  Of the currently available therapies, none offers a cure; therefore, the 
main aims of existing treatments are to reduce the occurrence of acute flares, to increase the 
time between relapses to reduce pruritus and the resulting sleep disturbance.
9,13
Currently available therapies for the treatment of AD have multiple limitations.  The topical 
therapies have drawbacks related to the duration of use due to the potential for local and 
systemic side effects (eg,corticosteroid use islimited to 2to 4weeks) and to the body 
regions of use (eg, mid-high potencycorticosteroids are not approved for use on the face 
and/or intertriginous areas).  For AD patients not responding to topical therapies and 
phototherapy, off-label use of systemic agents, which include both oral corticosteroids and 
oral immunosuppressants, remain the last viable treatment option.  Systemic therapy options 
are associated with potentially severe adverse effects and require careful monitoring.  The 
risk of toxicity and side effects remain a concern when systemic agents are used.  For these 
reasons the use of these agents is limited to short courses or intermittent therapy.  Therefore, 
the predominant unmet medical need in the treatment of ADis an effective therapeutic agent 
without restrictions on long-term or continuous usewithout significant side effects.
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As mentioned above, a variety of pro-inflammatory cytokines such as IL-4, IL-13, IL-17, 
IL-22, IL-31 and IFN, have been suggested to have a role in the pathogenesis of AD.  Many 
of these pathogenic cytokines use the JAK1 for signaling.  Therefore, JAK1 isan attractive 
therapeutic target for AD.
1.3.3.Nonclinical Pharmacokinetics and Metabolism
Systemic exposures (peak concentration [C
max] andarea under the concentration-time curve 
[AUC]) to PF-04965842 after repeat dosing increased with increasing dose in rats (up to 
200mg/kg/day) and cynomolgus monkeys (up to 100mg/kg/day).  The invivo clearance 
across species was predicted well by their respective invitro hepatic microsome and 
hepatocyte data.  PF-04965842 followed one-compartment PK across species.  PF-04965842 
binding to plasma proteins was approximately 60% across rat, monkey and human, 
approximately 45% in mouse, and approximately 80% in rabbit.  Clearance phenotyping of 
PF-04965842 indicated that CYP3A4 is the primary route of metabolism.  However, a 
number of other CYP450s (1A2, 2B6, 2C8, 2C9, 2C19, and 2D6), each contributing 10% to 
the metabolism of PF-04965842, combine to make asignificant contribution to the clearance 
of PF-04965842.  No in vitro evidence of aldehyde oxidase metabolism of PF-04965842 was 
detected in human cytosol.  Primary metabolites identified were oxidative hydroxylations and 
N-demethylation consistent with CYP450 as the primary clearance route.  No unique human 
metabolites of PF-04965842 were evident when compared to the safety species of rat and 
cynomolgus monkey. 
PF-04965842 did not inhibit the major CYP450 enzymes (IC50>100M) by competitive 
inhibitionor time-dependent inhibition (without the reduced form of nicotinamide adenine 
dinucleotide phosphate [NADPH]).  In the presence of NADPH, PF-04965842 caused 
relatively weak time-dependent inhibition of CYP2C8 (IC50, 51M), CYP2C19 (IC50, 
42M), CYP2D6 (IC
50, 92M), and CYP3A4/5 (IC50, 40 to 81M).  PF-04965842 dose 
dependently induced CY3A4 mRNA (EC5061M; maximum fold induction in vitro 
[E
max],22) and CYP2B6 (EC50, 9.5M; Emax, 3.5) in 3lots of hepatocytes.  Enzyme activity 
of CYP2B6 increased >2-fold at 30M in 1 of 3lots of hepatocytes.  Conversely, 
PF-04965842 caused a dose-dependent decrease in CYP3A4 and CYP1A2 enzyme activities 
in all 3lots of hepatocytes.  PF-04965842 did not significantly inhibit OATP1B1, OATP1B3, 
or OCT2 transport with estimated IC50values of >300M.  However, PF-04965842 showed 
some potential to inhibit transport by MDR1 (IC50=100M), MATE1 (IC50=5.5M) and 
MATE2K (IC50=11M). 
SimCYP modeling usingexposures from the 400mg QD dose (B7451001) indicated a low 
risk of drug-drug interaction (DDI) perpetrated by PF-04965842 through mechanisms of 
CYP450 inhibition and induction or through transporter interactions. Thus, there is a low 
likelihood of DDI with oral contraceptives. 
1.3.4.Biopharmaceutics Properties
PF-04965842 is an anhydrous free base that is fully crystalline and non-hydroscopic.  High 
solubility was measured in acidic conditions as predicted for a calculated pKa of 6.7.  In 
simulated intestinal fluids (fasted and fed) the measured solubility ranged between0.03 to 
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0.05mg/mL.  PF-04965842 is highly permeable based on the high permeability value 
(15.6x10-6cm/sec) obtained in the cell based permeability cell assay using Ralph Russ 
canine kidney cells (RRCK) which have little or no functional P-glycoprotein(P-gp).  The 
efflux ratio of 3.61determined in the Madin Darby canine kidney cell line/multidrug 
resistance 1gene (MDCK/MDR1) assay indicate that PF-04965842 isa P-gp substrate. 
1.4.Safety Data
1.4.1.Non-Clinical Safety
PF-04965842 was evaluated in repeat-dose rat and cynomolgus monkey oral gavage toxicity 
studies up to 6-and 9-months in duration, respectively. In addition, invitro and invivo 
genetic toxicology and safety pharmacology studies were conducted. Dose range-finding and 
definitive Embryo-Fetal Development (EFD)studies were conducted in rats and rabbits. In 
addition, an in vivophotoxicity study was conducted in pigmented Long-Evans rats.
In the 6-month toxicity study in rats and the 9-month toxicity study in cynomolgus monkeys, 
test article-related findings were generally consistent with the expected immunomodulatory 
pharmacology of PF-04965842. In the rat study, adverse, test article-related viral infection in 
the prostate occurred at 70mg/kg/day, which was likely secondary to 
over-immunosuppression.  Based on this finding, the no observed adverse effect level
(NOAEL)in the 6-month study in rats was 45 and 70mg/kg/day for males and females, 
respectively. In general, all test article-related effects observed at 70mg/kg/day in rats had 
reversed by the end of the 12-week recovery phase, except for lower body weight gain and 
food consumption and scabs, which persisted during the recovery period and lower 
monocytes, which demonstrated partial recovery.  The NOAEL in the 9-month study in 
cynomolgus monkeys was the highest dose of 75mg/kg/day. The majority of test 
article-related effects observed at 35mg/kg/day in monkeys demonstrated reversal by the end 
of the 12-week recovery phase, except for the Tcell-dependent antibody response (TDAR), 
which demonstrated partial recovery.
PF-04965842 was negative for genotoxicity in a bacterial mutation assay and anin vivo
micronucleus assay, but was positive in the in vitromicronucleus assay in TK6, a human 
lymphoblast cell line, following a 27-hour continuous treatment without metabolic activation.  
Follow-up testing demonstrated that the positive in vitromicronucleus was related to an 
aneugenic mechanism, which was only seen at high in vitroconcentrations that significantly 
exceed anticipated exposuresin the planned clinical trials. The lack of human risk is further 
supported by the negative result in the in vivo micronucleus assay in rats even at high 
systemic concentrations up to the maximum tolerated dose. 
In the definitive EFD study in rats, the maternal NOAEL was 60mg/kg/dayand, based on 
decreased embryo-fetal survival at 60mg/kg/day and increased incidence of skeletal 
variations at 30 and 60mg/kg/day, the developmental NOAEL was 10mg/kg/day.  In the 
definitive EFD study in rabbits, the maternal and developmental NOAEL was the highest 
dose tested, 75mg/kg/day.
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Although PF-04965842 absorbs light in the UVB/visible range, no evidence of cutaneous or 
ocular phototoxicity was noted after oral administration to pigmented Long-Evans rats 
followed by a single exposure to ultraviolet radiation (UVR).  Therefore, PF-04965842 does 
not have significant phototoxicity potential in vivo.
In the liver, PF-04965842-related minimal to mild increases in serum transaminases (alanine 
aminotransferase [ALT]and aspartate aminotransferase [AST]) occurred in the 7-day, 
1-month, and6-month studies in rats (at 70mg/kg/day) and in the 1-month study in 
cynomolgus monkeys (at 40mg/kg/day).  In the 1-month study, increased liver weights 
occurred in rats (at 200mg/kg/day) and cynomolgus monkeys (at 80mg/kg/day) and 
periportal hepatocyte hypertrophy occurred in rats at 200mg/kg/day.  However, there were 
no microscopic changes in the liver in any study in rats or cynomolgus monkeys that were 
consistent with hepatocytedegeneration, necrosis, or inflammation, and as such these 
findings in serum hepatic enzymes were not considered adverse. 
Physeal dystrophy was observed in the 1-month study in rats at 75mg/kg/day and was 
consistent with test article-related effects onbone growth in young, growing rats during a 
rapid period of growth.  No microscopic findings in the bone physis were observed in the 
6-month toxicity study in rats or 1-month or 9-month toxicity studies in cynomolgus 
monkeys.  Since the growth plate is closed (inactive) in the adult humans, the finding of the 
physeal dystrophy of the growth plate in rats would not be expected to pose any risk to 
subjects in the planned clinical trials.
Skin changes (eg, erosions/ulceration, epidermal hyperkeratosis, and/or dermal 
inflammation)were observed in rats at 25mg/kg/day in the 1-month study and at
45mg/kg/day in the 6-month study. In addition, increasedincidence of alopecia and 
thinning hair coat was observed at 75mg/kg/day infemales in the 9-month monkeystudy. 
These findings were not adverse based on the limited severity, localized distribution, 
infrequent occurrence, lack of microscopic correlate (for cynomolgus monkeys) and/or 
because they did not affect the overall health of the animals. 
In summary,the nonclinical program supports the planned clinical trials with PF-04965842.
1.4.2.Clinical Experience 
1.4.2.1.First-in-Human (B7451001) Data
The first-in-human (FIH) study (B7451001) with PF-04965842 was a combination, within 
cohort, randomized, double blind study inhealthy adult Western and Japanese subjects.  The 
Western subjects in Cohorts1 through 7 received single doses of 3, 10, 30 100, 200, 400 or 
800mg of PF-04965842 or placebo in a dose escalation format and multiple doses of 30, 
100, 200 or 400mg QD and 100or 200mg BID twice daily for 10days.  The protocol was 
amended to include a Japanese cohort (Cohort8) in order to support development of the 
compound in Japan.  The subjects in this cohort received a single dose of 800mg during the 
single ascending dose (SAD) period of the study, followed by 200mg BID for 10days 
during the multiple ascending dose (MAD) period of the study. 
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1.4.2.1.1.Safety Data
All cohorts:During the SAD phase, 24subjects had a total of 64treatment-emergent adverse 
events (TEAEs), 36 of which were considered to be treatment-related.  During the MAD 
phase, 35subjects had a total of 97TEAEs, 59of which were considered to be 
treatment-related.  There were no deaths, serious adverse events (SAEs), severe adverse 
events (AEs), and temporary discontinuations or dose reductions due to AEs reported in this 
study.  Two subjects discontinued from the study during the SAD phase (1subject each in 
the PF-04965842 100mg and PF-04965842 800mg groups, respectively) due to AEs.  Two 
subjects who received PF-04965842 400mg during the MAD phase discontinued due to 
treatment-related AEs.  The system organ classes (SOCs) with the greatest number of 
subjects reporting AEs were Gastrointestinal Disorders, Nervous System Disorders, and Skin 
and Subcutaneous Tissue Disorders.  Most TEAEs reported in the SOCs of Gastrointestinal 
Disorders and Nervous System Disorders were treatment-related.  The most frequently 
reported TEAEs across all treatment groups were headache, which was experienced by 
13subjects, diarrhea and nausea, each of which was experienced by 11subjects.  Most of the 
TEAEs were mild in severity.  Overall, 25 and 40subjects had laboratory abnormalities 
during the SAD and MAD phases, respectively. 
Western and Japanese Cohorts (800 mg SAD; 200 mg BID MAD): During the SAD phase, 
7 Western subjects had a total of 26TEAEs, 19 of which were considered to be 
treatment-related; while 10Japanese subjects had a total of 23TEAEs, 11of which were 
considered to be treatment-related.  During the MAD phase, 10Western subjects had 
30TEAEs, 19 of which were considered to be treatment-related, while 8Japanese subjects 
had 16TEAEs, 8 of which were considered to be treatment-related.  There were no deaths, 
SAEs, severe AEs, temporary discontinuations or dose reductions due to AEs reported in this 
study.  One (1) Japanese subject who received PF-04965842 800mg discontinued from the 
study during the SAD phase due to a treatment-related AE.  The SOCs with the greatest 
number of subjects reporting AEs were Gastrointestinal Disorders, and Skin and 
Subcutaneous Tissue Disorders.  Most TEAEs reported in the SOCs of Gastrointestinal 
Disorders were treatment-related.  Most of the TEAEs were mild in severity.  In the SAD 
phase, 8 out of 20Western subjects had laboratory abnormalities and 6 out of 12Japanese 
subjects had laboratory abnormalities.  None of the laboratory, vital signs, or 
electrocardiogram(ECG)abnormalities were considered to be clinically significant or 
reported as AEs by the investigator. 
1.4.2.2.Bioavailability (BA) study Safety Data
B7451004 wasa Phase1, open-label, single-dose, 3-way crossover study to evaluate the BA
of a solid dose formulation of PF-04965842 relative to a suspension formulation under 
fasting conditions and the effect of food on the BAof the solid dosage formulation of 
PF-04965842 in healthy subjects.  Twelve(12)healthy subjects wereenrolled and 
randomized to 1 of6possible treatment sequences.  Single oral doses of PF-04965842
4×100mg tabletunder fasted and fed conditions and PF-04965842400mgsuspension 
under fasted condition was generally well tolerated inhealthy subjectsevaluated in this 
study.  There was no discernible difference in the frequency of AEs between fasted and fed 
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states and between the PF-049658424×100mg tablet and PF-04965842400mg oral 
suspension.
1.4.2.3.B7451005 Study Safety Data
B7451005 was a Phase2, randomized, double-blind, placebo controlled study to evaluate 
safety and efficacy of PF-04965842 in patients with moderate to severe psoriasis.  There 
were 59subjects enrolled and randomized to one of three treatment groups (200mgQD, 
400mg QD, and 200mg BID) or placebo. 
Preliminary data showed that PF-04965842 appeared generally well toleratedin this 4week 
study.  The only serious adverse event reported in the study occurred in the placebo group.  
However, the AEs occurred at a higher frequency among subjects receiving PF-04965842 
than those receiving placebo.  The AEs were more frequent in the 400mg QD and 
200mgBID dose groups than in the 200mg QD group.  The most common AEs were those
affecting the hematological and gastrointestinal system.  The majority of the hematological 
lab abnormalities occurred in the 200mg BID group.  There were a greater number of events 
in the infections and infestations category in the active treatment groups compared to the 
placebo group. 
1.5.Summary of PF-04965842 Pharmacokinetics
PF-04965842was rapidlyabsorbed following single dose oral solution/suspension 
administration over the dose range3mg to 200mgwith time to maximum absorption (Tmax)
ranging between0.55to 0.77hours. MedianTmaxat doses of 400mg and 800mg were 
1.5and 3.9hours,respectively, which indicated the slowerabsorption compared to lower 
doses.  PF-04965842showedamonophasic decline at dose <100mg withbiphasic profiles at 
doses 100mg. Cmaxfollowing the single-dose administration generally increased in 
proportion to the dose from 3mg to 800mg. In contrast, both area under the plasma 
concentration-time curve from time zero extrapolated to infinity (AUCinf)and area under the 
plasma concentration time profile from time zero to the last quantifiable concentration
(AUClast)were dose proportional in the range of 3mg to 200mg, while a greater than 
proportional increase was observed atdoses of 400 and 800mg.  Thearithmetic mean
terminal phase half-life(t
½) was 1.9 to 4.9hours.
Following QD administration over the dose range30mg to 400mg and 100mg and
200mgBIDfor 10days, median Tmaxranged between0.50to 0.77hours.  Afterattainment 
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 
an arithmeticmean terminal phase t
½between2.8 to 5.0hours. Although Cmaxgenerally 
increased in proportion to the dose up to 100mg BID, it increased more than the dose 
increasedat 400mg QD and 200mg BID. The same trend was also observed for area under 
the plasma concentration-time curve (AUCtau) over the dosing interval (tau=12 or 24hours). 
Theobserved accumulation ratio (Rac) following200mg BID was 2.0 and 2.5for AUC
tau
and Cmax,respectively. Racwas 1.1to 1.5at other doses. Therefore, the results showed that 
drug concentration accumulation is minimal after repeatedoraladministration at lower doses, 
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consistent with the prediction from t
½.  Urinary recovery of PF-04965842 was low, with 
<5%of the dose recovered unchanged in urine across all doses and regimens in all cohorts. 
At a single 800-mg dose,the geometric mean (%CV) Cmax(ng/mL)was similar in Western 
(n=5; 3819 (26)) and Japanese subjects(n=10; 3660 (48)).  However, geometric mean 
AUCinf(ng*hr/mL)was 26% higher in Western subjects (n=5; 27540 (35))than that 
observed in Japanese subjects(n=9; 21860 (43)).  Geometric mean (%CV) Cmaxand AUC
tau
following multiple-dose administration of 200mg BID were 17% and 56% higher, 
respectively, in the Western subjects (n=5) than in Japanese subjects(n=6). 
The bioavailability of a solid dose formulation of PF-04965842 relative to a suspension 
formulation was evaluated in an open label, single-dose, 3-way crossover study in 12healthy 
subjects under fastingand fedconditions(study B7451004).  The extent of absorption 
(AUC
(0-)) of the tablet was equivalent to that of the suspension(90% CIfor 
tablet/suspensionratio: (90.31, 103.21) while peak concentrations (C
max) werelower (90% CI 
for tablet/ratio: (62.88, 100.46)on average for the tablet relative to suspension.  
Co-administration of 400mg (4 x100mg)of thetablet with breakfast resulted in equivalent 
geometric mean AUC(0-)between fasted and fed conditions and a small mean decrease
(<5%)in C
max.  The magnitude of decrease in C
maxwas not considered to be clinically 
important.  Overall, PF-04965842 can be administered with or without food.
1.6.Summary of PF-04965842 Pharmacodynamics
1.6.1.First-in-Human (B7451001) Data
Decreases in high-sensitivity C-reactive protein (hsCRP) post-dose from baseline were 
observed in all PF-04965842 treatment groups fromDay2 to Day10.  Maximal reductions in 
hsCRP concentrations relative to baseline were generally observed on Day10 pre-dose 
across all treatment groups.  On Day10 pre-dose, the median percent change from baseline 
in hsCRP levels were -51%, -61%, -73%, -77%, -85%, and -80% for PF-04965842 
30mgQD, 100mg QD, 200mg QD, 400mg QD, 100mg BID and 200mg BID treatment 
groups, respectively, compared with a change of -22% for the placebo group.
Maximal median percent decreases from baseline in IP-10 occurred at 16hours post-dose at 
Day10 for most of the treatment groups.  The median percent decrease from baseline in 
IP-10 levels 16hours post-dose on Day10 were -42%, -43%, -47%, -52%, -48%, and -56% 
for PF-04965842 30mg QD, 100mg QD, 200mg QD, 400mg QD,100mg BID and 
200mgBID treatment groups, respectively, compared with a decrease of -17% for the 
placebo group.
Decreases in reticulocyte counts from baseline were observed in all PF-04965842 treatment 
groups during dosing period.  Maximal reductions inreticulocyte counts relative to baseline 
were generally observed 24hours post-dose on Day10 with median percent decrease from 
baseline in reticulocyte counts of -36%, -9%, -15%, -36%, -54%, and -45% for PF-04965842 
30mg QD, 100mg QD, 200mg QD, 400mgQD, 100mg BID and 200mg BID treatment 
groups, respectively, compared with a decrease of -21% for the placebo group.
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In comparison to placebo, PF-04965842 100mg BID and 200mg BID appeared to decrease 
neutrophil counts.  Maximal reduction in neutrophil absolute counts were seen on Day10 at 
6hours post-dose with median percent change from baseline of -47% and -42% for 
PF-04965842 100mg BID and 200mg BID treatment groups, respectively, compared with 
median percent change from baseline of -3%, -4%, 0%, -13, and -19% for the placebo, 
30mgQD, 100mg QD, 200mg QD, and 400mg QD treatment groups, respectively.
1.6.2.B7451005 Study Data
Preliminary results of biomarkers (IP-10 and hsCRP) showed rapid reduction in all active 
treatment groups.  The effect was morepronounced in the BID than the QD groups. 
1.7.Summary of Benefits and Risks 
The anticipated risks associated with PF-04965842 in relation to anemia are minimal because 
erythropoietin signals through the JAK2 dimers.  Thus, in comparison to pan-JAK inhibitors, 
PF-04965842’s selectivity to erythropoietin may provide clear advantage in regard to anemia.  
However, the 10-day dosing duration in thePhase1 study B7451001 was not long enough to 
test for anemia.  Also, PF-04965842’s lesser effect on IL-15 which is linked to non-killer 
(NK) cells may provide further differentiation from pan-JAK inhibitors and may prove to be 
beneficial in terms of lesser effect on immune functions related to viral infections and tumor 
surveillance. 
Overall, the safety profile observed during the Phase1 program for PF-04965842appears to 
be acceptable at dosages of up to 800mg administered asa single dose and up 400mg when
administered as repeat doses of either 400mg QD or 200mg BID.  The preliminary data 
from the 4week POC Psostudy showed that PF-04965842 appeared generally well tolerated 
up to 400mg QD or 200mg BID.  The data generated in the development program to date
support the further development of PF-04965842 and its advancement to a POC study in AD.
1.8.Rationale
1.8.1.Study Rationale
PF-04965842 is a selective inhibitor of JAK1.  The selective inhibition of JAK1 will lead to 
modulation of multiple cytokines which play a critical role in the pathogenesis of AD 
(eg,IL-4, IL-13, IL-17, IL-22, IL-31, and IFN).  Dupilumab, a fully human monoclonal 
antibody that blocks the activity of IL-4 and IL-13 signaling, has shown efficacy in patients 
with AD.2  Systemic treatment with dupilumab in adults with moderate to severe AD resulted 
in marked reductions in signs and symptoms of AD, and associated biomarker levels.  
Topical tofacitinib, a pan JAK inhibitor, recently completed a 4weekPhase2a trial that 
demonstratedthe efficacy of JAK inhibition in mild to moderate AD(study A3921214).  In
this study, significantly greater efficacy was observed with topical tofacitinib vs. vehicle in 
reducing the signs and symptoms of AD, with a suitable safety and local tolerability profile.  
In addition, oral tofacitinib has shown therapeutic effect in 6patients with recalcitrant AD.
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JAK1-selective inhibitors such as PF-04965842, spare dose-limiting effects of pan-JAK 
inhibition by preserving JAK2 homodimer signaling and thus provide the potential for safer 
and efficacious oral treatments for AD.  Oclacitinib, a JAK1 inhibitor, has already 
demonstrated efficacy and is approved for the treatment of canine atopic dermatitis.4
B7451006 is a Phase 2b study to evaluate the efficacy and safety of PF-04965842 in 
comparison to placebo in patients with moderate to severe atopic dermatitis using the 
Investigator Global Assessment.
Clinical evaluations of AD in this study will include Investigator Global Assessment (IGA), 
Eczema Area and Severity Index (EASI), Body Surface Area (BSA) involvement, and 
SCORing Atopic Dermatitis (SCORAD).
PF-04965842 efficacy will also be evaluated via patient reported outcomes (PROs): Pruritus 
numerical rating scale (NRS) score, Patient Global Assessment (PtGA), Dermatology Life 
Quality Index (DLQI), Patient Oriented Eczema Measure (POEM), 
 
 and Hospital and Anxiety Depression Scale 
(HADS). 
The study will provide samples for exploratory analysis of pharmacodynamic biomarkers for 
JAK1 inhibition such as IP-10 (CXCL10), hsCRP, CCL17 (TARC), IL-31, total IgE.  
Samples will also be collected for flow-cytometric (fluorescence-activated cell sorting
[FACS]) assessment of lymphocyte subsets. 
1.8.2. Dose Selection Rationale 
This Phase 2b study will evaluate the efficacy and safety of PF-04965842 in patients with 
moderate to severe AD.  The study will assess 4 PF-04965842 doses of 10 mg, 30 mg, 
100 mg and 200 mg administered orally once daily (QD) for 12 weeks.  Listed in Table 1 are 
the predicted geometric mean (%CV) PK parameter values following QD dosing for 
12 weeks which were derived from population PK modeling of the human PK data from the 
FIH study (B7451001). 
Table 1.  Predicted Geometric Mean PK Parameters following QD Dosing
Dose mg QD x 12 weeks
Geometric Mean
Safety Marginsa
Cmax,ss
ng/mL
AUCtau
ng.hr/mL
Cmax,ss
AUCtau
10
33.2(9)
83.7 (33)
156
659
30
135.0 (9)
386 (36)
38
143
100
632.6 (7)
2197 (39)
8.1
25
200
1525 (6)
5928 (37)
3.4
9.3
(  ) = % coefficient of variation; AUC
tau=Area under the concentration-time curve over the dosing interval 
0-24 hours; Cmax,ss= Peak plasma concentration at steady state; QD = Once daily
a.
NOAEL in cynomolgus monkeys, 75 mg/kg/day; Day 273 combined male and female total Cmax,ss= 1910 ng/mL; total 
AUCtau =55200 ng•h/mL.
The doses selected for this study are supported by significant safety margins from the repeat 
dose toxicity study up to 9 months in monkeys.  The dose range should allow 
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characterization of the dose response for efficacy over a 20-fold range and anchoring at the 
lower end with a minimally effective dose.
The selective inhibition of JAK1 will lead to modulation of multiple cytokine pathways 
implicated in the pathophysiology of AD, eg IL-4, IL-13, IL-17, IL-22, IL-31, and INF.  In
study B7451001, mechanistic biomarkers hsCRP and IP-10 related to IL-6 and IFN, 
respectively, were measured in healthy subjects.
A classic indirect response model was used to estimate the reduction of hsCRP, IP-10 and 
safety biomarkers (neutrophils, platelets and reticulocytes) as well as to project the potential 
impact on signaling of the various cytokines that may be associated with efficacy in AD over 
a range of PF-04965842 exposures (Table2).  The baseline values for hsCRP, IP-10 and 
safety biomarkers (neutrophils, platelets and reticulocytes) in subjects with AD are 
comparable to those observed in healthy subjects and subjects with psoriasis.  The modeling 
predicts maximum percent reduction for the safety biomarkers in the absence of 
compensatory mechanism due to short duration of the studies conducted to date. 
Table2.
Modeled Predicted Geometric Mean Percent Reduction in Pathways 
Signaling and Biomarkers
10 mg
30 mg
100 mg
200 mg
IL-4
0.26
1.20
5.83
12.9
IL-4 HT-29
1.21
4.74
18.4
34.5
IL-13
0.35
1.57
7.45
16.2
IL-13 HT-29
1.31
5.18
20.3
37.6
IL-22
0.31
1.41
6.68
14.5
IL-31
2.58
9.28
31.3
51.7
hsCRP
9.02
23.0
43.3
59.1
IP-10
1.31
4.64
14.0
23.8
Neutro-phils
0.11
0.50
2.36
5.71
Reticulo-cytes (Abs)
0.96
4.59
18.3
32.8
Platelets
0.78
3.63
11.6
26.9
As previously described there are multiple cytokinesinvolved in the manifestation of AD, 
thus, the main driver of disease or the relative contribution of the cytokines to efficacy is not 
understood.  However, Dupilumab an antibody to the receptors for IL-4 and IL-13 has 
demonstrated efficacy in AD.  In study B7451005,  in subjects with psoriasis,which 
evaluated 200mg and 400mg QD and 200mg BID of PF-04965842 for 28days, all active 
treatments decreased itch severity score at 7days post dose, the first evaluation timepoint.  
IL-31 has a pivotal role in itch manifestation in ADand modeling predicted approximately a 
52% reduction of IL-31 stimulation of Signal Transducers and Activators of Transduction 
(PSTAT)-6 signaling by the 200mg QD dose. 
Preliminary assessment of safety data from study B7541005 showedthat the majority of the 
hematological laboratory abnormalities occurred in the 200mg BID group.  Based on this 
finding a BID regimen will not be evaluated in AD.  Reductions in absolute reticulocyte 
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count were observed at all dose levels with the maximum mean % decrease occurring in the 
200 mg BID group (57.3%) compared to 21.5% and 17.9% in the 400 mg QD and 
200 mg QD groups, respectively.  There were platelet reductions in all active treatment 
groups.  Platelet counts <100,000/mm3were observed in the 400 mg QD and 200 mg BID 
cohorts, with the majority of cases occurring in the BID cohort.  There were no cases of 
platelet counts <100,000/mm3in the 200 mg QD group.  No bleeding events relative to 
thrombocytopenia were reported during the clinical trial.
The projected reductions suggest that at least 1 dose should be active with acceptable safety 
and tolerability appropriate for the long term treatment of adult subjects with moderate to 
severe AD.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Primary Objectives
The primary objective of this study is to evaluate the efficacy of 4 QD dose levels
(10, 30, 100, and 200 mg) of PF-04965842 relative to placebo in adult subjects with 
moderate to severe atopic dermatitis, using the Investigator’s Global Assessment 
(IGA).
2.2. Secondary Objectives
To evaluate the effect of PF-0465842 on additional efficacy endpoints and patient 
reported outcomes over time in adult subjects with moderate to severe atopic 
dermatitis.
To evaluate the safety and tolerability of PF-0465842 over time in adult subjects with 
moderate to severe atopic dermatitis.
2.3.


 
2.4. Endpoints
2.4.1. Primary Endpoints
Proportion of subjects achieving the IGA for clear (0) or almost clear (1) and 
2 points improvement from baseline at Week 12.  The baseline will be defined as the 
IGA score on Day 1 pre-dose.
2.4.2. Secondary Endpoints
2.4.2.1. Efficacy Endpoints
Baseline is defined as the score for each assessment on Day 1 pre-dose.
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2.4.2.1.1.Key Secondary Efficacy Endpoint
Percent change from baselinein the eczema area and severity index (EASI)Total 
score at Week12. 
2.4.2.1.2.Secondary Efficacy Endpoints
Proportion of subjectsachieving theIGA forclear (0) or almost clear (1) and 
2pointsimprovementfrom baseline at all scheduled time points except Week12.
Percent change from baselinein the EASItotal score at all scheduled time points 
except Week 12.
Proportion of subjectsachieving 3points improvement in the pruritus numerical 
rating scale (NRS) from baselineat all scheduled time points.
Percent change from baseline in the pruritus NRS from baselineat all scheduled time 
points.
Proportion of subjects achieving 2pointsimprovementin the IGA from baseline at 
all scheduled time points. 
Proportion of subjects achieving a 50%, 75% and 90% improvement in the EASI 
Total score (EASI50, EASI75, EASI90) at all scheduled time points.
Change from baseline in affected body surface area (BSA) at all scheduled time 
points.
Change from baseline in SCORing atopic dermatitis (SCORAD) at all scheduled time 
points. 
Proportion of subjects achieving a 50%and 75%improvementinSCORAD 
(SCORAD50, SCORAD75)from baselineat all scheduled time points.
2.4.2.2.Safety Endpoints
Incidenceof treatment-emergent adverse events.
Incidence of specific clinical laboratory abnormalities (anemia, neutropenia, 
thrombocytopenia, lymphopenia, lipid profile, liver function tests[LFTs]).
2.4.2.3.Patient-Reported Outcome (PRO) Endpoints
Baseline is defined as the score for each assessment on Day1 pre-dose.
Change from baseline in Pruritus NRS score at all scheduled time points.
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Proportion of subjects with patient global assessment (PtGA) of AD of clear (0) or 
almost clear (1) and 2 points improvement from baseline at all scheduled time 
points. 
Change from baseline in dermatology life quality index (DLQI) total score at all 
scheduled time points. 
Change from baseline in patient Oriented Eczema Measure (POEM) at all scheduled 
time points.
Change from baseline in the hospital and anxiety depression scale (HADS) at all 
scheduled time points. 
2.4.3.

 
 


 
3. STUDY DESIGN
This Phase 2b, multi-center, randomized, double-blind, 5-arm, parallel group study will 
enroll a total of approximately 250 subjects (providing approximately 200 completers, 
40 subjects per treatment group).  The study will be conducted at approximately 60 sites.
Figure 1.  Study Design Schematic
PF-04965842 =30 mg QD, n= 50
PF-04965842 = 100 mg QD, n= 50 
Placebo, n= 50
PF-04965842 = 10 mg QD, n= 50
Follow-up
4 weeks
Screening
35 days
12 weeks
PF-04965842 = 200 mg QD, n= 50 
CCI
CCI
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Subjects who have chronic ADthat has been present for at least 1year (prior to screening 
visit) and affected BSAof10%, EASI 12and IGA 3 at the screening and baseline visits
will be included in the study.  Subjects must also havea documented history of inadequate 
response to treatment with topical medications given for at least 4weeks, or for whom 
topical treatments are otherwise medically inadvisable (eg, because of important side effects 
or safety risks)within 12months of the first dose of study drug.  Subjects will be randomized 
to 1of 4treatment groups orplacebo in the ratio of 1:1:1:1:1.  Investigators, subjects, and the 
sponsor study team will be blinded as to treatment group. 
Subjects will be screened within 35days prior to the first dose of study drug to confirm that 
they meet the subject selection criteria for the study.  There will be a 12-week double-blind 
treatment period as well as a 4-week follow up period.
An interim analysis may be performed when approximately a total of 110randomized 
subjects complete 6weeks of study or discontinue prematurely from study in order to assess 
the percent change of EASI score from baseline as wellas other safety and efficacy 
endpoints such as IGA response as appropriate.  Please refer to Section 9.4fordetails.
4.SUBJECT SELECTION
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
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Evidence of a personally signed and dated informed consent document indicating that 
the subject has been informed of all pertinent aspects of the study. 
2. Male or female subjects between 18-75years of age, inclusive, at time of informed 
consent.
3. Subjects who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests and other study procedures.
4. Male subjects able to father children and female subjects of childbearing potential and 
at risk for pregnancy must agree to use a highly effective method of contraception 
(per Section 4.4.2) throughoutthe study and for at least 28days after the last dose of 
assigned treatment.
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Female subjects who are not of childbearing potential (eg,meet at least 1 of the 
following criteria):
Have undergone a documented hysterectomy and/or bilateral oophorectomy;
Have medically confirmed ovarian failure; or 
Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12consecutive months with no alternative pathological or 
physiological cause; status may be confirmed by having a serum follicle 
stimulating hormone (FSH) level confirming the post-menopausal state.
5. Must have the following atopic dermatitis criteria:
a. Have a clinical diagnosis of chronic atopic dermatitis (also known as atopic 
eczema) for at least 1year prior to Day1 and has confirmed atopic dermatitis 
(Hanifin and Rajka criteria of AD refer to Appendix2) at the Screening visit.
b. Have inadequate response to treatment with topical medications given for at least 
4weeks, or for whom topical treatments are otherwise medically inadvisable 
(eg,because of important side effects or safety risks) within 12months of the first 
dose of study drug.
c. Moderate to severe AD (affected BSA10 %, IGA >3, and EASI >12 at the 
screening and baseline visits). 
6. Must agree to avoid prolonged exposure to the sun and not to use tanning booths, sun 
lamps or other ultraviolet light sources during the study.
7. If receiving concomitant medications for any reasonother than AD, must be on a 
stable regimen, which is defined as not starting a new drug or changing dosage within 
7days or 5half-lives (whichever is longer) prior to Day1.  Subject must be willing to 
stay on a stable regimenduring the duration of the study. 
4.2.Exclusion Criteria
Subjects with any of the following characteristics/conditionswill not be included in the 
study:
1. Severeacute or chronic medical or psychiatric condition or laboratory abnormality 
that may increase the risk associated with study participation or investigational 
product administration or may interfere with the interpretation of study results and, in 
the judgment of theinvestigator or Pfizer (or designee), would make the subject 
inappropriate for entry into this study.
2. Currently have activeforms of other inflammatory skin diseases.
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3. Have evidence of skin conditions (eg, psoriasis, seborrheic dermatitis, Lupus) at the 
time of Day1 that would interfere with evaluation of atopic dermatitis or response to 
treatment.
4. Have received any of the following treatment regiments specified in the timeframes 
outlined below: 
Within 6 months of first dose of study drug:
Any cell-depleting agents including but not limited to rituximab: within 
6months of first dose of study drug or 5half-lives (if known), whichever is 
longer, or until lymphocyte countreturns to normal, whichever is longer.
Within 12 weeks of first dose of study drug:
Any studieswith JAK inhibitors.
Other biologics: within 12weeks of first dose of study drug or 5half-lives (if 
known), whicheveris longer.
Within 8 weeks of first dose of study drug:
Participation in other studies involvinginvestigational drug(s) within 8 weeks 
of first dose of study drug or within 5 half-lives (if known), whichever is 
longer
Note: Any investigational or experimental therapy taken or procedure 
performed for AD, psoriasis, psoriatic arthritis or rheumatoid arthritis in the 
previous 1year should be discussed with the Pfizer Medical Monitor (or 
designee).  Subjects cannot participate in studies of other investigational or 
experimental therapies or procedures at any time during their participation in 
this study.
Within 6 weeks of first dose of study drug:
Have been vaccinatedwithlive or attenuated live vaccine.
Within 4 weeks of first dose of study drug:
Use of oral immunesuppressants (eg, cyclosporineA [CsA], azathioprine, 
MTX, Celcept, systemiccorticosteroids, mycophenolate-mofetil, IFN-) 
within 4weeks of first dose of study drug or within 5half-lives (if known), 
whichever is longer.
Phototherapy(NB-UVB) or broad band phototherapy.
Regularuse (more than 2visits per week) of a tanning booth/parlor.
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Within 1week of first dose of study drug:
Topical treatmentsthat could affect atopic dermatitis(eg, corticosteroids, 
calcineurin inhibitors, tars, antibiotic creams, topical antihistamines)
Note: Corticosteroidinhalers and intranasal sprays are allowed for stable 
asthma patients.
Herbalmedicationswithunknown properties or known beneficial effects for 
AD.
5. Pregnant femalesubjects, breastfeeding femalesubjects, or male subjects able to 
father children andfemalesubjects of childbearing potential who are unwilling or 
unable to use a highly effective method of contraception as outlined in this protocol 
(per Section4.4.2) forthedurationof the study and for at least 28days after last dose
of investigational product.
6. Have current or recent history of clinically significant severe, progressive, or 
uncontrolled renal, hepatic, hematological, gastrointestinal, metabolic, endocrine, 
pulmonary, cardiovascular, psychiatric, immunologic/rheumatologicor neurologic 
disease; or have any other severe acute or chronic medical or psychiatric condition or 
laboratory abnormality that may increase the risk associated with study participation 
or investigational product administration, or interfere with the interpretation of study 
results; or in the opinion of the investigator or Pfizer (or designee), the subject is 
inappropriate for entry into this study, or unwilling/unable to comply with STUDY 
PROCEDURESand Lifestyle Guidelines.
7. Have a history of any lymphoproliferative disorder such as Epstein Barr Virus (EBV)
related lymphoproliferative disorder, history of lymphoma, leukemia, or signs and 
symptoms suggestive of current lymphatic or lymphoid disease.
8. Have a history (single episode) of disseminated herpes zoster or disseminated herpes 
simplex, or a recurrent (more than one episode of) localized, dermatomal herpes 
zoster.
9. Have a history of systemic infection requiring hospitalization, parenteral 
antimicrobial therapy, or as otherwise judged clinically significant by the investigator 
within 6months prior to Day1 (for exception regarding latentTuberculosis(TB)
infection see Exclusion Criterion19or skin infections that lead to hospitalizationssee 
Exclusion Criterion10).
10.Have active chronic or acute skin infection (except latent TB infection see Exclusion 
Criterion 20) requiring treatment with systemic antibiotics, antivirals, antiparasitics, 
antiprotozoals, or antifungals within 2weeks prior to Day1, or superficial skin 
infections within 1week prior to Day1.  NOTE: patients may be rescreened after 
infection resolves.
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11.Have a history of alcohol or substance abusewithin 6months prior to Day1that in 
the opinion of the investigator will preclude participation in the study.
12.A Screening 12-lead ECGthat demonstrates clinically significant abnormalities 
requiring treatment (eg, acute myocardial infarction, serious tachy-or brady-
arrhythmias) or that are indicative of serious underlying heart disease 
(eg,cardiomyopathy, major congenital heart disease, low voltage in all leads, Wolff–
Parkinson–White syndrome).
13.Have a known immunodeficiency disorder or a first-degree relative with a hereditary 
immunodeficiency.
14.Have any malignancies or have a history of malignancies with the exception of 
adequately treated or excised non-metastatic basal cell or squamous cell cancer of the 
skin or cervical carcinoma in situ.
15.Have undergone significant trauma or major surgery within 1month of the first dose 
of study drug.
16.Require treatment with prohibited concomitant medication(s) (Section 5.8and
Appendix3) or have receiveda prohibited concomitant medication within 7days or 
5half-lives (whichever is longer) prior to Day1.
17.History of human immunodeficiency virus (HIV)or positive HIV serology at 
screening, 
18.Infected with hepatitisB or hepatitisC viruses.  For HepatitisB, all subjects will
undergo testing for HepatitisB Surface Antigen (HBsAg) and HepatitisB Core 
Antibody (HBcAb).  Subjects who are HBsAg positive are not eligible for the study.  
Subjects who are HBsAg negative and HBcAb positive willbe reflex tested for 
HepatitisB Surface Antibody (HBsAb) and if HBsAb is positive, may be enrolled in 
the study; if HBsAb is negative, the subject is not eligible for the study.
19.Have evidence of active or latent or inadequately treated infection with 
Mycobacterium tuberculosis (TB) as defined by the following:
a. A positiveQuantiFERON-TB Gold (QFT-G) In-Tube test or positive
Mantoux/Purified Protein Derivative (PPD) tuberculin skin test performed at or 
within the 12weeksprior to Day1is exclusionary; a negative test is required for 
eligibility.  It is recommended that subjects with a history of Bacille Calmette 
Guérin (BCG) vaccination be tested with the QFT-G test since the Mantoux/PPD 
tuberculin skin test may be positive due to vaccination.  See Section 7.3.5for
requirementsfor Mantoux/PPD tuberculin skin testing.  A QFT-G or 
Mantoux/PPD tuberculin skin test is not required if the subject has previously 
received a documented adequate course of therapy for either latent or active TB 
infection or is currently receiving a documented adequate treatment for latent TB 
infection; 
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b. Ahistory of either untreated or inadequately treated latent or active TB infection;
c. If a subject has previously received an adequate course of therapy for either latent 
(9months 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, neither a QFT-G test nor a Mantoux/PPD tuberculin skin 
test is needed, but a chest radiograph(s) (per local standard/guidelines) must be 
obtained if not performed within 12weeks prior to Day1.  To be considered 
eligible for the study, the radiograph(s) must be negative for active tuberculosis 
infection as determined by a qualified radiologist.  Documentation of adequate 
treatment for TB and negative chest radiograph(s) results must be obtained prior 
to Day1.  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 
regimen recommended by the health ministry or expert panel in the locale;
d. A subject who is currently being treated for active TB infection is to be excluded.
20.ANYof the following abnormalities in clinical laboratory tests at screening, as 
assessed by the study-specific laboratory and confirmed by a single repeat, if deemed 
necessary:
Absolute neutrophil count of <2.5x 109/L(<2500/mm3).
Hemoglobin <10.0g/dL or hematocrit <30%; 
Platelet count below the lower limit of normal (LLN)at Screening;
Absolutelymphocyte count of <0.5x 109/L (<500/mm
3); 
Estimated Creatinine Clearance <40mL/min based on the age appropriate 
calculation,or serum creatinine >1.5times the upper limit of normal (ULN);
AST or ALT values >2times the ULN; 
Total bilirubin 1.5times the ULN; subjects with a history of Gilbert
's syndrome 
may have a direct bilirubin measured and would be eligible for this study 
provided the direct bilirubin is ULN;
In the opinionof the investigatoror sponsor, have any uncontrolled clinically 
significant laboratory abnormality that would affect interpretation of study data or 
the subject’s participation in the study.
21.Subjects who are investigational 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 directly involved in the conduct of 
the study.
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4.3.Randomization Criteria 
Subjects will be randomized into the study provided they have signed an informed consent 
document to participate in the study, have undergone all screening procedures, and have met 
all inclusion and none of the exclusion criteria for participation in the study at Day1.  A 
computer-generated randomization schedule will be used to assign subjects to the treatment 
groups using and Interactive Voice Response System (IVRS).
4.4.Lifestyle Guidelines 
In order to participate in the study, subjects must be aware of the following life style 
guidelines and restrictions that apply during and after the study period. 
On study visit days (Day1, Week6, Week12, and End of Study [EOS]), comply with 
fasting requirement for at least 8hours prior to the visit. 
On study visit days, do not smoke or ingest caffeine during the 30minutes prior to 
blood pressure and heart rate measurements. 
On study visit days, do not take the dose of study drug until instructed to do so by the 
investigator or designated study site staff.
On study visit days, showering orbathing is permitted prior to attending the study 
visit, but do not apply emollientDiscontinue and avoid using certain medications and 
treatments (Section 4.2, Section 5.8.2, andAppendix3). 
Agree to use proper contraception methods (Section 4.4.2).
4.4.1.Surgery
During the study, no electivesurgery should occur without first consulting with the Pfizer 
Medical Monitor or designee.  Preferably, elective surgery should occur before the study or 
be delayed until participation in the study is completed. 
The Pfizer Medical Monitor or designee should be notified if a subject requires surgery 
(including dental surgery) during the study to determine whether the subject should 
discontinue from the study and/or discontinue study drug prior to the surgical procedure.  In 
general, planned surgical procedures should not be performed unless the study drug has been 
discontinued for at least 28days(unless otherwise advised by the Pfizer Medical Monitor or 
designee).  The Pfizer Medical Monitor or designee should be notified as soon as possible if 
a subject undergoes a surgical procedure without first informing the study staff.
4.4.2.Contraception
All male subjects who are able to father children and female subjects who are of childbearing 
potentialand are sexually active and at risk for pregnancy 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 28daysafter the last dose of investigational product.  The 
investigator or hisorher designee, in consultation with the subject, will confirm that the 
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subject has selectedan appropriate method of contraception for the individual subject (and 
his or her partner)from the permitted list of contraception methods (see below) and instruct 
the subject in its consistent and correct use.  Subjects need to affirm that they meet the 
criteria for correct use ofat least 1of the selected methods of contraception.  The investigator 
or his/her designee will discuss with the subject the need to use highly effective 
contraception consistently and correctly according to the Schedule of Activitiesand
document such conversation in the subject’s chart.  In addition, the investigator or his or her 
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 the subject’s partner. 
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. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg,oral, inserted, injected, implanted or transdermal) provided the subject 
plans to remain on the same treatment throughout the entire study and has been using 
that hormonal contraceptive for an adequate period of time to ensure effectiveness.
2. Correctly placed copper -containing intrauterine device (IUD). 
3. Male condom or female condom used WITH a spermicide (ie, foam, gel, film, cream, 
or suppository).  For countries where spermicide is not available or condom plus 
spermicide is not accepted as highly effective contraception, this option is not 
appropriate.
4. Male sterilization with absence of sperm in the post vasectomy ejaculate.
5. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
6. Female partner who meets the criteria for non-childbearing potential, as described 
below:
Female subjects of non-childbearing potential must meet at least one of the following 
criteria:
Have undergone a documented hysterectomy and/or bilateral oophorectomy;
Have medically confirmed ovarian failure; or 
Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12consecutive months with no alternative pathological or 
physiological cause; status may be confirmed by havinga serum FSH level 
confirming the post-menopausal state.
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All other female subjects (including females with tubal ligations) will be considered to be of 
childbearing potential.
4.5.Sponsor’s Qualified Medical Personnel
The contact information for the sponsor
's appropriately qualified medical personnel for the 
study is documented in thestudy contact list located in the coordinator’s manual and 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 investigational compound identifiers, subject study numbers, 
contact information for the investigational site, and contact details for a contact center in the 
event that the investigational 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 investigational 
staff ifthey are seeking advice on medical questions or problems; however, it should be used
only in the event that the established communication pathways between the investigational 
site and the study team are not available. It is therefore intended to augment,but not replace, 
the established communication pathways between the investigational site and the study team 
for advice on medical questions or problems that may arise during the study.The contact 
number is not intended for use by the subject directly, and if a subject calls that number, he 
or she will be directed back to the investigational site.
4.6.Rater Qualifications 
Clinical evaluations of atopic dermatitis will be performed by an experienced and qualified 
dermatologist (board certified or equivalent).  An experienced and qualified 
non-dermatologist physician or experienced medical professional with experience in the 
conduct of AD clinical trials may be permitted to perform the clinical evaluations of atopic 
dermatitiswhen designated by primary site Investigator.  The evaluator must receive and 
document protocol specific and applicable efficacy assessment scales training prior to 
performing these evaluations.  To assure consistency and reduce variability, the same 
evaluator must assess all dermatological clinical evaluations for any individual subject 
throughout thestudy whenever possible; a back-up experienced and qualified, 
protocol-trained evaluator will only be allowed and documented in case of emergency or 
special situations when the designated evaluator is unable to perform the evaluation. 
5.STUDY TREATMENTS 
PF-04965842 will be administeredorally at one of the following 4doses: 10, 30, 100, or 
200mgadministered QD for 12weeks.  In addition, one cohort will receive 
PF-04965842-matching placebo.
For the purposes of this study, and per International Conference on Harmonization (ICH)
guidelinesinvestigational product is defined as a pharmaceutical form of an active ingredient 
or placebo being tested or used as a reference in a clinical trial, including a product with a 
marketing authorization when used or assembled (formulated or packaged) in a way different 
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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).
5.1.Allocation to Treatment
Allocation of subjects to treatment groups will proceed through the use of an Interactive 
Response Technology (IRT) System (Interactive Web Response (IWR)/Interactive Voice 
Response (IVR) system).  The site personnel (study coordinator or specified designee) will 
be required to enter or select information including but not limited to the user’s identification 
(ID) and password, protocol number, the subject number and the date of birth of the subject.  
The site personnel will thenbe provided with a treatment assignment and dispensable unit 
(DU) or container number when drug is being supplied via the IRT.  The IRT system will 
provide a confirmation report containing the subject number and DU or container number 
assigned.  The confirmation report must be stored in the site’s files. 
There is a 24hour a day, 365days a year IRT helpdesk available for any questions or issues.  
The study specific IRT reference manual will provide the contact information and further 
details on the use of the IRT. 
Note: The IRT is the source of the subject number.  The IRT system will provide the subject 
number at the end of the first IRT subject transaction. 
5.2.Breaking the Blind
The study will be subject and investigator blinded.  At all times, treatment and randomization 
information will be kept confidential and will not be released to the investigator, the study 
staff, or the sponsor’s study team until following the conclusion of the study, with the 
exception described in this section. 
At the initiation of the study, the study site will be instructed on procedures for breaking the 
blind.  Blinding codes should only be broken in emergency situations for reasons of subject 
safety.  The method will be either a manual or electronic process.  When the blindfor a 
subject has been broken, the reason must be fully documentedand entered on the Case 
Report Form (CRF).  Whenever possible, the investigator should contact Pfizer before 
breaking the blind.  If the blind is broken, the investigator should promptly inform the Pfizer 
Clinician or Medical Monitor.  The subject for whom the blind has been broken will be 
discontinued from the study and undergo the early termination (ET) procedures.
Unblinding plan for interim analysis will be specified in Section 9.4.
5.3.Subject Compliance
Subject compliance will be verified by the accounting of investigational productat each visit.  
When investigational productis administered at the research facility, it will be administered 
under the supervision of study personnel.
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Compliance of the investigational product will be monitored by delegated site personnel by 
the accounting of unused medication returned by the subject at the study visits.  Compliance 
will be documented on the CRF and source document.  If compliance is <80%, the 
investigator or designee is to counsel the subject and ensure steps are taken to improve 
compliance.  Subjects interrupting investigational product for more than 4 consecutive days 
or for a total of more than 7 days between visits are to be discussed with the Sponsor for 
possible withdrawal from the study.
 
 
 
 
. 
5.4. Investigational Product Supplies
5.4.1. Dosage Form(s) and Packaging
Blinded PF-04965842 and its matched placebo will be provided as tablets for oral 
administration.  The 10-mg and 50-mg tablets and their matching placebos will be supplied 
in separate blister cards and labeled according to local regulatory requirements.
When received by the pharmacy, PF-04965842 and matching placebo will be in containers 
that will sufficiently blind all site staff to content within the blisters (ie, active versus 
placebo). 
5.4.2. Preparation and Dispensing
The investigational product should be dispensed using a drug management system at each 
dispensing visit.  A qualified staff member will dispense the investigational product via 
unique container numbers in blister cards provided, in quantities appropriate for the study 
visit schedule.  The subject/caregiver should be instructed to maintain the product in the 
blister cards provided throughout the course of dosing and return the blister cards to the site 
at the next study visit.
5.5. Administration
Subjects should take the medication orally for 12 weeks; Subjects will be encouraged to 
take the medication after breakfast whenever it is possible; however, for study visit days, 
subjects are to be instructed to refrain from dosing at home, and are to take the dose in the 
clinic.
Subjects will swallow the investigational product whole, and will not manipulate or chew the 
medication prior to swallowing.  Investigational product may be taken with or without food, 
other than on study visit days where fasting is required.  The exception will be on study visit 
CCI
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days when subjects will be instructed to refrain from dosing at home, and will take the dose 
at the clinic.
5.6.Investigational Product Storage 
The investigator, or an approved representative, eg, pharmacist, will ensure that all 
investigational products, including any comparative agents and/or marketed products are 
stored in a secured area with controlled access under recommended storage conditions and in 
accordance with applicable regulatory requirements. 
Investigational product should be stored in its original container and in accordance with the 
drug label.  See the Investigational Product Manual (IP Manual) for storage conditions of the 
product.
Storage conditions stated in the SRSD(ie, IB)will be superseded by the storage conditions 
stated in the labeling.
Site systems must be capable of measuring and documenting (for example, via alog), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products).  This should be 
captured from the time of investigational product receipt throughout study.  Even for 
continuous monitoring systems, a log or site procedure that ensures active daily evaluation 
for excursions should be available.  The operation of the temperature monitoring device and 
storage unit (for example, refrigerator), as applicable, should be regularly inspected to ensure 
it is maintained in working order. 
Any excursions from the product label storage conditions should be reported upon discovery.  
The site should actively pursue options for returning the product to the storage conditions, as 
described in the labeling, as soon as possible.  Deviations from the storage requirements, 
including any actions taken, must be documented and reported to the sponsor. 
Once an excursion is identified, the investigational product must be quarantined and not used 
until the sponsor provides documentation of permission to use the investigational product.  It 
will not be considered a protocol deviation if the sponsor approves the use of the 
investigational product after the temperature excursion.  Use of the investigational product 
prior to sponsor approval will be considered a protocol deviation.Specific details regarding 
information the site should report for each excursion will be provided to the site in the IP 
Manual. 
Site staff will instructsubjects on the proper storage requirements for take home 
investigational products. 
5.7.Investigational Product Accountability 
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies. To ensure adequate records, all 
drug supplies will be accounted for in the drug accountability inventory forms as instructed 
by Pfizer and will be monitored by the accounting of unused investigational product returned 
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by the subjects.  At the end of the clinical trial, all drug supplies unallocated or unused by the 
subjects must be returned to Pfizer or its appointed agent, or destroyed in an approved 
manner unless otherwise authorized by Pfizer.  In either case, the forms must identify the 
investigational product, including batch or code numbers, and account for its disposition on a 
subject-by-subject basis, including specific dates and quantities. 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  If destruction is authorized to take place at the study 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.All bottles must be returned to 
the investigator by the subject.
5.7.1.Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg,at the site).If destruction is authorized to take place at the study 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.
5.8.Concomitant Treatment(s)
Subjects will abstain from all concomitant medicationsas described in the Inclusionand
Exclusion Criteriasections of the protocol. 
Medications that are taken in the Screening/Washout period (after informed consent is 
obtained and before the first dose of study drug) will be documented as prior medications.  
Medications taken after the first dose of study drug has been administered will be 
documented as concomitant medications.  All concomitant medications taken during the 
study must be recorded in study records with indication, daily dose, and start and stop dates 
of administration.  Subjects will be queried about concomitant medication (including topical 
medications and treatments, over-the-counter and prescription medications and treatments, 
and vaccinations) at each study visit.  Any new concomitant medications or dose changes to 
current concomitant medications should be evaluated for potential new or worsening adverse 
events.
The start date, stop date, and indication for all therapies will be recorded on the CRF.
5.8.1.Permitted Concomitant Medications
The following concomitant ADtherapies are permitted during the study:
Oral antihistamines.
Subjects will be provided a non-medicated study emollient and a sunscreen at the 
Screening visit.  Subjects will start the emollient 7days prior to Day1 through to the 
follow up visit and use the sunscreen as needed.  The non-medicated study emollient 
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and sunscreen are the only topical products permitted to be used on atopic dermatitis 
skin during the study.  If a subject has a history of intolerability or currently does not 
tolerate the non-medicated study emollient or sunscreen or if the product is 
unavailable, the investigator should contact the Pfizer clinician or designee for 
approval to use an alternative topical treatment; the approved alternative 
non-medicated emollient and sunscreen should be documented in study records.
A subject who is receiving a permitted concomitant medication for any reason must be on a 
locally-approved medication and dose for the treated indication, and this must be 
documented in the CRF.  Subjects are not allowed any other investigational drugs or 
treatments during the study. 
Subjects should refrain from starting new or changing doses of permitted prescription or 
non-prescription drugs, vitamins, and dietary supplements within 7days or 5half-lives 
(whichever is longer) prior to Day1 and prior to study visits throughout the study, unless 
otherwise noted below.
Acetaminophen may be used intermittently (not to exceed 1g/day).  Vitamin and mineral 
supplements of standard potency are allowed in amounts not known to be associated with 
adverse effects (such as hypervitaminosis). 
Subjects should report any changes to permitted medications during the study to the 
investigator as soon as they occur.  Medication changes must be documented in the subject’s 
record and CRF.
Unless a prohibited medication or treatment, subjects may be administered any other 
medications necessary for the treatment of concomitant medical disorders as deemed 
necessary by the treating physician.  Following Day1, addition of concomitant medications 
or any change in the dosage should be limited to those considered medically essential. 
5.8.2.Prohibited Medications and Treatments
Subjects are required to discontinue and avoid using certain medications and treatments (see 
Inclusion/Exclusion Criteriaand Appendix3).  Subjectsshould be instructed at each visit to 
contact the study site investigator promptly if there are any intended changes or additions to 
concomitant medications. 
All medications and treatments that could affect atopic dermatitis must be discontinued
except oral antihistamines.  Due to the potential to affect atopic dermatitis with ultraviolet 
light exposure, subjects must also avoid prolonged exposure to the sun and avoid the use of 
tanning booths, sun lamps or other ultraviolet light sources during the study. 
For the purposes of this protocol, dietary supplements are defined as vitamins, minerals, 
purified food substances, and herbals with pharmaceutical properties.  Vitamins, minerals 
and purified food substances are allowed in amounts not known to be associated with adverse 
effects (such as hypervitaminosis).
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Herbals supplements are only allowed on a case by case basis; please contact the Pfizer staff.  
Herbal medications with unknown properties or known beneficial effects for ADor that are 
known to have an effect on drug metabolism (eg St. John’s Wort)must be discontinued at 
least 1week or 5half-lives (whichever is longer)before the first dose of investigational 
product. 
Restrictions on certain vaccinations are described in Section 5.8.3. 
5.8.3.Vaccinations
Vaccination with live virus, attenuated live virus, or any live viral components is prohibited 
within the 6weeks priorto the first dose of study drug, during the study, and for 6weeks 
after the last dose of investigational product.  Similarly, current routine household contact 
with individuals who have been vaccinated with live vaccine components should be avoided 
during treatment and for 6weeks following completion of treatment. 
Such vaccines include: FluMist(intranasal influenza vaccine), attenuated rotavirus vaccine, 
varicella (chickenpox) vaccine, attenuated typhoid fever vaccine, oral polio vaccine, MMR 
(measles, mumps, rubella) vaccine and vaccinia (smallpox) vaccine.  Following vaccination 
with live component vaccines, the virus may be shed in bodily fluids, including stool, and 
there is a potential riskthat the virus may be transmitted.
6.STUDY PROCEDURES 
Refer to the Schedule of Activityfor adetailed list of a detailed list of study procedures as 
they should be conducted at each respective visit.  Visit windows are based on Day1 visit.
Subjects are required to fast for at least 8hours prior to all visits that include lipidprofile 
paneltesting (Day1, Week6, Week12, and EOS).  During the fasting period, subjects 
should refrain from all food and liquids (water and non-studymedications are permitted). 
Due to possible need for PPD testing and chest radiograph, screening procedures may be 
performed over more than 1visit in the 35days prior to the Day1 visit. 
Visits should occur in the morning and prior to the subject’s doseon Day1, Week 6, 
Week 12, and EOS.  To assure consistency and reduce variability, all study visits should 
occur in the morningwhenever possible.  On days of study visits, subjects will receive their 
dose at the clinicduring their study visit.
Urine pregnancy test must be performed prior to dosing with the investigational productfor 
female subjects of childbearing potentialthrough to the EOS visit.
Non-medicated studyemollientand sunscreen will be provided to subjects atthe Screening 
Visitand re-supplied during the study as applicable.  Prior to attending a study visit, subjects 
are allowed to shower but shouldnot moisturize.  However, they may apply study provided 
emollientupon completion of all clinic visit study procedures.Subjects will start the study 
provided emollient 7days prior to Day1 through to the EOS visit. 
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Refer to Appendix11for guidelineson subject safety monitoring and discontinuation. 
6.1.Visit 1, Screening
Subjects will be screened within 35days prior to administration of the investigational 
product to confirm that they meet the subject selection criteria for the study.  The investigator 
(or an appropriate delegate at the investigator site) will obtain informed consent from each 
subject in accordance with the procedures described in the Subject Information and Consent
section.
If the Mantoux PPD tuberculin skin test is given, the subject must return between 
48-72hours post-injection for induration evaluation.
Screening laboratory tests with abnormal results may be repeated once to confirm abnormal 
results; the last value will be used to determine eligibility.  If results return to normal within 
the 5-week screening period, the subject may enter the study.  Sites will be permitted to 
re-screen subjects (with a new screening number) who initially do not meet eligibility criteria 
once.
The following procedures will be completed:
Obtain written informed consent.
Review Inclusion and Exclusion criteria.
Register subject in Impala.
Demography. 
Complete medical history, including history of drug, alcohol and tobacco use.  
Smoking status and average weekly alcohol consumption (units/week) will also be 
collected, where a unit contains 12g of pure alcohol, an amount equivalent to that 
contained in 5oz (a glass) of wine, 12oz of beer, or 1.5oz of 90proof of spirits.
Complete AD disease history includes collection of details of AD: AD diagnosis, the 
use of topical treatments, systemic treatments and other treatments for AD.
Obtain complete medication history of all prescription or nonprescription drugs, and 
dietary and herbal supplements taken within 35days prior to the planned first dose.  
The following timeframes prior to the planned first dose must be used for collection 
of the following Current/Prior Medications:
2years:Lipid-lowering medications;
3years: Previous drug treatments for ADincludes use of topical treatments, 
systemic treatments and other any treatments.
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Conduct complete physical examination.
Obtain vital signs including pulse rate, blood pressure, respiratory rate (after at least 
5 minutes of rest) and oral or tympanic temperature.
Obtain weight 
Obtain height.
Chest X-ray (if previous chest X-ray has not been performed within 12 weeks of 
Day 1, may require a visit to a different location).
Perform single 12-lead electrocardiogram (ECG).
Obtain samples for laboratory testing: Blood chemistry, hematology, urinalysis, 
serum FSH or pregnancy test, HIV, HBsAg, HBcAb, and HCVAb. 
Mantoux Purified Protein Derivative (PPD) skin test or QuantiFERON–TB
 Gold
 
test (unless performed within 12 weeks of Day 1).  If Mantoux PPD tuberculin skin 
test is performed, the subject must return between 48-72 hours post-injection for 
evaluation of induration.
Conduct clinical evaluations including IGA, EASI, BSA, and SCORAD.
Dispense ePRO handheld device.    
 will be collected daily in selected 
country/ies daily starting 3 days prior to Day 1 through to the End of Study visit. 
Dispense study emollient and sunscreen.  Subjects will start the emollient 7 days prior 
to Day 1 through to the end of study visit.
Assess for occurrence of Adverse Events: The SAE reporting period starts with the 
signing of the informed consent. 
6.2. Study Period
6.2.1. Visit 2, Day 1/Week 0
Review of Inclusion/Exclusion Criteria.
If subject meets all Inclusion/Exclusion criteria, officially randomize subject into the 
study.
Review any changes in the subject’s prior and concomitant treatment information.
Obtain vital signs including pulse rate, blood pressure, respiratory rate (after at least 
5 minutes of rest) and oral or tympanic temperature.
Obtain weight.
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Conduct complete physical examination. 
Obtain fastingsamples for blood chemistry including lipid profile.
Obtain samples for other laboratory testing: hematology, urinalysis, urine pregnancy 
test (female subjects of childbearing potential only), EBV, CMV, HSV1, HSV2, 
VZV, IgE, hsCRP, IP-10, IL-31, CCL17, TBNK, T cell subsets, and exploratory 
biomarker samples. 
Perform Fitzpatrick skin type assessment. 
Photography (at selected sites).
Conduct clinical evaluations including IGA, EASI, BSA, and SCORAD.
Administer PROs including Pruritus NRS, PtGA, DLQI, POEM, and HADS.
Note: The Pruritus NRS will be assessed daily from Day 1 to 15.
Review   
 (in selected country/ies) as necessary. 
Perform single 12-lead ECG.
Obtain Prep D1 sample for banked biospecimen pharmacogenomics testing.
Confirm proper contraception is being used.
Administer first dose of study drug to subject.
Dispense study drug supply to the subject.
Assess for occurrence of Adverse Events by spontaneous reporting of adverse events 
and by asking the subjects to respond to a non-leading question such as “How do you 
feel?” 
6.2.2. Visit 3, Day 8/Week 1 ( 1 day)
Conduct targeted physical examination.
Obtain vital signs including pulse rate, blood pressure, respiratory rate (after at least 
5 minutes of rest) and oral or tympanic temperature.
Obtain samples for laboratory testing: hematology and urine pregnancy test (female 
subjects of childbearing potential only). 
Conduct clinical evaluations including IGA, EASI, BSA, and SCORAD.
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Administer PROs including Pruritus NRS, PtGA, DLQI, POEM, and HADS. 
Note: The Pruritus NRS will be assessed daily from Day 1 to 15.
Review   
 (in selected country/ies) as necessary. 
Confirm proper contraception is being used.
Review any changes in the subject’s concomitant treatments information.
Perform drug accountability procedures.
Administer study drug to the subject.
Dispense study drug to the subject.
Assess for occurrence of Adverse Events by spontaneous reporting of adverse events 
and by asking the subjects to respond to a non-leading question such as “How do you 
feel?”
6.2.3. Visit 4, Day 15/Week 2 ( 1 day)
Conduct targeted physical examination.
Obtain vital signs including pulse rate, blood pressure, respiratory rate (after at least 
5 minutes of rest) and oral or tympanic temperature.
Obtain samples for laboratory testing: blood chemistry, hematology, urine pregnancy 
test (female subjects of childbearing potential only), IgE, hsCRP, CXCL-10, IL-31, 
CCL17, TBNK, and T cell subsets.
Obtain samples for PK analysis prior to dosing.
Conduct clinical evaluations including IGA, EASI, BSA, and SCORAD.
Administer PROs including Pruritus NRS, PtGA, DLQI, POEM, and HADS. 
Review   
 (in selected country/ies) as necessary. 
Confirm proper contraception is being used.
Review any changes in the subject’s concomitant treatments information.
Perform drug accountability procedures.
Administer study drug to the subject.
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Dispense study drug to the subject.
Assess for occurrence of Adverse Events by spontaneous reporting of adverse events 
and by asking the subjects to respond to a non-leading question such as “How do you 
feel?”
6.2.4. Visit 5, Day 29/Week 4 ( 1 day)
Conduct targeted physical examination.
Obtain vital signs including pulse rate, blood pressure, respiratory rate (after at least 
5 minutes of rest) and oral or tympanic temperature.
Obtain samples for laboratory testing: hematology, urine pregnancy test (female 
subjects of childbearing potential only), IgE, hsCRP, IP-10, IL-31, CCL17, TBNK, 
T cell subsets, and exploratory biomarker samples. 
Obtain samples for PK analysis prior to dosing.
Conduct clinical evaluations including IGA, EASI, BSA, and SCORAD.
Administer PROs including Pruritus NRS, PtGA, DLQI, POEM, and HADS. 
Review   
 (in selected country/ies) as necessary. 
Confirm proper contraception is being used.
Review any changes in the subject’s concomitant treatments information.
Perform drug accountability procedures.
Administer study drug to the subject.
Dispense study drug to the subject.
Assess for occurrence of Adverse Events by spontaneous reporting of adverse events 
and by asking the subjects to respond to a non-leading question such as “How do you 
feel?”
6.2.5. Visit 6, Day 43/Week 6 ( 1 day)
Conduct targeted physical examination.
Obtain vital signs including pulse rate, blood pressure, respiratory rate (after at least 
5 minutes of rest) and oral or tympanic temperature.
Obtainfastingsamples for blood chemistry including lipid profile.
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Obtain samples for laboratory testing: hematology, urinalysis, urine pregnancy test 
(female subjects of childbearing potential only), EBV, CMV, HSV1, HSV2, VZV, 
IgE, hsCRP, IP-10, IL-31, CCL17, TBNK, and T cell subsets. 
Prior to dosing, obtain samples for PK analysis (the first PK sample is to be 
collected 2 hours (30 minutes) prior to dosing; the second PK sample is to be 
collected immediately prior to dosing).
Photography (at selected sites).
Conduct clinical evaluations including IGA, EASI, BSA, and SCORAD.
Administer PROs including Pruritus NRS, PtGA, DLQI, POEM, and HADS. 
Review   
 (in selected country/ies) as necessary. 
Confirm proper contraception is being used.
Review any changes in the subject’s concomitant treatments information.
Perform drug accountability procedures.
Administer study drug to the subject.
Obtain samples for PK analysis at 0.5 hour (15 minutes) after dosing. 
Dispense study drug to the subject.
Assess for occurrence of Adverse Events by spontaneous reporting of adverse events 
and by asking the subjects to respond to a non-leading question such as “How do you 
feel?”
6.2.6. Visit 7, Day 57/Week 8 ( 3 day)
Conduct targeted physical examination.
Obtain vital signs including pulse rate, blood pressure, respiratory rate (after at least 
5 minutes of rest) and oral or tympanic temperature.
Obtain samples for laboratory testing: hematology and urine pregnancy test (female 
subjects of childbearing potential only), IgE, hsCRP, IP-10, IL-31, CCL17, TBNK, 
T cell subsets, and exploratory biomarker samples.
Obtain samples for PK analysis prior to dosing.
Photography at selected sites (at PI’s discretion).
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Conduct clinical evaluations including IGA, EASI, BSA, and SCORAD.
Administer PROs including Pruritus NRS, PtGA, DLQI, POEM, and HADS. 
Review   
(in selected country/ies) as necessary. 
Confirm proper contraception is being used.
Review any changes in the subject’s concomitant treatments information.
Perform drug accountability procedures.
Administer study drug to the subject.
Dispense study drug to the subject.
Assess for occurrence of Adverse Events by spontaneous reporting of adverse events 
and by asking the subjects to respond to a non-leading question such as “How do you 
feel?”
6.2.7. Visit 8, Day 85/Week 12 ( 3 day)
Conduct complete physical examination.
Obtain vital signs including pulse rate, blood pressure, respiratory rate (after at least 
5 minutes of rest) and oral or tympanic temperature.
Obtainfastingsamples for blood chemistry including lipid profile.
Obtain samples for laboratory testing: hematology, urinalysis, urine pregnancy test 
(female subjects of childbearing potential only), EBV, CMV, HSV1, HSV2, VZV, 
IgE, hsCRP, IP-10, IL-31, CCL17, TBNK, T cell subsets, and exploratory biomarker 
samples. 
Prior to dosing, obtain samples for PK analysis (the first PK sample is to be 
collected 2 hours (30 minutes) prior to dosing; the second PK sample is to be 
collected immediately prior to dosing).
Photography at selected sites (at PI’s discretion).
Conduct clinical evaluations including IGA, EASI, BSA, and SCORAD.
Administer PROs including Pruritus NRS, PtGA, DLQI, POEM, and HADS. 
Review   
 (in selected country/ies) as necessary. 
Perform single 12-lead ECG.
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Confirm proper contraception is being used.
Review any changes in the subject’s concomitant treatments information.
Perform drug accountability procedures.
Administer study drug to the subject.
Obtain samples for PK analysis at 1 hour (30 minutes), 2 hour (30 minutes), and 
4 hour (30 minutes), after dosing. 
Assess for occurrence of Adverse Events by spontaneous reporting of adverse events 
and by asking the subjects to respond to a non-leading question such as “How do you 
feel?”
6.3. Follow-up Visits
6.3.1. Visit 9, Day 92/Week 13 ( 3 day)
Conduct targeted physical examination.
Obtain vital signs including pulse rate, blood pressure, respiratory rate (after at least 
5 minutes of rest) and oral or tympanic temperature.
Obtain samples for laboratory testing: hematology and urine pregnancy test (female 
subjects of childbearing potential only).
Conduct clinical evaluations including IGA, EASI, BSA, and SCORAD.
Review   
 (in selected country/ies) as necessary. 
Confirm proper contraception is being used.
Review any changes in the subject’s concomitant treatments information.
Assess for occurrence of Adverse Events by spontaneous reporting of adverse events 
and by asking the subjects to respond to a non-leading question such as “How do you 
feel?”
6.3.2. Visit 10, Day 99/Week 14 ( 3 day)
Conduct targeted physical examination.
Obtain vital signs including pulse rate, blood pressure, respiratory rate (after at least 
5 minutes of rest) and oral or tympanic temperature.
Obtain samples for laboratory testing: blood chemistry, hematology and urine 
pregnancy test (female subjects of childbearing potential only).
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Conduct clinical evaluations including IGA, EASI, BSA, and SCORAD.
Administer PROs including Pruritus NRS, PtGA, DLQI, POEM, and HADS. 
Review   
 (in selected country/ies) as necessary. 
Confirm proper contraception is being used.
Review any changes in the subject’s concomitant treatments information.
Assess for occurrence of Adverse Events by spontaneous reporting of adverse events 
and by asking the subjects to respond to a non-leading question such as “How do you 
feel?”
6.3.3. Visit 11, End of Study Visit, Day 113/Week 16 ( 3 day) or Early Termination 
Visit
The following procedures will be completed:
Conduct complete physical examination.
Obtain vital signs including pulse rate, blood pressure, respiratory rate (after at least 
5 minutes of rest) and oral or tympanic temperature.
Obtain weight.
Perform single 12-lead ECG.
Obtainfastingsamples for blood chemistry including lipid profile.
Obtain samples for laboratory testing: hematology, urinalysis, urine pregnancy test 
(female subjects of childbearing potential only), EBV, CMV, HSV1, HSV2, VZV, 
IgE, hsCRP, IP-10, IL-31, CCL17, TBNK, T cell subsets, and exploratory biomarker 
samples. 
Conduct clinical evaluations including IGA, EASI, BSA, and SCORAD.
Administer PROs including Pruritus NRS, PtGA, DLQI, POEM, and HADS. 
Review   
 (in selected country/ies) as necessary. 
Confirm proper contraception is being used.
Review any changes in the subject’s concomitant treatments information.
If early termination visit, perform drug accountability procedures.
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Assess for occurrenceof Adverse Eventsby spontaneous reporting of adverse events 
and by asking the subjects to respond to a non-leading question such as “How do you 
feel?”
6.4.Subject Withdrawal
Withdrawal of consent: Subjects who request to discontinue study treatment will remain in 
the study and must enter into the Follow-up Period with their first follow-up visit occurring 
1week after their last doseto be followed for protocol specified follow-up procedures.  The 
only exception to this is when a subject specifically withdraws consent for any further 
contact with him or her or persons previously authorized by the subject to provide this 
information.  Subjects should notify the investigator in writing of the decision to withdraw 
consent from future follow-up, whenever possible.  The withdrawal of consent should be 
explained in detail in the medical records by the investigator, as to whether the withdrawal is 
only from further receipt of investigational product or also from study procedures and/or post 
treatment study follow-up, and entered on the appropriate CRF page.  In the event that vital 
status (whether the subject is alive or dead) is being measured, publicly available information 
should be used to determine vital status only as appropriately directed in accordance with 
local law.
Lost to follow-up: All reasonable efforts must be made to locate subjects to determine and 
report their ongoing status.  This includes follow-up with persons authorized by the subject 
as noted above.  Lost to follow-up is defined by the inability to reach the subject after a 
minimum of 2documented phone calls, faxes, or e-mails as well as lack of response by the 
subject to 1registered mail letter.  All attempts should be documented in the subject’s 
medical records.  If it is determined that the subject has died, the site will use permissible 
local 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 
staffand 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.
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 or behavioral 
reasons, or the inability of the subject to comply with the protocol-required schedule of study 
visits or procedures at a given study site.  Subjects who are requestedto discontinue study 
treatment will remain in the study and mustenter into the Follow-up Period with their first 
follow-up visit occurring 1 week after their last dose.
See Appendix11for guidelines on subject safety monitoring and discontinuation.  The early 
termination visit only applies to subjects who are randomized and then are prematurely 
withdrawn from the study treatment.
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If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  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 all unused investigational 
product(s),request thatthe subject return for a final visit, if applicable, and follow up with 
the subject regarding any unresolved AEs.
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.
7.ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator that may make it unfeasible to 
perform the test.  In these cases the investigator will 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 this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible.  The 
study team will be informed of these incidents in a timely fashion.
7.1.Pregnancy Testing
For female subjects of childbearing potential, a serum pregnancy test, with sensitivity ofat 
least 25mIU/mL, will be performed at screening, and a urine pregnancy test will be 
performed at every visit including the end of treatment (EOT/ET)and follow-upvisits.  A 
negative pregnancy result is required before the subject may receive the investigational 
product.  Pregnancy tests will also be done whenever 1menstrual cycle is missed during the 
active treatment period (or when potential pregnancy is otherwise suspected), and at the end 
of the study to confirm the subject has not become pregnant during the study.  Pregnancy 
tests may also be repeated as per request of institutional review boards (IRBs)/ethics 
committees (ECs) or if required by local regulations. 
In the case of a positive confirmed pregnancy, the subject will discontinue use of 
investigational productand be withdrawn from the study.
7.2.Banked Biospecimens 
7.2.1.Markers of Drug Response
Studying the variation in genetic markers and other biomarkers may help to explain some of 
the variability in response seen with some drugs among different individuals.  This is referred 
to as pharmacogenomic/biomarker research.  Comparing the deoxyribonucleic acid (DNA), 
ribonucleic acid (RNA), protein, and metabolite variation patterns of subjects who respond 
well and those who respond poorly to treatment may help to better define the most 
appropriate group of patients in which to target a given treatment.  Collecting biospecimens 
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for exploratory pharmacogenomic/biomarker analyses and retaining them in the Pfizer 
BioBank makes it possible to better understand the drug’s mechanism of action and to seek 
explanations for differences in, for example, exposure, efficacy, tolerability, or safety not 
anticipated prior to the beginning of the study.  Providing these biospecimens is a required 
study activity for study sites and subjects, unless prohibited as such by local regulations or 
ethics committee decision.
To protect subjects’ confidentiality, the banked biospecimens and data generated from them 
will be coded with the subject’s studyID number.  Samples will be kept in a facility 
accessible only by swiping abadge.  Data will be stored on password-protected computer 
systems.  The key between the code and the subject’s personal identifiers will be held at the 
study site; the researchers using the biospecimens and data generated from them will not 
have access to the key nor any personally identifying information.  Biospecimens will be 
used onlyfor the purposes described here and in the informed consent document/subject 
information sheet; any other uses require additional ethical approval.  Unless a time 
limitation is required by local regulations or ethical requirements, biospecimens will be 
stored indefinitely to allow for future research on the topics described here, including 
research conducted during the lengthy drug development process and also postmarketing 
research.  Subjects can withdraw their consent for the use of their biospecimens at any time 
by making a request to the investigator, in which event any remaining biospecimen will be
destroyed; data already generated from the biospecimens will continue to be stored to protect 
the integrity of existing analyses.  It is very unlikely that results generated from the 
biospecimens will have any clinical, diagnostic, or therapeutic implications for the individual 
study participants.  Subjects are notified in the informed consent document/subject 
information sheet that their results will not be given to them, unless required by local laws or 
regulations, in which case results will be returnedvia the investigator.  Results will not be 
provided to family members or other physicians, nor will they be recorded in the subject’s 
medical record.  There is no intention to contact subjects after completion of the clinical 
study.
A 4-mL blood biospecimen Prep D1 (K2edetic acid [ethylenediaminetetraacetic acid]
[EDTA]whole blood collection optimized for DNA analysis)will be collected at the 
baseline visit to be retained for potential pharmacogenomic/biomarker analyses related to 
drug response, unless prohibited by local regulations or ethics committee decision.  For 
example, putative safety biomarkers, drug-metabolizing enzyme genes, drug-transport 
protein genes, or genes thought to be related to the mechanism of drug action may be 
examined.  The banked biospecimens will be collected from all subjects unless prohibited 
by local regulations or ethics committee decision.  Detailed collection, processing, storage, 
and shipment instructions are provided inthelaboratory manual. 
It is possible that the useof these biospecimens may result in commercially viable products.  
Subjects will be advised in the informed consent document/subject information sheet that 
they will not be compensated in this event.
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7.2.2.Additional Research
Unless prohibited by local regulations or ethics committee decision, subjects will be asked to 
indicate on the consent form whether they will allow the banked biospecimens to also be 
used for the following research:
Biospecimens may be used as controls.  This includes use in case-control studies of 
diseases for which Pfizer is researching drug therapies; use in characterizing the 
natural variation among people in genes, RNA, proteins, and metabolites; and use in 
developingnew technologies related to pharmacogenomics/biomarkers. 
Subjects need not provide additional biospecimens for the uses described in this section; the 
biospecimen specified in the Markers of Drug Responsesection will be used.  Subjects may 
still participate in the clinical study if they elect notto allow their banked biospecimens to be 
used for the additional purposes described in this section.
7.3.Safety Assessments
Safety will be assessed by the spontaneous reporting of AEs, physical examinations and 
clinical laboratory results in all subjects who receive at least one dose of the investigational 
product.  Unscheduled safety assessments may be performed at any time during the study to 
assess any perceived safety concerns.  Investigators and Pfizer Clinicians (or designees) will 
review individual subject data throughout the conduct of the study to ensuresubjects’ 
well-being.
7.3.1.Vitals Signs
Vital signs (blood pressure, pulse, respiratory rates and temperature) will be measured after 5 
minutes of rest as indicated in the Schedule of Activities. 
It is preferred that body temperature be collected using the tympanic or oral methods and that 
the same method be used consistently throughout the study. 
Blood pressure (BP) will be measured using a standard calibrated blood pressure measuring 
device.  A BP device that uses multiple cuff sizes based on the arm circumference is the 
required type of device.  The appropriate cuff size for the subject must be used to ensure 
accurate measurement.  The arm circumference at the midpoint of the length of the upper arm 
should be measured to determine the appropriate cuff size in accordance with the 
specifications of the BP measuring device.  The same properly sized and calibrated blood 
pressure cuff will be used to measure blood pressure each time. 
Subjects should be seated in a chair, back supported, and arms bared (free of restrictions such 
as rolled-up sleeves, etc.) and supported at heart level.  Measurements should be taken on the 
same arm at each visit (preferably non-dominant).  Subjects should refrain from smoking or 
ingesting caffeine during the 30minutes preceding the measurements.  Measurements should 
begin after at least 5minutes of rest. 
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Heart rate should be measured at approximately the same time as BP for a minimum of 
30seconds.  When the timing of BP and pulse (heart) rate measurements coincides with a 
blood collection or other study procedure, BP and pulse (heart) rate should be obtained first.
7.3.2. Medical History, Physical Exam, Height, and Weight
Complete AD disease historyincludes collection of details of AD at Screening: AD 
diagnosis, the use of topical treatments, systemic treatments and other treatments for AD.  
Medical history in addition to AD history including disease duration and extent of disease, 
cardiac history and smokinghistory will be collected at Screening.  Height and weight will 
be measured without the subject wearing shoes.  Height (inches or centimeters) and weight 
(lbs or kg) will be measured and recorded in the source document at the screening visit.  
Weight (lbs or kg) will continue to be measured and recorded at various timepoints, see 
Schedules of Activities.
Complete physical examinations must be performed by the investigator, sub-investigator or a 
qualified health professional per local guidelines.  Complete physical examinations consist of 
assessments of general appearance; skin; head, eyes, ears, nose and throat (HEENT); mouth, 
heart; lungs; breast (optional); abdomen; external genitalia (optional); extremities; neurologic 
function; and lymph nodes.
Targeted physical examinations must be performed by the investigator, sub-investigator or a 
qualified health professional per local guidelines and should include skin, heart, lung, and 
abdomen and examination of body systems where there are symptom complaints by the 
subject. 
Complete and Targeted physical examinations are performed at various time points, see 
Schedules of Activities.
7.3.3.Chest X-Ray
Chest radiograph (posterior-anterior and lateral views are recommended, however local 
guidelines should be followed) or other appropriate diagnostic image (ie, computed 
tomography[CT] or magnetic resonance imaging[MRI]) with no evidence of current, active 
TB or previous inactive TB, general infections, heart failure or malignancy taken at screening 
or within 12weeks prior to Study Day1 and read by a qualified radiologist.  Documentation 
of the official reading must be located and available in the source documentation.
7.3.4.Electrocardiogram
Single 12-lead ECGs should be collected at times specified in the Schedule of Activities. 
All scheduled ECGs should be performed after the subject has rested quietly for at least 
10minutes in a supine position and prior to any blood collection. 
The screening ECG values will serve as each subject’s baseline values.  To ensure safety of 
the subjects, a qualified individual (eg sub-investigator) at the investigator site will make 
comparisons to baseline measurements.  A paper or digital copy of the ECG should be filed
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in the subject’s chart and must be available to the Sponsor upon request.  Any clinically 
significant changes will be recorded and evaluated further, as clinically warranted.  In some 
cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead placement as 
contributing to the ECG abnormality. 
7.3.5.QuantiFERON-TB Gold In-Tube Testand Mantoux/Purified Protein 
Derivative (PPD) Tuberculin Skin Test
QuantiFERON-TB Gold In-Tube is an in vitro diagnostic test using a peptide cocktail 
simulating ESAT-6, CFP-10and TB 7.7proteins to stimulate cells in heparinized whole 
blood.  Detection of interferon-gamma by Enzyme-Linked Immunosorbent Assay (ELISA) is 
used to identify in vitro responses to these peptide antigens that are associated with 
Mycobacterium tuberculosisinfection.  QuantiFERON
-TB Gold In-Tube is an indirect test 
for M.tuberculosis infection (including disease) and is intended for use in conjunction with 
risk assessment, radiography and other medical and diagnostic evaluations.
Test results will be reported as positive, negative or indeterminate.  In the case of an 
indeterminate result, repeat tests may be permitted for the purpose of determining eligibility
 
of subjects to enroll in this study.  It is recommended that subjects with a history of BCG 
vaccination be tested with the QFT-G test since the Mantoux/PPD tuberculin skin test may be 
positive due to vaccination.  A positive QFT-G test is exclusionary.  The procedure for using 
this test and interpreting the results will be described fully in the laboratory manual, which 
will be provided to investigators.
Subjects can be TB screened using the Mantoux/PPD Tuberculin Skin Test.  Mantoux/PPD 
testing can also be performed if there are indeterminate QFT-G test results.  Subjects must 
have a Mantoux/PPD tuberculin skin test administered and then evaluated by a health care 
professional 48to 72hours later.  A positive Mantoux/PPD tuberculin skin test is 
exclusionary.
The Mantoux/PPD Tuberculin Skin Test consists of an intracutaneous injection of 
5Tuberculin Units (5TU) PPD in 0.1mL of solution (according to local standard) on the 
volar aspect of the forearm, using a short beveled 26-or 27-gauge needle.  The test is read 
according to local standard 48to 72hours after injection.
7.3.6.Special Safety Assessment
In case of a suspected viral skin infection (eg,herpes zosterandherpes simplex), a specimen 
for viral DNA should be obtained for confirmation.  Details for such collection will be 
provided in the laboratory manual. 
7.4.Skin Type Assessment
As part of baseline characteristics, a skin type assessment will be done at the Day1 visit 
using the Fitzpatrick Skin Phototype assessment (Appendix4).  Thisis used to classify a 
person’s skin type by their response to sun exposure (ie, burning or tanning).
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7.5.Clinical Laboratory Tests
7.5.1.Blood Volume
Total blood sampling volume planned for this study is approximately 439mL.  Further 
details regarding the collection, processing, storage, and shipping of the blood samples will
be provided in the lab manual.
7.5.2.Laboratory Tests
The following laboratory tests will be performed at time points identified in the Schedule of 
Activities.  Unscheduled clinical labs may be obtained at any time during the studyto assess 
any perceived safety concerns at the investigator’s discretion.
Sample collection, labeling, storage, and shipping information can be found in the laboratory 
manual.  All laboratory tests with clinically important changes from baseline identified after 
administration of investigational product will be followed until the value stabilizes.
Subjects must abstain from all food and drink (except water and non-study 
medications) for an8-hour overnight fast prior to labs that include the lipid profile 
panelon Day1, Week6, Week12, and EOS.  All other labs (including PK sample 
collections) do not require fasting.
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Laboratory Tests
Hematology
Serum Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
Reticulocyte count
Platelet count
WBC count with differential
Total neutrophils (%, Abs)
Eosinophils (%, Abs)
Monocytes (%, Abs)
Basophils (%, Abs)
Lymphocytes (%, Abs)
BUN and Creatinine
Creatine Phosphokinase
Glucose 
Na+, K+, Cl-,Ca++
Total CO2 (Bicarbonate)
AST,  ALT
Total Indirect & Direct Bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
Lipid Profile Panelf:
Total cholesterol
LDL 
HDL
Triglycerides
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Microscopyand/or 
culture
d
HIVa
HBsAga
HBcAba
HbsABb
HCVAba
Serum pregnancy testa, c
Urine pregnancy test c
FSHa, g
QFT-G or other IGRA, or 
PPDe
EBV, CMV, HSV1, HSV2, 
VZV
Total IgE
hsCRP
IP10 (CXCL10)
IL-31
CCL17(TARC)
TBNK
T cell subtypes
a At Screening only.
b HepB reflex testing only if  HBsAg negative but HBcAb positive. 
c Females of childbearing potential.
d Only if urine analysisis positive for blood, protein, nitrites, or leukocyte esterase.
e PPD results should be read within 48 to 72hours.
f Lipid Profile Panel requires at least an 8hour fast. Lipid profile panel will be completed at Day1, Week 6,
Week 12, and EOS, and will include total cholesterol, LDL, HDL, and triglycerides. 
g Females of non-child bearing potential.
Clinically significant abnormal findings should be recorded as AEs. Abnormal test results 
determined to be caused from laboratory error should not be reported as AEs.  Clinically 
significant 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.  Refer to Appendix11forlaboratory discontinuation criteria.
7.5.2.1.Viral Surveillance
Blood sample (8mL) for the analysis of CMV, EBV, HSV-1,HSV-2and VZVwill be 
collected according to the times outlined in the Schedule of Activities.  Additionalsample 
collection instructions will be provided in the lab manual. 
7.6.Efficacy Assessments
7.6.1.InvestigatorGlobal Assessment (IGA)
The clinical evaluator of atopic dermatitis will perform an assessment of the overall severity 
of atopic dermatitis and assign an IGA score and category as described in Table3.  The
assessment will be a static evaluation without regard to the score at a previousvisit. 
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Table3.
Investigator Global Assessment (IGA) Score
Score
Category
Description
0
Clear
Atopic dermatitis is cleared, except for any residual discoloration 
(post-inflammatory hyperpigmentation and/or hypopigmentation).
1
Almost 
Clear
Overall, the atopic dermatitis is not entirely cleared and remaining lesions 
are light pink (not including post inflammatory hyperpigmentation) and/or; 
have barely palpable hard thickened skin and/or papules and/or; have barely 
perceptible lichenification; excoriation and oozing/crusting are absent.
2
Mild
Overall, the atopic dermatitis consists of lesions that are light red; with 
slight, but definite hard thickened skin and/or papules; with slight, but 
definite linear or picked scratch marks or penetrating surface injury; with 
slight, but definite thickened skin, fine skin markings, and lichenoid scale; 
oozing/crusting is absent.
3
Moderate
Overall, the atopic dermatitis consists of lesions that are red; with easily 
palpable moderate hard thickened skin and/or papules; with moderate linear 
or picked scratch marks or penetrating surface injury; with moderate 
thickened skin, coarse skin markings, and coarse lichenoid scale; with slight 
oozing/crusting.
4
Severe
Overall, the atopic dermatitis consists of lesions that are deep, dark red; with 
severe hard thickened skin and/or papules; with severe linear or picked 
scratch marks or penetrating surface injury; with severe thickened skin with 
very coarse skin markings and lichenoid scale; with moderate to severe 
oozing/crusting.
The IGA will exclude scalp, palms, and solesfrom the assessment/scoring..
7.6.2.Eczema Area and Severity Index (EASI)
The EASI quantifies the severity of a subject’s atopic dermatitis based on both severity of 
lesion clinical signs and the percent of BSA affected.  EASI is a composite scoring by the 
atopic dermatitis clinical evaluator of the degree of erythema, induration/papulation, 
excoriation, and lichenification (each scored separately) for each of four body regions, with 
adjustment for the percent of BSA involved for each body region and for the proportion of 
the body region to the whole body.
Lesion Severity by Clinical Signs:The basic characteristics of atopic dermatitis lesions -
erythema, induration/papulation, excoriation, and lichenification -provide a means for 
assessing the severity of lesions.  Assessment of these four main clinical signs is performed 
separately for four body regions: head and neck, upper limbs, trunk (including axillae and 
groin) and lower limbs (including buttocks).  Average erythema, induration/papulation, 
excoriation, and lichenification are scored for each body region according to a 4point scale: 
0=absent; 1=mild; 2=moderate; 3=severe.  Morphologic descriptors for each clinical 
sign severity score are shown in Table4.
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Table4. Clinical Sign Severity Scoring Criteria for the Eczema Area and Severity 
Index (EASI)
Score
Description*
Erythema (E)
0
Absent
None; may have residual discoloration (post-inflammatory hyperpigmentation 
and/or hypopigmentation).
1
Mild
Light pink to light red
2
Moderate
Red
3  
Severe
Deep, dark red
Induration/Papulation (I)
0
Absent
None
1
Mild
Barely palpable to slight, but definite hard thickened skin and/or papules
2
Moderate
Easily palpable moderate hard thickened skin and/or papules
3  
Severe
Severe hard thickened skin and/or papules
Excoriation (Ex)
0
Absent
None
1
Mild
Slight, but definite linear or picked scratch marks or penetrating surface injury
2
Moderate
Moderate linear or picked scratch marks or penetrating surface injury
3  
Severe
Severe linear or picked scratch marks or penetrating surface injury
Lichenification (L)
0
Absent
None
1
Mild
Barely perceptible to slight, but definite thickened skin, fine skin markings, 
and lichenoid scale
2
Moderate
Moderate thickened skin, coarse skin markings, and coarse lichenoid scale
3  
Severe
Severe thickened skin with very coarse skin markings and lichenoid scale
The EASI will exclude scalp, palms, and soles from the assessment/scoring.
Percent BSA with Atopic Dermatitis:The number of handprints of skin afflicted with 
atopic dermatitis in a body region can be used to determine the extent (%) to which a body 
region is involved with atopic dermatitis(Table5).  When measuring, the handprint unit 
refers to the size of each individual subject’s hand with fingers in a closed position.
Table5.
Handprint Determination of Body Region Surface Area (BSA)
Body Region
Total Number of Handprints 
in Body Region*
Surface Area of Body Region 
Equivalent of One Handprint*
Head and Neck
10
10%
Upper Limbs
20
5%
Trunk (including axillae and 
groin/genitals)
30
3.33%
Lower Limbs (including buttocks)
40
2.5%
Handprint refers to the hand size of each individual subject.
* The number of handprints will be for the entire body region; these values will not be adjusted for exclusion 
of scalp, palms, and soles from the BSA assessment.
The extent (%) to which each of the four body regions is involved with atopic dermatitis is 
categorized to a numerical Area Score using a non-linear scaling method according to the 
following BSA scoring criteria (Table6).
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Table6.
Eczema Area and Severity Index (EASI) Area Score Criteria
Percent BSA with Atopic Dermatitis in a Body Region
Area Score
0%
0
>0 -<10%
1
10 -<30%
2
30 -<50%
3
50 -<70%
4
70 -<90%
5
90 -100%
6
Body Region Weighting: Each body region is weighted according to its approximate 
percentage of the whole body (Table7).
Table7.
Eczema Area and Severity Index (EASI) Body Region Weighting
Body Region
Body Region Weighting
Head and Neck
0.1
Upper Limbs
0.2
Trunk (including axillae and groin/genitals)
0.3
Lower Limbs (including buttocks)
0.4
* No adjustment for body regions excluded for assessment
In each body region, the sum of the Clinical Signs Severity Scores for erythema, 
induration/papulation, excoriation, and lichenification is multiplied by the Area Score and by 
the Body Region Weighting to provide a body region value, which is then summed across all 
four body regions resulting in an EASI score as described in Equation3.
Equation 3:  EASI=0.1Ah(Eh+Ih+Exh+Lh) + 0.2Au(Eu+Iu+ExU+Lu) + 
0.3At(Et+It+Ext+Lt) + 0.4Al(El+Il+Exl+Ll)
A = Area Score; E = erythema; I=induration/papulation; Ex = excoriation; L=lichenification; h = head and 
neck; u=upper limbs; t = trunk; l = lower limbs
The EASI score can vary in increments of 0.1 and range from 0.0 to 72.0, with higher scores 
representing greater severity of atopic dermatitis.
7.6.2.1.Body Surface Area –Efficacy (BSA Efficacy)
BSA Efficacy will be derived from the sum of the BSA in handprints across 4 body regions 
assessed as part of the EASI assessment (Table5).  Handprintrefers to that of each 
individual subject for their own measurement.  The BSA Efficacy ranges from 0 to100%, 
with higher values representing greater severity of atopic dermatitis.  Since the scalp, palms, 
and soles will be excluded from the BSA (Efficacy) assessment, the maximum possible value 
will be less than 100%.
7.6.3.Scoring Atopic Dermatitis (SCORAD)
SCORAD is a validated scoring index for atopic dermatitis, which combinesextent (0-100), 
severity (0-18), and subjective symptoms (0-20) based on pruritus and sleep loss, each scored 
(0-10). 
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Extent (A, maximum of 100%)
To determine extent of AD, rule of 9 is used to calculate body surface area affected by AD as 
a percentage of the whole body surface area.  Body surface area as percentage of total body 
surface area for each body region is as follows:
Head and neck 9%; 
Upper limbs 9% each; 
Lower limbs 18% each; 
Anterior trunk 18%; 
Back 18%; 
1% for genitals. 
The score for each body region is added up to determine the BSAaffected by AD (A), which 
has a possible maximum of 100%. 
Severity (B, maximum of 18)
A representative area of AD is selected.  In this area, the severity of each of the following 
signs is assessed as none (0), mild (1), moderate (2) or severe (3). 
Erythema (reddening);
Edema (swelling);
Oozing/crusting;
Excoriation (scratch marks);
Skin thickening (lichenification);
Xerosis (dryness) (this is assessed in an area where there is no inflammation).
The severity scores are added together to give 
'B
' (maximum of 18).
Subjective Symptoms (C, maximum of 20)
Subjective symptom (ie. itch and sleeplessness) are each scored by the subject or caregiver 
using a numeric rating scale (NRS) where “0” is no itch (or no sleeplessness) and “10” is the 
worst imaginable itch (or sleeplessness).  These scores are added to give 
'C
' (maximum 
of20). 
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SCORAD Total Score
The SCORAD for an individual is calculated by the formula: A/5 + 7B/2 + C (can range 
from 0 to 103). 
7.7. Patient-Reported Outcomes (PROs)
 
 
 
 
 
 
 
 
 
7.7.1. Pruritus Numeric Rating Scale (NRS) 
Severity of Pruritus
The severity of itch (pruritus) due to atopic dermatitis will be assessed using a horizontal 
NRS (Appendix 6).  Subjects will be asked to assess their “worst itching due to atopic 
dermatitis over the past 24 hours” on a NRS anchored by the terms “no itching” (0) and 
“worst possible itching” (10).
Frequency of Pruritus
The frequency of itch (pruritus) due to atopic dermatitis will be assessed using a horizontal 
NRS (Appendix 6).  Subjects will be asked to assess “frequency of itching due to atopic 
dermatitis over the past 24 hours” on a NRS anchored by the terms “never/no itching” (0) 
and “always/constant itching” (10).
The pruritus NRS should be completed as per Schedule of Activities. 
7.7.2. Patient Global Assessment (PtGA)
The PtGA asks the subject to evaluate the overall cutaneous disease at that point in time on a 
single-item, 5-point scale (Appendix 5).  The same category labels used in the Physician’s 
Global Assessment will be used for the Patient Global Assessment, ie, “severe (4)”, 
“moderate (3)”, “mild (2)”, “almost clear (1)”, and “clear (0)”.  The PtGA should be 
completed as per Schedule of Activities.
7.7.3. Dermatology Life Quality Index (DLQI)
The DLQI is a general dermatology questionnaire that consists of 10 items that assess subject 
health-related quality of life (daily activities, personal relationships, symptoms and feelings, 
leisure, work and school, and treatment) (Appendix 7).  It has been extensively used in 
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clinical trials for AD.  The DLQI is a psychometrically valid and reliable instrument that has 
been translated into several languages, and the DLQI total scores have been shown to be 
responsive to change.  The minimally important difference for the DLQI has been estimated 
as a 2 to 5 point change from baseline.  The DLQI should be completed as per Schedule of 
Activities.
7.7.4. Patient-Oriented Eczema Measure (POEM)
The POEM is a 7-item PRO measure used to assess the impact of AD over the past week
(Appendix 8).  The POEM should be completed as per Schedule of Activities.
7.7.5. Hospital and Anxiety Depression Scale (HADS)
The HADS is a 14-item PRO measure used to detect states of anxiety and depression over the 
past week (Appendix 9).  The HADS should be completed as per Schedule of Activities.
7.7.6.
 
 
 
 
 
7.8. Photography of Atopic Dermatitis Treated with Study Drug
For subjects at a selected study site(s), photographs of treatment-eligible atopic dermatitis 
will be obtained (according to the separately provided Photography Instructions) at Day 1 
and Week 6.  Areas photographed should be recorded in study documents so that the same 
atopic dermatitis body region(s) will be photographed at Week 6.  Additional photographs 
may also be taken at Week 8 and/or Week 12 at the investigator’s discretion. 
Photographic services may be provided through a central photography lab selected by the 
sponsor.  Detailed procedures to assure consistency will be provided separately in a central 
photography lab instruction manual.
7.9. Pharmacokinetics
7.9.1. Plasma for Analysis of PF-04965842
During all study periods, blood samples (4 mL) to provide approximately 1.2-1.5 mL of 
plasma for PK analysis will be collected into appropriately labeled tubes containing K2EDTA 
at times specified in the STUDY PROCEDURESsection of the protocol.
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Blood will be collected at the time points identified in the Schedule of Activitiessection of 
the protocol.  All efforts will be made to obtain the pharmacokinetic samples at the exact 
nominal time relative to dosing.  The exact time of the sample collection is to be noted on the 
source document and data collection tool (eg, CRF).  Samples obtained outside the windows 
specified in the Schedule of Activitieswill be considered a protocol deviation.
The plasma will be stored in appropriately labeled screw-capped polypropylene tube 
at approximately -20C within 1hour of collection.
Further details regarding the collection, processing, storage and shipping of the blood
samples will be provided in the lab manual.
Samples will be analyzed using a validated analytical method in compliance with
Pfizer standard operating procedures. 
The PK samples must be processed and shipped as indicated to maintain sample 
integrity.  Any deviations from the PK processing steps, 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 sample deemed outside of established stability, or of questionable 
integrity, will be considered a protocol deviation.
As part of understanding the pharmacokinetics of the study drug, samples may be 
used for metabolite identification and/or evaluation of the bioanalytical method.  
These data will be used for internal exploratory purposes and will not be included in 
the clinical report.
7.9.2.Shipment of Pharmacokinetic Samples
The shipment address and assay lab contact information will be provided to the Investigator
site prior to initiation of the study.  The central laboratory will provide collection materials
and directions for packaging and shipment of samples and will forward samples to the
contract analytical laboratory.  The contract analytical laboratory will be provided with
randomization codes so that only samplesin the PF-04965842 treatment groups are assayed.  
Placebo samples may be assayed in the event of suspected error in subject randomization.  
Refer to the central lab vendor manual for further information.
7.10.Pharmacodynamics Markers
The pharmacodynamics (PD) samples must be processed and shipped as indicated to 
maintain sample integrity.  Any deviations from the PD processing steps, including any 
actions taken, mustbe 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.  
Depending on sampling and transport constraints, it is possible that not all biomarker samples 
will be collected in all study regions.
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All efforts will be made to obtain the PD samples at theexact nominal time relative to 
dosing.  Please consult the laboratory manual(s) for final instructions on sample collection, 
storage, and shipping requirements.  These manual(s) supersede the instructions listed in the 
applicable protocol sections.  Samples that are handled according to the respective manual 
guidance are considered “per protocol”.
Samples will be analyzed using fit for purpose or validated analytical methodsin compliance 
with Pfizer standard operating procedures.
As part of understanding the pharmacodynamics of the study drugand the disease under 
study, samples may be used for evaluation of the bioanalytical method.  These data will be 
used for internal (ie, Pfizer) exploratory purposes and will not be included in the clinical 
report.
7.10.1.Samples for IP-10 Analysis
Blood samples (3mL) to provide approximately 1.2mL serum for the analysis of IP-10 will 
be collected into appropriately labeled tubes containing no preservative, anticoagulant or 
serum separator according to the times outlined in the Schedule of Activities.
The blood will be allowed to clot in an upright position at ambient temperature for 
approximately 30min.  Place the clotted samples into an ice bath for approximately 10min 
prior to centrifugation.  The serum will be transferred to appropriately labeled screw-capped 
polypropylene tubes and stored according to the laboratory manual.
Note: During all steps after the sample is clotted, the sample will be kept on ice until 
transferred to frozen storage.
7.10.2.Samples for hs-CRP Analysis
Blood samples (3.5mL) to provide approximately 1.2mL serum for the analysis of hs-CRP 
will be collected into appropriately labeled 3.5mL Goldtop tubesaccording to the times 
outlined in the Schedule of Activities. 
Samples will be allowed to clot at room temperature for 30minutes.  The serum will be 
transferred to an appropriately labeled screw-capped polypropylene tube and stored 
according to the laboratory manual.
7.10.3.Samples for ImmunoglobulinE(IgE) Analysis
Blood sample (4mL) to provide approximately 1.5 mLserum for the analysis of 
immunoglobulin (IgE) will be collected into a serum tube according to the times outlined in 
the Schedule of Activities.
Samples will be allowed toclot at room temperature for at least 30minutes.  The serum will 
be transferred to appropriately labeled screw-capped polypropylene tubes and stored 
according to the laboratory manual.
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7.10.4.Samples for FACS analysis (T cell, B cell, and NK cell subsets)
Bloodsamples (5mL) for the assessment of percent and absolute lymphocyte subsets will be 
collected and will be analyzed by FACS to identify Tcell, Bcell, and NKcell subsets 
according to the times outlined in the Schedule of Activities.  Sampletube should be 
completely filled to ensure correct final preservative concentration.  Immediately after the 
sample is drawn, gently invert the tube 180and back, for at least 1minuteto thoroughly 
mix the blood with the anti-coagulant.  The samples should be appropriately labeled(ie, date 
and time of collection, subject ID, sample ID, and protocol number).  All samples must be 
immediately shippedto the FACS lab at ambient temperature (18C -25C). 
7.10.5.Samples for FACS Analysis: T-cell subtypeprofiling
Blood samples (4mL) for the assessment of Tcell subsets will be collected in appropriately 
labeled tubes, and will be analyzed by FACS to measure the frequency of Th1, Th2, Th9, 
Th22, Th17 and Th17/Th1 cell subsets according to the times outlined in the Schedule of 
Activities. 
Sample tube should be completely filled to ensure correct final preservative concentration.  
Immediately after the sample is drawn, gently invert the tube 180and back, for at least 
1minute to thoroughly mix the blood with the anticoagulant.  Samples must be immediately 
shipped to the FACS lab at ambient temperature (18C-25C). 
7.10.6.Samples for IL-31 Analysis
Blood samples (2mL) to provide approximately 0.6mL plasma for the analysis ofIL-31will
be collected into appropriately labeled tubes, pre-chilled in a wet ice bath for at least 
5minutes prior to blood collection.  Samples will be collected according to the times outlined 
in the Schedule of Activities.
Immediately after allowing the tube to completely fill, gently invert the tube 8times,and 
return the tube to the wet ice bath.  Within 30 minutes of collection, centrifuge at
1,500-2,000xg for approximately 10minutes at 4C.  The plasmawill be transferred to 
appropriately labeled screw-capped polypropylene tubes and stored according to the 
laboratory manual.
7.10.7.Samples for CCL17 (TARC) Analysis
Blood samples (4mL) to provide approximately 1.2mL serum for the analysis of CCL17 
(TARC) will be collected into appropriately labeled tubes according to the times outlined in 
the Schedule of Activities. 
Samples will be allowed to clot at room temperature for 30minutes.  The serum will be 
transferred to an appropriately labeled screw-capped polypropylene tube and stored 
according to the laboratory manual.
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7.10.8.Serum for Exploratory Analysis
Blood samples (10mL) to provide approximately 3mL serum will be collected into 
appropriately labeled tubes according to the times outlined in the Schedule of Activities.  
These samples may be used for the evaluation of exploratory biomarkers that may include 
markers related to atopic dermatitis and/or other inflammatory conditions and/or the 
mechanism of action of PF-04965842.  These samples are for biomarker analysis and will not 
be used for genetic testing.
Detailed processing, storage and shipment instructions will be provided in the lab manual.
7.10.9.Cell-free Plasma for Exploratory Analysis
Blood samples (10mL) will be collected into appropriately labeled tubes according to the 
times outlined in the Schedule of Activities.  Thesesamples may be used for the evaluation 
of exploratory biomarkers from cell-free plasma that may include markers related to atopic 
dermatitis and/or other inflammatory conditions and/or the mechanism of action of 
PF-04965842.  These samples are for biomarker analysis and will not be used for genetic 
testing.
Detailed processing, storage and shipment instructions will be provided in the lab manual.
7.10.10.Gene Expression Analysis
Blood samples (2.5mL) for the assessment of gene expression (mRNA analysis) will be 
collected in appropriately labeled PAXgene Blood RNA Tubes.  Samples will be collected 
according to the times outlined in the Schedule of Activities.  Thesesamples may be used for 
the evaluation of exploratory biomarkers that may include markers related to atopic 
dermatitis and/or other inflammatory conditions and/or the mechanism of action of 
PF-04965842.  These samples are for biomarker analysis and will not be used for genetic 
testing.
Detailed Processing, Storage and Shipment Instructions will be provided in the Lab Manual.
7.10.11.Shipment of Pharmacodynamic Samples
The shipment address and assay lab contact information will be provided to the investigator 
site prior to initiation of the study.
8.ADVERSE EVENT REPORTING
8.1.Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as a 
serious adverse event (SAE) requiring immediate notification to Pfizer or its designated 
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representative.  For all AEs, sufficient information should be obtained by the investigator to 
determine the causality of the AE.  The investigator is required to assess causality.  
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.
As part of ongoing safety reviews conducted by the sponsor, any nonserious 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.
8.2.Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the subject provides informed consent, which is obtained prior to the subject’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 28calendar days after the last 
administration of the investigational product.  SAEs occurring to a subject after the active 
reporting period has ended should be reported to the sponsor if the investigator becomes 
aware of them; at a minimum, all SAEs that the investigator believes have at least a 
reasonable possibility of being related to investigational product are to be reported to the 
sponsor.
AEs (serious and non-serious) should be recorded on the case report form (CRF) from the 
time the subject has taken at least 1 dose of investigational product through the subject’s last 
visit. 
8.3.Definition of an Adverse Event
An AE is any untoward medicaloccurrence in a clinical investigation 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 symptoms and signs;
Changes in physical examination findings;
Hypersensitivity;
Progression/worsening of underlying disease;
Drug abuse;
Drug dependency.
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Additionally, they may include the signs or symptoms resulting from:
Drug overdose;
Drug withdrawal;
Drug misuse; 
Drug interactions;
Extravasation;
Exposure during pregnancy (EDP);
Exposure via breastfeeding;
Medication error;
Occupational exposure.
8.4.Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong subject, at the wrong time, or at the wrong dosage strength 
Such medication errors occurring to a study participant are to be capturedon the medication 
error CRF,which is a specific version of the AE page,and on the SAE form when 
appropriate.  In the event of medication dosing error, the sponsor should be notified 
immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:
Medication errors involving subject exposure to the investigational product;
Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the AE page 
and, if applicable, any associated AE(s) are captured on an AE CRF page.
8.5.Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 
Test result is associated with accompanying symptoms; and/or
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Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or
Test result leads to a change in study dosing 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 
reporting as an AE.
8.6.Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:
Results in death;
Is life-threatening (immediate risk of death);
Requires inpatient hospitalization or prolongation of existing hospitalization;
Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);
Results in congenital anomaly/birth defect.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in anemergency 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.
8.6.1.Protocol-Specified Serious Adverse Events 
There are no protocol-specified SAEs inthis study.  All SAEs will be reported by the 
investigator as described in previous sections, and will be handled as SAEs in the safety 
database (see the section on Serious Adverse Event Reporting Requirements). 
8.6.2.Potential Cases of Drug-Induced Liver Injury 
Abnormal values in AST and/or ALT levels concurrent with abnormal elevations in total 
bilirubin level that meet the criteria outlined below in the absence of other causes of liver 
injury are considered potential cases of drug-induced liver injury (potential Hy’s law cases) 
and should always be considered important medical events. 
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The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the subject’s individual baseline values and underlying conditions.  Subjects who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:
Subjects with AST or ALT and total bilirubinbaseline values within the normal range 
who subsequently present with AST or ALT values 3 times the ULN concurrent 
with a total bilirubin value 2 × ULN with no evidence of hemolysis and an alkaline 
phosphatase value 2× ULN or not available;
For subjects with preexisting ALT OR AST ORtotal bilirubin values above the 
ULN, the following threshold values should be used in the definition mentioned 
above:
For subjects with preexisting AST or ALT baseline values above the normal 
range:AST or ALT values 2times the baseline values and 3 ×ULN, or 
8×ULN (whichever is smaller).
Concurrent with
For subjects with preexisting values of total bilirubin above the normal range: 
Total bilirubin level increased from baseline by an amount of at least 1 × ULN or
if the value reaches 3 ×ULN (whichever is smaller).
The subject should return to the investigational site and be evaluated as soon as possible, 
preferably within 48hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment. 
In addition to repeating measurements of AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl 
transferase, prothrombin time (PT)/international normalized ratio (INR), and alkaline 
phosphatase.  A detailed history, including relevant information, such as review of ethanol, 
acetaminophen, recreational drug, and supplement consumption, family history, occupational 
exposure, sexual history, travel history,history of contact with a jaundiced person, surgery, 
blood transfusion, history of liver or allergic disease, and work exposure, should be collected.  
Further testing for acute hepatitis A, B, or C infection and liver imaging (eg, biliary tract) 
may be warranted.  All cases confirmed on repeat testing as meeting the laboratory criteria 
defined above, with no other cause for LFT abnormalities identified at the time, should be 
considered potential Hy’s law cases irrespective of availability of all the results of the 
investigations performed to determine etiology of the abnormal LFTs.  Such potential Hy’s 
law cases should be reported as SAEs.
8.7.Hospitalization
Hospitalization is defined as any initial admission (even less than 24hours) 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 
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wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be 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 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;
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE and the resulting 
appendectomy should be recorded as treatment of the AE.
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8.8.Severity Assessment
If required on the AE CRFs, 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.
8.9.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 in the CRF, as appropriate, 
and report such an assessment in accordance with the SAE reporting requirements if 
applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an 
AE; generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the sponsor (see the section on Reporting Requirements).  If the 
investigator
's causality assessment is "unknown but not related to investigational product," 
this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated withstudy procedures, 
the investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
8.10.Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product; 
An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).
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2. A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or isexposed 
during his partner’s pregnancy. 
If a study subject or study subject’s partner becomes or is found to be pregnant during the 
study subject’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer drug safety unit on an 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) using the EDP supplemental form.  This must be done irrespective of whether an 
AE has occurred and within 24hours of awareness of the exposure.  The information 
submitted should include the anticipated date of delivery (see below for information related 
to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer of the outcome as a follow-up 
to the initial EDP supplemental form.  In the case of a live birth, the structural integrity of the 
neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) for 
termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless preprocedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported as SAEs follows: 
Spontaneous abortion includes miscarriage and missed abortion;
Neonatal deaths that occur within 1month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product. 
Additional information regarding the EDP may be requested by the investigator.  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 study 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.
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8.11.Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whethera healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to the drug safety unit within 24hours of the 
investigator’s awareness, using the SAE report form, regardless of whether there is an 
associated AE/SAE.  Since the information does not pertain to a subject enrolled in the study, 
the information is not reported on a CRF; however, a copy of the completed SAE report form 
is maintained in the investigator site file.
8.12. Withdrawal Due to Adverse Events (See Also the Section on Subject Withdrawal )
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page. 
When a subject withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.13.Eliciting Adverse Event Information
The investigator is to reportall directly observed AEs and all AEs spontaneously reported by 
the study subject.  In addition, each study subject will be questioned about AEs.
8.14.Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
8.14.1.Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24hours of investigator awareness of the 
event. 
In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be made 
immediately, irrespective of the extent of available AE information.  This time frame also 
applies to additional new information (follow-up) on previously forwarded SAE reports as 
well as to the initial and follow-up reporting of EDP, exposure via breastfeeding, and 
occupational exposure cases. 
In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (eg, if an outpatient study subject initially seeks treatment elsewhere), the 
investigator is to report the event within 24hours after learning of it and document the time 
of his or her first awareness of the AE.
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For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the time frames for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes of the event, such as concomitant 
medications, vaccines, and/or 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 or its 
designated representative. 
8.14.2.Nonserious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE 
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.
8.14.3.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.
9.DATA ANALYSIS/STATISTICAL METHODS
This section outlines the key planned statistical summaries and analyses for the data collected 
in this study.  A comprehensive overall Statistical Analysis Plan (SAP) will be provided prior 
to the un-blinding of the trial.  The SAP may modify the plans outlined in the protocol; 
however, any major modifications of planned analyses will be reflected in a protocol 
amendment if it is modified before data un-blinding.  If, after the trial is un-blinded, changes 
are made to the SAP, then these deviations to the plan will be documented, along with an 
explanation as to why they occurred, in the Clinical Study Report (CSR).
9.1.Sample Size Determination
The sample size is based on the primary efficacy endpoint, IGA response rate of clear or 
almost clear and 2points improvement at Week12.  For IGA response rate at Week12, a
total of 250randomized subjects in the 5treatment groups (providing approximately 
200completers, 40completers per treatment group assuming 20% dropout rate) will provide 
approximately 95% power to detect a 33% difference between PF-04965842 and placebo 
assuming placebo response rate is approximately10%, and significance level is 0.0125 
(Bonferroni adjusted with 4comparisons). 
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9.2.Efficacy Analysis
9.2.1.Analysis of the Primary Endpoint 
When the 12week treatment period is completed, the analysis of the primary endpoint will 
be conducted.  The primary endpoint is the proportion of IGA responders at Week12 and the 
corresponding primary analysis will be based on the normal approximation for the difference 
in binomial proportions (such as IGA response rates) to test the superiority of each dose of 
PF-04965842 to placebo at Week 12.  Subjects who receive at least one investigational 
product and discontinue from the study before Week12will be considered as non-responders 
for the primary endpoint (IGA) for all subsequent visits during the treatment phase until 
Week 12.  Bayesian analysis using a non-informative prior (such as Jeffery's prior)may be 
employed if the normality assumption does not hold. 
Sensitivity analysis will be performed witha generalized linear mixed modelutilizing the 
data from all scheduled visits if there is no convergence issue.  This model will have fixed 
effects for time, treatment, time by treatment interaction and other potential covariates.  The 
dependent variable will be logit of the probability of “response”.  An unstructured correlation 
may be used to model the association between observations within a subject.  The modified 
intention-to-treat (mITT)population will be the subjects who receive at least one dose of 
randomized investigational product(PF-04965842orplacebo).  In addition, dose-response 
analysis using an Emax model may be provided for the primary endpoint. 
9.2.2.Analysis of the Secondary Endpoints
The key secondary endpoint is the percent change from baseline in EASI score atWeek 12.  
The treatment effect in each of the active treatment groups is the difference (mean percent 
change from baseline at Week12 in the active treatment group minus the mean percent 
change from baseline at Week12 in the placebo group) in the mean percent change from 
baseline of a EASI score at Week12. 
The estimates for treatment effect will be obtained by fitting the mixed-effect models 
repeated measures (MMRM) assumingmissing at random to the percent change of EASI 
score from baseline scoreif there is no convergence issue.  The model will include time , 
treatment (active doses and placebo), treatment by time interaction as fixed effects and 
baseline value as a covariate.  We will allow an unstructured variance-covariance matrix.  
Covariance matrices with other structure will be considered in sensitivity analysis.  Estimates 
and the appropriate confidence intervals will be presented. 
In addition to the primary analysis based on the pairwise evaluation of the treatment effects, 
we will explore the modeling of dose-response relationship for the key secondary endpoint.
MMRM will also be employed for other continuous endpoints such as percent change from 
baseline in the EASI total score at all scheduled time points, percent change from baseline in 
the pruritus NRS from baseline at all scheduled time points, change from baseline in affected 
BSA at all scheduled time points, and change from baseline in SCORAD at all scheduled 
time points.  Estimates of mean values and the mean differences from placebo at each week
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(along with 90% confidence intervals) will be reported.  Descriptive statistics of the actual
and change from baseline values will be calculated.
The binary secondary endpoints such as proportion of subjects achieving the IGA for clear 
(0) or almost clear (1) and 2 points improvement from baseline at all scheduled time points 
except Week 12, proportion of subjects with the IGA response of 2 points improvement 
from baseline at all scheduled time points, proportions of subjects achieving 50%, 75% and 
90% reduction in EASI total score from baseline at all scheduled time points , proportion of 
subjects with improvement (reduction) of the pruritus NRS 3 from baseline at all scheduled 
time points and Proportion of subjects achieving a 50% and 75% improvement in SCORAD 
(SCORAD50, SCORAD75) from baseline at all scheduled time points will be analyzed using 
the same method specified for the primary endpoint in Section 9.2.1.  We will calculate 
estimate and 90% confidence interval for the difference of proportions (each of the active 
doses against placebo) using normal approximation to the distribution of the observed 
difference in proportions.
9.2.3. Analysis of Other Endpoints
Other continuous endpoints such as change from baseline in   
 PtGA, DLQI, POEM, 
and HADS at all scheduled time points and change from baseline in the pruritus severity and 
frequency at all scheduled time points will be analyzed with the same method used for the 
continuous endpoints in Section 9.2.2.  For the binary endpoint such as proportion of subjects 
with PtGA of AD of clear (0) or almost clear (1) and 2 points improvement from baseline 
over 12 weeks, the same method used for the binary endpoint in Section 9.2.1will be 
employed.
Descriptive statistics will be generated for other endpoints such as incidence of 
treatment-emergent AEs (TEAE) and incidence of specific clinical laboratory abnormalities.
9.3. Safety Analysis
All subjects who receive investigational product (safety population) will be included in the 
safety analyses.  All the safety data will be summarized descriptively through appropriate 
data tabulations, descriptive statistics, categorical summaries, and graphical presentations.  
Safety endpoints for the study include:
On-treatment AEs and SAEs.
Withdrawals from active treatment due to AEs.
Serious infections, defined as any infection (viral, bacterial, and fungal) requiring 
hospitalization or parenteral antimicrobials. 
Safety laboratory tests (eg, anemia, neutropenia, thrombocytopenia, lymphopenia, 
lipid profile, LFTs).
Vital signs.
CCI
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ECG parameters if applicable.
Safety data will be reviewed and summarized on an ongoing basis during the study to
evaluate the safety of subjects.  A set of safety summary tables by treatment will be produced
to evaluate any potential risk associated with the safety and toleration of administering the
investigational product, continuous outcomes (eg, blood pressure, heart rate etc.) will be 
summarized using N, Mean, Median, Standard Deviation etc.  Categorical outcomes
(eg,occurrence of any adverse event) will be summarized by subject counts and percentage.  
Change from baseline on laboratory data and vital signs will be additionally summarized.  
Subject listings will also be produced for these safety endpoints.  The safety endpoints will
be listed and summarized in accordance with Pfizer Data Standards.  The safety analyses will
be carried out in the safety population, detailed analyses will be described in the SAP.
9.4.Interim Analysis 
An interim analysis may be performed when approximately 110randomized subjects 
complete 6weeks of study or discontinue prematurely from study in order to assess the 
percent change of EASI score from baseline as well as other efficacy and safety endpoints 
such as IGA response, itch response measured by NRS and hematological parameters as 
appropriate.  The actual interim analysis data cutoff date may vary slightly depending on the 
actual patient recruitment.  A non-binding futility analysis may be performed on the efficacy 
endpoints.  Modifications to the design such as adjustments to the final sample size or 
termination of enrollment of subjects in a treatment arm or stopping a treatment armmay be 
made upon review of the data.  Unless a safety concern arises, no decisions to stop the trial 
will be made based on this interim analysis.  Further information about the interim analysis 
will be specified in an Internal Review Committee (IRC) charter.
The study team and investigators will remain blinded to the results of the interim analysis.  It 
is expected that all interim analysis data from the treatment phase of the study will be as 
clean as possible and that all clinical relevant queries will have been addressed.  Access to 
the database containing individual treatment group assignments will be restricted to the 
unblinded support team including programmer, statistician, clinician and clinical 
pharmacologist.  Paper copies of the treatment assignments will not be kept and any copies 
printed for temporary checks of the data will be destroyed.
9.5.PK/PD Unblinding Plan
A PK/PD unblinding plan approved by the clinical lead, clinical pharmacology lead and 
statistical lead will be in place to describe the procedures to be employed in safeguarding the 
study blind for members of the PF-04965842 study team.  These procedures will be in 
accordance with applicable Pfizer SOPsfor releasing randomization codes and breaking the 
study blind.  Under this plan a group of statisticians, PK/PD data provider, PK/PD analyst 
and PK/PD support would be unblinded in order to initiate the building of statistical models 
of the PK, dose/response as well as exposure/response analysis models and conduct 
associated simulations.  The aim of this work would be to facilitate a comprehensive
interpretation of the study upon completion (at appropriate interim milestone).  This group 
will not serve on the study team during the period of early unblinding.  The unblinding may 
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occur after the last subject has been randomized.  The details of the procedures will be 
described in the PK/PD Unblinding Plan for Modelling and Simulation for study B7451006.  
In order to expedite the analyses of the exploratory biomarkers, an unblinded team may 
review the exploratory (ie, any data not explicitly stated as primary or secondary endpoint) 
and exposure data on an ongoing basis.  This group will minimally be comprised of 
bioanalyst and statistician, but may also include clinicians/precision medicine personnel, 
clinical pharmacologist and PK/PD analyst/support staff.  This group will be unblinded 
throughout the study in order to conduct the analyses of the exploratory biomarkers in 
accordance with an exploratory biomarker data analysis plan, and will be independent of the 
study team.  This unblinding process will not have any impact on the conduct of the study.  
The exploratory biomarker plan will be approved by the clinical lead, clinical pharmacology 
lead and statistical lead,and will be in place to describe the procedures to be employed in 
safeguarding the study blind for members of the study team.  These procedures will be in 
accordance with Pfizer SOPs related to Releasing Randomization Codes and Breaking the 
Blind.  The exploratory biomarker plan will outline the range of possible analyses and 
provide details of the decision-making process.
9.6.Analysis of Pharmacokinetics Endpoints
PK concentrations will be summarized and presented by treatment group with summary 
statistics and, where appropriate, non-compartmental PK parameters estimates will be 
provided.  A population PK model may be developed for the purpose of estimating PK 
parameters.  Population PK data for PF-04965842 will be summarized through appropriate 
data tabulations, descriptive statistics, and graphical presentation.  Data permitting, the 
relationship between exposure and clinical responses (efficacy and safety) and disease and 
mechanism related PD biomarkersduring treatment of subjects with moderate to severe AD
may be explored using eitherobserved or modeled exposures.  Any population analyses 
conducted will not be part of the clinical study report and may be reported separately.
9.7.Data Monitoring Committee 
This study will use an IRCtomonitor the safety of the subjects throughout the study and to
make recommendations to the study team.  Composition of the IRCand processes under 
which the IRC operates will be documented in an IRCcharter.
10.QUALITY CONTROL AND QUALITY ASSURANCE
Pfizeror its agent will conduct periodic monitoring visits during study conduct 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 study site may be subject to review 
by the institutional review board (IRB)/ethics committee (EC), and/or to quality
 assurance 
audits performed by Pfizer, or companies working with or on behalf of Pfizer, and/orto 
inspection by appropriate regulatory authorities.
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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 study site for the inspection and will allow Pfizer or its agent, 
whenever feasible, to be present during the inspection.  The investigator will promptly 
provide copies of the inspection findings to Pfizer or its agent.  Before response submission 
to the regulatory authorities, the investigator will provide Pfizer or its agents with an 
opportunity to review and comment on responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11.DATA HANDLING AND RECORD KEEPING
11.1.Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the hospital
's or the physician
's subject chart.  In 
these cases, data collected on the CRFs must match the data in those charts. 
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigativesite as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2.Record Retention
To enable evaluations and/or 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, and 
detailed records of treatment disposition, and adequate documentation of relevant 
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correspondence (eg,letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to the ICH guidelines, according to local 
regulations, or as specified in the clinical study agreement (CSA), whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or an independent third party arranged by Pfizer.  
Investigator records must be kept for a minimum of 15years 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.
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 legal and regulatory requirements, as well as 
the general principles set forth inthe International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki.  Note: The 
Declaration of Helsinki (World Medical Association 2013, as mandated by local law) will be 
followed except that the investigational product PF-04965842 will not be made available to 
subjects after they have finished the study.
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
12.3.Subject Information and Consent
All parties will ensure protection of subject personal data and will not include subject names 
or other identifiable data inany reports, publications, or other disclosures, except where 
required by law. 
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When study data arecompiled for transfer to Pfizer and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by a numerical code based on a 
numbering system provided by Pfizer in order to de-identify study subjects. The study site 
will maintain a confidential list of subjects who participated in the study,linking each 
subject’snumerical code to his or heractual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of subjects’personal data consistent 
with applicable privacy laws.
The informed consentdocuments 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 must be 
reviewed and approved by the sponsor, approved by the IRB/EC before use, and available for 
inspection. 
The investigator must ensure that each study subject is fully informed about the nature and
objectives of the study and possible risks associated with participation.  
The investigator, or a person designated by the investigator, will obtain written informed 
consent fromeach subject,before any study-specific activity is performed.  The investigator 
will retain the original of each subject
's signed consentdocument.
12.4.Subject Recruitment
Advertisements approved by ethics committees (or institutional review boards)and 
investigator databases may be used as recruitment procedures.  Use of ethics committee 
approved, generic, prescreening questionnaire to assess basic subject characteristics to 
determine general eligibility for this study is allowed.  This generic questionnairemay be 
used by sites as a phone script and/or to review internal databases to identify subjects.
Pfizer will have an opportunity to review and approve the content of any study recruitment 
materials directed to potential study subjects before such materials are used. 
12.5.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 
competent authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
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13.DEFINITION OF END OFTRIAL
13.1.End of Trial in a Member State 
End of trial in a Member State of the European Union is defined as the time at which it is 
deemed that a sufficient number of subjects have been recruited and completed the study as 
stated in the regulatory application (ie, clinical trial application [CTA]) and ethics application 
in the Member State.  Poor recruitment (recruiting less than the anticipated number in the 
CTA) by a Member State is not a reason for premature termination but is considered a 
normal conclusion to the study in that Member State.
13.2.End of Trial in All OtherParticipating Countries
End of trial in all otherparticipating countries is defined as last subject last visit (LSLV).
14.SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, orinvestigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of 
PF-04965842at any time.
If a study is prematurely terminated or discontinued, Pfizerwill promptly notify the 
investigator.  After notification, the investigator must contact all participating subjects and 
the hospital pharmacy (if applicable) within 7days.  As directed by Pfizer, all study materials 
must be collected and all CRFs completed to the greatest extent possible.
15.PUBLICATION OF STUDYRESULTS
15.1.Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial 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.govfor Pfizer-sponsored 
interventional studiesconducted 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 for studies in 
adult populations or within 6 months of the primary completion date for studies in pediatric 
populations.
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Primary completiondate 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 1year of the primary completion date for studies in adult populations or 
within 6months of the primary completion date for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has 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 
principal investigator of the results of the study based on information collected or generated 
by principal investigator, 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 30days before they are 
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 60days.
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 study sites, and that any subsequent publications by the 
principal investigator will reference that primary publication..  However, if a joint manuscript 
has not been submitted for publication within 12months 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 
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Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
ManuscriptsSubmitted 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 anyconflict 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. Auriemma, M., G. Vianale, P. Amerio and M. Reale (2013). "Cytokines and T cells in 
atopic dermatitis." Eur Cytokine Netw24(1): 37-44.
2.
Beck, L. A., D. Thaci, J. D. Hamilton, N. M. Graham, T. Bieber, R. Rocklin, J. E. Ming, 
H. Ren, R. Kao, E. Simpson, M. Ardeleanu, S. P. Weinstein, G. Pirozzi, E. Guttman-
Yassky, M. Suarez-Farinas, M. D. Hager, N. Stahl, G. D. Yancopoulos and A. R. Radin 
(2014). "Dupilumab treatment in adults with moderate-to-severe atopic dermatitis." N 
Engl J Med371(2): 130-139.
3.
Cornelissen, C., J. Luscher-Firzlaff, J. M. Baron and B. Luscher (2012). "Signaling by 
IL-31 and functional consequences." Eur J Cell Biol91(6-7): 552-566.
4.
Cosgrove, S. B., J. A. Wren, D. M. Cleaver, K. F. Walsh, S. I. Follis, V. I. King, J. K. 
Tena and M. R. Stegemann (2013). "A blinded, randomized, placebo-controlled trial of 
the efficacy and safety of the Janus kinase inhibitor oclacitinib (Apoquel(R)) in client-
owned dogs with atopic dermatitis." Vet Dermatol24(6): 587-597, e141-582.
5.
Deckers, I. A., S. McLean, S. Linssen, M. Mommers, C. P. van Schayck and A. Sheikh 
(2012). "Investigating international time trends in the incidence and prevalence of 
atopic eczema 1990-2010: a systematic review of epidemiological studies." PLoS One
7(7): e39803.
6.
Gittler, J. K., A. Shemer, M. Suarez-Farinas, J. Fuentes-Duculan, K.J. Gulewicz, C. Q. 
Wang, H. Mitsui, I. Cardinale, C. de Guzman Strong, J. G. Krueger and E. Guttman-
Yassky (2012). "Progressive activation of T(H)2/T(H)22 cytokines and selective 
epidermal proteins characterizes acute and chronic atopic dermatitis." J Allergy Clin 
Immunol130(6): 1344-1354.
7.
Homey, B., M. Steinhoff, T. Ruzicka and D. Y. Leung (2006). "Cytokines and 
chemokines orchestrate atopic skin inflammation." J Allergy Clin Immunol118(1): 
178-189.
8. Lee, C. H., H. Y. Chuang, C. H. Hong, S. K. Huang, Y. C. Chang, Y. C. Ko and H. S. 
Yu (2011). "Lifetime exposure to cigarette smoking and the development of adult-onset 
atopic dermatitis." Br J Dermatol164(3): 483-489.
9. Leung, D. Y. and T. Bieber (2003). "Atopic dermatitis." Lancet361(9352): 151-160.
10. Levy, L. L., J. Urban and B. A. King (2015). "Treatment of recalcitrant atopic 
dermatitis with the oral Janus kinase inhibitor tofacitinib citrate." J Am Acad Dermatol
73(3): 395-399.
11. Murray, P. J. (2007). "The JAK-STAT signaling pathway: input and output integration." 
J Immunol178(5): 2623-2629.
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Final Protocol, 22 December 2015
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12. O
'Sullivan, L. A., C. Liongue, R. S. Lewis, S. E. Stephenson and A. C. Ward (2007). 
"Cytokine receptor signaling through the Jak-Stat-Socs pathway in disease." Mol 
Immunol44(10): 2497-2506.
13. Ring, J., A. Alomar, T. Bieber, M. Deleuran, A. Fink-Wagner, C. Gelmetti, U. Gieler, J. 
Lipozencic, T. Luger, A. P. Oranje, T. Schafer, T. Schwennesen, S. Seidenari, D. 
Simon, S. Stander, G. Stingl, S. Szalai, J. C. Szepietowski, A. Taieb, T. Werfel, A. 
Wollenberg, U. Darsow, F. European Dermatology, D. European Academy of, 
Venereology, A. European Federation of, D. European Task Force on Atopic, D. 
European Society of Pediatric, A. Global and N. Asthma European (2012). "Guidelines 
for treatment of atopic eczema (atopic dermatitis) part I." J Eur Acad Dermatol 
Venereol26(8): 1045-1060.
14. Silverberg, J. I. and J. M. Hanifin (2013). "Adult eczema prevalence and associations 
with asthma and other health and demographic factors: a US population-based study." J 
Allergy Clin Immunol132(5): 1132-1138.
15. Slater, N. A. and D. S. Morrell (2015). "Systemic therapy of childhood atopic 
dermatitis." Clin Dermatol33(3): 289-299.
16. Tokura, Y. (2010). "Extrinsic and intrinsic types of atopic dermatitis." Journal of 
Dermatological Science58(1): 1-7.
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Appendix1.Abbreviations 
This is a list of abbreviations that may be used in the protocol. 
Abbreviation
Term
AD
atopic dermatitis
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATP
adenosine triphosphate
AUC
area under the concentration-time curve 
AUCinf
area under the plasma concentration-time curve from time zero to 
infinity
AUClast
area under the plasma concentration time curvefrom time zero 
extrapolated to the last quantifiable concentration
AUCtau
area under the plasma concentration-time curve from time zeroto 
24 hours
BA
bioavailability
BCG
bacille calmette guérin 
BP
blood pressure
BSA
body surface area
CDS
core data sheet
CL
clearance
Cmax
maximum plasma concentration
CMV
cytomegalovirus 
CRF
case report form
CSA
clinical study agreement
CsA
cyclosporine A 
CSF
cerebrospinal fluid
CT
computed tomography
CTA
clinical trial application
CTCAE
common terminology criteria for adverse events
DAI
dosage and administration instructions
DDI
drug-drug interaction
DLQI
dermatology life quality index 
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DU
dispensable unit
EASI
eczema area and severity index
EBV
epstein barr virus
EC
ethics committee
ECG
electrocardiogram
EDMC
external data monitoring committee 
EDP
exposure during pregnancy
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Abbreviation
Term
EDTA
edetic acid (ethylenediaminetetraacetic acid)
EFD
embryo-fetal development
ELISA
enzyme-linked immunosorbent assay 
EOT
end of treatment
EPO
erythropoietin
ET
early termination
EU
European Union
EudraCT
European Clinical Trials Database
FACS
fluorescence-activated cell sorting
FDA
Food and Drug Administration (United States)
FDAAA
Food and Drug Administration Amendments Act (United States)
FIH
first-in-human
FSH
follicle-stimulating hormone
GCP
good clinical practice
GM-CSF
granulocyte-macrophage colony-stimulating factor
HADS
hospital and anxiety depression scale 
HBcAb
hepatitis B core antibody 
HBsAb
hepatitis B surface antibody 
HBsAg
hepatitis B surface antigen  
HEENT
head, eyes, ears, nose and throat
HIV
human immunodeficiency virus
HRQL
health-related quality of life
hsCRP
high-sensitivity C-reactive protein
IB
investigator’s brochure
ICH
International Conference on Harmonisation
ID
identification
IFN
interferon alfa
IFN
interferon gamma
IGA
investigator’s global assessment
IgE
immunoglobulin E
IL
interleukin 
IND
investigational new drug application
INR
international normalized ratio
IOBU-SDMC
Internal Oncology Business Unit-Safety Data Monitoring 
Committee
IP-10
interferon gamma-induced protein 10
IRB
institutional review board
IRC
internal review committee
IRT
interactive response technology
IUD
intrauterine device
IVRS
interactive voice responsesystem
IWR
interactive web response
JAK
janus kinase
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Abbreviation  
Term
LFT
liver function test
LLN
lower limit of normal 
LPD
local product document
LSLV
last subject last visit 
MAD
multiple ascending dose
MDCK/MDR1  
Madin Darby canine kidney cell line/multidrug resistance 1 gene 
mITT
modified intention-to-treat
MMRM
mixed-effect models repeated measures
MRI
magnetic resonance imaging
MTX
methotrexate
N/A
not applicable
NADPH
nicotinamide adenine dinucleotide phosphate 
NK
non-killer cells
NOAEL
no observed adverse effect level
NRS
numerical rating scale
OBU
oncology business unit
PCD
primary completion date
PD
pharmacodynamic
PFS
pre-filled syringe
P-gp
P-glycoprotein 
PK
pharmacokinetic
POC
proof-of-concept
POEM
patient Oriented Eczema Measure
POM
proof of mechanism 
PPD
purified protein derivative 
PRO
patient reported outcomes
PT
prothrombin time
PtGA
patient global assessment
QD
once daily
QFT-G
QuantiFERON-TB Gold 
Rac
accumulation ratio 
RNA
ribonucleic acid
RRCK
ralph russ canine kidney cells
SAD
single ascending dose
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SCL
supply chain lead
SCORAD
SCORing atopic dermatitis 
SIB
suicidal ideation and behavior
SOC
system organ class
SOP
standard operating procedure
CCI
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Abbreviation
Term
SPC
summary of product characteristics
SRSD
single reference safety document
STATs
signal transducers and activators of transcription
t
½
half life
TB
tuberculosis 
TDAR
Tcell-dependent antibody response
TEAE
treatment-emergent adverse event
TH1
type 1 helper T cell 
TH2
type 2 helper T cell 
Tmax
the time after administration of a drug when the maximum plasma 
concentration is reached
TYK2
tyrosine kinase 2
ULN
upper limit of normal
US
United States
USPI
United States package insert
UVA
ultraviolet A light
UVB
ultraviolet Blight
UVR
ultraviolet radiation
VAS
visual analogue scale
VZV
varicella zoster virus
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Appendix2.Diagnostic Criteria for Atopic Dermatitis
Asubject is to have a clinical diagnosis of atopic dermatitis according to the criteria of 
Hanifin and Rajka.
Hanifin and Rajka’s Diagnostic Criteria for Atopic Dermatitis
Major Criteria (must have at least three)
Pruritus
Typical morphology and distribution:
Adults: flexural lichenification or linearity
Children and infants: involvement of facial and extensor surfaces
Chronic or relapsing dermatitis
Personal or family history of atopy
Minor Criteria (must have at least three)
Xerosis
Icthyosis/keratosis pilaris/palmer hyperlinearity
Immediate (type 1) skin test reactivity
Elevated serum IgE
Early age at onset
Tendency to skin infections (Staphylococcus aureus, herpes simplex)/impaired cellular 
immunity
Hand/foot dermatitis
Nipple eczema
Conjunctivitis
Dennie-Morgan fold
Keratoconus
Anterior subcapsular cataracts
Orbital darkening
Facial pallor/erythema
Pityriasis alba
Anterior neck folds
Itch when sweating
Intolerance to wool and lipid solvents
Perifollicular accentuation
Food intolerance
Course influenced by environmental/emotional factors
White demographic/delayed blanch
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Appendix3.Prohibited Concomitant Medications
CYP3A4, 5,7 Inhibitors 
CYP3A Inducers
HIV antivirals:
efavirenz (Sustiva)
-delavirdine (Rescriptor)
nevirapine (Viramune)
-indinavir (Crixivan)
barbiturates
-nelfinavir (Viracept)
carbamazepine (Carbatrol, Tegretol)
-ritonavir (Kaletra, Norvir)
modafinil (Provigil)
-saquinavir (Fortovase)
phenobarbital
amiodarone (Cordarone, Pacerone)
Phenytoin (Dilantin, Phenytek)
cimetidine (Tagamet)
rifampin (Rifadin, Rifamate, Rifater)
ciprofloxacin (Cipro)
St. John
's wort
clarithromycin (Biaxin, Prevpac)
troglitazone (Rezulin)
diethyl-dithiocarbamate
pioglitazone (Actos)
diltiazem (Cardizem, Tiazac)
rifabutin (Mycobutin)
erythromycin 
fluconazole (Diflucan)
fluvoxamine (Luvox)
gestodene (Femodene, Melodene, Minulette, 
Mirelle, Triodene ED)
grapefruit juice and marmalade
itraconazole (Sporanox)
ketoconazole (Nizoral)
mifepristone (Mifeprex, RU486)
nefazodone (Serzone)
norfloxacin (Shibroxin, Noroxin)
Norflouxetine
Mibefradil
verapamil (Calan SR,Covera HS, Isoptin SR, 
Tarka, Verelan)
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Appendix4.Fitzpatrick Skin Type
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Appendix5.Patient Global Assessment (PtGA) 
Clear 
Almost Clear
Mild
Moderate
Severe
Clear 
Almost Clear
Mild
Moderate
Severe
Overall, how would you describe your Atopic Dermatitisright now?
Choose only ONE response.
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Appendix6.PruritusSeverity and Frequency
Severity of Pruritus
Select he number that best describes your itching due to Atopic Dermatitis over the past 
24hours (check one number only).
Frequency of Pruritus
Select the number that best describes frequency of itching due to Atopic Dermatitis over the 
past 24hours (check one number only).
10
9
8
7
6
5
4
3
2
1
0
10
9
8
7
6
5
4
3
2
1
0
No 
itching
Worst 
possible 
itching
10
9
8
7
6
5
4
3
2
1
0
10
9
8
7
6
5
4
3
2
1
0
Never /No 
itching
Always/constant 
itching
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Appendix7.Dermatology Life Quality Index (DLQI)
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Appendix8.Patient-Oriented Eczema Measure (POEM)
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Appendix9.Hospital and Anxiety Depression Scale (HADS)
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Appendix11.Guidelines for Subject Safety Monitoring and Discontinuation
These guidelines for subject safety monitoring and discontinuation are to be applied to all 
subjects in study B7451006.  Additional individual subject monitoring is at the discretion of 
the investigator and dependent on any perceived safety concerns.  Unscheduled clinical labs 
may be obtained at any time during the study to assess such concerns, and a subject may be 
withdrawn at any time at the discretion of the investigator.
Appendix11.1.Monitoring
The following laboratory abnormalities require re-testing within1 week:
Absolute neutrophil count <2000/mm3;
Hemoglobin <11.0g/dL;
Platelet count below <100,000/mm3;
Serum creatinine >upper limit of normal (ULN).
Appendix11.2.Discontinuation
Treatment with PF-04965842 will be discontinued and the subject withdrawn from this 
studyfor:
Adverse Events:
Serious infections, defined as any infection (viral, bacterial, and fungal) requiring 
parenteral antimicrobial therapy or hospitalization;
Other serious or severe AEs, after consultation with the Pfizer clinician.
Laboratory Abnormalities:
All the following laboratory abnormalities require discontinuation if they are confirmed.  
Confirmation through re-testing should occur within 1week:
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Laboratory Variable
Laboratory Value
Hematology
Absolute Neutrophil Count <1000/mm3; <1.0 x10
9/L
Hemoglobin
<10.0 g/dL; <6.2 mmol/L; <100 g/L
Platelet count
<75,000/mm3; <75.0x10
9/L
Lymphocytes
<500/mm3; <0.8x10
9/L
Chemistry
AST
>2.5xULN
ALT
>2.5xULN
Creatinine (serum)
>1.5x ULN
Total bilirubina
>1.5x ULN
a
Total bilirubin 1.5xULN; subjects with a history of Gilbert
's syndrome may have a direct bilirubin 
measured and would be eligible for this study provided the direct bilirubin is ULN
The following vital sign abnormality will require discontinuationif it is confirmed.  
Confirmation through re-testing should occur within 1week:
Diastolic: recurrent or persistent (24hrs) or symptomatic increase from baseline, in 
same posture, by >20mmHg.
Discontinuation/End of Treatment Monitoring for Adverse Events, Laboratory, and 
Vital Signs:
Any subject meeting discontinuation criteria must enter into the Follow-up Period with their 
first follow-up visit occurring 1week after their last dose, until the event has returned to 
normal or baseline levels or is deemed clinically stable.  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.  Additional follow-up visits 
may occur as needed until any clinically relevant abnormalities or adverse events have 
resolved, returned to a baseline state, or are deemed clinically stable.
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SAP_000.pdf: 
 
PF-04965842  
B7451006 
Statistical Analysis Plan 
 
 
PROTOCOL
 B7451006 
 
 
A
 PHASE 2B RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PARALLEL, 
MULTICENTER, DOSE-RANGING STUDY TO 
EVALUATE THE EFFICACY AND SAFETY PROFILE 
OF PF-04965842 IN SUBJECTS WITH MODERATE TO 
SEVERE ATOPIC DERMATITIS 
 
STATISTICAL
 ANALYSIS PLAN 
(SAP) 
 
 
Version: 2.1 
Author: 
 (Global Product Development) 
Date:  
May 9, 2017 
 
 
Page 1 of 39 
PPD
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Protocol B7451006         Statistical Analysis Plan 
 
 
TABLE OF CONTENTS 
LIST OF TABLES 
.....................................................................................................................4
 
LIST OF FIGURES 
...................................................................................................................4
 
APPENDICES 
...........................................................................................................................4
 
1. AMENDMENTS FROM PREVIOUS VERSION(S) 
...........................................................5
 
2. INTRODUCTION 
.................................................................................................................7
 
2.1. Study Design 
.............................................................................................................7 
2.2. Study Objectives .......................................................................................................8 
2.2.1. Primary Objective 
.........................................................................................8
 
2.2.2. Secondary Objectives ...................................................................................8 
2.2.3. Exploratory Objectives 
.................................................................................8 
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING 
..................................8
 
4. HYPOTHESES AND DECISION RULES 
...........................................................................9
 
4.1. Statistical Hypotheses ...............................................................................................9 
4.2. Decision Rules 
...........................................................................................................9 
4.2.1. Dose Response Modeling 
.............................................................................9 
4.2.2. Multiplicity Adjustment................................................................................9
 
4.2.3. Decision Rules for the Interim Analysis 
.......................................................9 
4.2.4. Efficacy Analysis and Sample Size Justification 
........................................10 
5. ANALYSIS SETS ...............................................................................................................10
 
5.1. Full Analysis Set .....................................................................................................10 
5.2. Safety Analysis Set 
..................................................................................................10 
5.3. Pharmacokinetic Analysis Set 
.................................................................................10
 
5.4. Treatment Misallocations 
........................................................................................10 
5.5. Protocol Deviations 
.................................................................................................11 
5.5.1. Deviations Assessed Prior to Randomization 
.............................................11
 
5.5.2. Deviations Assessed Post-Randomization 
..................................................11 
6. ENDPOINTS AND COVARIATES 
...................................................................................11
 
6.1. Efficacy Endpoint(s), Health Outcome and Biomarkers 
.........................................11 
6.1.1. Primary Endpoint 
........................................................................................11 
6.1.2. Secondary Endpoints 
..................................................................................11 
6.1.2.1. Efficacy Endpoints 
....................................................................11 
Page 2 of 39 
 
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Protocol B7451006         Statistical Analysis Plan 
 
 
6.1.2.2. Key Secondary Efficacy Endpoints 
...........................................11 
6.1.2.3. Secondary Efficacy Endpoints 
..................................................12 
6.1.2.4. Safety Endpoints .......................................................................12 
6.1.2.5. Patient Reported Outcome (PRO) Endpoints 
............................12 
6.2. Exploratory Endpoints 
.............................................................................................13 
6.3. Covariates 
................................................................................................................13 
7. HANDLING OF MISSING VALUES 
................................................................................13
 
7.1. Efficacy Data 
...........................................................................................................13 
7.2. Pharmacokinetic Concentrations and Biomarker Data ...........................................13
 
7.3. Patient Reported Outcomes (PRO) Data 
.................................................................14 
7.4. Safety Endpoints .....................................................................................................14 
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES 
..........................14
 
8.1. Statistical Methods 
..................................................................................................14 
8.1.1. Statistical Methods for Binary Variables 
....................................................15 
8.1.1.1. Primary Analysis 
.......................................................................15 
8.1.1.2. Other Analysis of Binary Data 
..................................................16 
8.1.1.3. Safety Data 
................................................................................16 
8.1.2. Statistical Methods for Continuous Variables 
............................................16 
8.1.3. Statistical Methods for Time_to_Event Variables 
......................................17 
8.2. Statistical Analyses .................................................................................................17
 
8.2.1. Standard Analyses ......................................................................................17 
8.2.2. Statistical Analyses for Efficacy, Health Outcomes and Biomarkers ........18
 
8.2.2.1. Analysis for the Primary Endpoint 
............................................18 
8.2.2.2. Analyses for the Secondary Endpoints 
......................................18 
8.2.2.3. Analyses for the Exploratory Endpoints ...................................20 
8.2.2.4. Analyses for the Patient-Reported Outcome (PRO) 
Endpoints 
...........................................................................................20 
8.2.3. Statistical Analyses for Safety 
....................................................................21 
8.2.4. PK and PK/PD Analyses ............................................................................21 
8.2.5. Brief Summary of Major Efficacy, Health Outcome and Biomarker 
Analyses 
...........................................................................................................22
 
9. REFERENCES ....................................................................................................................23
 
10. APPENDICES 
...................................................................................................................23 
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Protocol B7451006         Statistical Analysis Plan 
 
 
 
LIST OF TABLES 
Table 1.
 Visit Window Definition for Analysis (update wider visit windows) 
..................23 
 
LIST OF FIGURES 
Figure 1.
 Study Design Schematic 
.........................................................................................8
 
 
APPENDICES 
Appendix 1. DEFINITION AND USE OF VISIT WINDOWS IN REPORTING 
.................23
 
Appendix 2. Investigator’s Global Assessment (IGA) 
............................................................24 
Appendix 3. Eczema Area and Severity Index (EASI) 
............................................................24
 
Appendix 4. Body Surface Area (BSA) 
...................................................................................26 
Appendix 5. Scoring Atopic Dermatitis (SCORAD) 
...............................................................26
 
Appendix 6. Pruritus Numeric Rating Scale (NRS) 
................................................................27
 
Appendix 7. Patient Global Assessment (PtGA) 
.....................................................................28
 
Appendix 8. Dermatology Life Quality Index (DLQI) 
............................................................28 
Appendix 9. Patient-Oriented Eczema Measure (POEM) 
.......................................................29
 
Appendix 10. Hospital and Anxiety Depression Scale (HADS) 
.............................................30
 
Appendix 11. Example SAS Code for Generalized Linear Mixed model for IGA 
.................32 
Appendix 12. Example SAS Code for Analyses OF Dose-Response Models ........................33 
Appendix 13. Estimate and Confidence Interval for Risk Difference (Proportion 
Difference) Using GLIMMIX Procedure with link=logit 
....................................35
 
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Protocol B7451006         Statistical Analysis Plan 
 
 
1. AMENDMENTS FROM PREVIOUS VERSION(S)  
Version Date 
Author(s
) 
Summary of Changes/Comments 
2.1  
May 09, 
2017 
 
 
 Section 5.1 excluded subjects from site 1015 (a total of 4 
subjects) from FAS  
2.0  
May 02, 
2017 
 
 
 Section 3 interim analysis re-written to clarify goals and 
time of IA 
 Section  7.1  re-written  to  clarify  the  missing  value 
imputation proposal on efficacy data 
 Section  8.1.1  removed  summary  statistics  for  NR  and 
LOCF imputation. Summary stats will only be generated 
for FAS with OC except a few key efficacy endpoints 
 Section  8.1.1.1  removed  sensitivity  analyses  using 
GLMM on FAS with NR and LOCF. Logistic regression 
with  NR  imputation  will  be  performed  regardless  of 
GLMM convergence  
 Section  8.1.1.3  changed  Santner  and  Snell  method  to 
Chan and Zhang method 
 Section  8.1.2  added  ANCOVA  analysis  for  percent 
change from baseline in EASI with LOCF imputation  
 Section 8.1.3 added statistical methods for time-to-event 
variables 
 Section  8.2.2.1  removed  sensitivity  analyses  using 
GLMM on FAS with NR and LOCF 
 Section 8.2.2.2.1 clarified that sensitivity analysis will be 
performed  using  ANCOVA  on  FAS  with  LOCF 
imputation 
 Section  8.2.2.2.2  changed  
logistic  regression  analysis  at 
each time point with LOCF imputation to NR imputation 
 Section 6.1.2.3 added four more secondary endpoints:1) 
in the pruritus numerical rating scale (NRS) from 
baseline at all scheduled time points 2) Percent change 
from baseline in SCORing atopic dermatitis (SCORAD) 
at all scheduled time points 3) Time to achieving  3 
points improvement in NRS 4) Time to achieving  4 
points improvement in NRS  
 Section 8.2.2.2.2 added survival analysis for time to NRS 
response 
 Section 8.2.2.2.2 added: 
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Protocol B7451006         Statistical Analysis Plan 
 
 
points improvement in the pruritus numerical rating scale 
(NRS)  from  baseline  at  all  scheduled  time  points”, 
non-responders.”  And  “For  endpoint  “Proportion  of 
numerical  rating  scale  (NRS)  from  baseline  at  all 
scheduled time points”, only subjects with baseline NRS  
 
 Section 8.2.2.4 sensitivity analysis was removed 
 Section  8.2.3  Santner  and  Snell  changed  to  Chan  and 
Zhang method 
 Section  8.2.5  summary  table  of  statistical  analysis 
updated   
1.0 
March 
09, 2016 
 
 
First version 
 
 
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2. INTRODUCTION 
Note: in this document any text taken directly from the protocol is italicised.  
This study B7451006 is a phase 2b POC study which is planned to assess four PF-04965842 
once daily (QD) doses (10, 30, 100, 200 mg) relative to placebo over 12 weeks to 
characterize the efficacy and safety of PF-04965842 in subjects with moderate to severe 
Atopic Dermatitis AD.  The objectives of the study are to demonstrate the efficacy of 
PF-04965842 by showing improvement in disease severity in patients with moderate to 
severe AD as measured by the Investigator’s Global Assessment (IGA) and Eczema Area and 
Severity Index (EASI) scores, and safety to support further clinical development of 
PF-04965842.  
Complete information for this compound may be found in the single reference safety 
document (SRSD), which for this study is the Investigator’s Brochure (IB). 
2.1. Study Design 
This Phase 2b, multi-center, randomized, double-blind, 5-arm, parallel group study will 
enroll a total of approximately 250 subjects (providing approximately 200 completers, 40 
subjects per treatment group). The study will be conducted at approximately 60 sites. 
Subjects who have chronic AD that has been present for at least 1 year (prior to screening 
visit) and affected BSA of > 10%, EASI > 12 and IGA > 3 at the screening and baseline 
visits will be included in the study. Subjects must also have a documented history of 
inadequate response to treatment with topical medications given for at least 4 weeks, or for 
whom topical treatments are otherwise medically inadvisable (eg, because of important side 
effects or safety risks) within 12 months of the first dose of study drug. Subjects will be 
randomized to 1 of 4 treatment groups or placebo in the ratio of 1:1:1:1:1. Investigators, 
subjects, and the sponsor study team will be blinded as to treatment group.   
Subjects will be screened within 35 days prior to the first dose of study drug to confirm that 
they meet the subject selection criteria for the study. There will be a 12-week double-blind 
treatment period as well as a 4-week follow up period.  
An interim analysis may be performed when approximately a total of 110 randomized 
subjects complete 6 weeks of study or discontinue prematurely from study in order to assess 
the percent change of EASI score from baseline as well as other safety and efficacy endpoints 
such as IGA response as appropriate. 
 
  
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Figure 1.  Study Design Schematic 
 
 
2.2. Study Objectives 
2.2.1. Primary Objective 
 The primary objective of this study is to evaluate the efficacy of 4 QD dose levels (10, 
30, 100, and 200 mg) of PF-04965842 relative to placebo in adult subjects with 
moderate to severe atopic dermatitis, using the Investigator's Global Assessment 
(IGA). 
2.2.2. Secondary Objectives 
 To evaluate the effect of PF-0465842 on additional efficacy endpoints and patient  
reported outcomes over time in adult subjects with moderate to severe atopic 
dermatitis. 
 To evaluate the safety and tolerability of PF-0465842 over time in adult subjects with 
moderate to severe atopic dermatitis. 
2.2.3. 
 
 
 
 
    
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING  
An interim analysis (IA) will be performed when approximately 50% subjects complete 6 
weeks of study or discontinue prematurely from study in order to assess the percent change 
of EASI score from baseline (primary endpoint for IA) as well as other efficacy and safety 
endpoints such as IGA response, itch response measured by Pruritus Numeric Rating Scale 
(NRS) and hematological parameters as appropriate. The study team and investigators will 
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Protocol B7451006         Statistical Analysis Plan 
 
 
remain blinded to the results of the interim analysis. It is expected that all interim analysis 
data from the treatment phase of the study will be as clean as possible and that all clinical 
relevant queries will have been addressed. Access to the database containing individual 
treatment group assignments will be restricted to the unblinded support team including 
programmer, statistician, clinician and clinical pharmacologist.  Paper copies of the 
treatment assignments will not be kept and any copies printed for temporary checks of the 
data will be destroyed. 
Interim analysis results will be used for internal business decision regarding future study 
planning. The results will have no impact on the ongoing study. Additional logistical details 
will also be provided in the Internal Review Committee (IRC) Charter.  
 
4. HYPOTHESES AND DECISION RULES 
4.1. Statistical Hypotheses 
Statistical inference will be made on the primary endpoint: Proportion of subjects achieving 
the IGA for clear (0) or almost clear (1) and ≥ 2 points improvement from baseline at Week 
12.  The null hypothesis is that there is no difference between any dose of 
PF-04965842 (200mg, 100mg, 30mg and 10mg) and placebo on the primary endpoint.  The 
alternative hypothesis is that at least one dose of PF-04965842 is superior to placebo on the 
primary endpoint.  
4.2. Decision Rules 
4.2.1. Dose Response Modeling 
A three-parameter Emax model will be employed for dose-response fitting for the primary 
endpoint (IGA response at Week 12). If a monotonic dose-response curve is detected, then 
model estimates and the corresponding treatment effect along with 95% confidence intervals 
will be reported.  
If the data do not support an Emax model, the decision rule may be based on pairwise 
comparison analysis. 
4.2.2. Multiplicity Adjustment 
The multiplicity adjustments are considered only in the analysis of the primary endpoint 
when the Emax model does not fit. Hochberg method (Hochberg, 1988) is used to account 
for that the null hypothesis will be rejected if a treatment effect is detected at Week 12.  The 
overall Type I family-wise error rate (FWER) is controlled at 0.05 (one-sided).  
4.2.3. Decision Rules for the Interim Analysis 
This study will not stop irrespective of whether statistical significance has been reached at 
the interim analysis for any efficacy endpoint. However the results from interim analysis may 
be used for internal planning purpose. 
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4.2.4. Efficacy Analysis and Sample Size Justification  
The sample size is based on the primary efficacy endpoint, IGA response rate of clear or 
almost clear and ≥2 points improvement at Week 12. For IGA response rate at Week 12, a 
total of 250 randomized subjects in the 5 treatment groups (providing approximately 200 
completers, 40 completers per treatment group assuming 20% dropout rate) will provide 
approximately 95% power to detect a 33% difference between PF-04965842 and placebo 
assuming placebo response rate is approximately 10%, and significance level is 0.0125 
(Bonferroni adjusted with 4 comparisons).   
5. ANALYSIS SETS 
5.1. Full Analysis Set 
As specified in the protocol, the analysis of the efficacy, health outcome and biomarker 
endpoints will be performed for the modified intent-to-treat (mITT) population, defined as all 
randomized subjects who receive at least 1 dose of investigational product.  This population 
is also called as the Full Analysis Set (FAS). All subjects from site 1015 (total = 4 subjects) 
will be excluded from FAS due to major protocol deviations. 
 
5.2. Safety Analysis Set 
The safety analysis set (SAS) will be all subjects who receive at least 1 dose of 
investigational product.  The safety analysis set will include the follow-up period.  The safety 
analysis set excluding follow-up period data may be conducted as a sensitivity analysis. 
The final safety database will include all reported safety data at the time of database release.  
5.3. Pharmacokinetic Analysis Set 
The pharmacokinetic analysis set (PKAS) will be the subset of subjects from the safety 
analysis set who provide at least one pharmacokinetic concentration. 
5.4. Treatment Misallocations  
If a subject was: 
• Randomized but not treated: the subject will appear on the subject evaluation table as 
randomized but not treated; this is the extent of how much the subject will be reported; 
• Treated but not randomized: the subject will be reported under the treatment they actually 
received for all safety analyses, but will not be included in the efficacy analyses; 
• Randomized but took incorrect treatment: If a subject received the incorrect treatment for 
the whole duration of the study, then the subject will be reported under their randomized 
treatment group for all efficacy analysis, but will be summarized under the treatment they 
actually received for all safety analyses; if a subject received the incorrect treatment at 
only some dosing occasions then the subject will be reported under their randomized 
treatment group for both efficacy and safety analyses.  If sufficient doses were incorrect 
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and therefore deemed a major protocol deviation, the subjects may be excluded as 
sensitivity analysis.  
5.5. Protocol Deviations 
The following sections describe any protocol deviations that relate to the statistical analyses.  
It is possible that unexpected deviations will arise, becoming known only after the study has 
been active for a long period of time; hence more deviations may be added.  A full list of 
protocol deviations for the study report will be compiled prior to database closure.  
5.5.1. Deviations Assessed Prior to Randomization 
At screening phase prior to randomization, the investigator will assess and document subjects 
against the inclusion and exclusion criteria as set out in sections 4.1 and 4.2 of the protocol. 
5.5.2. Deviations Assessed Post-Randomization 
Post-randomization deviations include: 
• Subjects who receive excluded concomitant medications or rescue medications during the 
treatment period as described in Section 5.8  of the Protocol; 
• Subjects who were randomized but took incorrect treatment; 
• Subjects not satisfying the eligibility criteria, although, not identified until after 
randomization occurred. 
Any significant deviation or violations from the protocol will be reviewed by the clinical 
team during the course of the study and prior to database closure and a decision taken 
regarding evaluation for each analysis set. 
6. ENDPOINTS AND COVARIATES 
For all clinically planned measures, visits should occur within a window of the scheduled 
visit, which can be found in Appendix 1.  
6.1. Efficacy Endpoint(s), Health Outcome and Biomarkers 
6.1.1. Primary Endpoint  
• Proportion of subjects achieving the IGA for clear (0) or almost clear (1) and   2 
points improvement from baseline at Week 12. The baseline will be defined as the 
IGA score on Day 1 pre-dose. 
6.1.2. Secondary Endpoints 
6.1.2.1. Efficacy Endpoints 
6.1.2.2. Key Secondary Efficacy Endpoints 
• Percent change from baseline in the eczema area and severity index (EASI) Total 
score at Week 12. 
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6.1.2.3. Secondary Efficacy Endpoints 
• Proportion of subjects achieving the IGA for clear (0) or almost clear (1) and ≥ 2 
points improvement from baseline at all scheduled time points except Week 12. 
• Percent change from baseline in the EASI total score at all scheduled time points 
except Week 12. 
• Proportion of subjects achieving ≥ 3 points improvement in the pruritus numerical 
rating scale (NRS) from baseline at all scheduled time points. 
• Proportion of subjects achieving ≥ 4 points improvement in the pruritus numerical 
rating scale (NRS) from baseline at all scheduled time points 
• Time to achieving ≥ 3 points improvement in NRS  
• Time to achieving ≥ 4 points improvement in NRS 
• Percent change from baseline in the pruritus NRS from baseline at all scheduled time 
points. 
• Proportion of subjects achieving ≥ 2 points improvement in the IGA from baseline at 
all scheduled time points.  
• Proportion of subjects achieving a ≥ 50%, 75% and 90% improvement in the EASI 
Total score (EASI50, EASI75, EASI90) at all scheduled time points.  
• Change from baseline in affected body surface area (BSA) at all scheduled time 
points.  
• Change from baseline in SCORing atopic dermatitis (SCORAD) at all scheduled time 
points.  
• Percent change from baseline in SCORing atopic dermatitis (SCORAD) at all 
scheduled time points. 
• Proportion of subjects achieving a ≥ 50% and 75% improvement in SCORAD 
(SCORAD50, SCORAD75) from baseline at all scheduled time points. 
6.1.2.4. Safety Endpoints 
• Incidence of treatment emergent adverse events. 
• Incidence of specific clinical laboratory abnormalities (anemia, neutropenia, 
thrombocytopenia, lymphopenia, lipid profile, liver function tests [LFTs]). 
6.1.2.5. Patient Reported Outcome (PRO) Endpoints 
• Change from baseline in Pruritus NRS score at all scheduled time points. 
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 Proportion of subjects with patient global assessment (PtGA) of AD of clear (0) or 
points.  
 Change from baseline in dermatology life quality index (DLQI) total score at all 
scheduled time points.  
 Change from baseline in patient Oriented Eczema Measure (POEM) at all scheduled 
time points.  
 Change from baseline in the hospital and anxiety depression scale (HADS)  at all 
scheduled time points.   
6.2. 
 
 
 
 
 
 
  
 
 
 
6.3. Covariates  
For variables expressed as change from baseline, the baseline value will also be included in 
the analysis model as a covariate.  
7. HANDLING OF MISSING VALUES 
In general missing values will not be imputed for descriptive statistics. 
7.1. Efficacy Data 
For the binary efficacy data such as IGA response, subjects who receive at least one 
investigational product and discontinue from the study before Week 12 will be considered as 
non-responders (NR) for all subsequent visits during the treatment phase until Week 12. 
For the continuous efficacy endpoints such as percent change from baseline in EASI score at 
Week 12, the observed case (OC) approach and the last efficacy observation carrying 
forward (LOCF) missing value imputation will both be considered. The efficacy endpoints 
will be set to missing after rescue treatment is used. The LOCF method will then be used to 
impute missing values. 
7.2. Pharmacokinetic Concentrations and Biomarker Data  
 Concentrations outside the limit of quantification 
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In summary statistics for pharmacokinetic and biomarker data, assayed values below 
the lower limit of quantification (LLOQ) will be set to zero.  Other imputations (eg, ½ 
LLOQ) may also be considered in other analyses (eg, Pop-PK and PK/PD analyses), 
if deemed appropriate.  In listings values below LLOQ will be reported as “<LLOQ” 
where LLOQ will be replaced with the numerical value for the lower limit of 
quantification.  The LLOQ for various PK and biomarker concentrations will be 
noted in all tables and listings.  
• Missing concentrations 
If a concentration value is not collected or cannot be analyzed due to bad samples, it 
will be considered as missing data and will not be imputed.  
• Missing actual sampling time  
If actual sampling time (date or hour) value is missing, the protocol-stated nominal 
time will be used. 
7.3. Patient Reported Outcomes (PRO) Data  
Some of the analyses of PRO endpoints will be based on the OC data.  If missing values 
happen at the item level within a PRO, the developer’s guideline on missing value imputation 
will be considered. 
7.4. Safety Endpoints 
Missing data for safety endpoints will not be imputed and will be left as missing. The follow-
up period will be included for the safety endpoint. A sensitivity analysis maybe carried out 
excluding the follow-up period.  
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES 
All efficacy analyses described in this section will only apply to the data in the treatment 
period to the end of week 16 (Week 0 to 16).   
Percentages will be presented to one decimal place in all summaries.  Minimum and 
maximum values will be presented to the same number of decimal places as collected on the 
CRF or within the laboratory screening panel; mean and median will be presented to one 
further decimal place; standard deviation will be presented to two further places. 
Whilst every effort has been made to pre-specify all analyses in this statistical analysis plan, 
should any additional exploratory analyses be found to be required after unblinding, the 
analyses and the reasons for them will be fully detailed in the clinical study report. 
In all data presentations, results will be sorted by increasing dose level, starting with Placebo. 
8.1. Statistical Methods 
The following sub-sections contain the descriptions of the methods that will be used in the 
analysis of the various endpoints in this study.  The choice of analysis method will be 
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dependent on the endpoint of interest (eg whether the endpoint is a primary, key secondary or 
exploratory endpoint or whether the endpoint is efficacy or safety).  The analysis methods to 
be used for each endpoint will be covered in Section 8.2.5. 
8.1.1. Statistical Methods for Binary Variables 
For all binary endpoints, a summary of the number of responders based on FAS with OC in 
each treatment arm at each time point will be produced and the response rate will also be 
plotted against time, by treatment group. In addition, similar tables and figures will be 
generated based on FAS with NR imputation for IGA response, EASI50/75/90 and NRS 
response.  
8.1.1.1. Primary Analysis 
The primary analysis is the analysis of the primary endpoint, IGA clear (0) or almost clear 
(1) and ≥ 2 points improvements at Week 12, based on the FAS population. NR approach 
will be used to handle missing values as described in Section 7.1.  
IGA response at Week 12 will be analyzed using the Emax dose-response model. The 
estimation of E0, Emax and ED50 will be reported in mean, standard deviation and 95% CI. 
These can be implemented by using PROC NLMIXED in SAS. 
The three parameter Emax model is a non-linear equation such that the expected response E 
with or without baseline disease severity in the model can be written as:  
Dose
ED
Dose
E
E
E
+
+
=
50
max
0
 
Where: 
E is the logit function for the log odds of response Logit(p). 
E0 is in placebo IGA response. 
Emax is the difference between maximum achievable response (at infinite dose) and baseline. 
ED50 is the dose that produces half maximal effect (E
0 + Emax/2).  
The 3-parameter Emax model describes a dose response that starts at E0 and smoothly 
increases to an asymptote. The fitted curve will be graphically displayed with 95% 
confidence band.    Model based estimation of treatment effect for each dose compared to 
placebo will be presented with 95% confidence interval. 
Sensitivity analyses for IGA will be performed with generalized linear mixed models 
(GLMM) on FAS population with OC. Fixed factors include treatment, covariates (baseline 
disease severity such as EASI score), visit and treatment by visit interaction. Random effect 
includes random intercept for each subject. These can be implemented with SAS PROC 
GLIMMIX. P-values and inference for odds ratios between treatments will be provided based 
on the link function of logit. A delta method will be used to obtain 90% confidence intervals 
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for the risk differences. The overall p-value for treatment effect at each time point may be 
also presented. In addition, logistic regression analysis including treatment, covariates 
(baseline disease severity) at each time point will be performed on FAS with NR missing 
value imputation. 
When an Emax model does not adequately capture the dose-response relationship or the 
Emax model does not converge, analysis from GLMM on FAS with OC and/or logistic 
regression on FAS with NR imputation may be considered for decision making to 
characterize the dose-response with dose being considered as a continuous variable. 
8.1.1.2. Other Analysis of Binary Data 
The analyses for other binary endpoints will be performed using GLMM on the FAS 
population with OC as described in Section 8.1.1.1. Logistic regression analysis may be 
performed on FAS with NR imputation in case of convergence issues from GLMM.  
8.1.1.3.  Safety Data 
An unconditional exact method for risk difference proposed by Chan and Zhang (1999)  will 
be used to compare each active dose to placebo.  P-values and 90% confidence intervals will 
be formed for tier 1 events and 90% confidence intervals will be formed for tier 2 events.   
The exposure adjusted summaries for the Tier 1 and Tier 2 events will also be conducted. See 
Section 8.2.1 for the calculation of exposure.  
8.1.2. Statistical Methods for Continuous Variables 
Unless stated otherwise, descriptive summary statistics for continuous variables will be 
presented on FAS with OC by treatment group and will include the following:  n, mean, 
median, standard deviation, minimum and maximum. In addition, similar tables will be 
generated on FAS with LOCF imputation for EASI, NRS,  SCORAD scores and BSA.For 
longitudinal continuous variables, such as the percent changes from baseline of EASI score, 
percent changes from baseline of pruritus NRS score etc., the primary analysis will be 
conducted using a mixed model repeated measures (MMRM) analysis on FAS with OC.  
Each analysis will be performed with a restricted maximum likelihood (REML) MMRM 
analysis. The model will include treatment and visit as fixed factors, along with the 
interaction of treatment and visit. Baseline measurement such as baseline disease severity 
will be used as a covariate. An unstructured covariance structure will be used to model the 
within-subject variability. In the event there are difficulties with initially fitting an 
unstructured covariance matrix, a variety of methods will be used to facilitate the 
computations. The Kenward-Roger approximation will be used to estimate the denominator 
degrees of freedom. The model will be fit using SAS PROC MIXED. Least squares (LS) 
means of the treatment groups at each available visit along with 90% CIs will be presented. 
LS mean difference between treatment and placebo for each visit will be presented along 
with 90% confidence intervals. Least squares means and confidence intervals will be back 
transformed to an appropriate scale when necessary. In addition, ANCOVA including 
treatment and baseline disease severity on FAS with LOCF imputation will be performed.  
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For the key secondary endpoint (percent change of EASI score from baseline to Week 12), a 
dose-response relationship will be characterized by a three-parameter Emax model described 
in Section 8.1.1.1, in which case E denotes the percent change of EASI at Week12 and E0 
denotes the percent change of EASI at Week12 in placebo group.  
8.1.3. Statistical Methods for Time_to_Event Variables 
For time to event variables such as time to achieve NRS response, Kaplan-Meier analyses 
will be used to account for any right censoring, i.e., event not observed. Kaplan-Meier 
survival estimates and the number and percentage of subjects experiencing the relevant event 
or being censored will be summarized and plotted by treatment group. 90% CIs will be 
generated for the estimate of time to NRS response. 
8.2. Statistical Analyses 
8.2.1. Standard Analyses 
Study conduct and subject disposition 
The number of subjects randomized, treated, completing and discontinuing from the study, as 
well as the number of subjects in each analysis population will be summarized by treatment 
group.  For subjects who did not complete the study, the reasons for withdrawal from the 
study will be presented. 
Demography and baseline characteristics 
Demographic and baseline characteristics will be summarized by randomized treatment 
group for all randomized and treated subjects.  Continuous variables will be summarized 
using mean and standard deviation. Categorical variables will be summarized using relative 
frequency.  Key demographic and baseline variables to be summarized include: geographic 
region, age, gender, race, ethnicity, height, weight, body mass index, disease duration, 
baseline EASI score, baseline IGA, baseline NRS score etc. 
Exposure and compliance 
Exposure to the study therapy is defined as the number of days the subject is known to be on 
study drug.  The exposure is roughly calculated as the date of the last visit (including the 
follow up visits) of the subject in this study minus the date of the first administration of the 
study therapy plus one.  Summary statistics will be provided for exposure by treatment 
group.   
For each subject, percent will then be calculated using the following formula:  
Percent Compliance = # doses actually administrated / # doses planned * 100%. 
The number of doses planned or actually administrated is counted up to the conclusion date 
of the treatment period.  Summary statistics will be provided to percent compliance by 
treatment group.  
Descriptive Statistics 
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Descriptive statistics for all primary, secondary and exploratory endpoints presented in 
Section 6 will be tabulated.   
8.2.2. Statistical Analyses for Efficacy, Health Outcomes and Biomarkers 
Unless stated otherwise, the analyses for efficacy, health outcomes and biomarkers will be 
based on the FAS population, as defined in Section 5.1.  A summary table of the analysis 
strategy for all the efficacy and health outcome is shown in Section 8.2.5. 
8.2.2.1. Analysis for the Primary Endpoint 
The primary efficacy endpoint is the IGA response at Week 12. The primary analysis data 
will be based on FAS population with NR as missing value imputation method. Baseline is 
defined as the score for each assessment prior to the first dosing. .  
The objective for the analysis of primary endpoint is to characterize the dose response in 
inducing clinical IGA reduction in subjects with moderate to severe atopic dermatitis. To 
achieve this objective, a three parameter Emax dose response model specified in Section 
8.1.1.1 will be used as the primary analysis approach to characterize the dose response 
relationship.  
As sensitivity analyses, GLMM will be employed on IGA response from all visits including 
follow-up. These analyses will be carried out on the FAS population with OC as described in 
Section 8.1.1.1. P-values and 90% confidence intervals for odds ratios between treatments 
and placebo will be computed at each visit. Logistic regression will be performed at each 
visit on FAS with NR as additional sensitivity analysis.  
8.2.2.2. Analyses for the Secondary Endpoints 
8.2.2.2.1. Analysis of continuous secondary endpoints 
All primary analyses for the continuous secondary endpoints are based on the FAS 
population with OC. Baseline is defined as the score for each assessment prior to the first 
dosing.  These endpoints include: 
• Percent change from baseline in the EASI total score at all scheduled time points 
• Percent change from baseline in the pruritus NRS at all scheduled time points 
• Change from baseline in affected body surface area (BSA) at all scheduled time 
points 
• Change from baseline in SCORing atopic dermatitis (SCORAD) at all scheduled time 
points 
• Percent change from baseline in SCORing atopic dermatitis (SCORAD) at all 
scheduled time points 
All continuous secondary endpoints including all time points will be analyzed using MMRM 
as described in Section 8.1.2. LS means at each time point will be computed. P values and 
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90% confidence intervals will also be computed for placebo adjusted effect (LS mean 
difference between treatment and placebo) at each time point. Sensitivity analysis will be 
performed using ANCOVA on FAS with LOCF imputation as described in Section 8.1.2.  
Dose response analysis on the percent change from baseline in the EASI total score at Week 
12 will be performed using a 3-parameter Emax model as described in Section 8.1.2.  
8.2.2.2.2. Analysis of binary secondary endpoints 
Unless otherwise stated, all primary analyses for the binary secondary endpoints are based on 
the FAS population with OC missing value imputation. Baseline is defined as the score for 
each assessment prior to the first dosing.  These endpoints include: 
Binary secondary endpoints include: 
• Proportion of subjects achieving the IGA for clear (0) or almost clear (1) and ≥2 
points improvement from baseline at all scheduled time points except Week 12 
• Proportion of subjects achieving ≥3 points improvement in the pruritus numerical 
rating scale (NRS) from baseline at all scheduled time points 
• Proportion of subjects achieving ≥ 4 points improvement in the pruritus numerical 
rating scale (NRS) from baseline at all scheduled time points 
• Proportion of subjects achieving ≥2 points improvement in the IGA from baseline at 
all scheduled time points 
• Proportion of subjects achieving a ≥50%, 75% and 90% improvement in the EASI 
total score (EASI50, EASI75, EASI90) at all scheduled time points 
• Proportion of subjects achieving a ≥50% and 75% improvement in SCORAD 
(SCORAD50, SCORAD75) from baseline at all scheduled time points 
All binary secondary endpoints at each visit (except Week 12 for IGA response) will be 
analyzed in the same fashion as the primary endpoint using GLMM. In the case of 
convergence issues, logistic regression analysis at each time point with NR imputation will 
be performed. 
For endpoint “Proportion of subjects achieving ≥ 3 points improvement in the pruritus 
numerical rating scale (NRS) from baseline at all scheduled time points”, subjects with 
baseline NRS ≤ 2 will be considered as non-responders. 
For endpoint “Proportion of subjects achieving ≥ 4 points improvement in the pruritus 
numerical rating scale (NRS) from baseline at all scheduled time points”, only subjects with 
baseline NRS  ≥  4 will be analyzed. 
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Change from baseline in pruritus NRS score at all scheduled time points 
Proportion of subjects with patient global assessment (PtGA) of AD of clear (0) or 
almost clear (1) and 2 points improvement from baseline at all scheduled time 
points 
Change from baseline in dermatology life quality index (DLQI) total score at all 
scheduled time points 
Change from baseline in patient Oriented Eczema Measure (POEM) at all scheduled 
time points 
Change from baseline in the hospital and anxiety depression scale (HADS) at all 
scheduled time points 
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Protocol B7451006         Statistical Analysis Plan 
 
 
The overall  
 score will be calculated as the mean of the 11 items representing 
 scale as shown in Appendix 14.  
 
8.2.3. Statistical Analyses for Safety  
The analysis population for safety is described in Section 5.2.  Safety and tolerability will be 
assessed by clinical review of all relevant parameters including adverse experiences (AEs) 
and laboratory tests.  A complete list of laboratory parameters can be obtained in Section 7.3 
of the protocol.  
All the tables, listings and graphs for adverse events, lab parameters and vital sign will 
follow Pfizer standards.  
A 3-tier approach will be used to summarize AEs. Under this approach, AEs are classified 
into 1 of 3 tiers.  
Tier-1 events: These are pre-specified events of clinical importance and are maintained in a 
list in the product’s Safety Review Plan. 
Tier-2 events: These are events that are not tier-1 but are “common”. A MedDRA Preferred 
Term (PT) is defined as a tier-2 event if there are at least 4 in any treatment group.  
Tier-3 events: These are events that are neither tier-1 nor tier-2 events. 
There will be no adjustment for multiple comparisons or stratification factors in the analyses 
unless specified.  For tier-1 and tier-2 events, the proportion of AEs observed in each 
treatment groups will be presented along with the point estimates and associated 90% 
confidence intervals of the risk difference for each active treatment compared with placebo. 
The exact methods (Chan and Zhang, 1999) and asymptotic approach will be employed for 
analysis of tier-1 and tier-2 events .  For tier-1 events p-values may be included in the 
presentations.  AEs will be arranged in the output sorted in descending point estimate of the 
risk difference within system organ class.  Footnotes in the outputs will include the methods 
used to derive any p-values and confidence intervals as per Pfizer standards. The exposure 
adjusted summaries for the Tier 1 and Tier 2 events will also be conducted. 
8.2.4. PK and PK/PD Analyses 
PK concentrations will be summarized and presented by treatment group with summary 
statistics and, where appropriate, non-compartmental PK parameters estimates will be 
provided. A population PK model may be developed for the purpose of estimating PK 
parameters. Population PK data for PF-04965842 will be summarized through appropriate 
data tabulations, descriptive statistics, and graphical presentation. Data permitting, the 
relationship between exposure and clinical responses (efficacy and safety) and disease and 
mechanism related PD biomarkers during treatment of subjects with moderate to severe AD 
may be explored using either observed or modeled exposures. Any population analyses 
conducted will not be part of the clinical study report and may be reported separately. 
Page 21 of 39 
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Protocol B7451006         Statistical Analysis Plan 
 
 
The PK/PD analysis plan will be detailed in another document. 
 
8.2.5. Brief Summary of Major Efficacy, Health Outcome and Biomarker Analyses  
Endpoints 
Primary, 
Secondary, or 
Exploratory 
Endpoint 
Analysis 
Including 
Follow-UP 
Missing 
Data 
Imputatio
n 
Primary or 
Sensitivity 
Approach 
IGA Response 
Primary/Secondary Emax 
Yes 
NR 
Primary 
IGA Response 
Primary/Secondary GLMM 
Yes 
OC 
Sensitivity 
IGA Response 
Primary/Secondary Logistic 
regression 
Yes 
NR 
Sensitivity 
Percent change of  
EASI  
Secondary 
MMRM 
Yes 
OC 
Primary 
Change of  EASI  
Secondary 
MMRM 
Yes 
OC 
Sensitivity 
Percent change  of 
NRS  
Secondary 
MMRM 
Yes 
OC 
Primary 
Change of BSA 
Secondary 
MMRM 
Yes 
OC 
Primary 
Change of SCORAD  Secondary 
MMRM 
Yes 
OC 
Primary 
Percent change of 
SCORAD 
Secondary 
MMRM 
Yes 
OC 
Primary 
Proportion of 
subjects achieving  ≥ 
3 NRS improvement 
Secondary 
GLMM 
Yes 
OC 
Primary 
Proportion of 
subjects achieving  ≥ 
4 NRS improvement 
New endpoint 
GLMM 
Yes 
OC 
Primary 
Proportion of 
subjects achieving  ≥ 
2 IGA improvement 
Secondary 
GLMM 
Yes 
OC 
Primary 
EASI50/EASI75/EA
SI90 
Secondary 
GLMM 
Yes 
OC 
Primary 
SCORAD50/SCOR
AD75 
Secondary 
GLMM 
Yes 
OC 
Primary 
Change of NRS 
PRO 
MMRM 
Yes 
OC 
Primary 
Change of DLQI 
PRO 
MMRM 
Yes 
OC 
Primary 
Change of POEM 
PRO 
MMRM 
Yes 
OC 
Primary 
Change of HADS 
PRO 
MMRM 
Yes 
OC 
Primary 
 
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Protocol B7451006        Statistical Analysis Plan 
 
 
 
9. REFERENCES  
1. Pfizer Clinical Protocol B7451006: A Phase 2B Randomized, Double-blind, Placebo-
controlled, Parallel, Multicenter, Dose-ranging Study to Evaluate the Efficacy and 
Safety Profile of PF-04965842 in Subjects with Moderate to Severe Atopic Dermatitis. 
2. Hochberg, Y, A sharpened Bonferroni procedure for multiple tests of significance, 
Biometrica, 1988, 75, 4: 800-802. 
3. Chan, I. S. F. and Zhang, Z. (1999), "Test-Based Exact Confidence Intervals for the 
Difference of Two Binomial Proportions," Biometrics, 55, 1202–1209. 
10. APPENDICES 
Appendix 1. DEFINITION AND USE OF VISIT WINDOWS IN REPORTING  
Note Day 1 in the table below is taken as the first day of dosing with study drug.  It may not 
be the same as the first study date which is the randomization date.  Also note that Day 0 
does not exist, so Day -1 is the day before Day 1.  Also the relative days (rel_day) from Day 
1 are defined as the visit date minus first dosing date plus one.  
Visit windows will be used for efficacy variables, and for any safety displays that display by 
week. 
Table 1. Visit Window Definition for Analysis (update wider visit windows) 
Visit 
No. 
Visit Label  
Target Day  Visit Window  
1 
Screening  
N/A 
-35≤rel_day≤-1 
2 
Baseline* 
1  
Rel_day= 1 
3 
Week 1 
8 
2≤rel_day≤11 
4 
Week 2 
15  
12≤rel_day≤22 
5 
Week 4 
29  
23≤rel_day≤36 
6 
Week 6 
43 
37≤rel_day≤50 
7 
Week 8 
57 
51≤rel_day≤71 
8 
Week 12 
85 
72≤rel_day≤88 
9 
Week 13 
92 
89≤rel_day≤95 
10 
Week 14 
99 
96≤rel_day≤106 
11 
Week 16 
113 
107≤rel_day≤120 
* Baseline analysis visit window may be considered as Rel_day≤1 in some 
analyses (eg, those involving change from baseline).  That is, in case that Day 1 
observation is missing, the last observation by the first dosing date may be 
considered as the baseline.   
 
 
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Protocol B7451006        Statistical Analysis Plan 
 
 
 
Appendix 2. Investigator’s Global Assessment (IGA)  
A subject is said to have achieved the IGA response when all the following are true: 
• IGA score is 0 (clear) or 1 (almost clear) 
• IGA score improvement ≥ 2 
Appendix 3. Eczema Area and Severity Index (EASI) 
The EASI quantifies the severity of a subject’s atopic dermatitis based on both severity of 
lesion clinical signs and the percent of BSA affected. EASI is a composite scoring by the 
atopic dermatitis clinical evaluator of the degree of erythema, induration/papulation, 
excoriation, and lichenification (each scored separately) for each of four body regions, with 
adjustment for the percent of BSA involved for each body region and for the proportion of the 
body region to the whole body. Lesion Severity by Clinical Signs: The basic characteristics 
of atopic dermatitis lesions - erythema, induration/papulation, excoriation, and 
lichenification - provide a means for assessing the severity of lesions. Assessment of these 
four main clinical signs is performed separately for four body regions: head and neck, upper 
limbs, trunk (including axillae and groin) and lower limbs (including buttocks). Average 
erythema, induration/papulation, excoriation, and lichenification are scored for each body 
region according to a 4 point scale: 0 = absent; 1 = mild; 2 = moderate; 3 = severe. 
Morphologic descriptors for each clinical sign severity score are shown in Table 4. 
Table 4. Clinical Sign Severity Scoring Criteria for the Eczema Area and Severity Index 
(EASI) 
 
Percent BSA with Atopic Dermatitis: The number of handprints of skin afflicted with atopic 
dermatitis in a body region can be used to determine the extent (%) to which a body region is 
involved with atopic dermatitis (Table 5). When measuring, the handprint unit refers to the 
size of each individual subject’s hand with fingers in a closed position. 
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Protocol B7451006        Statistical Analysis Plan 
 
 
 
Table 5. Handprint Determination of Body Region Surface Area (BSA) 
 
The extent (%) to which each of the four body regions is involved with atopic dermatitis is 
categorized to a numerical Area Score using a non-linear scaling method according to the 
following BSA scoring criteria (Table 6). 
Table 6. Eczema Area and Severity Index (EASI) Area Score Criteria 
 
Body Region Weighting: Each body region is weighted according to its approximate 
percentage of the whole body (Table 7). 
Table 7. Eczema Area and Severity Index (EASI) Body Region Weighting 
 
In each body region, the sum of the Clinical Signs Severity Scores for erythema, 
induration/papulation, excoriation, and lichenification is multiplied by the Area Score and by 
the Body Region Weighting to provide a body region value, which is then summed across all 
four body regions resulting in an EASI score as described in Equation 3. 
Equation 3: EASI = 0.1Ah(Eh+Ih+Exh+Lh) + 0.2Au(Eu+Iu+ExU+Lu) + 
0.3At(Et+It+Ext+Lt) + 0.4Al(El+Il+Exl+Ll) 
A = Area Score; E = erythema; I = induration/papulation; Ex = excoriation; L = 
lichenification; h = head and neck; u = upper limbs; t = trunk; l = lower limbs 
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Protocol B7451006        Statistical Analysis Plan 
 
 
 
The EASI score can vary in increments of 0.1 and range from 0.0 to 72.0, with higher scores 
representing greater severity of atopic dermatitis. 
Appendix 4. Body Surface Area (BSA) 
BSA Efficacy will be derived from the sum of the BSA in handprints across 4 body regions 
assessed as part of the EASI assessment (Table 5). Handprint refers to that of each individual 
subject for their own measurement. The BSA Efficacy ranges from 0 to 100%, with higher 
values representing greater severity of atopic dermatitis. Since the scalp, palms, and soles 
will be excluded from the BSA (Efficacy) assessment, the maximum possible value will be less 
than 100%. 
Appendix 5. Scoring Atopic Dermatitis (SCORAD) 
SCORAD is a validated scoring index for atopic dermatitis, which combines extent (0-100), 
severity (0-18), and subjective symptoms (0-20) based on pruritus and sleep loss, each 
scored (0-10). 
Extent (A, maximum of 100%) 
To determine extent of AD, rule of 9 is used to calculate body surface area affected by AD as 
a percentage of the whole body surface area. Body surface area as percentage of total body 
surface area for each body region is as follows: 
• Head and neck 9%; 
• Upper limbs 9% each; 
• Lower limbs 18% each; 
• Anterior trunk 18%; 
• Back 18%; 
• 1% for genitals. 
The score for each body region is added up to determine the BSA affected by AD (A), which 
has a possible maximum of 100%. 
Severity (B, maximum of 18) 
A representative area of AD is selected. In this area, the severity of each of the following 
signs is assessed as none (0), mild (1), moderate (2) or severe (3). 
• Erythema (reddening); 
• Edema (swelling); 
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Protocol B7451006        Statistical Analysis Plan 
 
 
 
• Oozing/crusting; 
• Excoriation (scratch marks); 
• Skin thickening (lichenification); 
• Xerosis (dryness) (this is assessed in an area where there is no inflammation). 
The severity scores are added together to give 'B' (maximum of 18). 
Subjective Symptoms (C, maximum of 20) 
Subjective symptom (ie. itch and sleeplessness) are each scored by the subject or caregiver 
using a numeric rating scale (NRS) where “0” is no itch (or no sleeplessness) and “10” is 
the worst imaginable itch (or sleeplessness). These scores are added to give “C” (maximum 
of 20). 
The SCORAD for an individual is calculated by the formula: A/5 + 7B/2 + C (can range 
from 0 to 103). 
Appendix 6. Pruritus Numeric Rating Scale (NRS) 
Severity of Pruritus 
The severity of itch (pruritus) due to atopic dermatitis will be assessed using a horizontal 
NRS (Appendix 6). Subjects will be asked to assess their “worst itching due to atopic 
dermatitis over the past 24 hours” on a NRS anchored by the terms “no itching” (0) and 
“worst possible itching” (10). 
Frequency of Pruritus 
The frequency of itch (pruritus) due to atopic dermatitis will be assessed using a horizontal 
NRS (Appendix 6). Subjects will be asked to assess “frequency of itching due to atopic 
dermatitis over the past 24 hours” on a NRS anchored by the terms “never/no itching” (0) 
and “always/constant itching” (10). The pruritus NRS should be completed as per Schedule 
of Activities. 
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Protocol B7451006        Statistical Analysis Plan 
 
 
 
 
Appendix 7. Patient Global Assessment (PtGA) 
The PtGA asks the subject to evaluate the overall cutaneous disease at that point in time on a 
single-item, 5-point scale (Appendix 5). The same category labels used in the Physician’s 
Global Assessment will be used for the Patient Global Assessment, ie, “severe (4)”, 
“moderate (3)”, “mild (2)”, “almost clear (1)”, and “clear (0)”. The PtGA should be 
completed as per Schedule of Activities. 
Appendix 8. Dermatology Life Quality Index (DLQI) 
The DLQI is a general dermatology questionnaire that consists of 10 items that assess 
subject health-related quality of life (daily activities, personal relationships, symptoms and 
feelings, leisure, work and school, and treatment) (Appendix 7). It has been extensively used 
inclinical trials for AD. The DLQI is a psychometrically valid and reliable instrument that 
has been translated into several languages, and the DLQI total scores have been shown to be 
responsive to change. The minimally important difference for the DLQI has been estimated 
as a 2 to 5 point change from baseline. The DLQI should be completed as per Schedule of 
Activities. 
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Protocol B7451006        Statistical Analysis Plan 
 
 
 
 
Appendix 9. Patient-Oriented Eczema Measure (POEM) 
The POEM is a 7-item PRO measure used to assess the impact of AD over the past week 
(Appendix 8). The POEM should be completed as per Schedule of Activities. 
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Protocol B7451006        Statistical Analysis Plan 
 
 
 
 
Appendix 10. Hospital and Anxiety Depression Scale (HADS) 
The HADS is a 14-item PRO measure used to detect states of anxiety and depression over the 
past week (Appendix 9). The HADS should be completed as per Schedule of Activities. 
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Protocol B7451006        Statistical Analysis Plan 
 
 
 
 
 
Page 31 of 39 
 
 
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Protocol B7451006        Statistical Analysis Plan 
 
 
 
Appendix 11. Example SAS Code for Generalized Linear Mixed model for IGA 
This code has been included as an example of generalized linear mixed model in SAS. The 
actual code may be adjusted, depending on the testing of programming and the data. No SAP 
amendment is needed if the actual code is different from the example code in this section.  
The common procedure of PROC GLIMMIX  has been used. As our decision criteria are 
based on differences in proportions this procedure allows us to back transform and express 
the data in this format. The following code was written assuming the format of the input 
dataset is of the form: 
DOSE 
id 
week 
IGA Response 
0  
1  
4 
0 
10  
2  
6 
0 
30  
3  
8 
0 
100  
4  
12 
1 
………. 
/* SAS example code */ 
*** Model: GLIMMIX MODEL ***; 
 
/* random trend logistic regression via GLIMMIX */ 
PROC GLIMMIX DATA=one METHOD= RSPLNOCLPRINT; 
CLASS id week; 
MODEL IGA = dose week dose*week / SOLUTION DIST=BINARY LINK=LOGIT; 
RANDOM INTERCEPT / SUBJECT=id TYPE=UN GCORR SOLUTION; 
RUN; 
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Protocol B7451006        Statistical Analysis Plan 
 
 
 
Appendix 12. Example SAS Code for Analyses OF Dose-Response Models 
This code has been included as an example to show possible ways of fitting an Emax model 
and in SAS. The actual code may be adjusted, depending on the testing of programming and 
the data. No SAP amendment is needed if the actual code is different from the example code 
in this section. The common procedure of PROC NLMIXED has been used. Therefore, 
PROC NLMIXED has also been used as the ESTIMATE statement allows you to specify the 
contrast of interest. As our decision criteria are based on differences in proportions this 
procedure allows us to back transform and express the data in this format. The following 
code was written assuming the format of the input dataset is of the form: 
DOSE LNDOSE COUNT  N 
0  
-9.2103  
5  
30 
10  
2.3025  
9  
30 
303.4012  11  
30 
100  
4.6052  
18  
30 
200  5.2983   
21  
30 
where 
 
DOSE=DOSE in mg, 
LNDOSE=log(DOSE+0.0001) 
COUNT=number of responses,  
N=number of subjects  
 
/* SAS example code */ 
 
*** Model 1: EMAX MODEL without covariate ***; 
 
**Degrees of freedom is number of subjects-number of parameters (3); 
proc nlmixed data=resp alpha=0.1 df=&df; 
 
 
** specify that ed50 must be positive; 
   bounds ed50>0; 
 
   eta = e0 + ((emax*dose)/(ed50+dose)); 
   expeta = exp(eta); 
   p = expeta/(1+expeta); 
 
   model count ~ binomial(n,p); 
 
 
** LOG(ODDS RATIOS) - TAKE EXP(ESIMATE) and EXP(CI) TO CALCULATE PARAMETER AND 
60% CI FOR MAIN BODY TABLE; 
 
** ACTUAL ESTIMATED PROPORTIONS ; 
  
   estimate 
'Model 1: Actual proportions 200mg
'  
             exp(e0 + (emax*200/(ed50+200)))/ (1 + exp(e0_int + (emax*200/(ed50+200)))); 
 
   estimate 
'Model 1: Actual proportions 100mg
'  
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Protocol B7451006        Statistical Analysis Plan 
 
 
 
             exp(e0 + (emax*100/(ed50+100)))/ (1 + exp(e0_int + (emax*100/(ed50+100)))); 
 
   estimate 
'Model 1: Actual proportions 30mg
'  
             exp(e0 + (emax*30/(ed50+30)))/(1 + exp(e0_int + (emax*30/(ed50+30)))); 
   estimate 
'Model 1: Actual proportions 10mg
'  
             exp(e0 + (emax*10/(ed50+10)))/(1 + exp(e0_int + (emax*10/(ed50+10)))); 
   estimate 
'Model 1: Actual proportions 0mg
'  
             exp(e0)/(1 + exp(e0_int)); 
 
** Differences among ACTUAL ESTIMATED PROPORTIONS ; 
  
   estimate 
'Model 1: proportion difference 200mg vs. placebo
'  
             exp(e0 + (emax*200/(ed50+200)))/ (1 + exp(e0_int + (emax*200/(ed50+200))))- exp(e0)/(1 + 
exp(e0_int)); 
   estimate 
'Model 1: proportion difference 100mg vs. placebo
'  
             exp(e0 + (emax*100/(ed50+100)))/ (1 + exp(e0_int + (emax*100/(ed50+100))))- exp(e0)/(1 + 
exp(e0_int)); 
 
   estimate 
'Model 1: proportions difference 30mg vs. placebo
'  
             exp(e0 + (emax*30/(ed50+30)))/(1 + exp(e0_int + (emax*30/(ed50+30)))) - exp(e0)/(1 + exp(e0_int)); 
   estimate 
'Model 1: proportion difference 10mg vs. placebo
'  
             exp(e0 + (emax*10/(ed50+10)))/(1 + exp(e0_int + (emax*10/(ed50+10))))- exp(e0)/(1 + exp(e0_int)); 
 
   ods output AdditionalEstimates=est 
              FitStatistics=loglike 
              ParameterEstimates=parms; 
 
run; 
 
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Protocol B7451006        Statistical Analysis Plan 
 
 
 
Appendix 13.  Estimate and Confidence Interval for Risk Difference (Proportion 
Difference) Using GLIMMIX Procedure with link=logit 
It is known that the estimate and CI on the logit scale can be obtained using GLIMMIX 
procedure with dist=binary and link=logit; and using link option in GLIMMIX will generate 
the estimate for proportions.  The variance of risk difference (proportion difference) cannot 
be directly obtained by GLIMMIX procedure using link=logit.  This appendix describes how 
to obtain the estimate and the confidence interval (CI) for risk difference (proportion 
difference) by delta method.  
Suppose that 1
pand 2
pare the two proportions of interest.  
)
1
log(
)
(
log
1
1
1
1
p
p
p
it
l
−
=
=
 and 
)
1
log(
)
(
log
2
2
2
2
p
p
p
it
l
−
=
=
are the logit for the two proportions.  Note that the1
l, 2
l, 1
p 
and 2
pcan be obtained by GLIMMIX procedure, and so are the covariance matrix for 1
l and 
2
l.   Our interest is to derive the variance of1
p- 2
p.  
Denote that
2
1
2
1
2
2
1
1
1
1
)
,
(
p
p
e
e
e
e
l
l
f
l
l
l
l
−
=
+
−
+
=
.  A Taylor series expansion of 
)
,
(
2
1l
l
f
about 
the values 
)
,
(
20
10 l
l
is given by:  
(
).
s
order term
higher 
or 
 
2nd
)
(
|
)
,
(
)
(
|
)
,
(
)
,
(
)
,
(
20
2
)
,
(
2
2
1
10
1
)
,
(
1
2
1
20
10
2
1
20
10
20
10
+
−
∂
∂
+
−
∂
∂
+
=
l
l
l
l
l
f
l
l
l
l
l
f
l
l
f
l
l
f
l
l
l
l
Therefore 
)
,
(
|
)
,
(
|
)
,
(
2
)
(
|
)
,
(
)
(
|
)
,
(
))
,
(
(
2
1
)
,
(
2
2
1
)
,
(
1
2
1
2
2
)
,
(
2
2
1
1
2
)
,
(
1
2
1
2
1
20
10
20
10
20
10
20
10
l
l
Cov
l
l
l
f
l
l
l
f
l
Var
l
l
l
f
l
Var
l
l
l
f
l
l
f
Var
l
l
l
l
l
l
l
l






∂
∂






∂
∂
+






∂
∂
+






∂
∂
≈
   
(1) 
Since  
2
1
2
1
)
1
(
)
,
(
1
1
l
l
e
e
l
l
l
f
+
=
∂
∂
 and 
2
2
2
1
)
1
(
)
,
(
2
2
l
l
e
e
l
l
l
f
+
−
=
∂
∂
,  
)
,
(
)
1
(
)
1
(
2
)
(
)
1
(
)
(
)
1
(
))
,
(
(
2
1
2
2
2
2
2
1
2
2
2
1
2
2
1
1
2
2
1
1
l
l
Cov
e
e
e
e
l
Var
e
e
l
Var
e
e
l
l
f
Var
l
l
l
l
l
l
l
l






+






+
−






+
+






+
≈
  
  
 
(2) 
Page 35 of 39 
 
 
090177e18dabc776\0.1\Draft\Versioned On:07-Feb-2018 10:11 (GMT)


Protocol B7451006        Statistical Analysis Plan 
 
 
 
Now take 
)
ˆ
,
ˆ
(
)
,
(
2
1
20
10
l
l
l
l
=
where 
)
ˆ
,
ˆ
(
2
1l
l
are the estimates of logits which are obtained by 
GLIMMIX procedure.  Then by analogy with the above result, the corresponding estimated 
variance of the estimator is given by 
)
ˆ
,
ˆ
(
)
1
(
)
1
(
2
)
ˆ
(
)
1
(
)
ˆ
(
)
1
(
))
ˆ
,
ˆ
(
(
ˆ
2
1
2
ˆ
ˆ
2
ˆ
ˆ
2
2
2
ˆ
1
2
2
ˆ
ˆ
2
1
2
2
1
1
2
ˆ
2
1
1
l
l
Cov
e
e
e
e
l
Var
e
e
l
Var
e
e
l
l
f
ar
V
l
l
l
l
l
l
l
l








+








+
−








+
+








+
≈
  
  
 
(3) 
In conclusion, using GLIMMIX the estimates of logit, variance of the estimate and the 
corresponding CI for 1
p- 2
p can be written as  
)
ˆ
ˆ
(
ˆ
ˆ
ˆ
 
:
CI
)%
1
(
));
ˆ
,
ˆ
(
(
ˆ
)
ˆ
ˆ
(
ˆ
;
1
1
ˆ
ˆ
2
1
2
/
1
2
1
2
1
2
1
ˆ
ˆ
ˆ
ˆ
2
1
2
2
1
1
p
p
ar
V
z
p
p
l
l
f
ar
V
p
p
ar
V
e
e
e
e
p
p
l
l
l
l
−
±
−
−
=
−
+
−
+
=
−
−a
a
   
  
  
  
 
(4) 
Where 
))
ˆ
,
ˆ
(
(
ˆ
2
1l
l
f
ar
V
is given in (3).  
Page 36 of 39 
 
 
090177e18dabc776\0.1\Draft\Versioned On:07-Feb-2018 10:11 (GMT)


CCI
090177e18dabc776\0.1\Draft\Versioned On:07-Feb-2018 10:11 (GMT)


CCI
090177e18dabc776\0.1\Draft\Versioned On:07-Feb-2018 10:11 (GMT)


CCI
090177e18dabc776\0.1\Draft\Versioned On:07-Feb-2018 10:11 (GMT)