Conditions: Dermatitis, Atopic
Keywords: atopic dermatitis atopic eczema eczema JAK janus kinase
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 387
Healthy volunteers: no

Brief summary:
B7451012 is a Phase 3 study to evaluate PF-04965842 in patients aged 12 years and older with a minimum body weight of 40 kg who have moderate to severe atopic dermatitis. The efficacy and safety of two dosage strengths of PF-04965842, 100 mg and 200 mg taken orally once daily, will be evaluated relative to placebo over 12 weeks of study participation. Eligible patients will have an option to enter a long-term extension study after completing 12 weeks of treatment.

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None

Interventions: intervention 1: PF-04965842 100 mg intervention 2: PF-04965842 200 mg intervention 3: Placebo
Intervention descriptions: intervention 1: PF-04965842 100 mg, administered as two tablets to be taken orally once daily for 12 weeks intervention 2: PF-04965842 200 mg, administered as two tablets to be taken orally once daily for 12 weeks intervention 3: Placebo, administered as two tablets to be taken orally once daily for 12 weeks

Protocol document:
Prot_001.pdf: 
PF-04965842 
B7451012 
Final Protocol Amendment 5, 05 June 2018 
 
 
 
Page 1 
 
 
A PHASE 3 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL GROUP, MULTI-CENTER STUDY TO EVALUATE THE EFFICACY 
AND SAFETY OF PF-04965842 MONOTHERAPY IN SUBJECTS AGED 12 YEARS 
AND OLDER, WITH MODERATE TO SEVERE ATOPIC DERMATITIS 
 
Investigational Product Number: 
PF-04965842 
Investigational Product Name: 
Not applicable (N/A) 
United States (US) Investigational New 
Drug (IND) Number: 
123554 
European Clinical Trials Database 
(EudraCT) Number: 
2017-003651-29 
Protocol Number: 
B7451012 
Phase: 
3 
 
 
 
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Document History 
Document 
Version Date 
Summary of Changes and Rationale 
Original protocol 
28 September 2017 
Not applicable (N/A) 
Amendment 1 
03 November 2017 
Until further evaluation of QT data for 
JAK1 has been obtained, additional 
monitoring, ECG exclusion criteria and 
discontinuation criteria were added for 
subject safety.  The following revisions 
were made to planned ECG assessments: 
• Addition of single ECG 
assessments to the Schedule of 
Activities at study visits 4, 5, 7 and 
follow-up.  
• Clarification that the baseline ECG 
will now be routinely performed for 
all subjects in the Schedule of 
Activities and Section 6.2.1. 
• Revision of exclusion criterion 
14 to exclude additional factors 
associated with QT/QTcF 
abnormalities and confirmation that 
Fridericia’s correction will be used.  
• Addition of a discontinuation 
criterion for prolonged QTcF 
interval to Appendix 4. 
• Modification of Sections 6 and 
7.2.5 to reflect ECG revisions.   
Section 1.4 Summary of Benefits and 
Risks, was revised to include a reference to 
recent Phase 1 QT findings. 
Based on FDA guidance, inclusion 
criterion 3 in Section 4.1 was revised for 
the following: EASI was changed from 
≥12 to ≥16 and Pruritus NRS ≥4 was 
added.  
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Based on FDA guidance, blood pressure 
and pulse rate assessments were revised to 
require pre- and post-dose monitoring at 
the baseline and week 12 visits, and to be 
performed approximately 1 hour post-dose 
at all other visits.  Schedule of activities 
and Section 6 were changed to reflect these 
revisions and sequence of assessments at 
the visits were reordered.  
Based on FDA guidance, the sequence of 
statistical testing and representational 
figure were revised in Section 9.2.2.  
Clarified in the Protocol Summary, 
Section 3 and Section 4.1, Inclusion 
Criterion 2, that the inclusion of adolescent 
subjects in the study would also require 
instruction from the sponsor.  
Text of the SCORAD subjective items 
endpoint was revised in the Protocol 
Summary and Section 2 Table 1, 
Objectives and Endpoints to align with 
data collection from the phase 2 studies. 
Section 5.3 Subject Compliance, was 
revised to clarify the purpose of the eDiary, 
and further define dosing compliance and 
medication errors. 
Clarified in Schedule of Activities and 
Sections 6, 7.1 and 7.5.2 that pregnancy 
testing for women of childbearing potential 
will also be performed on adolescents aged 
12 years and older, regardless of whether 
they have experienced menarche. 
Section 6.1 was revised to include 
reporting at the screening visit of any prior 
medications for which there was a history 
of intolerance or allergy, regardless of 
indication.  This information may be used 
for statistical subgroup analysis. 
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Version Date 
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Substance usage history collection was 
corrected to remove reference to “drug” 
substance and to adjust alcohol unit 
conversions in the Schedule of Activities, 
Section 6.1 and Section 7.2.2. 
Anticipated blood volume was updated in 
Section 7.5.1 based on central laboratory 
estimation. 
List of laboratory assessments was 
corrected to include red blood cell indices 
in the Schedule of Activities footnote and 
Section 7.5.2 Laboratory Table. 
Inaccurate text regarding deferral of 
sample collection for HCV RNA analysis 
was removed from Section 7.5.2.1. 
Section 7.6.2 was revised to clarify the 
assessment of Investigator’s Global 
Assessment. Table 3 summarizing 
Component Scoring Criteria was added. 
Section 7.7.1 Pruritus Numerical Rating 
Scale, was revised to include scale name 
and add a verbal label change for pruritus 
severity to align with the validated 
instrument.  A reference for the scale was 
added to Section 16 and Appendix 6 was 
updated to reflect these revisions. 
Appendix 3 listing of prohibited 
concomitant CYP inhibitors and inducers 
was extended to include CYP2C19 and 
CYP2C9 to ensure patient safety until 
metabolism studies are completed.   
Global corrections of typographical errors, 
table numbering and spelling were made.  
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Version Date 
Summary of Changes and Rationale 
Amendment 2 
28 February 2018 
Changes requested from MHRA 
specifically for United Kingdom: 
Section 13.1 outlining provisions for the 
end of trial date specific to EU Member 
States has been removed.  Section 13.1 
now clarifies that for all participating 
countries, the end of trial is defined as the 
last subject, last visit. 
Clarification in the Schedule of Activities, 
Section 6.1 and Section 7.5.2 that HIV 
testing is required for all subjects; removal 
of the statement “per local guidelines”. 
Amendment 3 
16 March 2018 
Applied changes from United Kingdom-
specific Amendment 2.  
The Protocol Summary and Section 1.2.2 
were modified to reflect the marketing 
authorization of dupilumab in Europe in 
September 2017. 
In the Protocol Summary and Section 2, 
the Safety Objective was removed from the 
Secondary Objectives and reclassified as a 
standalone objective.  
Clarified in the Protocol Summary and 
Section 2 that analysis of the Pruritus NRS 
Key Secondary and Secondary Endpoints 
will be based on the validated severity 
component of the Pruritus NRS.  The 
frequency component of the Pruritus NRS 
will be analyzed separately as an additional 
patient-reported outcome.  
Clarified in the Protocol Summary, 
Section 2, and Section 7.7.7 that the 
PSAAD total score, defined as the 11 items 
developed and validated to measure 
symptoms of atopic dermatitis, will be used 
in PSAAD analysis.  
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Clarified in the Protocol Summary and 
Section 2 that the correct Secondary 
Efficacy Endpoint is “Time from baseline 
to achieve at least 4 points improvement in 
the severity of pruritus NRS scale” rather 
than “Time to achieve a 4-point 
improvement in the pruritus NRS scale 
from baseline by Day 15”. 
Clarified that the country-specific age of 
majority will govern enrollment of 
subjects.  
It is now specified in the SOA and 
Section 6.1 that patients are to be provided 
with an emergency contact card at the 
Screening visit.  
In table of Laboratory Tests in 
Section 7.5.2 it was clarified that serum 
follicle stimulating hormone (FSH) will be 
analyzed for postmenopausal women who 
have been amenorrheic for at least 
12 consecutive months. 
In the interest of subject safety, it now 
states in the Schedule of Activities, 
Section 6.1, and Section 7.4 that for any 
subjects meeting exclusionary results in the 
C-SSRS, SBQ-R, and PHQ-8 the subject’s 
primary care physician (PCP) should be 
informed and the subject referred to a 
mental health professional, either by the 
PCP or the investigator.  
Section 1.5 was modified to clarify the 
safety findings in the Phase 2b study and 
remove redundancy in the text.  
The role of the E-DMC, including review 
of PK, efficacy, and safety data in 
adolescents, was clarified in Section 1.5.  
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Exclusion criterion number 4 in Section 4.2 
was modified to clarify that subjects 
receiving anti-coagulants or medications 
known to cause thrombocytopenia should 
be excluded unless considered safe to stop 
and washout these medications for the 
duration of the study. 
Exclusion criterion number 10 in 
Section 4.2 and Section 5.8.1 were 
modified to state that low dose acetyl 
salicylic acid is permitted at doses less than 
or equal to 100 mg.  A dose of 100 mg 
acetyl salicylic acid daily is standard for 
prophylaxis. 
Exclusion criterion number 18 in 
Section 4.2 and Section 6.1 were revised to 
clarify that QuantiFERON – TB Gold test 
is the preferred method of TB testing and 
Mantoux PPD tuberculin skin test should 
be performed as required per Section 7.2.4. 
Text was added to Section 4.4.1 to clarify 
the importance of continual contraception 
checks and for consistency with the 
existing Schedule of Activities footnote. 
Repetitive text regarding destruction of 
investigational product was removed from 
Section 5.7.1. 
In Section 5.8, text was added to clarify the 
recording of concomitant medications 
taken during the study to align with the 
Case Report Form (CRF).  
In Section 5.8.1, the text stating that the 
requirement to document in the CRF the 
treated indication for which subjects are 
receiving permitted concomitant 
medication was removed to align with the 
CRF. 
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Clarification was provided in Section 5.8.2 
that any herbal medications with unknown 
properties or known beneficial effects for 
AD are prohibited. 
In Section 6.1, details on the chest X-ray 
were provided for consistency with the 
existing Schedule of Activities footnote 
and Section 7.2.3.  
In Sections 6 and 7.2.1 it was specified that 
blood pressure will be taken while the 
subject is sitting to maintain consistency 
with the Schedule of Activities. 
Section 7.2.6 was modified to specify that 
in the case of suspected viral skin 
infection, viral DNA may be analyzed 
locally rather than centrally and results 
provided to the adjudication committee to 
support evaluation.  
Anticipated blood volume was updated in 
Section 7.5.1 based on central laboratory 
estimation.  
The Investigator’s Global Assessment 
(IGA) description in Section 7.6.2 was 
modified and Component Scoring Criteria 
table was removed to maintain consistency 
with the JAK1 AD Phase 2 program. 
The mechanism of capture of subjective 
items on the SCORAD in Section 7.6.4 
was revised to accurately reflect use of a 
visual analog scale instead of numerical 
rating scale to align with the validated 
measure. 
Clarification of PRO completion, including 
use of handheld devices and examples of 
PROs provided in the protocol appendices, 
was provided in Section 7.7. 
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In Section 7.7.1, it was clarified that 
frequency of pruritus assessment will be 
entered in the eDiary. 
The description of the DLQI in 
Section 7.7.4 was modified for clarity and 
to reflect the correct estimated minimally 
important difference of a 3 to 5 point 
change from baseline. 
Section 9.2.2 was modified to specify that 
hypothesis for pruritus will include only 
severity of pruritus.  Figure 2, The 
Schematic for Multiple Testing Procedure, 
was also updated to reflect severity of 
pruritus in the NRS4 and a header for the 
figure was added.  
Sections 9.2.3 and 9.2.4 were modified for 
clarity and readability.  
Section 9.4 was removed, as there is no 
interim analysis planned for this study.  
Global corrections to typographical errors, 
abbreviations, and definitions were made.  
Amendment 4  
24 April 2018 
Changes requested specifically for Czech 
Republic: 
Based on concerns for relapse, the 
exclusionary history of substance abuse 
was extended from 6 months to 12 months 
in exclusion criterion 13. 
Inclusion criterion 5 and Section 4.4.1 
were revised to remove reference of 
contraception use for female subjects less 
than 15 years of age based on country law.  
It was noted that abstinence will be 
confirmed for participation of this age 
group.  
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Amendment 5 
05 June 2018 
Changes requested specifically for Czech 
Republic: 
Based on regulatory request, the absolute 
lymphocyte value in exclusion criterion 19 
was revised from <0.50 x 109 /L 
(<500/mm3) to <0.75 x 109 /L (<750/mm3). 
 
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and institutional review boards (IRBs)/ethics committees 
(ECs).   
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TABLE OF CONTENTS 
LIST OF TABLES ...................................................................................................................15 
LIST OF FIGURES .................................................................................................................16 
APPENDICES .........................................................................................................................16 
PROTOCOL SUMMARY .......................................................................................................17 
SCHEDULE OF ACTIVITIES................................................................................................23 
1. INTRODUCTION ...............................................................................................................28 
1.1. Mechanism of Action/Indication .............................................................................28 
1.2. Background and Rationale ......................................................................................29 
1.2.1. Drug Development and Rationale ..............................................................29 
1.2.2. Atopic Dermatitis ........................................................................................29 
1.2.3. Non-Clinical and Phase 1 Data ...................................................................31 
1.2.4. Phase 2b in AD (B7451006) .......................................................................31 
1.3. Summary of PF-04965842 Clinical Pharmacokinetics ...........................................32 
1.3.1. Population Pharmacokinetics ......................................................................33 
1.4. Summary of Benefits and Risks ..............................................................................33 
1.5. Dose Selection Rationale ........................................................................................34 
2. STUDY OBJECTIVES AND ENDPOINTS .......................................................................35 
3. STUDY DESIGN.................................................................................................................37 
4. SUBJECT ELIGIBILITY CRITERIA .................................................................................38 
4.1. Inclusion Criteria .....................................................................................................38 
4.2. Exclusion Criteria ....................................................................................................40 
4.3. Randomization Criteria ...........................................................................................45 
4.4. Lifestyle Requirements ...........................................................................................45 
4.4.1. Contraception ..............................................................................................46 
4.4.2. Vaccine and Exposure to Infections Guidelines .........................................48 
4.4.2.1. Subject Specific Recommendations ..........................................48 
4.4.2.2. Guidance Regarding Household Contact Vaccine-Related 
Exposure ............................................................................................48 
4.4.3. Surgery ........................................................................................................49 
4.5. Sponsor’s Qualified Medical Personnel ..................................................................49 
5. STUDY TREATMENTS .....................................................................................................49 
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5.1. Allocation to Treatment ..........................................................................................50 
5.2. Breaking the Blind ..................................................................................................50 
5.3. Subject Compliance .................................................................................................50 
5.4. Investigational Product Supplies .............................................................................51 
5.4.1. Dosage Form(s) and Packaging ..................................................................51 
5.4.2. Preparation and Dispensing ........................................................................51 
5.5. Administration .........................................................................................................51 
5.6. Investigational Product Storage ..............................................................................52 
5.7. Investigational Product Accountability ...................................................................53 
5.7.1. Destruction of Investigational Product Supplies ........................................53 
5.8. Concomitant Treatment(s) .......................................................................................53 
5.8.1. Permitted Concomitant Medications ..........................................................54 
5.8.2. Prohibited Medications and Treatments .....................................................55 
6. STUDY PROCEDURES .....................................................................................................55 
6.1. Visit 1, Screening ....................................................................................................56 
6.2. Treatment Period .....................................................................................................58 
6.2.1. Visit 2, Day 1/Week 0 (Baseline) ...............................................................58 
6.2.2. Visit 3, Day 8/Week 1 (±1 day) ..................................................................59 
6.2.3. Visit 4, Day 15/Week 2 (±1 day) ................................................................60 
6.2.4. Visit 5, Day 29/Week 4 (±2 day) ................................................................61 
6.2.5. Visit 6, Day 43/Week 6 (±3 day) ................................................................62 
6.2.6. Visit 7, Day 57/Week 8 (±3 day) ................................................................62 
6.2.7. Visit 8, Day 85/Week 12 (±3 days) or Early Termination Visit .................63 
6.3. Follow-up Visits ......................................................................................................64 
6.3.1. Visit 9, Day 120/Week 16 (±3 day) ............................................................64 
6.4. Subject Withdrawal .................................................................................................65 
7. ASSESSMENTS ..................................................................................................................67 
7.1. Pregnancy Testing ...................................................................................................67 
7.2. Safety Assessments .................................................................................................68 
7.2.1. Vitals Signs .................................................................................................68 
7.2.2. Medical History, Physical Examination, Height, and Weight ....................68 
7.2.3. Chest X-Ray ................................................................................................69 
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7.2.4. Tuberculosis Testing ...................................................................................69 
7.2.5. Electrocardiogram .......................................................................................70 
7.2.6. Special Safety Assessment .........................................................................70 
7.3. Skin Type Assessment ............................................................................................71 
7.4. Assessment of Suicidal Ideation and Behavior .......................................................71 
7.4.1. Columbia Suicide Severity Rating Scale (C-SSRS) ...................................71 
7.4.2. Suicidal Behaviors Questionnaire-Revised (SBQ-R) .................................71 
7.4.3. Patient Health Questionnaire – 8 Items (PHQ-8) .......................................71 
7.5. Clinical Laboratory Tests ........................................................................................71 
7.5.1. Blood Volume .............................................................................................71 
7.5.2. Laboratory Tests .........................................................................................71 
7.5.2.1. Hepatitis Testing .......................................................................73 
7.5.2.2. Varicella Zoster Virus (VZV) IgG Antibody (Ab) Testing ......73 
7.5.2.3. Baseline Viral Screen ................................................................73 
7.6. Efficacy Assessments ..............................................................................................73 
7.6.1. Rater Qualifications ....................................................................................73 
7.6.2. Investigator’s Global Assessment (IGA) ....................................................74 
7.6.3. Eczema Area and Severity Index (EASI) ...................................................74 
7.6.3.1. Body Surface Area – Efficacy (BSA Efficacy) .........................77 
7.6.4. Scoring Atopic Dermatitis (SCORAD) ......................................................77 
7.7. Patient-reported Outcomes (PROs) .........................................................................78 
7.7.1. Pruritus Numerical Rating Scale (NRS) .....................................................79 
7.7.2. Patient Global Assessment (PtGA) .............................................................79 
7.7.3. EuroQol Quality of Life 5-Dimension 5-Level Scale (EQ-5D-5L) 
and EuroQol Quality of Life 5-Dimension Youth Scale (EQ-5D-Y) ..............79 
7.7.4. Dermatology Life Quality Index (DLQI) and Children’s 
Dermatology Life Quality Index (CDLQI) ......................................................80 
7.7.5. Patient-Oriented Eczema Measure (POEM) ...............................................80 
7.7.6. Hospital Anxiety and Depression Scale (HADS) .......................................80 
7.7.7. Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD) .......80 
7.7.8. Short Form-36 Health Survey, Version 2, Acute (SF-36v2, Acute) ..........81 
7.7.9. FACIT Fatigue Scale (FACIT-F) and Pediatric FACIT-F 
(Peds-FACIT-F) ...............................................................................................81 
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7.8. Pharmacokinetics ....................................................................................................81 
7.8.1. Plasma for Analysis of PF-04965842 .........................................................81 
7.8.2. Shipment of Pharmacokinetic Samples ......................................................82 
8. ADVERSE EVENT REPORTING......................................................................................82 
8.1. Requirements ...........................................................................................................82 
8.1.1. Additional Details on Recording Adverse Events on the CRF ...................83 
8.1.2. Eliciting Adverse Event Information ..........................................................84 
8.1.3. Withdrawal from the Study Due to Adverse Events (see also the 
Subject Withdrawal Section) ...........................................................................84 
8.1.4. Time Period for Collecting AE/SAE Information ......................................84 
8.1.4.1. Reporting SAEs to Pfizer Safety ...............................................84 
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF .................84 
8.1.5. Causality Assessment .................................................................................85 
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................85 
8.2. Definitions ...............................................................................................................85 
8.2.1. Adverse Events ...........................................................................................85 
8.2.2. Abnormal Test Findings .............................................................................86 
8.2.3. Serious Adverse Events ..............................................................................86 
8.2.4. Hospitalization ............................................................................................87 
8.3. Severity Assessment ................................................................................................88 
8.4. Special Situations ....................................................................................................88 
8.4.1. Protocol-Specified Serious Adverse Events ...............................................88 
8.4.2. Potential Cases of Drug-Induced Liver Injury ............................................88 
8.4.3. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure .....................................................90 
8.4.3.1. Exposure During Pregnancy ......................................................90 
8.4.3.2. Exposure During Breastfeeding ................................................92 
8.4.3.3. Occupational Exposure .............................................................92 
8.4.4. Medication Errors .......................................................................................92 
8.4.4.1. Medication Errors ......................................................................92 
9. DATA ANALYSIS/STATISTICAL METHODS ...............................................................93 
9.1. Sample Size Determination .....................................................................................93 
9.2. Efficacy Analysis ....................................................................................................93 
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9.2.1. Analysis Sets ...............................................................................................93 
9.2.2. Testing Procedure for Multiple Comparisons .............................................94 
9.2.3. Analysis of the Primary Endpoints .............................................................95 
9.2.4. Analysis of Secondary Endpoints ...............................................................96 
9.3. Safety Analysis ........................................................................................................96 
9.4. Analysis of Pharmacokinetic Endpoints .................................................................97 
9.5. External Data Monitoring Committee .....................................................................97 
9.6. Safety Adjudication Committees ............................................................................97 
10. QUALITY CONTROL AND QUALITY ASSURANCE .................................................97 
11. DATA HANDLING AND RECORD KEEPING .............................................................98 
11.1. Case Report Forms/Electronic Data Record .........................................................98 
11.2. Record Retention ...................................................................................................98 
12. ETHICS..............................................................................................................................99 
12.1. Institutional Review Board/Ethics Committee ......................................................99 
12.2. Ethical Conduct of the Study ................................................................................99 
12.3. Subject Information and Consent ..........................................................................99 
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................100 
13. DEFINITION OF END OF TRIAL .................................................................................101 
13.1. End of Trial in All Participating Countries .........................................................101 
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................101 
15. PUBLICATION OF STUDY RESULTS ........................................................................101 
15.1. Communication of Results by Pfizer ..................................................................101 
15.2. Publications by Investigators ..............................................................................102 
16. REFERENCES ................................................................................................................104 
 
LIST OF TABLES 
Table 1. 
Objectives and Endpoints .....................................................................................35 
Table 2. 
Investigational Product Administration ................................................................52 
Table 3. 
Investigator’s Global Assessment (IGA) Score ....................................................74 
Table 4. 
Clinical Sign Severity Scoring Criteria for the Eczema Area and Severity 
Index (EASI) .........................................................................................................75 
Table 5. 
Handprint Determination of Body Surface Area (BSA) .......................................76 
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Table 6. 
Eczema Area and Severity Index (EASI) Area Score Criteria .............................76 
Table 7. 
Eczema Area and Severity Index (EASI) Body Region Weighting .....................76 
 
LIST OF FIGURES 
Figure 1. 
Study Design Schematic .......................................................................................37 
Figure 2. 
Schematic for Multiple Testing Procedure ...........................................................95 
 
APPENDICES 
Appendix 1. Abbreviations ....................................................................................................108 
Appendix 2. Diagnostic Criteria for Atopic Dermatitis .........................................................113 
Appendix 3. Prohibited Concomitant Medications ................................................................114 
Appendix 4. Guidelines for Monitoring and Discontinuation ...............................................116 
Appendix 5. Fitzpatrick Skin Type ........................................................................................118 
Appendix 6. Pruritus Severity and Frequency (Pruritus NRS) ..............................................119 
Appendix 7. Patient Global Assessment (PtGA) ...................................................................120 
Appendix 8. European Quality of Life 5-Dimension 5-Level Scale (EQ-5D-5L) and 
European Quality of Life 5-Dimension Youth Scale (EQ-5D-Y) ......................121 
Appendix 9. Dermatology Life Quality Index (DLQI) and Children’s Dermatology Life 
Quality Index (CDLQI) ......................................................................................126 
Appendix 10. Patient-Oriented Eczema Measure (POEM) ...................................................128 
Appendix 11. Hospital Anxiety and Depression Scale (HADS) ...........................................129 
Appendix 12. Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD) 
Symptom Diary ...................................................................................................131 
Appendix 13. SF-36v2, Acute ...............................................................................................135 
Appendix 14. FACIT-F and Peds-FACIT-F ..........................................................................141 
Appendix 15. C-SSRS – Columbia Suicide Severity Rating Scale .......................................143 
Appendix 16. SBQ-R – Suicide Behaviors Questionnaire – Revised ...................................146 
Appendix 17. Patient Health Questionnaire – 8 Items ...........................................................147 
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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 by flaky skin lesions, intense pruritus, and a general deterioration 
in the quality of life.  Over the past 50 years, AD has become more prevalent, especially in 
industrialized, temperate countries such as the United States (US).1,2  Earlier reports indicated 
that, in up to 70% of cases, the disease greatly improves or resolves until late childhood, 
however more recent findings suggest that disease activity remains manifest for a prolonged 
period of time.  Based on a total of 7157 patients enrolled in the Pediatric Eczema Elective 
Registry (PEER) study, comprising a total of 22,550 person-years, it was concluded that 
symptoms associated with AD seem to persist well into the second decade of a child’s life 
and likely longer.3  At every age, more than 80% of PEER study subjects had symptoms of 
AD and/or were using medication to treat their AD. 
There are a limited number of treatments available for AD.  Current treatments for AD 
include emollients, topical corticosteroids (eg, betamethasone, clobetasol, fluocinonide), 
topical calcineurin inhibitors (eg, pimecrolimus, tacrolimus), and coal tar preparations.  
Crisaborole was approved as a topical treatment in December 2016 by the Food and Drug 
Administration (FDA) for use in patients with mild to moderate AD.  Additional treatments 
generally reserved for severe AD include phototherapy (eg, ultraviolet A light [UVA] with or 
without psoralen, ultraviolet B light [UVB] narrowband or broadband) and systemic agents 
(eg, corticosteroids, cyclosporine, recombinant interferon gamma (IFN-γ), mycophenolate 
mofetil, methotrexate [MTX], azathioprine, intravenous immunoglobulin).4  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, and to reduce 
pruritus and the resulting sleep disturbance.5,6 
Other systemic agents to treat AD are under clinical development or recently approved.  
Dupilumab, an injectable human monoclonal antibody targeting interleukin (IL) -4 and 
-13, was approved by the FDA in March 2017 and received marketing authorization in 
Europe in September 2017, and offers a novel mechanism of action for the treatment of 
moderate to severe AD.  However, the approved dosing for dupilumab as an initial dose of 
2 x 300 mg subcutaneous injections followed by 300 mg every other week injections may 
limit the desirability of this route of treatment. 
Key cytokines implicated in the pathophysiology of AD include IL-4, IL-5, IL-13, IL-31, 
and IFN-γ, require Janus kinase 1 (JAK1) for signal transduction; this suggests that selective 
JAK1 inhibitors that modulate the activity of these cytokines represent a compelling 
approach to the treatment of inflammatory skin diseases such as AD.7 
PF-04965842 is an orally bioavailable small molecule that selectively inhibits JAK1 by 
blocking the adenosine triphosphate (ATP) binding site.  PF-04965842 has a high degree of 
selectivity against other kinases: 28-fold selectivity over JAK2, >340-fold over JAK3 and 
43-fold over tyrosine kinase 2 (TYK2), as well as a good selectivity profile over the broader 
range of human kinases.  The selective inhibition of JAK1 will lead to modulation of 
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multiple cytokine pathways involved in the pathophysiology of AD, including 
IL-4, IL-5, IL-13, IL-31 and IFN-γ.  Data from a Phase 2b proof of concept (POC) study 
(B7451006) that evaluated subjects with moderate to severe AD have shown positive 
efficacy, as well as an acceptable safety profile, sufficient to support further clinical 
development in a larger Phase 3 program. 
Objectives and Endpoints:  
Primary Objective 
• To assess the efficacy of PF-04965842 compared with placebo in subjects aged 
12 years and older with moderate to severe AD. 
Secondary Objective 
• To evaluate the effect of PF-04965842 on additional efficacy endpoints and 
patient-reported outcomes over time in subjects aged 12 years and older with 
moderate to severe atopic dermatitis. 
Safety Objective 
• To evaluate the safety and tolerability of PF-04965842 in subjects aged 12 years and 
older with moderate to severe atopic dermatitis following 12 weeks of treatment. 
Pharmacokinetic Objective  
• To evaluate the pharmacokinetics (PK) of PF-04965842 in subjects aged 12 years and 
older with moderate to severe atopic dermatitis following 12 weeks of treatment. 
Endpoints 
Primary Endpoints: 
• Response based on the Investigator’s Global Assessment (IGA) score of clear (0) or 
almost clear (1) (on a 5-point scale) and a reduction from baseline of ≥2 points at 
Week 12.  The baseline will be defined as the IGA score on Day 1 pre-dose; 
• Response based on the Eczema Area and Severity Index 75% improvement from 
baseline (EASI-75) response at Week 12.  The baseline will be defined as the EASI 
score on Day 1 pre-dose.   
Key Secondary Efficacy Endpoints: 
• Response based on at least 4 points improvement in the severity of pruritus numerical 
rating scale (NRS) from baseline at Weeks 2, 4, and 12; 
• Change from Baseline in Pruritus and Symptoms Assessment for Atopic Dermatitis 
(PSAAD) total score at Week 12. 
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Secondary Efficacy Endpoints: 
• Response based on at least 4 points improvement in the severity of pruritus numerical 
rating scale (NRS) from baseline at all scheduled time points other than Weeks 2, 
4 and 12;   
• Time from baseline to achieve at least 4 points improvement in the severity of 
pruritus NRS scale; 
• Response based on the EASI-75 at all scheduled time points except Week 12; 
• Response based on the IGA of clear (0) or almost clear (1) and ≥2 point reduction 
from baseline at all scheduled time points except Week 12. 
Other Efficacy Endpoints: 
• Response based on a ≥50% and ≥90% improvement in the EASI total score 
(EASI-50 and EASI-90) at all scheduled time points; 
• Change from baseline in the percentage Body Surface Area (BSA) affected at all 
scheduled time points; 
• Response based on a ≥50% and ≥75% improvement in Scoring Atopic Dermatitis 
(SCORAD) (SCORAD-50, SCORAD-75) from baseline at all scheduled time points; 
• Change from baseline at all scheduled time points in SCORAD-subjective 
assessments of itch and sleep loss. 
Patient-Reported Outcomes: 
• Change from baseline at Week 12 in Dermatology Life Quality Index (DLQI) or 
Children’s DLQI (CDLQI) and at all other scheduled time points; 
• Change from baseline at Week 12 in Hospital Anxiety and Depression Scale (HADS) 
and at all other scheduled time points;  
• Change from baseline at Week 12 in Patient-Oriented Eczema Measure (POEM) and 
at all other scheduled time points;  
• Change from baseline of Patient Global Assessment (PtGA) at Week 12 and at all 
other scheduled time points;  
• Change from baseline of EuroQol Quality of Life 5-Dimension 5-Level Scale 
(EQ-5D-5L) or EuroQol Quality of Life 5-Dimension Youth Scale (EQ-5D-Y) at 
Week 12 and at all other scheduled time points; 
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• Change from baseline of Functional Assessment of Chronic Illness Therapy Fatigue 
Scale (FACIT-F) or Pediatric FACIT-F (Peds-FACIT-F) at Week 12 and at all other 
scheduled time points; 
• Change from baseline of Short Form-36v2 (SF-36v2), acute at Week 12 and at all 
other scheduled time points; 
• Response based on at least 4 points improvement in the frequency of pruritus 
numerical rating scale (NRS) from baseline at all scheduled time points;  
• Time from baseline to achieve at least 4 points improvement in the frequency of 
pruritus NRS scale. 
Safety Endpoints: 
• Incidence of treatment emergent adverse events; 
• Incidence of Serious Adverse Event (SAE)s and Adverse Event (AE)s leading to 
discontinuation; 
• The incidence of clinical abnormalities and change from baseline in clinical 
laboratory values, electrocardiogram (ECG) measurements, and vital signs. 
Pharmacokinetic Endpoint: 
• Population PK characterization in subjects aged 12 years and older with moderate to 
severe atopic dermatitis.  
Study Design 
This is a randomized, double-blind, placebo-controlled, parallel-group, Phase 3 study to 
evaluate the efficacy and safety of PF-04965842 monotherapy in subjects aged 12 years and 
older with moderate-to-severe AD and a body weight ≥40 kg.  The treatment duration is 
12 weeks.  Subjects will be screened within 28 days prior to the first dose of investigational 
product to confirm that they meet the subject selection criteria for the study.  A total of 
approximately 375 subjects will be enrolled from approximately 75 sites located globally.  
Adolescent subjects below the age of 18 years old (or country-specific age of majority) will 
only be enrolled in this study if instructed by the sponsor and approved by the country or 
regulatory/health authority.  If these approvals have not been granted, only subjects aged 
18 years (or country-specific age of majority) and older will be enrolled. 
Qualified subjects completing the 12 week treatment period of the study will have the option 
to enter a long-term extension (LTE) study B7451015.  Subjects discontinuing early from 
treatment, or who are otherwise ineligible for the LTE study will undergo a 4 week follow-up 
period in B7451012. 
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Subjects who have chronic moderate to severe AD as defined per the inclusion criteria will 
be randomized to receive 200 mg or 100 mg PF-04965842 once daily (QD), or matching 
placebo.  Investigators, subjects, and the sponsor study team will be blinded as to treatment 
group. 
After providing informed consent, subjects will be assessed for study eligibility at the 
screening visit.  For subjects younger than 18 years old (or country-specific age of majority), 
their parent(s)/legal guardian will provide supplementary or sole written consent and minor 
children will provide assent, according to local regulations and rules regarding ability to give 
assent and consent.  Subjects will undergo screening within 28 days prior to randomization.  
During the screening period, treatments for AD will be washed out, as applicable, according 
to eligibility requirements.  Subjects may be re-screened once if they fail the screening 
evaluation for reasons related to incidental transitory conditions, unless the reason for the 
screen failure is the disease severity inclusion criteria.  
Subjects who continue to meet eligibility criteria at baseline will undergo Day 1/baseline 
assessments and be randomized in a 2:2:1 ratio to receive 200 mg PF-04965842 (N=150) or 
100 mg PF-04965842 QD (N=150) or matching placebo (N=75) from Day 1.  
Randomization will be stratified by baseline disease severity (moderate [IGA = 3] vs. severe 
[IGA = 4] AD), and, age <18 and ≥18.  Eligible subjects must have a documented history of 
inadequate response or intolerance to treatment with topical AD medications or have required 
systemic therapies for control of their disease. 
Study Treatments 
• Doses of PF-04965842 will be 200 mg or 100 mg taken QD orally, or matching 
placebo.  
• Treatment duration will be 12 weeks (randomized period). 
• Subjects who do not enroll into the long term extension study, B7451015, will enter a 
4 week follow-up post treatment period. 
Statistical Methods 
A total sample of 375 subjects, with 150 on PF-04965842 200 mg QD, 150 on PF-04965842 
100 mg QD and 75 on placebo (2:2:1 randomization) would provide at least 95% power to 
detect a difference of at least 20% in IGA response rate between PF-04965842 200 mg QD 
(or PF-04965842 100 mg QD) and placebo, assuming the placebo response rate is 6% at 
Week 12. 
Furthermore, this will also provide at least 99% power to detect a difference of at least 
30% in EASI-75 response rate between PF-04965842 200 mg QD (or PF-04965842 100 mg 
QD) and placebo, assuming the placebo response rate is 15% at Week 12. 
These two endpoints are co-primary and both must achieve statistical significance to meet the 
primary objective. 
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There are five key hypotheses to be tested for each of the two PF-04965842 doses 
(200 mg QD and 100 mg QD) versus placebo, for the co-primary endpoints and two key 
secondary endpoints.  For these hypotheses, the familywise Type-I error rate will be strongly 
controlled at 5% using a sequential, Bonferroni-based iterative multiple testing procedure.  
This is described in further detail in the statistical analysis section of the protocol and in the 
statistical analysis plan (SAP). 
For analysis of the co-primary endpoints, the (Cochran-Mantel-Haenszel) test adjusted by 
randomization strata (baseline disease severity and age) will be used.  If a subject withdraws 
from the study, then this subject will be counted as a non-responder for endpoints after 
withdrawal.  
For continuous endpoints, a mixed-effect model with repeated measures (MMRM) will be 
used.  This model will include the factors (fixed effects) for treatment group, randomization 
strata (age group, disease severity), visit, treatment-by-visit interaction, and relevant baseline 
value.  Within the framework of MMRM, the treatment difference will be tested at the 
pre-specified primary time point, Week 12, as well as at the other time points by time 
point-specific contrasts from the MMRM model. 
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. 
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SCHEDULE OF ACTIVITIES 
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the STUDY PROCEDURES and 
ASSESSMENTS sections of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol.  
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities table, in order to 
conduct evaluations or assessments required to protect the well-being of the subject. 
Visit Identifiera 
Day -28 
Screening 
Day 1 
Week 0 
Baseline 
Day 8 
Week 1 
Call 
Day 15 
Week 2 
Day 29 
Week 4 
Day 43 
Week 6 
Call 
Day 57 
Week 8 
Day 85 
Week 12 
(EOT/ET)  
EOS, Follow- up 
Week 16 
(4 Weeks after 
EOT or ET) 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit Window 
None 
None 
±1 Day  
±1 Days 
±2 Days 
±3 Days 
±3 Days 
±3 Days 
±3 Days 
Enrollment Procedure 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Register subject using IRT system 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
Demographics, Medical History, Tobacco and 
Alcohol History, Atopic Dermatitis Disease 
Historyb 
X 
 
 
 
 
 
 
 
 
Review Prior/Concomitant Medications & 
Treatments 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense e-Diary and instruct subjects on use 
X 
 
 
 
 
 
 
 
 
Provide Patient Emergency Contact Card 
X 
 
 
 
 
 
 
 
 
Medical Procedures 
 
 
 
 
 
 
 
 
 
Complete Physical Examc 
X 
X 
 
 
 
 
 
X 
 
Targeted Physical Examc 
 
 
 
X 
X 
 
X 
 
X 
Vital Signsd 
X 
X 
 
X 
X 
 
X 
X 
X 
Additional Blood Pressure and Pulse Rate 
(post dose)d 
 
X 
 
 
 
 
 
X 
 
Weight 
X 
X 
 
 
 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
X 
 
Chest X-raye  
X 
 
 
 
 
 
 
 
 
ECG (12-lead) 
Xx 
X 
 
X 
X 
 
X 
X 
X 
Laboratory Assessments  
 
 
 
 
 
 
 
 
 
Serum chemistry and hematology (including 
coagulation panel)f 
X 
X 
 
X 
X 
 
X 
X 
X 
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Visit Identifiera 
Day -28 
Screening 
Day 1 
Week 0 
Baseline 
Day 8 
Week 1 
Call 
Day 15 
Week 2 
Day 29 
Week 4 
Day 43 
Week 6 
Call 
Day 57 
Week 8 
Day 85 
Week 12 
(EOT/ET)  
EOS, Follow- up 
Week 16 
(4 Weeks after 
EOT or ET) 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit Window 
None 
None 
±1 Day  
±1 Days 
±2 Days 
±3 Days 
±3 Days 
±3 Days 
±3 Days 
Lipid Panelf 
 
X 
 
 
X 
 
 
X 
X 
Urinalysis 
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 
HIV Testingi  
X 
 
 
 
 
 
 
 
 
Hepatitis B Surface Antigen (HBsAg), 
Hepatitis B Surface Antibody (HBsAb), 
Hepatitis B Core Antibody (HBcAb), 
Hepatitis C Antibody (HCV Ab), Hepatitis C 
Viral RNA (HCV RNA)j  
X 
 
 
 
 
 
 
 
 
Varicella Zoster Virus (VZV IgG Ab) 
(adolescents only, if applicable)k 
X 
 
 
 
 
 
 
 
 
Tuberculosis Testl   
X 
 
 
 
 
 
 
 
 
Pharmacokinetic  
 
 
 
 
 
 
 
 
 
Pharmacokinetic Blood Sampling (Pre-dose)m 
 
 
 
 
X 
 
 
 
 
Pharmacokinetic Blood Sampling (Post-dose)n 
 
 
 
 
X 
 
 
X 
 
Trial Treatment  
 
 
 
 
 
 
 
 
 
Randomization  
 
X 
 
 
 
 
 
 
 
Drug Dispensing 
 
X 
 
 
X 
 
X 
 
 
Investigational Product Accountability   
 
 
 
X 
X 
 
X 
X 
 
Investigational Treatment Administrationo 
 
     X---------------------------------------------------------------------------------------------X 
 
Review eDiary to assess completion 
 
 
X 
X 
X 
X 
X 
X 
 
Assess eligibility for B7451015v 
 
 
 
 
 
 
 
X 
 
Clinical Assessments  
 
 
 
 
 
 
 
 
 
Fitzpatrick Skin Type Assessment 
 
X 
 
 
 
 
 
 
 
Investigator’s Global Assessment (IGA)  
X 
X 
 
X 
X 
 
X 
X 
X 
SCORing Atopic Dermatitis (SCORAD) 
X 
X 
 
X 
X 
 
X 
X 
X 
Eczema Area and Severity Index (EASI) 
X 
X 
 
X 
X 
 
X 
X 
X 
Body Surface Area (BSA from EASI)  
X 
X 
 
X 
X 
 
X 
X 
X 
C-SSRSp  
X 
 
 
 
 
 
 
 
 
SBQ-Rp 
X 
 
 
 
 
 
 
 
 
PHQ-8p 
X 
 
 
 
 
 
 
 
 
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Visit Identifiera 
Day -28 
Screening 
Day 1 
Week 0 
Baseline 
Day 8 
Week 1 
Call 
Day 15 
Week 2 
Day 29 
Week 4 
Day 43 
Week 6 
Call 
Day 57 
Week 8 
Day 85 
Week 12 
(EOT/ET)  
EOS, Follow- up 
Week 16 
(4 Weeks after 
EOT or ET) 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit Window 
None 
None 
±1 Day  
±1 Days 
±2 Days 
±3 Days 
±3 Days 
±3 Days 
±3 Days 
Patient-reported Outcome  
 
 
 
 
 
 
 
 
 
Pruritus Numerical Rating Scale (NRS)q 
X------------------X 
X-----------------------------------------X 
X 
 
X 
X 
X 
Patient Global Assessment (PtGA) 
 
X 
 
X 
X 
 
X 
X 
X 
Dermatology Life Quality Index (DLQI or 
CDLQI)y 
 
X 
 
X 
X 
 
X 
X 
X 
Patient-Oriented Eczema Measure (POEM) 
 
X 
 
X 
X 
 
X 
X 
X 
Pruritus and Symptoms Assessment for 
Atopic Dermatitis (PSAAD)r 
X ------------------X X---------------------------------------------------------------------------------------------------------------------X 
Hospital Anxiety and Depression Scale 
(HADS) 
 
X 
 
X 
X 
 
X 
X 
X 
EQ-5D-5L (adults) or EQ-5D-Y (ages 12-17 
years) 
 
X 
 
X 
X 
 
X 
X 
X 
SF-36v2, Acutet 
 
X 
 
 
 
 
 
X 
X 
FACIT-F or Peds-FACIT-Fw 
 
X 
 
 
 
 
 
X 
X 
Safety 
 
 
 
 
 
 
 
 
 
Serious and non-serious adverse event 
monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Contraception Checks 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Sample for Baseline Viral Screenu 
 
X 
 
 
 
 
 
 
 
Abbreviations: AD = atopic dermatitis; BSA = body surface area; CDLQI = Children’s Dermatology Life Quality Index; C-SSRS = Columbia Suicide Severity 
Rating Scale; DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; ECG = electrocardiogram; EOS=End of Study; EOT = End of 
Treatment; ET= early termination; EQ-5D-5L = EuroQol Quality of Life 5-Dimension 5-Level Scale; EQ-5D-Y = EuroQol Quality of Life 5-Dimension, Youth 
Scale; FACIT-F = Functional Assessment of Chronic Illness Therapy Fatigue Scale;  FSH = follicle stimulating hormone; GGT= gamma-glutamyl transferase; 
HADS= Hospital Anxiety and Depression Scale; HBsAg = hepatitis B surface antigen; HBsAb = hepatitis B surface antibody; HBcAb = hepatitis B core 
antibody; HCVAb = hepatitis C antibody; HCV RNA = Hepatitis C Viral RNA; HIV = human immunodeficiency virus; HSV-1 = herpes simplex virus type 1; 
HSV2 = herpes simplex virus type 2; IGA = Investigator’s Global Assessment; IRT = Interactive Response System; NRS = numerical rating scale; 
Peds-FACIT-F = Pediatric Functional Assessment of Chronic Illness Therapy Fatigue Scale; PHQ-8 = Patient Health Questionnaire 8 items; POEM= 
Patient-Oriented Eczema Measure; PSAAD=Pruritus and Symptoms Assessment for Atopic Dermatitis; PtGA = Patient Global Assessment; RNA = Ribonucleic 
acid; SBQ-R = Suicide Behaviors Questionnaire-Revised; SCORAD = SCORing Atopic Dermatitis; SF-36v2 = Short Form-36 Health Survey Version 2; 
VZV = varicella zoster virus; VZV IgG Ab = varicella zoster virus immunoglobulin G antibody; 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.  
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c. 
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, lungs, and abdomen and examination of 
body systems where there are symptom complaints by the subject. 
d. Vital Signs include sitting blood pressure, pulse rate, respiratory rate, and temperature measured after at least 5 minutes of rest.  All vital signs at baseline 
and Week 12 must be performed prior to administration of investigational product and additional blood pressure and pulse rate assessments must be 
performed at least 1 hour following administration of investigational product.  All vital signs at all other on-site visits must be performed at least 1 hour 
following administration of investigational product.   
e. 
Chest X-ray or other appropriate diagnostic image (ie, CT or MRI) may be performed up to 12 weeks prior to Day 1.  Chest X-rays (posterior-anterior and 
lateral views) are required for adults and recommended for adolescents as per local guidelines and standard of care.  Official reading must be located and 
available in the source documentation. 
f. 
Serum chemistry includes: blood urea nitrogen (BUN), serum creatinine, creatine phosphokinase, glucose, Ca++, Na+, K+, Cl-, total CO2, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), total, indirect and direct bilirubin, alkaline phosphatase, 
lactate dehydrogenase, uric acid, albumin and total protein.  The 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, Week 4, Week 12 and EOS 
visits.  Hematology includes: Hemoglobin, hematocrit, red blood cell count and indices (MCH, MCHC, MCV, RBC Morphology), white blood cells, 
neutrophils (%, absolute), lymphocytes (%, absolute), monocytes (%, absolute), eosinophils (%, absolute), basophils (%, absolute), platelets, reticulocyte 
count and coagulation panel.  Coagulation panel includes: Activated Partial Thromboplastin Time (APTT), Prothrombin Time/International Normalized 
Ratio (PT/INR).  Laboratory tests with abnormal results (per Section 6.1 and Section 7.5.2) 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, including adolescents aged 12 years and older, regardless of whether 
they have experienced menarche.  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, including adolescents 
aged 12 years and older, regardless of whether they have experienced menarche.  
i. 
HIV testing will be performed for all subjects.  Subjects who are positive for HIV will be screen-failed.  
j. 
HBsAb reflex testing will be performed only if HBsAg negative but HBcAb positive.  Subjects who are positive for HCVAb and HCV RNA will be 
screen-failed. 
k. VZV IgG antibody testing is required to confirm eligibility in adolescent subjects who have not received at least one dose of a varicella vaccine. 
l. 
A documented TB test performed within 12 weeks prior to Day 1 is acceptable.  Subjects with a history of tuberculosis may not require TB testing as per the 
protocol exclusion criteria in Section 4.2.  Perform TB test procedure using the QuantiFERON-TB Gold In Tube Test (or Purified Protein Derivative).  A 
negative PPD test can be substituted for the QuantiFERON-TB Gold In-Tube test only if the central laboratory is unable to perform the 
QuantiFERON-TB Gold In-Tube test or cannot determine the results to be positive or negative and the Pfizer Medical Monitor approves it on a 
case-by-case basis.  In addition to protocol required TB testing, sites should follow their local standards for TB status determination, which may include 
chest X-ray.  See Section 7.2.3.  
m. A pharmacokinetic (PK) blood sample will be collected prior to dosing at the study site on Week 4.  
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n. PK blood samples will be collected at 0.5 hours (±15 min) postdose at the Week 4 visit and at 0.5 hours (±15 min) and 4.0 hours (±30 min) postdose at the 
Week 12 visit (EOT/ET).  For ET visits, if the subject discontinues before Week 4 do not collect PK samples.  If the ET visit occurs after Week 4, collect PK 
samples only if the subject takes the investigational product at the site visit.  
o. Subjects should take the medication from study Days 1 to 85.  Subjects will be encouraged to take the medication in the morning whenever 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. 
p. Site staff is to administer the C-SSRS, SBQ-R and PHQ-8 to all subjects at screening and score immediately.  Subjects who have recent or active suicidal 
ideation or behavior or clinically significant depression will be excluded from the study or discontinued from the study per Section 4.2, Section 7.4.1, 
Section 7.4.2 and Section 7.4.3.  For subjects meeting exclusionary results on the C-SSRS, SBQ-R and PHQ-8, it is recommended the subject's primary care 
physician (PCP) should be informed, and the subject referred to a mental health professional, either by the PCP or the investigator according to their usual 
practice. 
q. Pruritus Numerical Rating Scale (NRS) will be assessed using an eDiary, daily during the screening period and from Day 1 to 15.  After Day 15, the pruritus 
NRS will be completed only on study visit days in the eDiary.  At the Screening visit, site staff will dispense the ePRO device and review instructions for 
completion of the subject eDiary for the NRS.  At every visit, the study coordinator will review the eDiary for completeness and counsel the subject on how 
to complete the items in the daily eDiary, if needed.  
r. 
Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD) will be conducted to assess the severity and frequency of pruritus, symptoms and sleep 
collected daily in a subject e-diary during the screening period and from Day 1 through the End of Study visit in selected countries (See Section 7.7.7).  At 
the Screening visit, site staff will dispense the ePRO device and review instructions for completion of the subject eDiary for the PSAAD questionnaire.  
Subjects will be asked to record their assessment in their eDiary once a day before taking the investigational product.  At every visit, the study coordinator 
will review the eDiary for completeness and counsel the subject on how to complete the items in the daily eDiary, if needed.  
s. 
The contraception check is an opportunity to confirm that contraception, if assigned, is used consistently and correctly.  It also facilitates continual 
reassessment of child-bearing potential in women.  This allows for implementing necessary changes to contraception; for example, investigators may need to 
ensure alternative contraceptive methods if new concomitant disease contraindicates a selected method of contraception, or if a subject is demonstrably no 
longer of child-bearing status (as per protocol) then they will no longer require contraception.  Continual reassessment of contraceptive needs is imperative. 
t. 
SF-36v2 will be completed by adult subjects only.  Adolescents 12-17 years of age will not complete this assessment. 
u. A serum sample will be collected at baseline but analyzed only if the subject has suspected varicella or herpes zoster.  In that event, the sample would be 
analyzed for HSV1, HSV2 and VZV.  
v. Subjects who complete EOT will be assessed for eligibility for participation in long-term extension study B7451015 as noted in Section 6.2.7. 
w. FACIT-F will be completed by adult subjects only.  Adolescents 12-17 years of age will complete the Peds-FACIT-F instead.  
x. A single 12-lead ECG will be performed at screening and all other on-site visits and interpreted by a central reader.  Clinically significant or exclusionary 
ECG findings at the screening or baseline visits will require screen failure.   
y. DLQI will be completed by adult subjects only.  Adolescents 12-17 years of age will complete the CDLQI instead.  
 
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1. INTRODUCTION 
1.1. Mechanism of Action/Indication 
PF-04965842 is a Janus kinase 1 (JAK1) inhibitor that is being investigated as a treatment for 
patients with Atopic Dermatitis (AD).  
The Janus kinase (JAK) family, including JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2), 
is a group of cytoplasmic tyrosine kinases that mediate signal transduction via interactions 
with Type 1 and Type 2 cytokine receptors critical for leukocyte activation, proliferation, 
survival and function.  Cytokine receptors demonstrate restricted association with JAKs such 
that different receptors or receptor classes preferentially utilize a given JAK dimer or trimer 
combination to transduce their signal.  JAK1 pairs with JAK3 to mediate γ-common cytokine 
signaling and also with JAK2 or TYK2 to transmit the signals of additional cytokines 
important in inflammation and immune responses including interleukin (IL) -4, -5, -6, 
-13,-21, -31, interferon gamma (IFN-γ), and interferon alpha (IFN-α).  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.  
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.  
Key cytokines implicated in the pathophysiology of AD include IL-4, IL-5, IL-13, IL-31, 
and IFN-γ, require Janus kinase 1 (JAK1) for signal transduction; this suggests that selective 
JAK1 inhibitors that modulate the activity of these cytokines represent a compelling 
approach to the treatment of inflammatory skin diseases such as AD.7 
PF-04965842 is an orally bioavailable small molecule that selectively inhibits JAK1 by 
blocking the ATP binding site.  PF-04965842 has a high degree of selectivity against other 
kinases: 28-fold selectivity over JAK2, >340-fold over JAK3 and 43-fold over TYK2, as 
well as a good selectivity profile over the broader range of human kinases.  The selective 
inhibition of JAK1 will lead to modulation of multiple cytokine pathways involved in the 
pathophysiology of AD, including IL-4, IL-5, IL-13, IL-31 and IFN-γ.  Data from a Phase 2b 
proof of concept (POC) study (B7451006) that evaluated subjects with moderate to severe 
AD have shown positive efficacy, as well as an acceptable safety profile, sufficient to support 
further clinical development in a larger Phase 3 program. 
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1.2. Background and Rationale 
1.2.1. Drug Development and Rationale 
PF-04965842 is being developed as an oral treatment for patients with moderate to severe 
AD based on its mechanism of action, and the clinical results obtained in Phase 1 and 
Phase 2 studies.  The clinical development program for PF-04965842 includes healthy 
volunteers, subjects with psoriasis and subjects with AD.   
Additional information for this compound may be found in the single reference safety 
document (SRSD), which for this study is the Investigator’s Brochure (IB).  
1.2.2. Atopic Dermatitis 
Atopic dermatitis, also known as atopic eczema, is a common, chronic, inflammatory skin 
disorder characterized by flaky skin lesions, intense pruritus, and a general deterioration in 
the quality of life.  Over the past 50 years, AD has become more prevalent, especially in 
industrialized, temperate countries such as the US.1,2  AD is one of the most common, 
chronic, relapsing childhood dermatoses, impacting 15-30% of all children in the US and 
many have disease that persists into adulthood with a lifetime prevalence of those affected in 
childhood reported to be 34%.8  Earlier reports indicated that, in up to 70% of cases, the 
disease greatly improves or resolves until late childhood, however more recent findings 
suggest that disease activity remains manifest for a prolonged period of time.  Based on a 
total of 7157 patients enrolled in the Pediatric Eczema Elective Registry (PEER) study, 
comprising a total of 22,550 person-years, it was concluded that symptoms associated with 
AD seem to persist well into the second decade of a child’s life and likely longer.3  At every 
age, more than 80% of PEER study subjects had symptoms of AD and/or were using 
medication to treat their AD.  In 833 AD patients who were aged 20 years or older when they 
visited the clinic and 45 years or older when they responded to a follow-up questionnaire, 
59% responded that they had defined persistent AD at some time during the last 12 months.9   
The majority of studies conducted across multiple age groups suggest a continued decrease in 
prevalence with older age.10  Adult-onset AD does also occur, though it is less common.  The 
prevalence of AD in adults is estimated to be 10%.11  Recent studies have indicated that 
adults with AD are more likely to smoke cigarettes, drink alcohol, and have a sedentary 
lifestyle, potentially associated with increased comorbidities, such as asthma and 
cardiovascular disease.12 
Although great strides have been made in understanding the causes, the complex 
pathophysiology of AD is still not completely understood.  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 scratching, typically 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 AD lesions.13  
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Acute AD lesions have been associated with the Type 2 helper T cell (TH2) phenotype, 
showing dominance of IL-4, -5, -13, and -31 secretion.13,14,7  Recent research showed that a 
small increase of Type 1 helper T cell (TH1)-associated genes has been also detected in acute 
phase.15  
While IL-4-producing TH2 cells may drive the development of atopic skin lesions, chronic 
lesions show either the coexistence of both IL-4-producing TH2 and IFN-γ -producing TH1 
cells or TH1 dominance.13  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 also supports IL-31’s role in 
pruritus and inflammation in AD.14,7   
There are a limited number of treatments available for AD.  Current treatments for AD 
include emollients, topical corticosteroids (eg, betamethasone, clobetasol, fluocinonide), 
topical calcineurin inhibitors (eg, pimecrolimus, tacrolimus), and coal tar preparations.  
Crisaborole was approved as a topical treatment in December 2016 by the FDA for use 
in patients with mild to moderate AD.  Additional treatments generally reserved for severe 
AD include phototherapy (eg, ultraviolet A light [UVA] with or without psoralen, 
ultraviolet B light [UVB] narrowband or broadband) and systemic agents (eg, corticosteroids, 
cyclosporine, recombinant IFN-γ, mycophenolate mofetil, methotrexate [MTX], 
azathioprine, intravenous immunoglobulin).4  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, reduce pruritus and the resulting sleep 
disturbance.5,6   
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 is limited to 2 to 4 weeks) and to the body 
regions of use (eg, mid-high potency corticosteroids 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.   
Other systemic agents to treat AD are under clinical development or recently approved.  
Dupilumab, an injectable human monoclonal antibody targeting interleukin (IL)-4 and 
-13, was approved by the FDA in March 2017 and received marketing authorization in 
Europe in September 2017, and offers a novel mechanism of action for the treatment of 
moderate to severe AD.  However, the approved dosing for dupilumab as an initial dose of 
2 x 300 mg subcutaneous injections followed by 300 mg every other week injections may 
limit the desirability of this route of treatment. 
Therefore, the predominant unmet medical need is an oral therapy with an acceptable safety 
profile for long term use which is effective for refractory AD.   
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As mentioned above, a variety of pro-inflammatory cytokines such as IL-4, IL-13, IL-22, 
IL-31 and IFN-γ, have been suggested to have a role in the pathogenesis of AD.  Many of 
these pathogenic cytokines use the JAK1 for signaling.  Therefore, JAK1 is an attractive 
therapeutic target for AD. 
1.2.3. Non-Clinical and Phase 1 Data  
Data from nonclinical and Phase 1 programs supports the planned clinical trials with 
PF-04965842 and further information is in the current version of the Investigator’s Brochure 
(IB). 
1.2.4. Phase 2b in AD (B7451006)  
B7451006 was a Phase 2b proof-of-concept trial in adults (ages 18-75) with AD investigating 
doses of 10, 30, 100, and 200 mg PF-04965842 or placebo taken once daily (QD) for up to 
12 weeks.  The primary endpoint in this study was the proportion of subjects achieving an 
IGA score of clear (0), or almost clear (1), and a ≥2-point improvement from baseline at 
Week 12.  The baseline was defined as the IGA score on Day 1 pre-dose.  
At Week 12, IGA response rates of PF-04965842 100 mg and 200 mg dose groups were 
significantly greater than placebo in patients with moderate to severe AD.  The IGA response 
rates of the 200 mg and 100 mg groups were 44.5% and 27.8%, compared to 6.3% in the 
placebo group, (P= 0.0032 and 0.0184, respectively).  The percent change from baseline 
(% CFB) in EASI scores at Week 12 were significantly higher for both the 200 mg and 
100 mg groups compared to placebo (P<0.0001 and P=0.0091, respectively).  PF-04965842 
demonstrated a rapid onset of action.  In the 200 mg group, IGA and EASI scores improved 
until week 4 and week 6, respectively, and maintained their effect through 12 weeks of 
treatment.  Response rates at Week 12 for the 10 mg and 30 mg groups were not significantly 
different from placebo.  A key differentiating feature for the JAK1 inhibitor is rapid 
resolution of itch associated with AD.  Significant separation from placebo was achieved for 
the pruritus NRS score as early as 2 days after initiation of treatment for the 200 mg dose 
group. 
Overall, the results demonstrated dose-dependent increases in responses at Week 12 for key 
efficacy endpoints (IGA, EASI and pruritus NRS score). 
PF-04965842 appeared generally safe and well tolerated in this study.  AEs and SAEs were 
numerically higher in subjects receiving PF-04965842 compared to placebo, but did not 
appear to increase with dose.  The most common AEs were in the infections and infestations, 
skin and subcutaneous tissue disorders and gastrointestinal disorders system organ class 
(SOC), and the majority of the AEs were mild.  There were 2 cases of herpes zoster, one in 
the 10 mg group (not treatment related), and one in the 30 mg group (treatment related).  
There were dose-dependent decreases in platelet counts observed in the study, which 
plateaued at Week 4, and were not generally clinically relevant.  Further details of the 
clinical Phase 2 development program can be found in the Investigator’s Brochure (IB). 
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1.3. Summary of PF-04965842 Clinical Pharmacokinetics  
PF-04965842 was rapidly absorbed following single dose oral solution/suspension 
administration over the dose range 3 mg to 200 mg with time to maximum absorption (Tmax) 
ranging between 0.55 to 0.77 hours (B7451001).  Median Tmax at doses of 400 mg and 
800 mg were 1.5 and 3.9 hours, respectively, which indicated the slower absorption 
compared to lower doses.  PF-04965842 showed a monophasic decline at dose <100 mg with 
biphasic profiles at doses ≥100 mg.  Observed peak plasma PF-04965842 concentrations 
(Cmax) following the single-dose administration generally increased in proportion to the dose 
from 3 mg to 800 mg.  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 3 mg to 200 mg, while a greater than proportional increase was observed at 
doses of 400 and 800 mg.  The arithmetic mean terminal phase half-life (t½) was 1.9 to 
4.9 hours. 
Following QD administration over the dose range 30 mg to 400 mg and 100 mg and 
200 mg twice a day (BID) for 10 days, median Tmax ranged between 0.50 to 0.77 hours 
(B7451001).  After attainment of Cmax, the disposition of PF-04965842 was consistent with 
that observed following single-dose administration, showing a biphasic decline following all 
but the lowest dose and an arithmetic mean terminal phase t½ between 2.8 to 5.0 hours.  
Although Cmax generally increased in proportion to the dose up to 100 mg given twice daily 
(BID), it increased more than the dose increased at 400 mg QD and 200 mg BID.  The same 
trend was also observed for area under the plasma concentration-time curve (AUCtau) over 
the dosing interval (tau = 12 or 24 hours).  The observed accumulation ratio (Rac) following 
200 mg BID was 2.0 and 2.5 for AUCtau and Cmax, respectively.  Rac was 1.1 to 1.5 at other 
doses.  Therefore, the results showed that drug concentration accumulation is minimal after 
repeated oral administration at lower doses consistent with the prediction from t½.  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 percent coefficient of variation (%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)) (B7451001).  
Geometric mean (%CV) Cmax and AUCtau following multiple-dose administration of 200 mg 
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 12 healthy 
subjects under fasting and fed conditions (study B7451004).  The extent of absorption 
(AUCinf) of the tablet was equivalent to that of the suspension (90% confidence interval (CI) 
for tablet/suspension ratio: (90.31, 103.21) while peak concentrations (Cmax) were lower 
(90% CI for tablet/ratio: (62.88, 100.46)) on average for the tablet relative to suspension.  
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Co-administration of 400 mg (4 x 100 mg) of the tablet with food resulted in equivalent 
geometric mean AUCinf between fasted and fed conditions and a small mean decrease 
(<5%) in Cmax.  The magnitude of decrease in Cmax was not considered to be clinically 
important.  Overall, PF-04965842 can be administered with or without food. 
1.3.1. Population Pharmacokinetics 
Population PK analysis was conducted by pooling data from two Phase 1 studies (B7451001, 
first-in-human study, and B7451004, relative bioavailability study) in healthy subjects and 
the proof-of-concept study (B7451006) in AD patients.  A total of 2465 PK observations 
from 354 subjects were included in the analysis and the data were described using a 
2 compartment model with first-order absorption.  The estimates of systemic 
clearance/fraction of dose absorbed (CL/F) and volume of distribution/fraction absorbed 
(V/F) were 44.8 L/hr and 147 L with inter individual variability (IIV) values of 63% and 
35% (expressed as % CV) respectively.  Clearance (CL/F) of AD patients was estimated to 
be ~38% lower than that of healthy subjects; residual variability was estimated to be higher 
in AD patients compared to the value in healthy subjects (66% vs. 36% CV).  Baseline body 
weight, race, age and sex were tested as covariates on clearance and did not appear to impact 
the PK of PF-04965842.  Therefore, CL/F of PF-04965842 in adult patients is expected to be 
representative of adolescent patients, and similar systemic exposures are expected at the 
same dose for adolescent patients in the same weight range as the adults.  In order to ensure 
similarity of systemic exposure, only adolescent patients with body weight ≥40 kg will be 
included in the study.  This is based on the lowest body weight of 44.5 kg evaluated in the 
prior population PK analysis in adult patients where no effect of body weight on oral 
clearance was found.  Therefore, no adjustment of the adult dose is needed for adolescent 
subjects planned for enrolment in this study. 
1.4. Summary of Benefits and Risks 
There was clinically meaningful benefit demonstrated in the Phase 2b Proof of Concept study 
in adult patients with moderate to severe AD.  The potential risks of treatment include those 
that were noted in Phase 2b and/ or those based on the pharmacology of JAK1 inhibitors and 
include viral reactivation, serious and opportunistic infections, hematopoietic effects 
(including reduced platelet count), and malignancy and immunoproliferative disorders.  In 
the Phase 1 Study B7451001 there were 6 subjects, 1 in the placebo group and 5 in a 
PF-04965852 treated group, with a QTcF (QT interval with Fridericia’s correction) interval 
meeting the threshold for characterization for absolute QTcF interval (450 to <480 msec) 
and/or QTcF interval change (30 ≤ to <60 msec).  Further information is available in the 
Investigator’s Brochure.  Appropriate risk evaluation and mitigation strategies have been 
incorporated into this protocol.  
Overall, there is a favorable benefit-risk profile to support the continued development into 
Phase 3 of PF-04965842 in the treatment of patients, 12 years of age and older, with AD for 
both the 100 and 200 mg dose. 
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1.5. Dose Selection Rationale 
Dose selection for Phase 3 was based on efficacy and safety of PF-04965842 from a 
dose-ranging Phase 2b study, B7451006 that evaluated a 20-fold dose range (10 mg to 
200 mg QD) in adult subjects with AD.  The 200 mg QD dose is expected to provide efficacy 
similar to that of currently approved systemic treatments in moderate to severe AD, based on 
dose-response modeling of IGA response in the Phase 2 study, and was therefore selected as 
the high dose for evaluation in Phase 3 studies.  An additional dose of 100 mg QD was also 
selected for evaluation in Phase 3, since this dose is expected to provide clinically meaningful 
difference from placebo in IGA response, and is also expected to differentiate from the 
higher dose in terms of expected efficacy and systemic exposure.  Both 100 mg and 
200 mg QD doses demonstrated acceptable safety and tolerability in the Phase 2 study.  
There was no evidence of dose-dependent changes in safety endpoints such as serious 
infections or adverse events.  Dose-response was evident only for changes from baseline in 
platelet counts.  Mean platelet count decreases from baseline were observed with a nadir at 
Week 4.  At Week 4 the mean platelet count and the 90% CI were within the normal 
reference range for the 100 mg dose and 200 mg dose.  The mean platelet counts increased 
towards baseline after Week 4.  One (1) PF-04965842 treated subject with an AE of 
thrombocytopenia had a value less than 0.5 x lower limit of normal.  There were no reported 
adverse clinical effects potentially associated with reduced platelet counts, such as bleeding 
events, observed in the Phase 2 study.  Further details are available in the IB.  
Since body weight did not appear to be a significant determinant of PK across the weight 
range evaluated in the Phase 2b study, adolescents aged 12 years and older weighing 40 kg or 
more will be administered the same dose as the adults (ie, 100 mg QD and 200 mg QD).  
(See Section 1.3.1 Population Pharmacokinetics).  The PK, efficacy, and safety data collected 
in adolescents will be monitored periodically by an external data monitoring committee 
(E-DMC) to ensure acceptable benefit risk for this patient population.  The PK data from the 
first 20 adolescent patients will be analyzed to confirm the dose concentration relationship 
and assess consistency with adult data.  The totality of data collected in adolescents and 
adults will be used to evaluate the final dosing recommendations in this patient group and 
will be further utilized to predict dosing in younger patients for the pediatric development 
program. 
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2. STUDY OBJECTIVES AND ENDPOINTS 
Study objectives and corresponding endpoints are provided in Table 1.  
Table 1. 
Objectives and Endpoints 
Primary Objective: 
Primary Endpoints: 
To assess the efficacy 
of PF-04965842 
compared with placebo 
in subjects aged 
12 years and older 
with moderate to 
severe AD. 
The following co-primary endpoints will be tested: 
• 
Response based on the Investigator’s Global Assessment (IGA) score of clear (0) or 
almost clear (1) (on a 5 point scale) and a reduction from baseline of ≥2 points at 
Week 12.  The baseline will be defined as the IGA score on Day 1 pre-dose; 
• 
Response based on the Eczema Area and Severity Index 75% improvement from baseline 
(EASI-75) response at Week 12.  The baseline will be defined as the EASI score on Day 1 
pre-dose. 
Secondary Objective: 
Secondary Endpoints: 
To evaluate the effect 
of PF-04965842 on 
additional efficacy 
endpoints and patient 
reported outcomes 
over time in subjects 
aged 12 years and 
older with moderate to 
severe atopic 
dermatitis. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Key Secondary Endpoints: 
• 
Response based on at least 4 points improvement in the severity of pruritus numerical 
rating scale (NRS) from baseline at Weeks 2, 4, and 12; 
• 
Change from Baseline in Pruritus and Symptoms Assessment for Atopic Dermatitis 
(PSAAD) total score at Week 12.  
Secondary Efficacy Endpoints: 
• 
Response based on at least 4 points improvement in the severity of pruritus numerical 
rating scale (NRS) from baseline at all scheduled time points other than Weeks 2, 4 and 
12;   
• 
Time from baseline to achieve at least 4 points improvement in the severity of pruritus 
NRS scale; 
• 
Response based on the EASI-75 at all scheduled time points except Week 12;  
• 
Response based on the IGA of clear (0) or almost clear (1) and ≥2 point reduction from 
baseline at all scheduled time points except Week 12. 
Other Efficacy Endpoints: 
• 
Response based on a ≥50% and ≥90% improvement in the EASI total score (EASI-50 and 
EASI-90) at all scheduled time points; 
• 
Change from baseline in the percentage Body Surface Area (BSA) affected at all 
scheduled time points; 
• 
Response based on a ≥50% and ≥75% improvement in SCORAD (SCORAD50, 
SCORAD75) from baseline at all scheduled time points; 
• 
Change from baseline at all scheduled time points in SCORAD subjective assessments of 
itch and sleep loss. 
Patient-reported Outcomes: 
• 
Change from baseline at Week 12 in Dermatology Life Quality Index (DLQI) or 
Children’s DLQI (CDLQI) and at all other scheduled time points; 
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Table 1. 
Objectives and Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
Change from baseline at Week 12 in Hospital Anxiety and Depression Scale (HADS) and 
at all other scheduled time points;  
• 
Change from baseline at Week 12 in Patient-Oriented Eczema Measure (POEM) and at all 
other scheduled time points;  
• 
Change from baseline of Patient Global Assessment (PtGA) at Week 12 and at all other 
scheduled time points;  
• 
Change from baseline of EuroQol Quality of Life 5-Dimension 5-Level Scale 
(EQ-5D-5L) or EuroQol Quality of Life 5-Dimension Youth Scale (EQ-5D-Y) at 
Week 12 and at all other scheduled time points; 
• 
Change from baseline of Functional Assessment of Chronic Illness Therapy Fatigue Scale 
(FACIT-F) or Pediatric FACIT-F (Peds-FACIT-F) at Week 12 and at all other scheduled 
time points; 
• 
Change from baseline of Short Form-36v2 (SF-36v2), acute at Week 12 and at all other 
scheduled time points; 
• 
Response based on at least 4 points improvement in the frequency of pruritus numerical 
rating scale (NRS) from baseline at all scheduled time points;  
• 
Time from baseline to achieve at least 4 points improvement in the frequency of pruritus 
NRS scale. 
Safety Objective 
Safety Endpoints 
To evaluate the safety 
and tolerability of 
PF-04965842 in 
subjects aged 12 years 
and older with 
moderate to severe 
atopic dermatitis 
following 12 weeks of 
treatment. 
• 
Incidence of treatment emergent adverse events; 
• 
Incidence of SAEs and AEs leading to discontinuation; 
• 
The incidence of clinical abnormalities and change from baseline in clinical laboratory 
values, ECG measurements, and vital signs. 
PK Objectives  
PK Endpoint 
To evaluate the PK of 
PF-04965842 in 
subjects aged 12 years 
and older with 
moderate to severe 
atopic dermatitis 
following 12 weeks of 
treatment. 
• 
Population PK characterization in subjects aged 12 years and older with moderate to 
severe atopic dermatitis. 
 
AD = Atopic dermatitis; AE = Adverse Event; BSA = Body Surface Area; CDLQI = Children’s Dermatology Life 
Quality Index; DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; ECG = 
Electrocardiogram; EQ-5D-5L = EuroQol; Quality of Life measure; 5-Dimension 5-Level Scale; EQ-5D-Y = EuroQol 
Quality of Life 5-Dimension Youth Scale; FACIT-F = Functional Assessment of Chronic Illness Therapy Fatigue Scale; 
Peds-FACIT-F = Pediatric FACIT-F; HADS = Hospital Anxiety and Depression Scale; IGA = Investigator’s Global 
Assessment; NRS = pruritus numerical rating scale; PK = pharmacokinetics; SCORAD = Scoring Atopic Dermatitis; 
POEM = Patient-Oriented Eczema Measure; PtGA = Patient Global Assessment; PSAAD = Pruritus and Symptoms 
Assessment for Atopic Dermatitis; SF-36v2 = Short Form-36 Version 2; SAE = Serious Adverse Event 
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3. STUDY DESIGN 
This is a randomized, double-blind, placebo-controlled, parallel-group, Phase 3 study to 
evaluate the efficacy and safety of PF-04965842 monotherapy in subjects aged 12 years and 
older with moderate to severe AD and a body weight ≥40 kg.  The treatment duration is 
12 weeks.  Subjects will be screened within 28 days prior to the first dose of investigational 
product to confirm that they meet the subject selection criteria for the study.  A total of 
approximately 375 subjects will be enrolled from approximately 75 sites located globally.  
Adolescent subjects below the age of 18 years old (or country-specific age of majority) will 
only be enrolled in this study if instructed by the sponsor and approved by the country or 
regulatory/health authority.  If these approvals have not been granted, only subjects aged 
18 years (or country-specific age of majority) and older will be enrolled.  A study design 
schematic is presented in Figure 1. 
Figure 1. Study Design Schematic 
 
Qualified subjects completing the 12-week treatment period of the study will have the option 
to enter a long-term extension (LTE) study B7451015.  Subjects discontinuing early from 
treatment, or who are otherwise ineligible for the LTE study will undergo a 4 week follow-up 
period in B7451012. 
Subjects who have chronic moderate to severe AD as defined per the inclusion criteria will 
be randomized to receive 200 mg or 100 mg PF-04965842 once daily (QD), or matching 
placebo.  Investigators, subjects, and the sponsor study team will be blinded as to treatment 
group. 
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After providing informed consent, subjects will be assessed for study eligibility at the 
screening visit.  For subjects younger than 18 years old (or country-specific age of majority), 
their parent(s)/legal guardian will provide supplementary or sole written consent and minor 
children will provide assent, according to local regulations and rules regarding ability to give 
assent and consent.  Subjects will undergo screening within 28 days prior to randomization.  
During the screening period, treatments for AD will be washed out, as applicable, according 
to eligibility requirements.  Subjects may be re-screened once if they fail the screening 
evaluation for reasons related to incidental transitory conditions, unless the reason for the 
screen failure the disease severity inclusion criteria.  
Subjects who continue to meet eligibility criteria at baseline will undergo Day 1/baseline 
assessments and be randomized in a 2:2:1 ratio to receive 200 mg PF-04965842 (N=150) or 
100 mg PF-04965842 QD (N=150) or matching placebo (N=75) from Day 1.  
Randomization will be stratified by baseline disease severity (moderate [IGA = 3] vs. severe 
[IGA = 4] AD), and, age <18 and ≥18.  Eligible subjects must have a documented history of 
inadequate response or intolerance to treatment with topical AD medications or have required 
systemic therapies for control of their disease. 
4. SUBJECT ELIGIBILITY CRITERIA 
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular subject is suitable for this protocol.  
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study.  
4.1. Inclusion Criteria 
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 or their parent(s)/legal guardian, if applicable, have been informed 
of all pertinent aspects of the study.  
2. Male or female subjects of 12 years of age or older, at the time of informed consent 
and body weight ≥40 kg.  Adolescent subjects below the age of 18 years old (or 
country-specific age of majority) will only be enrolled in this study if instructed by 
the sponsor and approved by the country or regulatory/health authority.  If these 
approvals have not been granted, only subjects aged 18 years (or country-specific 
age of majority) and older will be enrolled. 
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3. Meet all the following atopic dermatitis criteria: 
• Clinical diagnosis of chronic atopic dermatitis (also known as atopic eczema) for 
at least 1 year prior to Day 1 and has confirmed atopic dermatitis (Hanifin and 
Rajka criteria of AD; refer to (Appendix 2) at the Screening and Baseline visits; 
• Documented recent history (within 6 months before the screening visit) of 
inadequate response to treatment with topical medications for at least 4 weeks, or 
for whom topical treatments are otherwise medically inadvisable (eg, because of 
important side effects or safety risks), or who have required systemic therapies for 
control of their disease; 
• Moderate to severe AD (affected BSA ≥10%, IGA ≥3, EASI ≥16, and Pruritus 
NRS ≥4 at the baseline visit). 
4. Willing and able to comply with scheduled visits, treatment plan, laboratory tests 
and other study procedures. 
5. Female subjects who are of child-bearing potential (which includes all female 
subjects aged 12 years and older, regardless of whether they have experienced 
menarche) must not be intending to become pregnant, currently pregnant, or 
lactating.  The following conditions apply: 
a. Female subjects of childbearing potential must have a confirmed negative 
pregnancy test prior to randomization; 
b. Female subjects of childbearing potential must agree to use a highly effective 
method of contraception (as per Section 4.4.1) for the duration of the active 
treatment period and for at least 28 days after the last dose of investigational 
product. 
For Czech Republic only, 5 b. is revised and 5 c. is added to require:  
b. Female subjects of childbearing potential ≥15 years of age who are at risk of 
pregnancy must agree to use a highly effective method of contraception (as per 
Section 4.4.1) for the duration of the active treatment period and for at least 
28 days after the last dose of investigational product; 
c. Female subjects less than 15 years of age must not be sexually active, and 
abstinence per the below definition should be confirmed prior to enrollment. 
NOTE: Sexual abstinence, defined as completely and persistently refraining from all 
heterosexual intercourse (including during the entire period of risk associated with 
study treatments) may obviate the need for contraception ONLY if this is the 
preferred and usual lifestyle of the subject.  
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6. Female subjects of non-childbearing potential must 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 12 consecutive months with no alternative pathological or 
physiological cause and have a serum follicle-stimulating hormone (FSH) level 
confirming the postmenopausal state. 
All other female subjects (including female subjects with tubal ligations) are 
considered to be of childbearing potential. 
7. 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. 
8. If receiving concomitant medications for any reason other than AD, must be on a 
stable regimen, which is defined as not starting a new drug or changing dosage 
within 7 days or 5 half-lives (whichever is longer) prior to Day 1 and through the 
duration of the study. 
4.2. Exclusion Criteria 
Subjects with any of the following characteristics/conditions will not be included in the 
study: 
1. Other acute or chronic medical or psychiatric condition including recent (within the 
past year) or active suicidal ideation or behavior or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the subject inappropriate for entry into 
this study. 
2. Any psychiatric condition including recent or active suicidal ideation or behavior 
that meets any of the following criteria:  
• Suicidal ideation associated with actual intent and a method or plan in the past 
year: “Yes” answers on items 4 or 5 of the Columbia suicide severity rating scale 
(C-SSRS) (Appendix 15); 
• Previous history of suicidal behaviors in the past 5 years: “Yes” answer (for 
events that occurred in the past 5 years) to any of the suicidal behavior items of 
the C-SSRS; 
• Any lifetime history of serious or recurrent suicidal behavior; 
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• Suicidal behaviors questionnaire – revised (SBQ-R) total score ≥8 (Appendix 16); 
• Clinically significant depression: patient health questionnaire – 8 items (PHQ-8) 
total score ≥15 (Appendix 17); 
• The presence of any current major psychiatric disorder that is not explicitly 
permitted in the inclusion/exclusion criteria; 
• In the opinion of the investigator or Pfizer (or designee) exclusion is required. 
3. A current or past medical history of conditions associated with thrombocytopenia, 
coagulopathy or platelet dysfunction. 
4. Receiving anti-coagulants or medications known to cause thrombocytopenia, 
(unless considered safe to stop and washout for the duration of the study). 
5. Currently have active forms of other inflammatory skin diseases, ie, not AD or have 
evidence of skin conditions (eg, psoriasis, seborrheic dermatitis, Lupus) at the time 
of Day 1 that would interfere with evaluation of atopic dermatitis or response to 
treatment. 
6. Vaccinated or exposed to a live or attenuated vaccine within the 6 weeks prior to 
the first dose of investigational product, or is expected to be vaccinated or to have 
household exposure to these vaccines during treatment or during the 6 weeks 
following discontinuation of investigational product. 
7. Adolescent subjects 12 to <18 years old without documented evidence of having 
received at least one dose of the varicella vaccine in countries where the vaccine is 
approved and standard of care or those who do not have evidence of prior exposure 
to varicella zoster virus (VZV) based on serological testing (ie, varicella zoster 
virus immunoglobulin G antibody [VZV IgG Ab]) at screening. 
8. Subjects who have received prior treatment with any JAK inhibitors. 
9. Participation in other studies involving investigational drug(s) within 8 weeks or 
within 5 half-lives (if known) whichever is longer, prior to study entry and/or 
during study participation. 
Note: Any investigational or experimental therapy taken or procedure performed for 
AD, psoriasis, psoriatic arthritis or rheumatoid arthritis in the previous 1 year 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. 
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10. Have received any of the following treatment regimens specified in the timeframes 
outlined below: 
Within 1 year of first dose of investigational product: 
• Prior treatment with non B cell-specific lymphocyte depleting agents/therapies 
(eg, alemtuzumab [CAMPATH], alkylating agents [eg, cyclophosphamide or 
chlorambucil], total lymphoid irradiation, etc).  Subjects who have received 
rituximab or other selective B lymphocyte depleting agents (including 
experimental agents) are eligible if they have not received such therapy for at 
least 1 year prior to study baseline and have normal cluster of differentiation (CD) 
19/20+ counts by fluorescence-activated cell sorting (FACS) analysis. 
Within 12 weeks of first dose of investigational product: 
• Other biologics: within 12 weeks of first dose of investigational product or 
5 half-lives (if known), whichever is longer. 
Within 6 weeks of first dose of investigational product: 
• Use of dupilumab. 
Within 4 weeks of first dose of investigational product:  
• Use of oral immunosuppressive drugs (eg, cyclosporine A [CsA], azathioprine, 
methotrexate, systemic corticosteroids, mycophenolate-mofetil, IFN-γ) within 
4 weeks of first dose of investigational product or within 5 half-lives (if known), 
whichever is longer;  
• Phototherapy narrowband UVB (NB-UVB) or broad band phototherapy; 
• Regular use (more than 2 visits per week) of a tanning booth/parlor; 
• Herbal medications with unknown properties or known beneficial effects for AD. 
Within 1 week of first dose of investigational product: 
• Anti-platelet drugs.  
Note: low dose acetyl salicylic acid (≤100 mg QD) is permitted, for the purpose of 
cardiovascular prophylaxis, at the discretion of the investigator. 
Within 72 hours of first dose of investigational product: 
• Topical treatments that could affect atopic dermatitis (eg, corticosteroids, 
calcineurin inhibitors, tars, antibiotic creams, topical antihistamines). 
Note: Corticosteroid inhalers and intranasal sprays are allowed for stable asthma 
patients. 
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11. Have a history of any lymphoproliferative disorder such as Epstein Barr Virus 
(EBV) related lymphoproliferative disorder, history of lymphoma, leukemia, or 
signs or symptoms suggestive of current lymphatic or lymphoid disease. 
12. Infection History: 
a. Have a history of systemic infection requiring hospitalization, parenteral 
antimicrobial therapy, or as otherwise judged clinically significant by the 
investigator within 6 months prior to Day 1. 
b. Have active chronic or acute skin infection requiring treatment with systemic 
antibiotics, antivirals, antiparasitics, antiprotozoals, or antifungals within 2 weeks 
prior to Day 1, or superficial skin infections within 1 week prior to Day 1. 
c. A subject known to be infected with Human Immunodeficiency Virus (HIV), 
Hepatitis B, or Hepatitis C (Section 7.5.2). 
d. 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. 
13. Have a history of alcohol or substance abuse within 6 months prior to Day 1 that in 
the opinion of the investigator will preclude participation in the study.  
For Czech Republic only, exclusion criterion 13 states: 
Have a history of alcohol or substance abuse within 12 months prior to Day 1 that 
in the opinion of the investigator will preclude participation in the study.  
14. A Screening 12-lead ECG that 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) or criteria associated with Q wave interval (QT)/ 
Fridericia-corrected Q wave interval (QTcF) abnormalities including: 
• A marked prolongation of QTcF interval (>450 milliseconds [ms]) on the 
screening ECG; 
• A history of additional risk factors for Torsade de Pointes (TdP) (eg, heart failure, 
hypokalemia, family history of Long QT Syndrome); 
• Use of concomitant medications that prolong the QT/QTcF interval. 
15. Have a known immunodeficiency disorder or a first-degree relative with a 
hereditary immunodeficiency. 
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16. 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. 
17. Require treatment with prohibited concomitant medication(s) (Section 5.8.2 and 
Appendix 3) or have received a prohibited concomitant medication within the 
specified time frame prior to the first dose of study medication. 
18. Have evidence of active or latent or inadequately treated infection with 
Mycobacterium tuberculosis (TB) as defined by the following: 
• A positive QuantiFERON-TB Gold (QFT-G) In-Tube test or positive 
Mantoux/Purified Protein Derivative (PPD) tuberculin skin test (if appropriate per 
Section 7.2.4) performed at or within the 12 weeks prior to Day 1 is 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 7.2.4 for requirements for 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; 
• A history of either untreated or inadequately treated latent or active TB infection; 
• If a subject has previously received an adequate course of therapy for either latent 
(9 months of isoniazid in a locale where rates of primary multi-drug TB resistance 
are <5% or an acceptable alternative regimen) or active (acceptable multi-drug 
regimen) TB infection, neither a QFT-G test nor a Mantoux/PPD tuberculin skin 
test is needed, but a chest radiograph(s) is required for adults, and recommended 
for adolescents per local standard/guidelines, if not performed within 12 weeks 
prior to Day 1.  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 Day 1.  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; 
• A subject who is currently being treated for active TB infection is to be excluded. 
19. ANY of 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 <1.2 x 109/L (<1200/mm3); 
• Hemoglobin <10.0 g/dL or hematocrit <30%; 
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• Platelet count of <150 x 109/L (<150,000/mm3); 
• Absolute lymphocyte count of <0.50 x 109 /L (<500/mm3);   
For Czech Republic only, the following absolute lymphocyte count applies:  
Absolute lymphocyte count of <0.75 x 109 /L (<750/mm3). 
• Estimated Creatinine Clearance <40 mL/min based on the age appropriate 
calculation, or serum creatinine >1.5 times the upper limit of normal (ULN); 
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) values 
>2 times the ULN; 
• Total bilirubin ≥1.5 times 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. 
20. In the opinion of the investigator or sponsor, have any uncontrolled clinically 
significant laboratory abnormality that would affect interpretation of study data or 
the subject’s participation in the study. 
21. Have undergone significant trauma or major surgery within 1 month of the first 
dose of investigational product. 
22. Investigator site staff members directly involved in the conduct of the study and 
their family members, site staff members otherwise supervised by the investigator, 
or subjects who are Pfizer employees, including their family members, directly 
involved in the conduct of the study.  
4.3. Randomization Criteria  
Subjects will be randomized into the study provided they or their parent(s)/legal guardian, if 
applicable, 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 Day 1.  A computer-generated randomization 
schedule will be used to assign subjects to the treatment groups using an Interactive 
Response Technology (IRT). 
4.4. Lifestyle Requirements  
In order to participate in the study, subjects must be aware of the following lifestyle 
guidelines and restrictions that apply during and after the treatment period. 
• On study visit days (Day 1, Weeks 4, 12 and End of Study [EOS]), subjects must 
comply with fasting requirement for at least 8 hours prior to the visit.  Water and 
permitted non-study medications are allowed (see Section 5.8.1). 
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• On study visit days, subjects must not smoke or ingest caffeine during the 30 minutes 
prior to blood pressure and heart rate measurements. 
• On study visit days, subjects must not take the dose of investigational product until 
instructed to do so by the investigator or designated study site staff. 
• On study visit days, showering or bathing is permitted prior to attending the study 
visit, but subjects must not moisturize or apply emollient.  Non-medicated emollient 
is allowed after the visit.  Discontinue and avoid using certain medications and 
treatments (Section 4.2, Section 5.8.2, and Appendix 3). 
• Agree to use one highly effective method of contraception (as specified in 
Section 4.4.1, as applicable. 
4.4.1. Contraception 
All female subjects who are of childbearing potential which includes all female subjects aged 
12 years and older, regardless of whether they have experienced menarche, who are, in the 
opinion of the investigator, sexually active and at risk for pregnancy with their partner(s) 
must agree to use a highly effective method of contraception consistently and correctly for 
the duration of the active treatment period and for at least 28 days after the last dose of 
investigational product.   
For Czech Republic only, the contraception paragraph above is revised to require:   
Female subjects less than 15 years of age must be abstinent from sexual activity in order to 
participate in the study.  All other female subjects of childbearing potential, regardless of 
whether they have experienced menarche, who are, in the opinion of the investigator, 
sexually active and at risk for pregnancy with their partner(s) must agree to use a highly 
effective method of contraception consistently and correctly for the duration of the active 
treatment period and for at least 28 days after the last dose of investigational product. 
The investigator or his or her designee, in consultation with the subject, will confirm that the 
subject has selected an appropriate method of contraception for the individual subject and her 
partner from the permitted list of contraception methods (see below) and will confirm that the 
subject has been instructed in its consistent and correct use.  At time points indicated in the 
Schedule of Activities, the investigator or designee will inform the subject of the need to use 
highly effective contraception consistently and correctly and document the conversation and 
the subject’s affirmation in the subject’s chart (subjects needs to affirm their consistent and 
correct use of at least 1 of the selected methods of contraception).  In addition, the 
investigator or designee will instruct the subject to call immediately if the selected 
contraception method is discontinued or if pregnancy is known or suspected in the subject or 
the partner.  
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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, 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 separate spermicide product (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). 
NOTE: Sexual abstinence, defined as completely and persistently refraining from all 
heterosexual intercourse (including during the entire period of risk associated with the study 
treatments) may obviate the need for contraception ONLY if this is the preferred and usual 
lifestyle of the subject. 
The contraception check is an opportunity to confirm that contraception, if assigned, is used 
consistently and correctly.  It also facilitates continual reassessment of child bearing potential 
in women.  This allows for implementing necessary changes to contraception; for example, 
investigators may need to ensure alternative contraceptive methods if new concomitant 
disease contraindicates a selected method of contraception, or if a subject is demonstrably no 
longer of child bearing status (as per protocol) then they will no longer require contraception.  
Continual reassessment of contraceptive needs is imperative. 
For countries in the EU: 
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, 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. 
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2. Correctly placed copper-containing intrauterine device (IUD). 
3. Male sterilization with absence of sperm in the post-vasectomy ejaculate. 
4. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive 
procedure (provided that occlusion has been confirmed in accordance with the 
device’s label). 
NOTE: Sexual abstinence, defined as completely and persistently refraining from all 
heterosexual intercourse (including during the entire period of risk associated with the study 
treatments) may obviate the need for contraception ONLY if this is the preferred and usual 
lifestyle of the subject. 
4.4.2. Vaccine and Exposure to Infections Guidelines 
4.4.2.1. Subject Specific Recommendations 
It is recommended that all subjects should be up-to-date with respect to standard of care 
vaccinations (as defined by their country health ministry) or AD guidelines.  Vaccination of 
subjects with live components is prohibited within the 6 weeks prior to first dose of 
investigational product.  Adolescent subjects without documented evidence of having 
received at least one dose of the varicella vaccine or those who are without evidence of 
previous varicella zoster exposure as confirmed by VZV IgG Ab serological testing are 
excluded.  
4.4.2.2. Guidance Regarding Household Contact Vaccine-Related Exposure 
Current routine household contact with children and others who have been vaccinated with 
live vaccine components may pose a risk during treatment and for 6 weeks following 
completion of the study.  Some of these vaccines include varicella (“chickenpox”) vaccine, 
oral polio vaccine, and the inhaled flu vaccine.  Following vaccination with live component 
vaccines, the virus may be shed in bodily fluids, including stool, and there is a potential risk 
that the virus may be transmitted.  General guidelines for immunosuppressed subjects 
suggest that exposure (through routine contact) should be avoided following vaccination (of 
others) with these vaccines for the stated time period: 
a. Varicella or attenuated typhoid fever vaccination for 4 weeks following vaccination. 
b. Oral polio vaccination for 6 weeks following vaccination. 
c. Attenuated rotavirus vaccine for 10 days following vaccination. 
d. FluMist (inhaled flu vaccine) for 1 week following vaccination. 
Subjects should avoid exposure to vaccinated or infected persons and contact the investigator 
promptly should they develop signs or symptoms of infections. 
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4.4.3. Surgery 
During the study, no elective surgery 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 investigational product prior to the surgical 
procedure.  In general, planned surgical procedures should not be performed unless the 
investigational product has been discontinued for at least 28 days (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. 
4.5. Sponsor’s Qualified Medical Personnel 
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the 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 product identifiers, subject study numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
subject’s participation in the study.  The contact number can also be used by investigator 
staff if they are seeking advice on medical questions or problems; however, it should be used 
only in the event that the established communication pathways between the investigator site 
and the study team are not available.  It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study.  The contact 
number is not intended for use by the subject directly, and if a subject or their parent(s)/legal 
guardian calls that number, he or she will be directed back to the investigator site. 
5. STUDY TREATMENTS 
For this study, the investigational products are PF-04965842 and placebo.  PF-04965842 will 
be administered orally at doses of 100 mg or 200 mg given QD for 12 weeks based on 
treatment assignment.  In addition, one treatment group will be assigned to receive 
PF-04965842-matching placebo.  
For the purposes of this study, and per International Conference on Harmonisation (ICH) 
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference/comparator in a clinical trial, 
including a product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use (ICH E6 1.33).   
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5.1. Allocation to Treatment 
Allocation of subjects to treatment groups will proceed through the use of an Interactive 
Response Technology (IRT) 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 then be provided with a treatment assignment 
and dispensable unit (DU) or container number when investigational product 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 24 hour a day, 365 days a year IRT help desk 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 
Investigators, subjects and the sponsor study team will be blinded as to treatment group.  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 an electronic process.  When the blind for a subject has been 
broken, the reason must be fully documented and 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. 
5.3. Subject Compliance 
For self-administration of the investigational product at home, compliance will be captured 
and completed by the subject.  Subjects will be issued an electronic dosing diary (eDiary) and 
will be educated to record the time of their daily dosing, once they have taken the 
investigational product.  
When investigational product is administered at the research facility, it will be administered 
under the supervision of study personnel. 
Compliance with the dosing of investigational product will be monitored and verified by 
delegated site personnel through a combination of the accounting of unused investigational 
product returned by the subject at the study visits, review of the dosing diary, and discussion 
with the subject which will be documented in the source documents.   
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Investigational product should be taken in the morning.  Subjects should be instructed that if 
a dose is inadvertently missed then it should be taken as soon as remembered, but not within 
12 hours of the next scheduled dose.  
The following compliance cases will be considered medication errors and will be discussed 
with the sponsor for possible withdrawal from the study: 
• Subjects interrupting investigational product for more than 4 consecutive days or for a 
total of more than 7 days between visits;   
• Subjects administering >8 tablets in one day or administering ≥4 tablets/day for 
4 consecutive days;   
• Subjects who have an overall compliance of <80% or >120% between visits. 
Any deviation from protocol specified dosing should be recorded as a protocol deviation and 
the investigator or designee is to counsel the subject and parent(s)/legal guardian (if 
applicable) and ensure steps are taken to improve compliance.  In addition, if the compliance 
deviation reaches the thresholds defined above it should also be recorded as a medication 
error (see Section 8.4.4). 
5.4. Investigational Product Supplies 
5.4.1. Dosage Form(s) and Packaging 
Blinded PF-04965842 and its matched placebo will be provided as 100 mg tablets for oral 
administration.  The 100 mg tablets and their matching placebos will be supplied in separate 
bottles 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 bottles (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 bottles provided, in quantities appropriate for the study visit 
schedule.  The subject/caregiver should be instructed to maintain the product in the bottles 
provided throughout the course of dosing and return the bottles to the site at the next study 
visit.  
5.5. Administration 
Subjects will be dispensed two (2) bottles at each dispensing visit and given clear dosing 
instructions to take one tablet from each bottle, once daily, preferably in the morning, at 
approximately the same time of day.  Subjects should take the investigational product orally 
once a day for 12 weeks, 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 on site visit days. 
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Table 2. 
Investigational Product Administration 
Treatment Assignment 
QD Dosing* 
100 mg QD 
Bottle A 100 mg - 1 tablet  
Bottle B Placebo - 1 tablet 
200 mg QD 
Bottle A 100 mg - 1 tablet 
Bottle B 100 mg - 1 tablet 
Placebo 
Bottle A Placebo - 1 tablet  
Bottle B Placebo - 1 tablet 
* Bottle A and B designations are used for example purposes only. 
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.  
A guidance document with detailed dosing instructions will also be provided to subjects to 
support at-home dosing. 
5.6. Investigational Product Storage  
The investigator, or an approved representative, eg, pharmacist, will ensure that all 
investigational products are stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements.  
Investigational product should be stored in their original container and in accordance with the 
labels.  See the Investigational Product Manual (IP Manual) for storage conditions of the 
product. 
Any storage conditions stated in the SRSD will be superseded by the storage conditions 
stated on the product label. 
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products).  This should 
be captured from the time of investigational product receipt throughout the study.  Even for 
continuous-monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order.  
Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery.  The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer.  
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Once an excursion is identified, the investigational product must be quarantined and not used 
until Pfizer provides documentation of permission to use the investigational product.  It will 
not be considered a protocol deviation if Pfizer approves the use of the investigational 
product after the temperature excursion.  Use of the investigational product prior to Pfizer 
approval will be considered a protocol deviation.  Specific details regarding information the 
site should report for each excursion will be provided to the site in the IP Manual.  
Receipt of materials, door opening and closing, and other routine handling operations where 
the products are briefly out of the temperature range described in the labeling are not 
considered excursions. 
Site staff will instruct subjects on the proper storage requirements for take home 
investigational products.  
5.7. Investigational Product Accountability  
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be 
accounted for using a drug accountability form/record.  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 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.  
All bottles of investigational product must be brought back to the site at every visit for 
inspection by the site staff and all bottles/unused investigational product must be returned to 
the investigator by the subject at the relevant visit(s). 
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 investigator site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented. 
5.8. Concomitant Treatment(s) 
Subjects will abstain from all concomitant medications as described in Section 4.2 and 
Appendix 3 of the protocol.  Medications that are taken in the Screening/Washout period 
(after informed consent is obtained and before the first dose of investigational product) will 
be documented as prior medications.  Medications taken after the first dose of investigational 
product has been administered will be documented as concomitant medications.  All 
concomitant medications taken during the study must be recorded in study records with 
indication (if atopic dermatitis), reference to any associated adverse event, dose, and start and 
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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. 
5.8.1. Permitted Concomitant Medications 
The following concomitant AD therapies are permitted during the study: 
• Oral antihistamines;  
• Topical non-medicated emollient.  
The following concomitant medications are permitted during the study: 
• Corticosteroid inhalers and intranasal sprays are allowed for stable asthma patients; 
• Ophthalmic corticosteroids are allowed for patients receiving a stable dose to treat 
rhinoconjuntivitis; 
• Low dose acetyl salicylic acid (≤100 mg QD) is permitted, for the purpose of 
cardiovascular prophylaxis, at the discretion of the investigator; 
• Acetaminophen/paracetamol may be used intermittently (not to exceed 1 g/day);  
• Vitamin and mineral supplements of standard potency are allowed in amounts not 
known to be associated with adverse effects (such as hyper-vitaminosis). 
For the purposes of this protocol, dietary supplements are defined as vitamins, minerals, and 
purified food substances.  Vitamins, minerals and purified food substances are allowed in 
amounts not known to be associated with adverse effects (such as hyper-vitaminosis). 
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 Day 1, addition of concomitant medications 
or any change in the dosage should be limited to those considered medically essential. 
A subject who is receiving a permitted concomitant medication for any reason must be on a 
locally-approved medication and dose, 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 7 days or 5 half-lives 
(whichever is longer) prior to Day 1 and prior to study visits throughout the study, unless 
otherwise noted below.  
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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.  
5.8.2. Prohibited Medications and Treatments 
Subjects are required to discontinue and avoid using certain medications and treatments (see 
Section 4.2, Inclusion Criteria and Exclusion Criteria, and Appendix 3).  Subjects should 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 not to use tanning 
booths, sun lamps or other ultraviolet light sources during the study.  
Subjects who received prior treatment with JAK inhibitors are to be excluded from the study.  
Herbal medications with unknown properties or known beneficial effects for AD must be 
discontinued at least 4 weeks before the first dose of investigational product.  
Restrictions on certain vaccinations are described in Section 4.4.2. 
The Pfizer study team is to be notified of any prohibited medications taken during the study.  
After consulting with the Medical Monitor, the investigator will make a judgement on the 
ongoing eligibility of any subject with prohibited medication use during the study.  
6. STUDY PROCEDURES  
Refer to the Schedule of Activities for a detailed list of study procedures as they should be 
conducted at each respective visit.  
Due to possible need for PPD testing and chest radiograph, screening procedures may be 
performed over more than 1 visit in the 28 days prior to the Day 1 visit.  
Visit windows are based on Day 1 visit.  To assure consistency and reduce variability, all 
study visits should occur in the morning whenever possible.  On days of study visits, subjects 
will receive their dose at the clinic during the visit.  
Subjects are required to fast for at least 8 hours prior to all visits that include lipid profile 
panel testing (Day 1, Week 4, Week 12, and EOS).  During the fasting period, subjects 
should refrain from all food and liquids (water and permitted non-study medications are 
allowed).  
ECGs will be interpreted by a central reader for all visits. 
Urine pregnancy test must be performed prior to dosing with the investigational product for 
female subjects of childbearing potential, including adolescents aged 12 years and older, 
regardless of whether they have experienced menarche, through to the EOS visit. 
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Prior to attending a study visit, subjects are allowed to shower and bathe but should not 
moisturize or apply emollient.  
Refer to Appendix 4 for guidelines on subject safety monitoring and discontinuation.  
6.1. Visit 1, Screening 
Subjects will be screened (Visit 1) within 28 days prior to administration of the 
investigational product to confirm that they meet the subject selection criteria for the study.  
The investigator (or an appropriate delegate at the investigator site) will obtain informed 
consent from each subject, or parent(s)/legal guardian (and assent from the subject, as 
appropriate), in accordance with the procedures described in the Subject Information and 
Consent in Section 12.3.  
If the Mantoux PPD tuberculin skin test is given, the subject must return between 
48-72 hours 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 4-week screening period, the subject may enter the study.  
The following procedures will be completed:  
• Obtain written informed consent; for subjects aged less than the legal age of majority 
(legal adulthood) in the subject’s country, obtain written informed consent from 
parent(s)/legal guardian, and informed assent from the patient (if age appropriate 
according to local regulations); 
• Register subject using the IRT system; 
• Collect demography; 
• Administer C-SSRS, SBQ-R and PHQ-8.  Subjects meeting any of the criteria 
specified in Exclusion Criterion 2 as described in Section 4.2 on the C-SSRS, SBQ-R 
and PHQ-8 should be excluded from participation; it is recommended the subject’s 
primary care physician (PCP) should be informed, and the subject referred to a mental 
health professional, either by the PCP or the investigator according to their usual 
practice; 
• Complete medical history, including history of alcohol and tobacco use.  Smoking 
status and average weekly alcohol consumption (units/week) will also be collected, 
where a unit contains 12 g of pure alcohol, an amount equivalent to that contained in 
5 oz/150 ml (a glass) of wine, 12 oz/360 ml of beer, or 1.5 oz/45 ml of 90 proof 
(45% alcohol by volume) of spirits; 
• Complete AD disease history includes collection of details of AD: AD diagnosis and 
duration, the use of topical treatments, systemic treatments and other treatments for 
AD; 
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• Obtain complete medication history of all prescription or nonprescription drugs, and 
dietary and herbal supplements taken within 28 days prior to the planned first dose, 
except as noted below:   
The following timeframe prior to the planned first dose must be used for collection of 
the following Current/Prior Medications: 
• 1 year: Previous drug treatments for AD including the use of topical treatments, 
systemic treatments and other treatments;  
• Any previous history of intolerance/allergy to any drug, regardless of indication. 
• Obtain vital signs including pulse rate, sitting blood pressure, respiratory rate and oral 
or tympanic temperature (after at least 5 minutes of rest); 
• Obtain weight; 
• Obtain height; 
• Perform a single 12-lead electrocardiogram (ECG).  Clinically significant or 
exclusionary ECG findings require screen failure;   
• Conduct complete physical examination; 
• Dispense electronic patient reported outcome (ePRO) handheld device and instruct 
subject in how to use the device.  Instruct the subject to begin daily completion of the 
PSAAD (in selected countries) and pruritus NRS questionnaire;  
• Pruritus NRS will be collected daily in a subject eDiary during the screening period 
and from Day 1 to 15 and then on study visit days;  
• PSAAD will be collected daily in a subject eDiary during the screening period and 
from Day 1 through the End of Study visit, in selected countries;  
• Chest X-ray (posterior-anterior and lateral views) or other appropriate diagnostic 
image (ie, computerized tomography [CT] or magnetic resonance imaging [MRI]) are 
required for adults and recommended for adolescents (based on local guidelines and 
standard of care).  Official reading must be located and available in the source 
documentation.  Chest X-ray may be performed up to 12 weeks prior to Day 1; 
• Obtain samples for laboratory testing: serum chemistry, hematology (including 
coagulation panel), urinalysis, serum FSH (postmenopausal women) or serum 
pregnancy test (women of childbearing potential, including adolescents aged 12 years 
and older, regardless of whether they have experienced menarche), HIV, hepatitis B 
surface antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis B surface 
antibody (HBsAb), hepatitis C viral antibody (HCV Ab), hepatitis C viral ribonucleic 
acid (HCV RNA) (see Section 7.5.2.1), VZV IgG antibody testing for adolescent 
subjects who have not received at least one dose of a varicella vaccine; 
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• QuantiFERON – TB Gold test (unless performed within 12 weeks of Day 1).  If 
Mantoux PPD tuberculin skin test is required to be performed instead, per 
Section 7.2.4, the subject must return between 48-72 hours post-injection for 
evaluation of induration (see Section 7.2.4 for further details on TB testing); 
• Conduct clinical evaluations including IGA, SCORAD, EASI and BSA (calculated in 
the EASI); 
• Assess need for contraception and adherence to applicable lifestyle requirements 
(Section 4.4).  Establish willingness and ability to comply with lifestyle requirements 
going forward in the study; 
• Review Inclusion and Exclusion criteria for subject eligibility; 
• Assess for occurrence of Adverse Events: The adverse event and SAE reporting 
period starts with the signing of the informed consent document; 
• If the subject is eligible for continued participation, provide subject with emergency 
contact card. 
6.2. Treatment Period 
6.2.1. Visit 2, Day 1/Week 0 (Baseline) 
• Administer patient-reported outcomes (PROs) including: PtGA, DLQI (or CDLQI), 
POEM, HADS, EQ-5D-5L (or EQ-5D-Y), SF-36v2, Acute and FACIT-F (or 
Peds-FACIT-F).  SF-36v2 will be completed by adult subjects only;  
• Adolescents 12-17 years of age will not complete the SF-36v2.  Adolescents 12-17 
years of age will complete the CDLQI instead of the DLQI, the EQ-5D-Y instead of 
the EQ-5D-5L and Peds-FACIT-F instead of the FACIT-F; 
• Review eDiary pruritus NRS and PSAAD completion (in selected countries) and 
review eDiary procedures with subject as necessary; 
• Review any changes in the subject’s prior and concomitant medications and treatment 
information; 
• Obtain pre-dose vital signs including pulse rate, sitting blood pressure, respiratory 
rate and oral or tympanic temperature (after at least 5 minutes of rest); 
• Obtain weight; 
• Perform a single 12-lead electrocardiogram (ECG). Clinically significant or 
exclusionary ECG findings require screen failure;  
• Conduct complete physical examination;  
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• Obtain fasting samples for laboratory testing: serum chemistry, hematology 
(including coagulation panel), lipid profile, and urinalysis;  
• Urine pregnancy test (female subjects of childbearing potential, including adolescents 
aged 12 years and older, regardless of whether they have experienced menarche).  A 
negative urine pregnancy test must be obtained prior to dosing with the 
investigational product;  
• Collect sample for viral surveillance: Herpes simplex virus (HSV) HSV-1, HSV-2 
and VZV; 
• Conduct clinical evaluations including Fitzpatrick Skin Type Assessment, IGA, 
SCORAD, EASI and BSA (calculated in the EASI); 
• Assess need for contraception and adherence to applicable lifestyle requirements 
(Section 4.4).  Establish willingness and ability to comply with lifestyle requirements 
going forward in the study; 
• Review of Inclusion/Exclusion Criteria; 
• If subject continues to meet all Inclusion/Exclusion criteria, officially randomize 
subject into the study; 
• Dispense investigational product  to the subject; 
• Administer first dose of investigational product to subject; 
• Obtain an additional pulse rate and sitting blood pressure (after at least 5 minutes of 
rest).  Pulse rate and sitting blood pressure must be performed at least 1 hour 
following the first dose of investigational product; 
• Assess and record any Adverse Events since the last visit.  
6.2.2. Visit 3, Day 8/Week 1 (±1 day) 
• Call subject and confirm compliance with daily completion of pruritus NRS and 
PSAAD (in selected countries);  
• Verbally confirm subject has been compliant with study dosing and entry in the 
eDiary.  Review eDiary procedures with subject as necessary; 
• Review any changes in the subject’s concomitant medications and treatment 
information; 
• Assess need for contraception and adherence to applicable lifestyle requirements 
(Section 4.4).  Establish willingness and ability to comply with lifestyle requirements 
going forward in the study; 
• Assess and record any Adverse Events since the last visit. 
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6.2.3. Visit 4, Day 15/Week 2 (±1 day) 
• Administer PROs including PtGA, DLQI (or CDLQI), POEM, HADS and EQ-5D-5L 
(or EQ-5D-Y);   
• Adolescents 12-17 years of age will complete the CDLQI instead of the DLQI and the 
EQ-5D-Y instead of the EQ-5D-5L; 
• Review pruritus NRS and PSAAD completion (in selected countries) and review 
eDiary procedures with subject as necessary.  Instruct subject that pruritus NRS will 
now be completed only at visits on site and in the eDiary and will no longer be 
completed on a daily basis at home; 
• Urine pregnancy test (female subjects of childbearing potential, including adolescents 
aged 12 years and older, regardless of whether they have experienced menarche).  A 
negative urine pregnancy test must be obtained prior to dosing with the 
investigational product;  
• Administer investigational product at clinic; 
• Perform a single 12-lead electrocardiogram (ECG); 
• Conduct targeted physical examination; 
• Obtain samples for laboratory testing: serum chemistry, hematology (including 
coagulation panel), and urinalysis;  
• Conduct clinical evaluations including IGA, SCORAD, EASI and BSA (calculated in 
the EASI); 
• Obtain vital signs including pulse rate, sitting blood pressure, respiratory rate and oral 
or tympanic temperature (after at least 5 minutes of rest).  Vital signs must be 
performed at least 1 hour following administration of investigational product; 
• Assess need for contraception and adherence to applicable lifestyle requirements 
(Section 4.4).  Establish willingness and ability to comply with lifestyle requirements 
going forward in the study; 
• Review any changes in the subject’s concomitant medications and treatments 
information; 
• Review eDiary to assess completion; 
• Perform drug accountability procedures; 
• Assess and record any Adverse Events since the last visit. 
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6.2.4. Visit 5, Day 29/Week 4 (±2 day) 
• Administer PROs including PtGA, DLQI (or CDLQI), POEM, HADS and EQ-5D-5L 
(or EQ-5D-Y);   
• Adolescents 12-17 years of age will complete the CDLQI instead of the DLQI and the 
EQ-5D-Y instead of the EQ-5D-5L; 
• Review PSAAD daily completion (in selected countries) and pruritus NRS 
completion for this visit in the eDiary;  
• Perform a single 12-lead electrocardiogram (ECG); 
• Conduct targeted physical examination; 
• Obtain fasting samples for laboratory testing: serum chemistry, hematology 
(including coagulation panel), lipid profile, and urinalysis;  
• Urine pregnancy test (female subjects of childbearing potential, including adolescents 
aged 12 years and older, regardless of whether they have experienced menarche).  A 
negative urine pregnancy test must be obtained prior to dosing with the 
investigational product;  
• Obtain a blood sample for PK analysis prior to dosing, administer investigational 
product at clinic, and obtain a second PK blood sample 0.5 hours post dose;  
• Obtain vital signs including pulse rate, sitting blood pressure, respiratory rate and oral 
or tympanic temperature (after at least 5 minutes of rest) and oral or tympanic 
temperature.  Vital signs must be performed at least 1 hour following administration 
of investigational product; 
• Conduct clinical evaluations including IGA, SCORAD, EASI and BSA (calculated in 
the EASI); 
• Assess need for contraception and adherence to applicable lifestyle requirements 
(Section 4.4).  Establish willingness and ability to comply with lifestyle requirements 
going forward in the study; 
• Review any changes in the subject’s concomitant medications and treatments 
information; 
• Review eDiary to assess completion; 
• Perform drug accountability procedures; 
• Dispense investigational product to the subject; 
• Assess and record any Adverse Events since the last visit. 
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6.2.5. Visit 6, Day 43/Week 6 (±3 day) 
• Call subject and confirm compliance with daily completion of PSAAD (in selected 
countries); 
• Verbally confirm subject has been compliant with study dosing and entry in the 
eDiary.  Review eDiary procedures with subject as necessary;   
• Review any changes in the subject’s concomitant medications and treatment 
information; 
• Assess need for contraception and adherence to applicable lifestyle requirements 
(Section 4.4).  Establish willingness and ability to comply with lifestyle requirements 
going forward in the study; 
• Assess and record any Adverse Events since the last visit. 
6.2.6. Visit 7, Day 57/Week 8 (±3 day) 
• Administer PROs including PtGA, DLQI (or CDLQI), POEM, HADS and EQ-5D-5L 
(or EQ-5D-Y); 
• Adolescents 12-17 years of age will complete the CDLQI instead of the DLQI and the 
EQ-5D-Y instead of the EQ-5D-5L; 
• Review PSAAD daily completion (in selected countries) and pruritus NRS 
completion for this visit in the eDiary;  
• Urine pregnancy test (female subjects of childbearing potential, including adolescents 
aged 12 years and older, regardless of whether they have experienced menarche).  A 
negative urine pregnancy test must be obtained prior to dosing with the 
investigational product;  
• Administer investigational product at clinic; 
• Perform a single 12-lead electrocardiogram (ECG); 
• Conduct targeted physical examination; 
• Obtain samples for laboratory testing: serum chemistry, hematology (including 
coagulation panel), and urinalysis;  
• Conduct clinical evaluations including IGA, SCORAD, EASI and BSA (calculated in 
the EASI); 
• Obtain vital signs including pulse rate, sitting blood pressure, respiratory rate and oral 
or tympanic temperature (after at least 5 minutes of rest).  Vital signs must be 
performed at least 1 hour following administration of investigational product;  
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• Assess need for contraception and adherence to applicable lifestyle requirements 
(Section 4.4).  Establish willingness and ability to comply with lifestyle requirements 
going forward in the study; 
• Review any changes in the subject’s concomitant medications and treatments 
information; 
• Review eDiary to assess completion; 
• Perform drug accountability procedures; 
• Dispense investigational product to the subject;  
• Assess and record any Adverse Events since the last visit. 
6.2.7. Visit 8, Day 85/Week 12 (±3 days) or Early Termination Visit 
• Administer PROs including PtGA, DLQI (or CDLQI), POEM, HADS, EQ-5D-5L (or 
EQ-5D-Y), SF-36v2, Acute and FACIT-F (or Peds-FACIT-F).  SF-36v2 will be 
completed by adult subjects only;  
• Adolescents 12-17 years of age will not complete the SF-36v2.  Adolescents 12-17 
years of age will complete the CDLQI instead of the DLQI, the EQ-5D-Y instead of 
the EQ-5D-5L and Peds-FACIT-F instead of the FACIT-F;  
• Review PSAAD daily completion (in selected countries) and pruritus NRS 
completion for this visit in the eDiary;  
• Urine pregnancy test (female subjects of childbearing potential, including adolescents 
aged 12 years and older, regardless of whether they have experienced menarche).  A 
negative urine pregnancy test must be obtained prior to dosing with the 
investigational product; 
• Obtain pre-dose vital signs including pulse rate, sitting blood pressure, respiratory 
rate and oral or tympanic temperature (after at least 5 minutes of rest); 
• Obtain weight; 
• Obtain height; 
• Perform a single 12-lead electrocardiogram (ECG); 
• Conduct complete physical examination; 
• Obtain fasting samples for laboratory testing: serum chemistry, hematology 
(including coagulation panel), lipid profile, and urinalysis;  
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• Administer investigational product at clinic; 
• Obtain blood samples for PK analysis 0.5 hours and 4 hours post-dose.  For ET visits, 
if the subject discontinues before Week 4 do not collect PK samples.  If the ET visit 
occurs after Week 4, collect PK samples only if the subject takes the investigational 
product at the site visit; 
• Obtain an additional pulse rate and sitting blood pressure (after at least 5 minutes of 
rest).  Pulse rate and sitting blood pressure must be performed at least 1 hour 
following administration of investigational product; 
• Conduct clinical evaluations including IGA, SCORAD, EASI and BSA (calculated in 
the EASI); 
• Assess need for contraception and adherence to applicable lifestyle requirements 
(Section 4.4).  Establish willingness and ability to comply with lifestyle requirements 
going forward in the study; 
• Review any changes in the subject’s concomitant medication and treatments 
information; 
• Review eDiary to assess completion; 
• Perform drug accountability procedures; 
• Assess and record any Adverse Events since the last visit; 
• Subjects who complete the trial to this visit will be assessed for eligibility for 
participation in long-term extension study B7451015.  Subjects who are not eligible 
or are not interested are to continue to Visit 9 (see Section 6.3.1). 
6.3. Follow-up Visits 
6.3.1. Visit 9, Day 120/Week 16 (±3 day)  
• Administer PROs including PtGA, DLQI (or CDLQI), POEM, HADS, EQ-5D-5L (or 
EQ-5D-Y), SF-36v2, Acute and FACIT-F (or Peds-FACIT-F).  SF-36v2 will be 
completed by adult subjects only; 
• Adolescents 12-17 years of age will not complete the SF-36v2.  Adolescents 12-17 
years of age will complete the CDLQI instead of the DLQI, the EQ-5D-Y instead of 
the EQ-5D-5L and Peds-FACIT-F instead of the FACIT-F;  
• Review PSAAD daily completion (in selected countries) and pruritus NRS 
completion for this visit in the eDiary; 
• Obtain vital signs including pulse rate, sitting blood pressure, respiratory rate and oral 
or tympanic temperature (after at least 5 minutes of rest); 
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• Perform a single 12-lead electrocardiogram (ECG); 
• Conduct targeted physical examination; 
• Obtain fasting samples for laboratory testing: serum chemistry, hematology 
(including coagulation panel), lipid profile, and urinalysis;  
• Urine pregnancy test (female subjects of childbearing potential, including adolescents 
aged 12 years and older, regardless of whether they have experienced menarche);  
• Conduct clinical evaluations including IGA, SCORAD, EASI and BSA (calculated in 
the EASI); 
• Assess need for contraception and adherence to applicable lifestyle requirements 
(Section 4.4).  Establish willingness and ability to comply with lifestyle requirements 
going forward in the study; 
• Review any changes in the subject’s concomitant medications and treatments 
information; 
• Assess and record any Adverse Events since the last visit. 
6.4. Subject Withdrawal 
Ongoing safety concern at the time of subject withdrawal from the study: 
If a subject has a clinically significant, treatment-emergent, abnormality at the time of 
withdrawal from the study, the Pfizer Medical Monitor (or designee) should be notified and 
every effort should be made to arrange follow-up evaluations at appropriate intervals to 
document the course of the abnormality.  All abnormal laboratory events of clinical 
significance should be followed until the laboratory values have returned to normal or 
baseline levels or are deemed clinically stable.  Follow-up for abnormal laboratory findings 
and adverse events by the investigator is required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.  
Refer to Appendix 4 for Guidelines for Monitoring and Discontinuation.  
Withdrawal of consent: 
Subjects (or parent(s)/legal guardian, as applicable) who request to discontinue receipt of 
study treatment will remain in the study.  If this request occurs at a scheduled visit, an end of 
treatment visit should be performed and the subject should enter into the follow-up period, 
with an end of study visit scheduled for 4 weeks after the end of treatment visit.  If the 
request occurs outside of a scheduled visit (eg, via telephone contact) the subject should be 
scheduled to return to site for an end of treatment visit within one week, and the subject 
should enter into the follow-up period, with an end of study visit scheduled for 4 weeks after 
the end of treatment visit.  
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The only exception to this is when a subject (or parent(s)/legal guardian, as applicable) 
specifically withdraws consent for any further contact with him or her or persons previously 
authorized by the subject to provide this information.  Subjects (or parent(s)/legal guardian, 
as applicable) should notify the investigator in writing of the decision to withdraw consent 
from future follow-up, whenever possible.  The withdrawal of consent should be explained in 
detail in the medical records by the investigator, as to whether the withdrawal is only from 
further receipt of investigational product or also from study procedures and/or posttreatment 
study follow-up, and entered on the appropriate CRF page.  In the event that vital status 
(whether the subject is alive or dead) is being measured, publicly available information 
should be used to determine vital status only as appropriately directed in accordance with 
local law. 
Lost to follow-up:  
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status.  This includes follow-up with persons authorized by the subject as noted above.  Lost 
to follow-up is defined by the inability to reach the subject after a minimum of 2 documented 
phone calls, faxes, or e-mails as well as lack of response by the subject to 1 registered mail 
letter.  All attempts should be documented in the subject’s medical records.  If it is 
determined that the subject has died, the site will use locally permissible methods to obtain 
the date and cause of death.  If the investigator’s use of a third-party representative to assist 
in the follow-up portion of the study has been included in the subject’s (or parent(s)/legal 
guardian, as applicable) informed consent, then the investigator may use a sponsor-retained 
third-party representative to assist site staff with obtaining the subject’s contact information 
or other public vital status data necessary to complete the follow-up portion of the study.  
The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information.  If, after all attempts, 
the subject remains lost to follow-up, then the last-known-alive date as determined by the 
investigator should be reported and documented in the subject’s medical records. 
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety (see also the 
Withdrawal From the Study Due to Adverse Events section) 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 that discontinue study treatment will remain in the 
study and must have their end of treatment visit within 1 week after their last dose, and will 
then enter the 4 week follow up period.  See Appendix 4 for Guidelines for Monitoring and 
Discontinuation.  
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 that the subject return for a final visit, if applicable, and follow up with 
the subject regarding any unresolved AEs. 
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If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent. 
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 manner. 
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.  
7.1. Pregnancy Testing 
For female subjects of childbearing potential, including adolescents aged 12 years and older, 
regardless of whether they have experienced menarche, a serum pregnancy test with a 
sensitivity of at least 25 mIU/mL, will be performed at screening.  A urine pregnancy test 
with a sensitivity of at least 25 mIU/mL, will be performed at every site visit including the 
End of Treatment (EOT) and follow-up visits to confirm the subject has not become pregnant 
during the study, and at the follow-up visit.  
A negative pregnancy test result is required before the subject may receive the investigational 
product.  Pregnancy tests will also be done whenever 1 menstrual cycle is missed during the 
active treatment period (or when potential pregnancy is otherwise suspected).  Pregnancy 
tests may also be repeated if requested by institutional review boards (IRBs)/ethics 
committees (Ecs) or if required by local regulations.  
Urine pregnancy tests must be sensitive to at least 25 mIU/mL and will be conducted with the 
test kit provided by the central laboratory in accordance with instructions provided in its 
package insert.  Subjects who have missed a menstrual period or who show an indeterminate 
or positive result on the urine test may not further progress in the study until pregnancy is 
ruled out using further diagnostic testing (eg, a negative quantitative serum pregnancy test 
conducted at a certified laboratory). 
In the case of a positive confirmed pregnancy, the subject will be withdrawn from 
administration of investigational product but may remain in the study. 
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7.2. Safety Assessments 
Safety will be assessed by the spontaneous reporting of AEs, physical examinations, vital 
signs 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 
ensure subjects’ well-being. 
7.2.1. Vitals Signs 
Vital signs (sitting blood pressure, pulse rate, respiratory rates and temperature) will be 
measured after 5 minutes of rest as indicated in the Schedule of Activities.  
Body temperature will be collected using the tympanic or oral methods and the same method 
should 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 30 minutes preceding the measurements.  Measurements should 
begin after at least 5 minutes of rest.  
Heart rate should be measured at approximately the same time as BP for a minimum of 
30 seconds.  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. 
7.2.2. Medical History, Physical Examination, Height, and Weight 
Complete AD disease history includes 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 will be collected at 
screening.  Medical history also includes history of alcohol and tobacco use.  Smoking status 
and average weekly alcohol consumption (units/week) will be collected, where a unit 
contains 12 g of pure alcohol, an amount equivalent to that contained in 5 oz/150 mL (a 
glass) of wine, 12 oz/360 mL of beer, or 1.5 oz/45 mL of 90 proof of spirits.  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 
time points, see Schedules of Activities. 
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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, lungs, 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. 
7.2.3. Chest X-Ray 
Chest radiograph (posterior-anterior and lateral views) are required for adults and 
recommended for adolescents (as per local guidelines and standard of care) 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, taken at screening or 
within 12 weeks prior to Study Day 1 and read by a qualified radiologist.  Documentation of 
the official reading must be located and available in the source documentation. 
7.2.4. Tuberculosis Testing 
At the time of screening, all subjects will undergo tuberculosis (TB) testing unless performed 
within 12 weeks of Day 1.  QuantiFERON-TB Gold In-Tube Test is the preferred testing 
method.  If the QuantiFERON-TB Gold In-Tube test cannot be performed, or if the results 
cannot be determined by the reference laboratory to be either positive or negative, then 
subjects may be screened using the Purified Protein Derivative (PPD) Tuberculin Skin Test 
(Mantoux method) with approval of the Pfizer Medical Monitor.  
In addition to TB testing as specified in this clinical protocol, a chest X-ray will be 
performed to aid in TB status determination for all adults, and recommended for adolescents 
according to local guidelines and standard of care and/or in countries with a high incidence 
rate of TB.  
QuantiFERON-TB Gold In-Tube is an in vitro diagnostic test using a peptide cocktail 
simulating ESAT-6, CFP-10 and TB 7.7 proteins 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 tuberculosis infection.  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. 
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A blood sample (approximately 3 mL) will be collected at screening for QuantiFERON-TB 
Gold In-Tube testing.  Following sample processing, the sample will be shipped to the 
sponsor’s designated reference laboratory for testing.  The procedure for processing and 
preparing the sample for shipment is described fully in the laboratory manual, which will be 
provided to investigators. 
A negative PPD test can be substituted for the QuantiFERON-TB Gold In-Tube test only if 
the central laboratory is unable to perform the QuantiFERON-TB Gold In-Tube test or 
cannot determine the results to be positive or negative and the Pfizer Medical Monitor 
approves it, on a case-by-case basis. 
Purified Protein Derivative (PPD) Test 
If the QuantiFERON-TB Gold In-Tube test cannot be performed, or if the results cannot be 
determined to be positive or negative, then subjects may be screened using the Purified 
Protein Derivative (PPD) Tuberculin Test (Mantoux method), with the approval of the Pfizer 
Medical Monitor.  
Subjects must have the PPD test administered and evaluated by a health care professional 
48 to 72 hours later in order to be eligible for the study, unless performed and documented 
within the last 3 months.  The test should be performed according to local standards with 
induration of <5 mm required for inclusion. 
7.2.5. Electrocardiogram 
A single 12-lead ECG will be collected at screening and all other on-site visits as specified in 
the Schedule of Activities.  ECGs reading will be performed by a central reader. 
All scheduled ECGs should be performed after the subject has rested quietly for at least 
10 minutes in a supine position.  
A subject’s screening ECG must be within normal limits prior to randomization. 
7.2.6. Special Safety Assessment 
In the event of a suspected opportunistic infection, effort should be made to identify the 
pathogen utilizing laboratory or other methods appropriate to the clinical situation.  
In case of a suspected viral skin infection (eg, herpes zoster and herpes simplex) or eczema 
herpeticum, a specimen for viral DNA may be analyzed locally for confirmation and results 
provided to the adjudication committee to support evaluation.   
For subjects with a past history of oral or genital HSV and a presentation consistent to prior 
infections, further laboratory analysis may be performed at the discretion of the investigator.  
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7.3. Skin Type Assessment 
As part of baseline characteristics, a skin type assessment will be done at the Day 1 visit 
using the Fitzpatrick Skin Type assessment (Refer to Appendix 5).  This is used to classify a 
person’s skin type by their response to sun exposure (ie, burning or tanning). 
7.4. Assessment of Suicidal Ideation and Behavior 
Subjects meeting exclusionary results as described in Section 4.2 on the C-SSRS, SBQ-R and 
PHQ-8 should be excluded from participation; it is recommended the subject’s primary care 
physician (PCP) should be informed, and the subject referred to a mental health professional, 
either by the PCP or the investigator according to their usual practice. 
7.4.1. Columbia Suicide Severity Rating Scale (C-SSRS) 
The Columbia Suicide Severity Rating Scale is a validated tool for investigative staff to use 
to evaluate suicidal ideation and behavior (Appendix 15).16  At the screening visit, if there 
are “yes” answers on items 4 or 5 in the past year or on any question in the suicidal behavior 
section of the C-SSRS in the past 5 years, the subject will not be included in the study.  
Trained site staff is to administer the C-SSRS to all subjects at screening and assess the 
subject’s eligibility based on the answers. 
7.4.2. Suicidal Behaviors Questionnaire-Revised (SBQ-R) 
The Suicidal Behaviors Questionnaire-Revised (Appendix 16) is a patient-reported 
questionnaire consisting of 4 items to assess suicidal ideation, suicide attempts, threat of 
suicidal behavior, and likelihood of suicidal behavior.  At the Screening Visit, if SBQ-R total 
score ≥8, the subject will not be included in the study.38  Site staff is to administer the SBQ-R 
to all subjects at screening and score immediately. 
7.4.3. Patient Health Questionnaire – 8 Items (PHQ-8) 
The Patient Health Questionnaire – 8 items (Appendix 17) is a patient-reported questionnaire 
consisting of 8 items to assess the subject’s depression level.  At Screening Visit, if PHQ-8 
total score ≥15, the subject will not be included in the study.39  Site staff is to administer the 
PHQ-8 to all subjects at screening and score immediately. 
7.5. Clinical Laboratory Tests 
7.5.1. Blood Volume 
Total blood sampling volume planned for this study is approximately 78 mL.  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 study to assess 
any perceived safety concerns at the investigator’s discretion. 
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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 
an 8-hour overnight fast prior to labs that include the lipid profile panel on Day 1, Week 4, 
Week 12, and EOS.  All other labs do not require fasting. 
Laboratory Tests 
Hematology 
Serum Chemistry 
Urinalysis 
Other 
Hemoglobin 
Hematocrit 
RBC count and indices 
(MCH, MCHC, MCV, RBC 
Morphology) 
Reticulocyte count 
Platelet count 
WBC count with differential 
Total neutrophils (%, Abs) 
Eosinophils (%, Abs) 
Monocytes (%, Abs) 
Basophils (%, Abs) 
Lymphocytes (%, Abs) 
Coagulation Panel 
Activated Partial 
Thromboplastin Time 
(APTT) Prothrombin 
Time/International 
Normalized Ratio 
(PT/INR) 
BUN and Creatinine 
Creatine Phosphokinase 
Glucose 
Na+, K+, Cl- ,Ca++ 
Total CO2 (Bicarbonate) 
AST, ALT 
GGT 
Total, Indirect & Direct Bilirubin 
Alkaline phosphatase 
Lactate dehydrogenase  
Uric acid 
Albumin 
Total protein 
Lipid Profile Panelf 
Total cholesterol 
LDL  
HDL 
Triglycerides 
pH 
Glucose (qual) 
Protein (qual) 
Blood (qual) 
Ketones 
Nitrites 
Leukocyte esterase 
Microscopy and/or 
cultured 
HIVa 
HBsAga 
HBcAba 
HBsAbb 
HCVAba 
HCV RNAb 
VZV IgG Abg 
Serum FSH (WONCBP 
only) or Pregnancy Testa, c 
Urine pregnancy testc 
QFT-G or PPD (if 
applicable)e 
HSV-1, HSV-2, VZV 
a. 
At Screening only. HIV testing will be performed for all subjects. 
b. 
HBsAb reflex testing only if HBsAg negative but HBcAb positive.  HCV RNA is reflex testing only if HCVAb is 
positive. 
c. 
Pregnancy testing for females of childbearing potential, including adolescents aged 12 years and older, regardless of 
whether they have experienced menarche; serum FSH for postmenopausal women who have been amenorrheic for at 
least 12 consecutive months. 
d. 
Microscopy with culture performed as appropriate.  
e. 
PPD results should be read within 48 to 72 hours.  
f. 
Lipid Profile Panel requires at least an 8 hour fast.  Lipid profile panel will be completed at Day 1, Week 4,  
Week 12, and EOS, and will include total cholesterol, LDL, HDL, and triglycerides.  
g. 
Only for adolescents who do not have documentation of at least one dose of varicella vaccine. 
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 Appendix 4 for Guidelines on Monitoring and Discontinuation. 
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7.5.2.1. Hepatitis Testing  
Hepatitis B testing: HB surface antigen (HBsAg), HB core antibody (HBcAb), HB surface 
antibody (HBsAb). 
Interpretation of Hepatitis B Testing Results:   
• HBsAg negative and HBcAb negative: Subject is eligible for the study; 
• HBsAg positive and HBcAb negative: Subject is excluded from study participation; 
• HBsAg negative and HBcAb positive and HBsAb positive: Subject is eligible for 
study; 
• HBsAg negative and HBcAb positive and HBsAb negative: Subject is excluded from 
study participation. 
Hepatitis C testing: Hepatitis C Antibody (HCV Ab), Hepatitis C Viral RNA (HCV RNA 
for confirmation of positive HCV Ab result).   
Interpretation of Hepatitis C Testing Results: 
• HCV Ab positive and HCV RNA positive: Subject is excluded from study 
participation.  
7.5.2.2. Varicella Zoster Virus (VZV) IgG Antibody (Ab) Testing 
Adolescent subjects without documented evidence of having received at least a single dose of 
the varicella vaccine in countries where the varicella vaccine is approved and standard of 
care will be tested for varicella zoster virus IgG Ab as described in the lab manual.  Subjects 
that lack evidence of prior exposure to varicella zoster virus based on serological VZV IgG 
Ab testing are excluded. 
7.5.2.3. Baseline Viral Screen  
A serum sample will be collected at baseline but analyzed only if the subject has suspected 
varicella or herpes zoster.  In that event, the sample would be analyzed for HSV1, HSV2 and 
VZV.  Additional sample collection instructions will be provided in the lab manual 
(Schedule of Activities).  The retained samples will be destroyed upon subject completion of 
this study or the long-term extension study.  
7.6. Efficacy Assessments 
7.6.1. 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 
dermatitis when designated by the primary site Investigator.  The evaluator must receive and 
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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 the study 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. 
7.6.2. Investigator’s Global Assessment (IGA) 
The Investigator’s Global Assessment of atopic dermatitis is scored on a 5-point scale (0-4), 
reflecting a global consideration of the erythema, induration and scaling.  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 Table 3.  The assessment 
will be a static evaluation without regard to the score at a previous visit.  
Table 3. 
Investigator’s 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 soles from the assessment/scoring. 
 
7.6.3. 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. 
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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) 
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. 
 
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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. 
Table 5. 
Handprint Determination of Body 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 (Table 6). 
Table 6. 
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 (Table 7). 
Table 7. 
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 
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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 
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. 
7.6.3.1. 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 (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%. 
7.6.4. 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 score 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 score of 100%.  
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Severity (B, maximum score 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)/papulation; 
• 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 score of 18). 
Subjective Symptoms (C, maximum score of 20) 
Subjective symptoms (ie, itch and sleep loss) are each scored by the subject using a visual 
analog scale (VAS) where “0” is no itch (or no sleep loss) and “10” is the worst imaginable 
itch (or sleep loss).  The value for each should reflect the average on a 10 point scale for the 
last 3 days/nights.  These scores are added to give 'C' (maximum score of 20).  
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) 
Subjects will complete the PROs at the clinic prior to other clinical activities and 
investigational product administration.  The PROs should be checked for completeness by 
the study site staff before proceeding with other steps of the clinical visit procedures.  
Compliance with scheduled PROs activities will be monitored.  Delegated site staff will 
oversee the administration of PROs at site visits to ensure protocol compliance.  Subjects are 
given a handheld device to complete the Pruritus NRS and PSAAD according to the 
Schedule of Activities.  Delegated site staff will review compliance at each visit and counsel 
as appropriate.  If a subject has repeated non-compliance, the subject should be re-trained on 
the device.  If a subject is unable to complete the PROs on the handheld device due to 
documented difficulty using the technological devices or other limitation, the subject will be 
permitted to enter or remain in the study.  In the event of electronic malfunction, a 
replacement device will be shipped to the site. 
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Examples of the validated paper versions of Patient Reported Outcomes instruments are 
included in the Appendices of this protocol.  In instances where an electronic device is used 
to collect the PRO data, the electronic version may differ slightly in format or wording 
compared with the paper version to facilitate electronic implementation. 
7.7.1. Pruritus Numerical Rating Scale (NRS)  
Severity of Pruritus  
The severity of itch (pruritus) due to atopic dermatitis will be assessed using the Pruritus 
Numerical Rating Scale, a validated horizontal NRS (Appendix 6).42  Subjects will be asked 
to assess their worst itching due to atopic dermatitis over the past 24 hours on an NRS 
anchored by the terms “no itch” (0) and “worst itch imaginable” (10).  This item will be 
administered to all subjects.  Subjects will enter the pruritus NRS assessment into an eDiary. 
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 an NRS anchored by the terms “never/no itching” 
(0) and “always/constant itching” (10).  This item will be administered to all subjects.  
Subjects will enter the pruritus NRS assessment into an eDiary. 
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 7).  The same category labels used in the Investigator’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.  This single-item scale will be administered to all 
subjects. 
7.7.3. EuroQol Quality of Life 5-Dimension 5-Level Scale (EQ-5D-5L) and EuroQol 
Quality of Life 5-Dimension Youth Scale (EQ-5D-Y) 
The EQ-5D is a validated, standardized, generic instrument that is the most widely used 
preference-based health-related quality of life questionnaire in cost-effectiveness and health 
technologies assessment (HTA) (Appendix 8).17-20  Recently, a version was developed called 
EQ-5D-5L with 5 response levels on each dimension compared to the 3 response levels in the 
EQ-5D-3L.17,19,21,23  A version of the instrument specifically developed and validated for use 
by youths age 12 through 17 years is called the EQ-5D-Y.24,25,26  
Measurement properties of the EQ-5D-5L demonstrated to be a valid version of the 3-level 
questionnaire that improved measurements by adding discriminatory power, reducing the 
ceiling, and establishing convergent and known-groups validity.19,18,21,23  Both the EuroQol 
EQ-5D-3L and EQ-5D-5L versions are well-established instruments used to measure health 
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7.7.8. Short Form-36 Health Survey, Version 2, Acute (SF-36v2, Acute)  
The SF-36v2 is a validated generic health status measure (Appendix 13).  It measures 
8 general health domains: physical functioning, role limitations due to physical health, bodily 
pain, general health perceptions, vitality, social functioning, role limitations due to emotional 
problems, and mental health.  These domains can also be summarized as physical and mental 
component summary scores.  The use of this scale is restricted to adult subjects and not for 
adolescents to complete.36  SF-36v2 will be completed by adult subjects only.  Adolescents 
12-17 years of age will not complete this assessment. 
7.7.9. FACIT Fatigue Scale (FACIT-F) and Pediatric FACIT-F (Peds-FACIT-F) 
The Functional Assessment of Chronic Illness Therapy Fatigue Scale (FACIT–F) is a 
validated subject completed questionnaire consisting of 13 items that assess fatigue.  
Instrument scoring yields a range from 0 to 52, with higher scores representing better overall 
health status (less fatigue) (Appendix 14).37  The FACT-F should be completed as per 
Schedule of Activities.  FACIT-F will be completed by adult subjects only.  Adolescents 
12-17 years of age will complete the Pediatric FACIT-F (Peds-FACIT-F) instead of the 
FACIT-F.40 
7.8. Pharmacokinetics 
7.8.1. Plasma for Analysis of PF-04965842 
During the study, blood samples (3 mL) to provide minimum 1 mL of plasma for PK analysis 
will be collected into appropriately labeled tubes containing potassium 
ethylenediaminetetraacetic acid (K2EDTA) at times specified in the STUDY PROCEDURES 
section of the protocol. 
Blood for PK analysis will be collected at the study site at the following time points: 
• Prior to dosing at Week 4;  
• At 0.5 hours (±15 min) postdose at Week 4;  
• At 0.5 hours (±15 min) and 4.0 hours (±30 min) postdose at Week 12.  
All efforts will be made to obtain the PK 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 SOA 
will be considered a protocol deviation.  For ET visits, if the subject discontinues before 
Week 4 do not collect PK samples.  If the ET visit occurs after Week 4, collect PK samples 
only if the subject takes the investigational product at the site visit. 
• The plasma will be stored in appropriately labeled screw-capped polypropylene tube 
at approximately -20°C within 1 hour of collection. 
• Further details regarding the collection, processing, storage and shipping of the blood 
samples will be provided in the lab manual. 
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All observed or volunteered events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
paragraphs. 
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the investigator are to be reported 
regardless of whether the event is determined by the investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information.  This time frame also applies to additional new (follow-up) information on 
previously forwarded reports.  In the rare situation that the investigator does not become 
immediately aware of the occurrence of an event, the investigator must report the event 
within 24 hours after learning of it and document the time of his/her first awareness of the 
event. 
For each event, the investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events section below).  In addition, the investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion.  
This information is more detailed than that recorded on the CRF.  In general, this will include 
a description of the event in sufficient detail to allow for a complete medical assessment of 
the case and independent determination of possible causality.  Any information relevant to 
the event, such as concomitant medications and illnesses, must be provided.  In the case of a 
subject death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer Safety.  Any pertinent additional information must be reported on the CT SAE 
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request. 
As part of ongoing safety reviews conducted by the sponsor, any non-serious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study. 
8.1.1. Additional Details on Recording Adverse Events on the CRF 
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information. 
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8.1.2. Eliciting Adverse Event Information 
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study subject/parent(s)/legal guardian, if applicable.  In addition, each study 
subject/parent(s)/legal guardian, if applicable, will be questioned about the occurrence of 
AEs in a non-leading manner. 
8.1.3. Withdrawal from the Study Due to Adverse Events (see also the Subject 
Withdrawal Section) 
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF.  
When a subject withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirements section above. 
8.1.4. Time Period for Collecting AE/SAE Information 
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each subject begins from the time the subject/parent(s)/legal guardian, if 
applicable, provides informed consent, which is obtained before the subject’s participation in 
the study (ie, before undergoing any study-related procedure and/or receiving investigational 
product), through and including a minimum of 28 calendar days; except as indicated below 
after the last administration of the investigational product. 
For subjects who are screen failures, the active collection period ends when screen failure 
status is determined. 
8.1.4.1. Reporting SAEs to Pfizer Safety 
All SAEs occurring in a subject during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form. 
SAEs occurring in a subject after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety. 
Follow up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment. 
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF 
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF. 
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment. 
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8.1.5. Causality Assessment 
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship on the CRF, and report such 
an assessment in accordance with the SAE reporting requirements, if applicable.  An 
investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE; generally the facts 
(evidence) or arguments to suggest a causal relationship should be provided.  If the 
investigator does not know whether or not the investigational product caused the event, then 
the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the sponsor.  If the investigator's causality assessment is “unknown but not 
related” to investigational product, this should be clearly documented on study records.  
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements. 
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities 
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations. 
8.2. Definitions 
8.2.1. Adverse Events 
An AE is any untoward medical occurrence in a study subject administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage.  Examples of AEs include, but are not limited to:  
• Abnormal test findings; 
• Clinically significant signs and symptoms; 
• Changes in physical examination findings; 
• Hypersensitivity; 
• Progression/worsening of underlying disease;  
• Drug abuse; 
• Drug dependency. 
Additionally, AEs may include signs and symptoms resulting from: 
• Drug overdose; 
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• Drug withdrawal; 
• Drug misuse;  
• Drug interactions; 
• Extravasation; 
• Exposure during pregnancy (EDP); 
• Exposure via breastfeeding; 
• Medication error; 
• Occupational exposure. 
8.2.2. Abnormal Test Findings 
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met:  
• Test result is associated with accompanying symptoms; and/or 
• Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or 
• Test result leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or 
• Test result is considered to be an AE by the investigator or sponsor. 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
recording as an AE. 
8.2.3. Serious Adverse Events 
A serious adverse event is any untoward medical occurrence at any dose that: 
• Results in death; 
• Is life-threatening (immediate risk of death); 
• Requires inpatient hospitalization or prolongation of existing hospitalization; 
• Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions); 
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• Results in congenital anomaly/birth defect. 
Or that is considered to be: 
• An important medical event. 
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse. 
8.2.4. Hospitalization 
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility, or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit is assessed for medical importance. 
Hospitalization does not include the following: 
• Rehabilitation facilities; 
• Hospice facilities; 
• Respite care (eg, caregiver relief); 
• Skilled nursing facilities; 
• Nursing homes; 
• Same-day surgeries (as outpatient/same-day/ambulatory procedures). 
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical 
AE is not in itself an SAE.  Examples include: 
• Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of a persistent pretreatment laboratory abnormality); 
• Social admission (eg, subject has no place to sleep); 
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• 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 SAEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE.  For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
AE. 
8.3. Severity Assessment 
If required on the AE page of the CRF, the investigator will use the adjectives MILD, 
MODERATE, or SEVERE to describe the maximum intensity of the AE.  For purposes of 
consistency, these intensity grades are defined as follows: 
MILD 
Does not interfere with subject's usual function. 
MODERATE 
Interferes to some extent with subject's usual function. 
SEVERE 
Interferes significantly with subject's usual function. 
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above. 
8.4. Special Situations 
8.4.1. Protocol-Specified Serious Adverse Events 
There are no protocol-specified SAEs in this study.  All SAEs will be reported to Pfizer 
Safety by the investigator as described in previous sections, and will be handled as SAEs in 
the safety database.  
8.4.2. Potential Cases of Drug-Induced Liver Injury 
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some subjects, transaminase elevations are a harbinger of a more 
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serious potential outcome.  These subjects fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  Subjects who experience a transaminase elevation above 3 times the upper limit of 
normal (× ULN) should be monitored more frequently to determine if they are an “adaptor” 
or are “susceptible.” 
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 × ULN) by several 
days or weeks.  The increase in TBili typically occurs while AST/ALT is/are still elevated 
above 3 × ULN (ie, AST/ALT and TBili values will be elevated within the same lab sample).  
In rare instances, by the time TBili elevations are detected, AST/ALT values might have 
decreased.  This occurrence is still regarded as a potential DILI.  Therefore, abnormal 
elevations in either AST OR ALT in addition to TBili that meet the criteria outlined below 
are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 
considered important medical events, even before all other possible causes of liver injury 
have been excluded. 
The threshold of laboratory abnormalities for a potential DILI case depends on the subject’s 
individual baseline values and underlying conditions.  Subjects who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values: 
• Subjects with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available; 
• For subjects with baseline AST OR ALT Or TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline: 
• Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller); 
• Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches >3 × ULN 
(whichever is smaller). 
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
The subject should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.  
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In addition to repeating measurements of AST and ALT and TBili, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile 
acids, alkaline phosphatase and acetaminophen drug and/or protein adduct levels.  
Consideration should also be given to drawing a separate tube of clotted blood and an 
anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology.  A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (either by 
itself or as a co-formulated product in prescription or over-the-counter medications), 
recreational drug, supplement (herbal) use and consumption, family history, sexual history, 
travel history, history of contact with a jaundiced person, surgery, blood transfusion, history 
of liver or allergic disease, and potential occupational exposure to chemicals, should be 
collected.  Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging 
(eg, biliary tract) may be warranted.  
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the liver function test (LFT) abnormalities has yet been found.  Such 
potential DILI (Hy’s law) cases are to be reported as SAEs, irrespective of availability 
of all the results of the investigations performed to determine etiology of the LFT 
abnormalities.  
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology. 
8.4.3. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure 
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness. 
8.4.3.1. Exposure During Pregnancy 
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if: 
• A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product; 
• An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products); 
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• A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.  
If a subject or subject’s partner becomes or is found to be pregnant during the subject’s 
treatment with the investigational product, the investigator must report this information to 
Pfizer Safety on the CT SAE Report Form and an EDP supplemental form, regardless of 
whether an SAE has occurred.  In addition, the investigator must submit information 
regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a subject 
reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or 
spillage) to Pfizer Safety using the EDP supplemental form.  This must be done irrespective 
of whether an AE has occurred and within 24 hours of awareness of the exposure.  The 
information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy). 
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
pre-procedure test findings are conclusive for a congenital anomaly and the findings are 
reported). 
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs. 
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows:  
• Spontaneous abortion includes miscarriage and missed abortion; 
• Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product; 
• Additional information regarding the EDP may be requested by the sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, 
the investigator will provide the subject with the Pregnant Partner Release of 
Information Form to deliver to his partner.  The investigator must document in the 
source documents that the subject was given the Pregnant Partner Release of 
Information Form to provide to his partner. 
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8.4.3.2. Exposure During Breastfeeding 
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding. 
8.4.3.3. Occupational Exposure 
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE. 
An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a subject enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file. 
8.4.4. Medication Errors  
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors. 
Safety Event 
Recorded on the CRF 
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness 
Medication errors 
All (regardless of whether 
associated with an AE) 
Only if associated with an 
SAE 
8.4.4.1. Medication Errors 
Medication errors may result from the administration or consumption of the investigational 
product by the wrong subject, or at the wrong time, or at the wrong dosage strength.  
Medication errors include: 
• Medication errors involving subject exposure to the investigational product; 
• Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject; 
• Refer to Section 5.3 for examples of medication errors related to compliance with 
investigational product. 
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Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page. 
In the event of a medication dosing error, the sponsor should be notified immediately. 
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF.   
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE. 
9. DATA ANALYSIS/STATISTICAL METHODS 
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (SAP), which will be 
maintained by the sponsor.  The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the co-primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment. 
9.1. Sample Size Determination 
Sample size for the study was based on the co-primary endpoints.  A sample of 150 subjects 
randomized to PF-04965842 200 mg QD, 150 subjects randomized to PF-04965842 
100 mg QD and 75 subjects randomized to placebo would provide at least 95% power to 
detect a difference in IGA response rate of at least 20% between PF-04965842 200 mg QD 
(or PF-04965842 100 mg QD) and placebo, assuming the placebo response rate is 6% at 
Week 12.  Furthermore, this will also provide at least 99% power to detect a difference in 
EASI-75 response rate of at least 30% between PF-04965842 200 mg QD (or PF-04965842 
100 mg QD) and placebo, assuming the placebo response rate is 15% at Week 12. 
The Type-I error for testing each individual co-primary endpoint was fixed at 5%.  Since 
both endpoints are co-primary, the study will meet its primary endpoint only if both 
hypotheses (corresponding to each co-primary endpoint) are rejected.  Therefore, the Type-I 
error rate remains controlled at 5% for testing the primary endpoint.  The power to reject 
both hypotheses when a true difference exists (alternative hypothesis is true) could be at least 
94% depending on the correlation between the endpoints. 
9.2. Efficacy Analysis 
9.2.1. Analysis Sets  
The primary analysis population for efficacy data will be the Full Analysis Set (FAS) defined 
as all randomized subjects receiving at least one dose of study medication.  The primary 
efficacy endpoint and the key secondary efficacy endpoints will also be analyzed for the 
Per-Protocol Analysis Set (PPAS) defined as a subset of FAS who had no major protocol 
violations.  The subjects excluded from the PPAS will be determined and documented before 
the study is un-blinded.  For all analyses, baseline value will be based on observations 
collected pre-dose.  
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9.2.2. Testing Procedure for Multiple Comparisons 
There are five key hypotheses to be tested for each of the two PF-04965842 doses 
(200 mg QD and 100 mg QD) versus placebo, for the co-primary endpoints and two key 
secondary endpoints.  The familywise Type-I error rate will be strongly controlled at 
5% using a sequential, Bonferroni-based iterative multiple testing procedure.  
The procedure will first test the co-primary endpoints (IGA and EASI75 at Week 12 for 
200 mg QD vs placebo) at the 5% level.  If this hypothesis is not rejected, then no further 
testing will be conducted.  If this hypothesis is rejected, then testing may continue on two 
paths: 
• The hypothesis for severity of pruritus (200 mg QD vs placebo at Week 2) will be 
tested at the 2.5% level.  If this hypothesis is rejected, then the unused alpha level 
of 2.5% will be passed on to the testing for the key secondary endpoints and the co-
primary endpoints for 100 mg QD vs placebo, in the order specified in Sequence A at 
a 5% significance level (see figure below).  Testing stops at any point where a 
hypothesis cannot be rejected. 
• If the hypothesis for severity of pruritus (200 mg QD vs placebo at Week 2) is not 
rejected at the 2.5% level, then the hypotheses for the key secondary endpoints and 
the co-primary endpoints for 100 mg QD vs placebo, in the order specified in 
Sequence A will be tested at a 2.5% significance level (see figure below).  If all 
hypotheses in this sequence are rejected, then the unused alpha level of 2.5% will be 
passed on to the testing of the hypothesis for severity of pruritus (200 mg QD vs 
placebo) at Week 2 at the 5% level. 
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9.2.4. Analysis of Secondary Endpoints 
The key secondary endpoints which are expressed as proportions such as the proportion of 
subjects achieving a 4-point improvement from baseline in the pruritus NRS measure will be 
analyzed using the same method as the for co-primary endpoints in Section 9.2.3.  This 
would also apply to any other binary endpoint in the study, such as EASI50, EASI90, 
SCORAD50, SCORAD75 or the proportion of subjects with PtGA of AD of clear (0) or 
almost clear (1) and ≥2 point improvement from baseline over 12 weeks.   
For continuous endpoints, such as percent change from baseline in the EASI total score or 
change from baseline in PSAAD, DLQI/CDLQI, POEM, HADS, SF-36v2, 
FACIT-F/Peds-FACIT, EQ-5D-5L/EQ-5D-Y and SCORAD and change from baseline in the 
pruritus severity and frequency using the NRS measure at all scheduled time points, a 
mixed-effect model with repeated measures (MMRM) will be used.  This model will include 
the factors (fixed effects) for treatment group, randomization strata (age group, disease 
severity), visit, treatment-by-visit interaction, and relevant baseline value.  Within the 
framework of MMRM, the treatment difference will be tested at the pre-specified primary 
time point, Week 12, as well as at the other time points by time point-specific contrasts from 
the MMRM model.  
9.3. Safety Analysis 
The safety data will be summarized in accordance with Pfizer Data Standards.  All subjects 
who receive investigational product (safety population) will be included in the safety 
analyses.  All safety data will be summarized descriptively through appropriate data 
tabulations, descriptive statistics, categorical summaries, and graphical presentations.  Safety 
endpoints for the study include: 
• Treatment-emergent AEs 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, hematology [including coagulation panel], chemistry and 
lipid profiles); 
• Vital signs; 
• ECG parameters if applicable. 
Change from baseline on laboratory data and vital signs will be additionally summarized. 
Subject listings will also be produced for these safety endpoints. 
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9.4. Analysis of Pharmacokinetic Endpoints  
Population PK data for PF-04965842 will be summarized through appropriate data 
tabulations, descriptive statistics, and graphical presentation.  A population PK model will be 
developed for the purpose of estimating PK parameters.  Additional details of the 
methodology will be captured in a separate modeling plan and the results will also be 
reported separately. 
9.5. External Data Monitoring Committee  
This study will use an external data monitoring committee (E-DMC).  The E-DMC will be 
responsible for ongoing monitoring of the efficacy, safety and PKs of subjects in the study 
according to the charter.  Pharmacokinetic data from the first 20 adolescent subjects will be 
analyzed and reviewed by the E-DMC.  The recommendations made by the E-DMC to alter 
the conduct of the study will be forwarded to Pfizer for final decision.  Pfizer will forward 
such decisions, which may include summaries of aggregate analyses of endpoint events and 
of safety data that are not endpoints, to regulatory authorities, as appropriate.  Composition 
of the E-DMC and processes under which the E-DMC operates will be documented in the 
E-DMC charter. 
9.6. Safety Adjudication Committees 
To help assess the specific, complex safety events related to malignancies, cardiovascular 
events, and opportunistic infection (including eczema herpeticum and other infections of 
special interest) in this study, Safety Adjudication Committees, consisting of clinical experts 
in each of the relevant clinical areas, will be set up to harmonize and standardize 
assessments.  In order to allow for an unbiased safety assessment, the members of these 
committees will be blinded to treatment assignment.  Further information about the Safety 
Adjudication Committees can be found in their respective charters, including a specific 
description of the scope of their responsibilities, a plan where communication timelines are 
defined, and the exact process and definitions used by each committee to adjudicate the 
safety events that they will adjudicate.  Other safety events for adjudication may be identified 
and included in the remit of the Safety Adjudication Committees as appropriate. 
10. QUALITY CONTROL AND QUALITY ASSURANCE 
Pfizer or 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 investigator site may be subject to 
review by the IRB/EC, and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities. 
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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 investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection.  The investigator site and 
investigator will promptly resolve any discrepancies that are identified between the study 
data and the subject's medical records.  The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent.  Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings. 
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process. 
11. DATA HANDLING AND RECORD KEEPING 
11.1. Case Report Forms/Electronic Data Record 
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study. 
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer. 
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry.  
In most cases, the source documents are the hospital or the physician subject chart.  In these 
cases, data collected on the CRFs must match the data in those charts.  
In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the CRF, and for which the CRF will stand as the source document. 
11.2. Record Retention 
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating subjects 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent/assent documents, copies of all CRFs, safety reporting forms, source 
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documents, and detailed records of treatment disposition, and adequate documentation of 
relevant correspondence (eg, letters, meeting minutes, and telephone call reports).  The 
records should be retained by the investigator according to the ICH guidelines, according to 
local regulations, or as specified in the clinical study agreement (CSA), whichever is longer. 
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or an independent third party arranged by Pfizer.  
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.   
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met. 
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/assent documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer. 
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation. 
12.2. Ethical Conduct of the Study 
The study will be conducted in accordance with the protocol, legal and regulatory 
requirements, and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
Helsinki. 
12.3. Subject Information and Consent 
All parties will ensure protection of subject personal data and will not include subject names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by law.  
When study data are compiled for transfer to Pfizer and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by numerical codes based on a 
numbering system provided by Pfizer in order to de-identify study subjects.  The investigator 
site will maintain a confidential list of subjects who participated in the study, linking each 
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subject’s numerical code to his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of subjects’ personal data consistent 
with applicable privacy laws. 
The informed consent/assent documents and any subject recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws. 
The informed consent/assent documents used during the informed consent process and any 
subject recruitment materials must be reviewed and approved by Pfizer, approved by the 
IRB/EC before use, and available for inspection.   
The investigator must ensure that each study subject, or his or her parent(s)/legal guardian if 
a minor, is fully informed about the nature and objectives of the study and possible risks 
associated with participation.  
Whenever consent is obtained from a subject’s parent(s)/legal guardian, the subject’s assent 
(affirmative agreement) must subsequently be obtained when the subject has the capacity to 
provide assent, as determined by the IRB/EC.  If the investigator determines that a subject’s 
decisional capacity is so limited he/she cannot reasonably be consulted, then, as permitted by 
the IRB/EC and consistent with local regulatory and legal requirements, the subject’s assent 
may be waived with source documentation of the reason assent was not obtained.  If the 
study subject does not provide his or her own consent, the source documents must record 
why the subject did not provide consent (eg, minor, decisionally impaired adult), how the 
investigator determined that the person signing the consent was the subject’s parent(s)/legal 
guardian, the consent signer’s relationship to the study subject (eg, parent, spouse), and that 
the subject’s assent was obtained or waived.  If assent is obtained verbally, it must be 
documented in the source documents. 
If the study includes minor subjects who reach the age of majority during the study, as 
recognized under local law, they must reconsent as adults to remain in the study.  If the 
enrollment of emancipated minors is permitted by the study age criteria, the IRB/EC, and 
local law, they must provide documentation of legal status to give consent without the 
permission of a parent or legal guardian.  
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject or the subject's parent(s)/legal guardian and the subject’s assent, 
when applicable, before any study-specific activity is performed.  The investigator will retain 
the original of each subject's signed consent/assent document. 
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately.  
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In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of. 
13. DEFINITION OF END OF TRIAL 
13.1. End of Trial in All Participating Countries 
End of trial in all countries is defined as the 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, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of 
PF-04965842 at any time. 
If a study is prematurely terminated, Pfizer will promptly notify the investigator.  After 
notification, the investigator must contact all participating subjects and the hospital pharmacy 
(if applicable) within 7 days.  As directed by Pfizer, all study materials must be collected and 
all CRFs completed to the greatest extent possible. 
15. PUBLICATION OF STUDY RESULTS 
15.1. Communication of Results by Pfizer 
Pfizer fulfills its commitment to publicly disclose clinical 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.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date (PCD) 
for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations. 
PCD is defined as the date that the final subject was examined or received an intervention for 
the purposes of final collection of data for the primary outcome, whether the clinical study 
concluded according to the pre-specified protocol or was terminated. 
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EudraCT 
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.  
www.pfizer.com 
Pfizer posts Public Disclosure Synopses (clinical study report 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 the 
principal investigator (PI) of the results of the study based on information collected or 
generated by the PI, whether or not the results are favorable to the Pfizer product.  However, 
to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “publication”) 
before it is submitted or otherwise disclosed. 
The investigator will provide any publication to Pfizer at least 30 days before it is submitted 
for publication or otherwise disclosed.  If any patent action is required to protect intellectual 
property rights, the investigator agrees to delay the disclosure for a period not to exceed an 
additional 60 days. 
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results. 
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all investigator sites, and that any subsequent publications 
by the PI will reference that primary publication.  However, if a joint manuscript has not 
been submitted for publication within 12 months of completion or termination of the study at 
all participating sites, the investigator is free to publish separately, subject to the other 
requirements of this section. 
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors. 
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Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA. 
If there is any conflict between the CSA and any attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues. 
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16. REFERENCES 
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Margolis JS, Abuabara K, Bilker W, et al. Persistence of mild to moderate atopic 
dermatitis. JAMA Dermatol 2014;150(6):593-600. 
4. 
Slater NA, Morrell DS. Systemic therapy of childhood atopic dermatitis. Clin Dermatol 
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Leung DY, Bieber T. Atopic dermatitis. Lancet 2003;361(9352):151-160. 
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Ring J, Alomar A, Bieber T, et al. Guidelines for treatment of atopic eczema (atopic 
dermatitis) part I. J Eur Acad Dermatol Venereol  2012;26(8):1045-60. 
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Auriemma M, Vianale G, Amerio P, et al. Cytokines and T cells in atopic dermatitis Eur 
Cytokine Netw 2012; 24(1):37-44. 
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Mortz C, Andersen K, Dellgren C, et al. Atopic dermatitis from adolescents to 
adulthood in the TOACS cohort: prevalence, persistence and comorbidities. Allergy 
2015;70:836-45.  
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Sandstrom M., Faergemann J. Prognosis and prognostic factors in adult patients with 
atopic dermatitis: a long-term follow-up questionnaire study. British J. of Dermatology 
2004;150:102-10. 
10. Deckers I, McLean AS, Linssen S, Mommers M, et al. Investigating international time 
trends in the incidence and prevalence of atopic eczema 1990-2010: a systematic review 
of epidemiological studies PLoS One 2012;7(7):e39803. 
11. Silverberg JI, Hanifin JM. Adult eczema prevalence and associations with asthma and 
other health and demographic factors: a US population-based study. J Allergy Clin 
Immunol 2013;132(5): 1132-1138. 
12. Lee CH, Chuang HY, Hong CH, Huang SK, et al. Lifetime exposure to cigarette 
smoking and the development of adult-onset atopic dermatitis.Br J Dermatol 
2011;164(3): 483-9. 
13. Homey B, Steinhoff M, Ruzicka T, et al. Cytokines and chemokines orchestrate atopic 
skin inflammation.J Allergy Clin Immunol 2006;118(1):178-89. 
14. Cornelissen C, Luscher-Firzlaff J, Baron JM, et al. Signaling by IL-31 and functional 
consequences. Eur J Cell Biol 2012;91(6-7):552-66. 
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15. Gittler JK, Shemer A, Suarez-Farinas M, Fuentes-Duculan J, et al. Progressive 
activation of T(H)2/T(H)22 cytokines and selective epidermal proteins characterizes 
acute and chronic atopic dermatitis. J Allergy Clin Immunol 2012;130(6):1344-54. 
16. Posner K, Oquendo MA, Gould M, et al. Columbia Classification Algorithm of Suicide 
Assessment (C-CASA): classification of suicidal events in the FDA's pediatric suicidal 
risk analysis of antidepressants. Am J Psychiatry 2007;164(7):1035-43. 
17. Rabin R, Gudex C, Selai C, et al. From translation to version management: a history and 
review of methods for the cultural adaptation of the EuroQol five-dimensional 
questionnaire. Value in Health 2014;17(1):70-6.   
18. Van Hout B, Janssen MF, Feng YS, et al. Interim scoring for the EQ-5D-5L: mapping 
the EQ-5D-5L to EQ-5D-3L value sets. Value in Health 2012;15(5):708-15.   
19. Ramos-Goñi JM, Pinto-Prades JL, Oppe M, et al. Valuation and modeling of EQ-5D-5L 
health states using a hybrid approach. Medical care 2017;55(7):e51-8.   
20. Yang Y, Brazier J, Longworth L. EQ-5D in skin conditions: an assessment of validity 
and responsiveness. Eur J Health Econ. 2015;16(9):927-939. 
21. Janssen MF, Pickard AS, Golicki D, et al. Measurement properties of the EQ-5D-5L 
compared to the EQ-5D-3L across eight patient groups: a multi-country study. Quality 
of Life Research. 2013;22(7):1717-27.   
22. Agborsangaya CB, Lahtinen M, Cooke T, Johnson JA. Comparing the EQ-5D 3L and 
5L: measurement properties and association with chronic conditions and multimorbidity 
in the general population. Health and quality of life outcomes 2014;12(1):74. 
23. Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new 
five-level version of EQ-5D (EQ-5D-5L). Quality of life research 2011;20(10):1727-36.  
24. Wille N, Badia X, Bonsel G, Burstrom K, Cavrini G, Devlin N, Egmar AC, Greiner W, 
Gusi N, Herdman M, Jelsma J  Development of the EQ-5D-Y: a child-friendly version 
of the EQ-5D.  Qual Life Res 2010 Aug;19(6):875-886.  
25. Ravens-Sieberer U, Wille N, Badia X, et al. Feasibility, reliability, and validity of the 
EQ-5D-Y: results from a multinational study. Qual Life Res 2010;19(6):887-97.  
26. EuroQol Group. EuroQolea new facility for the measurement of health-related quality 
of life. The EuroQol Group. Health Policy 1990;16:199-208. 
27. Simpson EL, Gadkari A, Worm M, et al. Dupilumab therapy provides clinically 
meaningful improvement in patient-reported outcomes (PROs): A phase IIb, 
randomized, placebo-controlled, clinical trial in adult patients with moderate to severe 
atopic dermatitis (AD). J Am Acad Dermatol. 2016;75(3):506-515. 
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28. Simpson EL, Bieber T, Guttman-Yassky E, et al. Two Phase 3 trials of dupilumab 
versus placebo in atopic dermatitis. N Engl J Med. 2016;375:2335-2348. 
29. Poole CD, Chambers C, Sidhu MK, et al. Health-related utility among adults with 
atopic dermatitis treated with 0.1% tacrolimus ointment as maintenance therapy over 
the long term: findings from the Protopic CONTROL study. Br J Dermatol 
2009;161(6):1335-40. 
30. Kim C, Park KY, Ahn S, et al. Economic impact of atopic dermatitis in Korean patients. 
Ann Dermatol. 2015;27(3):298-305.  
31. Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI): A simple practical 
measure for routine clinical use. Clinical and Experimental Dermatology 1994;19: 
210-216. 
32. Lewis-Jones MS, Finlay AY. The Children's Dermatology Life Quality Index (CDLQI): 
Initial validation and practical use. British Journal of Dermatology 1995;132:942-49.  
33. Ersser SJ, Cowdell F, Latter S, et al. Psychological and educational interventions for 
atopic eczema in children. The Cochrane Library. 2014;Jan 1.  
34. Schmitt J, Langan S, Williams H, et al. What are the best outcome measurements for 
atopic eczema? A systematic review. J Allergy Clinical Immunol 2007;120(6):1389-98.  
35. White D, Leach C, Sims R, et al. Validation of the Hospital Anxiety and Depression 
Scale for use with adolescents. Br J Psychiatry 1999;175(5):452-4.   
36. Ware J, Kosinski M, Bjorner J, et al. Determining important differences in scores. 
User's Manual for the SF-36v2® Health Survey. Lincoln (RI): QualityMetric 
Incorporated; 2007:125-33. 
37. Cella D, Lai JS, Chang CH, et al. Fatigue in cancer patients compared with fatigue in 
the general United States population. Cancer 2002;94(2):5 28-38.  
38. Osman A, Bagge CL, Gutierrez PM, et al. The Suicidal Behaviors 
Questionnaire-Revised (SBQ-R): validation with clinical and nonclinical samples. 
Assessment. 2001; 8(4):443-54. 
39. Kroenke K., Strine, T., Spitzer C., et al, The PHQ-8 as a measure of current depression 
in the general population 2009. J Affect Disord 2009;114(1-3);163–73.  
40. Lai J, Cella D, Holm S, et al, Measuring Fatigue for Children with Cancer: 
Development and Validation of the Pediatric Functional Assessment of Chronic Illness 
Therapy Fatigue (PEDSFACIT-F). J Pediatr Hematol Oncol 2007;29(7):471-9. 
41. Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol 
1980;92(suppl):44-7. 
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42. Yosipovitch G, Reaney M, Mastey V, et al. Validation of the peak pruritus numerical 
rating scale: Results from clinical studies of dupilumab in adult patients with 
moderate-to-severe atopic dermatitis: 5063. Journal of the American Academy of 
Dermatology. 2017 Jun 1;76(6):AB278. 
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Appendix 1. Abbreviations  
This following 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 curve 
AUCinf 
area under the curve from time zero extrapolated to infinity 
AUClast 
area under the curve from time zero to last quantifiable 
AUCtau 
area under the curve over dosing interval tau 
BBS 
Biospecimen Banking System 
BCG 
Bacille Calmette Guérin 
BID 
twice a day 
BP 
blood pressure 
BSA 
body surface area 
Cmax 
maximum concentration  
CD 
cluster of differentiation 
CDLQI 
Children’s Dermatology Life Quality Index 
CFB 
change from baseline 
CI 
confidence interval 
CL/F 
clearance/fraction of dose absorbed 
CO2 
carbon dioxide 
CK 
creatine kinase 
CRF 
case report form 
CSA 
clinical study agreement 
CsA 
cyclosporine A 
CS 
clinically significant 
CSF 
cerebrospinal fluid 
CSR 
clinical study report 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CT 
clinical trial 
CTA 
clinical trial application 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of variation 
DILI 
drug-induced liver injury 
DLQI 
Dermatology Life Quality Index 
DMC 
data monitoring committee 
DNA 
deoxyribonucleic acid 
DU 
dispensable unit 
EASI 
Eczema Area and Severity Index 
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Abbreviation 
Term 
EBV 
Epstein Barr virus 
EC 
ethics committee 
ECG 
electrocardiogram 
e-Diary 
electronic diary 
E-DMC 
external data monitoring committee  
EDP 
exposure during pregnancy 
ELISA 
Enzyme-Linked Immunosorbent Assay 
EMA 
European Medicines Agency 
EOS 
end of study 
EOT 
end of treatment 
EPO 
erythropoietin 
ePRO 
electronic Patient Reported Outcome  
EQ-5D-5L 
EuroQol Quality of Life 5-Dimension 5-Level Scale 
EQ-5D-Y 
EuroQol Quality of Life 5-Dimension Youth Scale 
ET 
early termination  
EU 
European Union 
EudraCT 
European Clinical Trials Database 
FACIT-F 
Functional Assessment of Chronic Illness Therapy Fatigue Scale 
FACs 
fluorescence-activated cell sorting 
FAS 
full analysis set 
FDA 
Food and Drug Administration  
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GM-CSF 
granulocyte-macrophage colony-stimulating factor 
HADS 
Hospital Anxiety and Depression Scale 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBcAb  
hepatitis B core antibody 
HCV 
hepatitis C virus 
HCVAb  
hepatitis C antibody 
HCV RNA 
hepatitis C viral ribonucleic acid 
HDL 
high-density lipoprotein  
HEENT 
head, eyes, ears, nose and throat 
HIV 
human immunodeficiency virus 
HRQL 
health-related quality of life 
hsCRP 
high-sensitivity C-reactive protein 
HSV 
herpes simplex virus 
HTA 
health technologies assessment  
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
ID 
identification 
IFN 
interferon 
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Abbreviation 
Term 
IFN-α 
interferon-alpha 
IFN-γ 
interferon-gamma 
IGA 
Investigator’s Global Assessment 
IgE  
Immunoglobulin E 
IgG 
immunoglobulin G 
IIV 
inter individual variability 
IL 
interleukin 
IND 
investigational new drug application 
INR 
international normalized ratio 
IP 
investigational product 
IRB 
institutional review board 
IRC 
internal review committee 
IRT 
interactive response technology 
IUD 
intrauterine device 
IWR 
interactive web response 
JAK 
Janus kinase 
JAK1 
Janus kinase 1 
K2EDTA 
dipotassium ethylenediaminetetraacetic acid 
LDL 
low-density lipoprotein 
LFT 
liver function test 
LSLV 
last subject last visit  
LTE 
long-term extension 
MAA 
marketing authorisation application 
MAR 
missing at random 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MMRM 
mixed-effect model with repeated measures 
MNAR 
missing not at random 
MnB 
meningitidis serogroup B 
MRI 
magnetic resonance imaging 
MTX 
methotrexate 
N/A 
not applicable 
NB-UVB 
narrowband ultraviolet B light 
NRS  
numerical rating scale 
PCD 
primary completion date 
PCP 
primary care physician 
PD 
Pharmacodynamics 
PEER Study 
Pediatric Eczema Elective Registry Study 
Peds-FACIT-F 
Pediatric Functional Assessment of Chronic Illness Therapy 
Fatigue Scale 
PFS 
prefilled syringe 
PGIC 
Patient Global Impression of Change 
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Abbreviation 
Term 
PGIS 
Patient Global Impression of Severity 
PGx 
Pharmacogenomics 
PHQ8 
Patient Health Questionnaire - 8 items 
PI 
principal investigator 
PK 
Pharmacokinetics 
POC 
proof of concept 
POEM 
Patient-Oriented Eczema Measure 
PPAS 
per-protocol analysis set 
PPD 
purified protein derivative test 
PRO 
patient reported outcome 
PSAAD 
Pruritus and Symptoms Assessment for Atopic Dermatitis 
PT 
prothrombin time 
PtGA  
Patient Global Assessment 
QD 
once daily 
QFT-G 
QuantiFERON-TB Gold 
QT 
Q wave interval 
QTc 
corrected Q wave interval 
QTcF 
QT interval with Fridericia’s correction  
Rac 
accumulation ratio  
RBC 
red blood cell 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBQ-R 
Suicide Behaviors Questionnaire-Revised 
SCORAD  
Scoring Atopic Dermatitis 
SF-36v2 
Short Form-36 Version 2 
SOC 
system organ class 
SOP 
standard operating procedure 
SRSD 
single reference safety document 
STAT 
signal transducers and activators of transcription 
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
Half-life 
Tmax 
time to maximum absorption 
TARC 
thymus and activation regulated chemokine 
TB 
tuberculosis 
TBili 
total bilirubin 
TdP 
Torsade de Pointes 
TH1 
type 1 helper T cell 
TH2 
type 2 helper T cell 
TYK2 
tyrosine kinase 2 
ULN 
upper limit of normal 
US 
United States 
UVA 
ultraviolet A light 
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Abbreviation 
Term 
UVB 
ultraviolet B light 
VAS 
visual analog scale 
V/F 
volume of distribution/fraction absorbed 
VZV  
varicella zoster virus 
WBC  
white blood cell 
WONCBP  
women of non-childbearing potential 
 
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Appendix 2. Diagnostic Criteria for Atopic Dermatitis 
Per Inclusion Criterion 3, a subject is to have a clinical diagnosis of atopic dermatitis 
according to the criteria of Hanifin and Rajka.41 
Hanifin and Rajka’s Diagnostic Criteria for Atopic Dermatitis 
Must have three or more basic features described below: 
Pruritus 
Typical morphology and distribution: 
Flexural lichenification in adults 
Facial and extensor eruptions in infants and children 
Chronic or chronically-relapsing dermatitis 
Personal or family history of atopy (asthma, allergic rhinitis, atopic dermatitis) 
Must have three or more following minor features: 
Xerosis 
Ichthyosis/palmar hyperlinearity, keratosis pilaris 
Immediate (type 1) skin test reaction 
Elevated serum IgE 
Early age of onset 
Tendency toward cutaneous infections (esp. staph. aureus and herpes simplex), impaired 
cell-mediated immunity 
Tendency toward non-specific hand or foot dermatitis 
Nipple eczema 
Cheilitis 
Recurrent conjunctivitis 
Dennie-Morgan infraorbital fold 
Keratoconus 
Anterior subcapsular cataracts 
Orbital darkening 
Facial pallor, facial erythema 
Pityriasis alba 
Anterior neck folds 
Itch when sweating 
Intolerance to wool and lipid solvents 
Periofollicular accentuation 
Food intolerance 
Course influenced by environmental and emotional factors 
White dermographism, delayed blanch 
 
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Appendix 3. Prohibited Concomitant Medications 
CYP3A 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) 
 
Mibefradil 
 
mifepristone (Mifeprex, RU486) 
 
nefazodone (Serzone) 
 
norfloxacin (Shibroxin, Noroxin) 
 
Norflouxetine 
 
verapamil (Calan SR,Covera HS, Isoptin SR, 
Tarka, Verelan) 
 
 
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CYP2C19 Inhibitors  
CYP2C19 Inducers 
Amitriptyline (Elavil) 
Enzalutamide (Xtandi) 
Clomipramine (Anafranil) 
Rifampin 
Fluconazole (Diflucan) 
 
Fluvoxamine (Luvox) 
 
Imipramine (Tofranil) 
 
Ticlopidine (Ticlid) 
 
Esomeprazole (Nexium) 
 
Fluoxetine (Prozac) 
 
Moclobemide 
 
Omeprazole (Prilosec) 
 
Voriconazole (Vfend) 
 
 
 
 
 
 
 
CYP2C9 Inhibitors  
CYP2C9 Inducers 
Fluconazole (Diflucan) 
Carbamazepine (Tegretol) 
Amiodarone (Cordarone) 
Enzalutamide (Xtandi) 
Fluvoxamine (Luvox) 
Rifampin 
Miconazole 
 
Oxandrolone (Oxandrin) 
 
Voriconazole (Vfend) 
 
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Appendix 4. Guidelines for Monitoring and Discontinuation  
Monitoring Criteria  
The following laboratory abnormalities require prompt retesting: 
• Neutrophil counts <1000 neutrophils/mm3; confirmed promptly by repeat testing, 
ideally within 3-5 days;  
• Lymphocyte count <500/mm3; confirmed promptly by repeat testing, ideally within 
3-5 days; 
• Platelet counts <75,000 platelets/mm3; confirmed promptly by repeat testing, ideally 
within 3-5 days;  
• Any single hemoglobin value <9.0 g/dL or one that drops ≥2 g/dL below baseline; 
confirmed promptly by repeat testing, ideally within 3-5 days;  
• Any single AST and/or ALT elevation >3 times the upper limit of normal regardless 
of accompanying symptoms or the total Bilirubin should prompt repeat testing.  This 
should also prompt review of Section 8.4.2; additional investigations must be 
conducted. 
Discontinuation Criteria 
Subjects must be permanently discontinued from treatment if they meet any of the following 
criteria at any point in the study: 
• Marked prolongation of the QTcF interval to >500 ms or >60 ms change from 
screening ECG. 
Note: any quoted lab value below must be confirmed by re-test, preferably within 48 hours. 
• Serious infection (see definition for Serious Adverse Events in Section 8.2.3). 
• Two sequential platelet counts <50,000/mm3.  If the subject has a platelet count 
<25,000/mm3, investigational product should be discontinued pending the 
confirmatory retest.  If the subject has a platelet count <50,000/mm3 and the 
confirmatory retest cannot be obtained within 48 hours, investigational product 
should be discontinued pending the confirmatory retest.  
• Any platelet count reduction thought to be associated with a bleeding event per the 
judgement of the investigator (or, if necessary/desired, following discussion with 
sponsor). 
• Two sequential neutrophil counts <500/mm3. 
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• Two sequential lymphocyte counts <500/mm3. 
• Two sequential hemoglobin assessments <8.0 g/dL or a decrease of more than 
30% from baseline value (either criteria or both). 
Any of the following: 
• Two sequential AST or ALT elevations >3 times the upper limit of normal with at 
least one Total Bilirubin value >2 times the upper limit of normal. 
• Two sequential AST or ALT elevations >3 times the upper limit of normal with an 
abnormal INR. 
• Two sequential AST or ALT elevations >3 times the upper limit of normal 
accompanied by symptoms consistent with hepatic injury. 
• Two sequential AST or ALT elevations >5 times the upper limit of normal, regardless 
of Total Bilirubin or accompanying symptoms. 
• Two sequential increases in serum creatinine that are >50% over the average of 
screening and baseline values AND an absolute increase in serum creatinine 
≥0.5 mg/dL.  At the time of study completion or discontinuation, if a patient should 
exhibit elevations in serum creatinine ≥33% above the average of screening and 
baseline values, they will be re-tested every 1 to 2 weeks until the serum creatinine 
elevation is fully reversed to within 10% of the average of screening and baseline 
values or has stabilized. 
• Other adverse event, per judgment of the investigator, requiring discontinuation from 
treatment (or, if necessary/desired, following discussion with sponsor). 
 
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Appendix 5. Fitzpatrick Skin Type  
 
 
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Appendix 6. Pruritus Severity and Frequency (Pruritus NRS) 
Severity of Pruritus 
On a scale of 0 to 10, with 0 being “no itch” and 10 being “worst itch imaginable”, how 
would you rate your itch at the worst moment during the previous 24 hours?  
 
 
 
 
 
Frequency of Pruritus 
Select the number that best describes frequency of itching due to Atopic Dermatitis over the 
past 24 hours (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 
itch
Worst  
itch  
imaginable
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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Appendix 7. Patient Global Assessment (PtGA) 
 
 
 
 
 
 
Clear 
Almost Clear
Mild 
Moderate 
Severe 
Overall, how would you describe your Atopic Dermatitis right now?
Choose only ONE response.
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Appendix 8. European Quality of Life 5-Dimension 5-Level Scale (EQ-5D-5L) and 
European Quality of Life 5-Dimension Youth Scale (EQ-5D-Y) 
EQ-5D-5L 
Under each heading, please check the ONE box that best describes your health TODAY. 
MOBILITY 
 
I have no problems walking 
 
I have slight problems walking 
 
I have moderate problems walking 
 
I have severe problems walking 
 
I am unable to walk 
 
SELF-CARE 
 
I have no problems washing or dressing myself 
 
I have slight problems washing or dressing myself 
 
I have moderate problems washing or dressing myself 
 
I have severe problems washing or dressing myself 
 
I am unable to wash or dress myself 
 
USUAL ACTIVITIES (eg, work, study, housework, family or 
leisure activities) 
 
I have no problems doing my usual activities 
 
I have slight problems doing my usual activities 
 
I have moderate problems doing my usual activities 
 
I have severe problems doing my usual activities 
 
I am unable to do my usual activities 
 
PAIN/DISCOMFORT 
 
I have no pain or discomfort 
 
I have slight pain or discomfort 
 
I have moderate pain or discomfort 
 
I have severe pain or discomfort 
 
I have extreme pain or discomfort 
 
SAMPLE
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ANXIETY/DEPRESSION 
 
I am not anxious or depressed 
 
I am slightly anxious or depressed 
 
I am moderately anxious or depressed 
 
I am severely anxious or depressed 
 
I am extremely anxious or depressed 
 
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• We would like to know how good or bad your 
health is TODAY. 
• This scale is numbered from 0 to 100. 
• 100 means the best health you can imagine. 
• 0 means the worst health you can imagine. 
• Mark an X on the scale to indicate how your 
health is TODAY. 
• Now, please write the number you marked on 
the scale in the box below. 
 
 
YOUR HEALTH TODAY = 
 
 
 
100
95
90
85
80
75
70
65
60
55
50
45
40
35
30
25
20
15
10
5
0
The best health 
you can imagine
The worst health 
you can imagine
 
SAMPLE
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EQ-5D-Y 
Describing your health TODAY 
Under each heading, please check the ONE box that best describes your health TODAY. 
Mobility (walking around) 
 
I have no problems walking around 
 
I have some problems walking around 
 
I have a lot of problems walking around 
 
Taking care of myself 
 
I have no problems taking a bath or shower by myself or getting 
dressed by myself 
 
I have some problems taking a bath or shower by myself or 
getting dressed by myself 
 
I have a lot of problems taking a bath or shower by myself or 
getting dressed by myself 
 
Doing usual activities (for example, going to school, hobbies, 
sports, playing, doing things with family or friends) 
 
I have no problems doing my usual activities 
 
I have some problems doing my usual activities 
 
I have a lot of problems doing my usual activities 
 
Having pain or discomfort 
 
I have no pain or discomfort 
 
I have some pain or discomfort 
 
I have a lot of pain or discomfort 
 
Feeling worried, sad, or unhappy 
 
I am not worried, sad, or unhappy 
 
I am a little worried, sad, or unhappy 
 
SAMPLE
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I am very worried, sad, or unhappy 
 
 
 
How good is your health TODAY  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• We would like to know how good or 
bad your health is TODAY. 
• This line is numbered from 0 to 100. 
• 100 means the best health you can 
imagine. 
• 0 means the worst health you can 
imagine. 
• Please mark an X on the scale to 
indicate how your health is TODAY. 
 
 
 
100
95
90
85
80
75
70
65
60
55
50
45
40
35
30
25
20
15
10
5
0
The best health 
you can imagine
The worst health 
you can imagine
 
 
SAMPLE
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P F -0 4 9 6 5 8 4 2  
B 7 4 5 1 0 1 2  
Fi nal Pr ot oc ol A me n d me nt 5 , 0 5 J u ne  20 1 8  
 
 
P a ge 1 2 6  
A p pe n di x  9. Der m at ol o g y Lif e Q u alit y I n de x ( D L QI) a n d C hil dre n’s Der m at ol o g y Life 
Q u alit y I n de x ( C D L QI)  
D E R M A T O L O G Y LI F E Q U A LI T Y I N D E X  
T he ai m of t his q uesti o n n aire is t o me as ure h o w m uc h y o ur s ki n pr o ble m h as affecte d 
y o ur lif e O V E R T H E  L A S T W E E K.  Ple ase tic k o ne b o x f or e ac h q uesti o n 
1.  O ver t h e last we e k, h o w itc h y, s o re, p ai nf ul or sti n gi n g h as y o ur 
s ki n b ee n ? 
V er y m u c h 
A l ot  
A little 
N ot at all  
 
 
 
 
 
2.  O ver t h e last we e k, h o w e m b a rr asse d or self c o nsci o us h a ve y o u b ee n 
beca use of y o ur s ki n ?  
V er y m u c h 
A l ot  
A little 
N ot at all  
 
 
 
 
 
3.  O ver t h e last we e k, h o w m u c h h as y o ur s ki n i nterfere d wit h y o u g oi n g  
s h o p pi n g or l o o ki n g after y o ur h o me  or g ar de n ? 
V er y m u c h 
A l ot  
A little 
N ot at all  
 
 
 
 
 
 
N ot rele va nt  
4.  O ver t h e las t we e k, h o w m u c h h as y o ur s ki n i nfl u e n ce d t h e cl ot hes 
y o u wear?  
V er y m u c h 
A l ot  
A little 
N ot at all  
 
 
 
 
 
 
N ot rele va nt  
5.  O ver t h e last we e k, h o w m u c h h as y o ur s ki n affecte d a n y s oci al or  
leis ure a cti vities?  
V er y m u c h 
A l ot  
A little 
N ot at all  
 
 
 
 
 
 
N ot rele va nt  
6.  O ver t h e last we e k, h o w m u c h h as y o ur s ki n ma d e it diffic ult f or y o u t o 
d o a n y s p o rt? 
V er y m u c h 
A l ot  
A little 
N ot at all  
 
 
 
 
 
 
N ot rele va nt  
7.  O ver t h e last we e k, h as y o ur s ki n pre ve nte d y o u fr o m w or ki n g  or  
st u d yi n g? 
yes 
n o  
 
 
 
N ot rele va nt  
 
If " N o", o ver t h e last wee k h o w m u c h h as y o ur s ki n b ee n a pr o ble m at 
w or k  or st u d yi n g? 
A l ot 
A 
little 
N ot at all  
 
 
 
 
8.  O ver t h e last we e k, h o w m u c h h as y o ur s ki n create d pr o ble ms wit h y o ur  
p art ne r  or a n y of y o ur cl ose fri e n ds  or rel ati ves ? 
V er y m u c h 
A l ot  
A little 
N ot at all  
 
 
 
 
 
 
N ot rele va nt  
9.  O ver t h e last we e k, h o w m u c h h as y o ur s ki n ca use d a n y 
se x u al diffic ulties? 
V er y m u c h 
A l ot  
A little 
N ot at all  
 
 
 
 
 
 
N ot rele va nt  
1 0.  O ver t h e last we e k, h o w m u c h of a pr o bl e m h as t h e tre at me nt f or y o ur 
s ki n b ee n, f or e xa m ple b y ma ki n g y o ur h o me mess y, or b y ta ki n g u p 
ti me ? 
V er y m u c h 
A l ot  
A little 
N ot at all  
 
 
 
 
 
 
N ot rele va nt  
Please c hec k y o u ha ve a ns were d E V E R Y q uesti o n.  T ha n k y o u. 
A Y Fi nla y, G K K h a n, A pril 1 9 9 2, T his m ust n ot b e c o pie d wit h o ut t h e p er missi o n of t h e a ut h ors.  
0 9 0 1 7 7 e 1 9 1 2f 2 8 af\ A p pr o v e d\ A p pr o v e d O n: 2 6- J u n- 2 0 1 9 0 9: 2 3 ( G M T)


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Appendix 10. Patient-Oriented Eczema Measure (POEM) 
 
 
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Appendix 11. Hospital Anxiety and Depression Scale (HADS) 
 
 
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CCI
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CCI
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CCI
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CCI
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Appendix 13. SF-36v2, Acute 
 
 
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Appendix 14. FACIT-F and Peds-FACIT-F 
 
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Appendix 15. C-SSRS – Columbia Suicide Severity Rating Scale 
 
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Appendix 16. SBQ-R – Suicide Behaviors Questionnaire – Revised 
 
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Appendix 17. Patient Health Questionnaire – 8 Items 
 
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SAP_000.pdf: 
Protocol B7451012 (PF-04965842) Statistical Analysis Plan
Page 1
TMF Doc ID: 98.03
PROTOCOL B7451012
A PHASE 3 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL GROUP, MULTI-CENTER STUDY TO EVALUATE THE EFFICACY 
AND SAFETY OF PF-04965842 MONOTHERAPY IN SUBJECTS AGED 12 YEARS 
AND OLDER, WITH MODERATE TO SEVERE ATOPIC DERMATITIS
STATISTICAL ANALYSIS PLAN 
(SAP)
Version:
4
Date:
23-APR-2019
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Protocol B7451012 (PF-04965842) Statistical Analysis Plan
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TABLE OF CONTENTS
TABLE OF CONTENTS.................................................................................................................2
LIST OF TABLES...........................................................................................................................4
LIST OF FIGURES .........................................................................................................................4
1. VERSION HISTORY..................................................................................................................5
2. INTRODUCTION .......................................................................................................................6
2.1. Study Objectives .............................................................................................................7
2.2. Study Design ...................................................................................................................9
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS .................................................................................................................10
3.1. Primary Endpoints.........................................................................................................10
3.2. Key Secondary Endpoints .............................................................................................10
3.3. Secondary Efficacy Endpoints ......................................................................................11
3.3.1. Additional Patient-Reported Outcomes (PRO) ................................................11
3.3.2. PK Endpoints....................................................................................................12
3.4. Baseline Variables.........................................................................................................12
3.5. Safety Endpoints ...........................................................................................................13
3.5.1. Adverse Events .................................................................................................13
3.5.2. Laboratory Data................................................................................................13
3.5.3. Vital Signs, including Height and Weight........................................................14
3.5.4. Physical Examinations......................................................................................14
4. ANALYSIS SETS .....................................................................................................................14
4.1. Full Analysis Set ...........................................................................................................14
4.2. Per Protocol Analysis Set..............................................................................................14
4.3. Safety Analysis Set........................................................................................................15
5. GENERAL METHODOLOGY AND CONVENTIONS..........................................................15
5.1. Hypotheses and Decision Rules ....................................................................................15
5.2. General Methods ...........................................................................................................17
5.2.1. Analyses of Binary Data...................................................................................17
5.2.2. Analyses of Non-Longitudinal Continuous Data .............................................18
5.2.3. Analyses of Longitudinal Continuous Data......................................................18
5.2.4. Analyses of Categorical Data ...........................................................................18
5.2.5. Analyses of Time to Event Data.......................................................................18
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5.2.6. Analyses of Tier-1 and Tier-2 Events...............................................................19
5.3. Methods to Manage Missing Data ................................................................................19
5.3.1. Binary Endpoints ..............................................................................................19
5.3.2. Continuous Endpoints.......................................................................................20
5.3.3. Time to Event Endpoints ..................................................................................21
6. ANALYSES AND SUMMARIES ............................................................................................21
6.1. Co-primary Endpoint - Week 12 IGA Response...........................................................21
6.1.1. Primary Analysis ..............................................................................................21
6.1.2. Additional/Supportive Analysis........................................................................21
6.2. Co-primary Endpoint - Week 12 EASI-75 Response ...................................................22
6.2.1. Primary Analysis ..............................................................................................22
6.2.2. Additional/Supportive Analyses.......................................................................22
6.3. Key Secondary Endpoints .............................................................................................22
6.3.1. Weeks 2, 4 and 12 NRS4 for severity Response ..............................................22
6.3.2. Week 12 Change from Baseline in PSAAD.....................................................23
6.4. Secondary Efficacy Endpoints ......................................................................................23
6.4.1. Week 8 NRS4 for severity Response................................................................23
6.4.2. Time to Achieve NRS4 for severity .................................................................23
6.4.3. Weeks 2, 4, 8 and 12 IGA Response ................................................................24
6.4.4. Weeks 2, 4, 8 and 12 EASI-50, EASI-90, EASI-100, SCORAD50, 
SCORAD75 Response .................................................................................24
6.4.5. Weeks 2, 4 and 8 EASI-75 Response...............................................................24
6.4.6. Weeks 2, 4, 8 and 12 Change from Baseline in Total EASI Score, 
Total SCORAD Score, Severity of Pruritus NRS, %BSA, 
SCORAD (VAS) of Sleep Loss ...................................................................24
6.4.7. Weeks 2, 4, 8 and 12 Response based on %BSA.............................................25
6.5. Additional PRO Endpoints............................................................................................25
6.5.1. Weeks 2, 4, 8 and 12 Change from Baseline in PRO Endpoints......................25
6.5.2. Weeks 2, 4, 8 and 12 PSAAD Response ..........................................................25
6.5.3. Weeks 2, 4, 8 and 12 PtGA Response ..............................................................25
6.5.4. Weeks 2, 4, 8 and 12 HADS Response in Adults.............................................26
6.5.5. Weeks 2, 4, 8 and 12 DLQI Response in Adults..............................................26
6.5.6. Weeks 2, 4, 8 and 12 CDLQI Response in Adolescents ..................................27
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6.5.7. Week 12 PRO Endpoints..................................................................................27
6.6. PK Endpoints.................................................................................................................27
6.7. Subset Analyses.............................................................................................................27
6.8. Baseline and Other Summaries and Analyses...............................................................28
6.8.1. Baseline Summaries..........................................................................................28
6.8.2. Study Conduct and Subject Disposition ...........................................................28
6.8.3. Study Treatment Exposure ...............................................................................28
6.8.4. Concomitant Medications and Non-drug Treatments.......................................29
6.9. Safety Summaries and Analyses ...................................................................................29
6.9.1. Adverse Events.................................................................................................29
6.9.2. Laboratory Data................................................................................................30
6.9.3. Vital Signs, including Height and Weight........................................................30
6.9.4. Electrocardiogram.............................................................................................30
6.9.5. Physical Examination .......................................................................................30
7. INTERIM ANALYSES.............................................................................................................30
8. REFERENCES ..........................................................................................................................30
9. APPENDICES ...........................................................................................................................32
LIST OF TABLES
Table 1.
Summary of Changes....................................................................................................5
Table 2
Study Objectives and Endpoints...................................................................................7
LIST OF FIGURES
Figure 1
Study Design Schematic...............................................................................................9
Figure 2
Schematic for Multiple Testing Procedure.................................................................16
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1. VERSION HISTORY
This is the third amendment of the Statistical Analysis Plan (SAP) for Study B7451012 and 
is based on Amendment 5 of the protocol dated 05JUN2018.
Table 1.
Summary of Changes
Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Changes
1
19 Feb 2018
Amendment 1
03 Nov 2017
N/A
N/A
2
22 Jun 2018
Amendment 3
16 Mar 2018
Clarification or 
completion of prior 
version
Added change from baseline in total EASI score and 
SCORAD score, respectively as endpoints in 
Section 3.2.3.
Added responder analyses based on PtGA, HADS, 
DLQI / CDLQI and POEM as endpoints in Section 
3.3.1.
Updated the definition of TEAE in Section 3.5.1.
Added text to include analyses for comparing active 
dose groups to Sections 5.2.1 through 5.2.4 and 
Section 6.
Removed references to the word “peak” in describing 
pruritus throughout the document.
Added further detail on the Efficacy Assessments and 
PROs within Appendices 4 and 6 through 8.
Additional minor changes to improve clarity and 
alignment with the protocol.
3
29 Mar 2019
Amendment 5
05 Jun 2018
Blinded data 
review / Regulatory 
(FDA) Input
Replaced jump to reference analysis with a tipping 
point analysis, which is a more general approach and 
includes jump to reference as a special case. See 
sections 5.3.1, 6.1.2, 6.2.2 and Appendix 3.
Added an additional analysis option for handling 
binary missing data in Section 5.3.1. Updated the 
analysis of the NRS4 endpoint as regards handling of 
missing data in Sections 6.3.1 and 6.4.1 to account for 
a technical error in the process of transmission and 
collection of electronic data with the device that led 
to the NRS data not being collected across several 
sites.
Added a responder endpoint based on recently 
published data on the PSAAD in Section 3.3.1.
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Removed (with justification) from Sections 3.3.1 and 
6.5, all references to the endpoint based on frequency 
of pruritus as based on the NRS.
Removed responder analysis based on POEM as an 
endpoint in Section 3.3.1.
Updated the definition of a treatment emergent 
adverse event (TEAE) in Section 3.5.1, in alignment 
with the latest CaPS algorithm.
Additional minor changes to improve clarity and 
alignment with the protocol.
4
23 Apr 2019
Amendment 5
05 Jun 2018
Clarification or 
completion of prior 
version
Updated the visit windows in Appendix 2 to remove 
any gaps in the study period.
Further clarified the definition for non-responder 
imputation and imputation strategy when there are too 
few missing observations in Section 5.3.1.
Updated the criteria for inclusion into the PPAS in 
Section 4.2.
2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data
collected in Study B7451012.  This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition or its analysis will also 
be reflected in a protocol amendment.
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2.1. Study Objectives
Study objectives and corresponding endpoints are provided in the Table 2 below.
Table 2
Study Objectives and Endpoints
Primary Objective:
Primary Endpoints:
To assess the efficacy of 
PF-04965842 compared 
with placebo in subjects 
aged 12 years and older 
with moderate to severe 
Atopic dermatitis (AD).
The following co-primary endpoints will be tested:

Response based on the Investigator’s Global Assessment (IGA) score of clear (0) or 
almost clear (1) (on a 5-point scale); and a reduction from baseline of 2 points at 
Week 12.  The baseline will be defined as the IGA score on Day 1 pre-dose.

Response based on the Eczema Area and Severity Index 75% improvement from
baseline (EASI-75) at Week 12.  The baseline will be defined as the EASI score on 
Day 1 pre-dose.
Secondary Objectives:
Secondary Endpoints:
To evaluate the effect of 
PF-04965842 on 
additional efficacy 
endpoints and patient 
reported outcomes over 
time in subjects aged 
12 years and older with 
moderate to severe atopic 
dermatitis.
Key Secondary Endpoints:

Response based on a 4 points of improvement in the numerical rating scale (NRS)
for severity of pruritus from baseline at Weeks 2, 4, and 12.

Change from Baseline in Pruritus and Symptoms Assessment for Atopic Dermatitis 
(PSAAD) at Week 12.
Secondary Efficacy Endpoints:

Response based on a 4 points of improvement in the numerical rating scale (NRS)
for severity of pruritus from baseline at Week 8.

Time to achieve a 4-point improvement in the numerical rating scale (NRS) for 
severity of pruritus from baseline.

Response based on the EASI-75 at all scheduled time points except Week 12.

Response based on the IGA for clear (0) or almost clear (1); and 2 points reduction 
from baseline at all scheduled time points except Week 12.
Other Efficacy Endpoints

Response based on a 50% and 90% improvement in the EASI total score 
(EASI-50 and EASI-90) at all scheduled time points.

Change from baseline in the percentage Body Surface Area (BSA) affected at all 
scheduled time points.

Response based on a 50% and 75% improvement in Scoring Atopic Dermatitis
(SCORAD50, SCORAD75) from baseline at all scheduled time points.

Change from baseline at all scheduled time points in SCORAD subjective Visual 
Analogue Scale (VAS) assessments of itch and sleep loss.
Additional Patient-reported Outcomes:

Change from baseline at Week 12 in Dermatology Life Quality Index (DLQI) or 
Children’s DLQI (CDLQI) and at all other scheduled time points.

Change from baseline at Week 12 in Hospital Anxiety and Depression Scale (HADS) 
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and at all other scheduled time points.

Change from baseline at Week 12 in Patient-Oriented Eczema Measure (POEM) and 
at all other scheduled time points.

Change from baseline of Patient Global Assessment (PtGA) at Week 12 and at all 
other scheduled time points.

Change from baseline of EuroQol Quality of Life 5-Dimension 5-Level Scale 
(EQ-5D-5L) or EuroQol Quality of Life 5-Dimension Youth Scale (EQ-5D-Y) at
Week 12 and at all other scheduled time points.

Change from baseline of Functional Assessment of Chronic Illness Therapy Fatigue 
Scale (FACIT-F) or Pediatric FACIT-F (Peds-FACIT-F) at Week 12 and at all other 
scheduled time points.

Change from baseline of Short Form-36 (SF-36), acute at Week 12 and at all other 
scheduled time points.

Response based on at least 4 points improvement in the frequency of pruritus 
numerical rating scale (NRS) from baseline at all scheduled time points.1

Time from baseline to achieve at least 4 points improvement in the frequency of 
pruritus NRS scale.1
Safety Objective
Safety Endpoints
To evaluate the safety and 
tolerability of 
PF-04965842 in subjects 
aged 12 years and older 
with moderate to severe 
atopic dermatitis 
following 12 weeks of 
treatment.

Incidence of Treatment Emergent Adverse Events (TEAEs).

Incidence of Serious Adverse Events (SAEs) and Adverse Events (AEs) leading to 
discontinuation.

The incidence of clinical abnormalities and change from baseline in clinical laboratory 
values, Electrocardiogram (ECG) measurements, and vital signs.
PK Objectives 
PK Endpoint
To evaluate the 
pharmacokinetics (PK) of 
PF-04965842 in subjects 
aged 12 years and older 
with moderate to severe 
atopic dermatitis 
following 12 weeks of 
treatment.

Population PK characterization in subjects aged 12 years old and above with moderate 
to severe atopic dermatitis.
                                                
1 The frequency of pruritus numerical rating scale (NRS) is listed as an endpoint in the protocol but will
not be analyzed. This is because, after its selection as an endpoint in the study protocol, evidence was 
uncovered that suggested the instrument did not have sufficient content validity. Specifically, the response scale 
for the frequency of pruritus NRS was found not to be ideally representative of the range of frequency levels 
from the perspective of the target population based on qualitative research. Data generated from this measure 
would not be easily interpretable. Therefore, the endpoint has been removed from this SAP.
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Protocol B7451012 (PF-04965842)
2.2. Study Design
This is a randomized, double
evaluate the efficacy and safe
older with moderate to severe
12 weeks.  Subjects will be sc
product to confirm that they m
approximately 375 subjects w
study design schematic is pre
Figure 1
Study Design Sc
Qualified subjects completing
to enter a long-term extension
treatment, or who are otherw
follow-up period in B745101
Subjects who have chronic m
have a documented history of
AD medications will be rand
or 100 mg PF-04965842 QD 
Randomization will be stratif
[IGA=4] AD) and age (age <
study team will be blinded as
A full schedule of activities f
Study Treatments

Doses of PF-0496584
placebo;
) Statistical Analysis Plan
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-blind, placebo-controlled, parallel-group, Phase
ety of PF-04965842 monotherapy in subjects age
e AD and a body weight 40 kg.  The treatment 
creened within 28 days prior to the first dose of 
meet the subject selection criteria for the study. 
will be enrolled from approximately 75 sites loca
esented in Figure 1.
chematic
g the 12-week treatment period of the study will
n (LTE) study B7451015.  Subjects discontinuin
ise ineligible for the LTE study, will undergo a 
12.
moderate to severe AD as defined per the inclusio
f inadequate response or intolerance to treatmen
omized in a 2:2:1 ratio to receive 200 mg PF-04
(N=150), or matching placebo (N=75) from Da
fied by baseline disease severity (moderate [IGA
<18 and 18 years).  Investigators, subjects, and 
s to treatment group.
for the study is provided in Appendix 9.
42 will be 200 mg or 100 mg taken QD orally, or
e 3 study to 
ed 12 years and 
duration is 
investigational 
 A total of 
ated globally.  A 
l have the option 
ng early from 
4-week 
on criteria and
nt with topical 
4965842 (N=150) 
ay 1.  
A=3] and severe 
the sponsor 
r matching 
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
Treatment duration will be 12 weeks;
Sample Size Determination
Sample size for the study was based on the co-primary endpoints.  A sample of 150 subjects 
randomized to PF-04965842 200 mg QD, 150 subjects randomized to PF-04965842 100 mg 
QD and 75 subjects randomized to placebo would provide at least 95% power to detect a 
difference in IGA response rate of at least 20% between PF-04965842 200 mg QD (or 
PF-04965842 100 mg QD) and placebo, assuming the placebo response rate is 6% at Week 
12.  Furthermore, this will also provide at least 99% power to detect a difference in 
EASI-75 response rate of at least 30% between PF-04965842 200 mg QD (or 
PF-04965842 100 mg QD) and placebo, assuming the placebo response rate is 15% at 
Week 12.
The Type-I error for testing each individual co-primary endpoint was set at 5%.  Since both 
endpoints are co-primary, the study will meet its primary endpoint only if both hypotheses 
(corresponding to each co-primary endpoint) are rejected. Therefore, the Type-I error rate 
remains controlled at 5% for testing the primary endpoints. The power to reject both 
hypotheses when a true difference exists (alternative hypothesis is true) could be at least 94% 
depending on the correlation between the endpoints.
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoints
The co-primary efficacy endpoints are:

Response based on the IGA score of clear (0) or almost clear (1); and a reduction 
from baseline of 2 points at Week 12;

Response based on the EASI 75% improvement from baseline (EASI-75) at 
Week 12.
Detailed descriptions of how the IGA and the EASI scores are derived are provided in 
Appendix 4 and Appendix 5 respectively.
3.2. Key Secondary Endpoints
The key secondary efficacy endpoints are:

Response based on ≥4 points improvement from baseline in the pruritus NRS (NRS4)
for severity at Weeks 2, 4 and 12;

Change from baseline in PSAAD score at Week 12.
Detailed descriptions of how the pruritus NRS and the PSAAD scores are derived are 
provided in Appendix 7 and Appendix 8 respectively.
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3.3. Secondary Efficacy Endpoints
The secondary efficacy endpoints are:

Response based on the EASI-75 at all scheduled time points except Week 12;

Response based on the IGA for clear (0) or almost clear (1); and 2 points reduction 
from baseline at all scheduled time points except Week 12;

Response based on the IGA for clear (0) at all scheduled time points;

Response based on a 50%, 90% and 100% improvement in the EASI total score 
(EASI-50, EASI-90 and EASI-100) at all scheduled time points;

Change from baseline at all scheduled time points in the EASI total score;

Change from baseline in %BSA (from EASI) affected at all scheduled time points;

Response based on achieving percent BSA < 5%;

Response based on a 50% and 75% improvement in SCORAD (SCORAD50, 
SCORAD75) from baseline at all scheduled time points.  A detailed description of the 
derivation of the SCORAD score is provided in Appendix 6;

Change from baseline at all scheduled time points in the SCORAD total score;

Change from baseline at all scheduled time points in SCORAD subjective VAS 
assessments of sleep loss.
3.3.1. Additional Patient-Reported Outcomes (PRO)

Response based on NRS4 for severity at Week 8;

Time to achieve a ≥4-point improvement in the numerical rating scale (NRS) for 
severity of pruritus from baseline;

Response based on achieving ≥1 (clinically important response or CIR) point 
improvement from baseline in the total PSAAD score at all scheduled time points;

Change from baseline in PSAAD score at all scheduled time points except Week 12;

Change from baseline in DLQI / CDLQI at all scheduled time points;

Response based on achieving a DLQI / CDLQI score < 2 (Basra et al. 2015) at all 
scheduled time points (among adult / adolescent subjects with a score ≥2 at baseline);
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
Response based on achieving ≥4-point improvement from baseline (Basra et al. 2015) 
in the DLQI score at all scheduled time points (among adult subjects with a score 
≥4 at baseline);

Response based on achieving ≥2.5-point improvement from baseline in the CDLQI
score at all scheduled time points (among adolescent subjects with a score ≥2.5 at 
baseline);

Change from baseline in each component (anxiety and depression) of the HADS
score at all scheduled time points;

Response based on achieving a score < 8 in each component (anxiety and depression) 
of the HADS score (Zigmond and Snaith, 1983) at all scheduled time points (among 
adult subjects with a score ≥8 at baseline);

Response based on achieving a score < 11 in each component (anxiety and 
depression) of the HADS score (Zigmond and Snaith, 1983) at all scheduled time 
points (among adult subjects with a score ≥11 at baseline);

Change from baseline in POEM at all scheduled time points;

Change from baseline in PtGA at all scheduled time points;

Response based on PtGA score of clear (0) or almost clear (1); and a reduction from 
baseline of 2 points at all scheduled time points (among subjects with a score ≥2 at 
baseline);

Change from baseline in EQ-5D-5L / EQ-5D-Y at all scheduled time points;

Change from baseline in FACIT-F / Peds-FACIT-F at Week 12;

Change from baseline in physical and mental component scores of SF-36v2, acute at 
Week 12.
3.3.2. PK Endpoints
The PK endpoints and the analysis methods for these endpoints are described in a separate 
analysis plan.
3.4. Baseline Variables
In general, for all analyses, baseline will be defined based on observations collected prior to 
first dose.  Baseline values for demographics, medical and other history, atopic dermatitis 
history will be based on measures collected at Visit 1 / Screening visit. Study Day 1 is 
defined as the day the subject receives first dose of study drug. For purposes of all other 
analyses including analyses for change from baseline, the baseline value will be defined as 
measured on Day 1 (before time of first dose, if time is available). If a value is missing on 
Day 1, then the last available observation before Day 1 will be used. For the PSAAD score, 
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baseline will be defined as the average of all values recorded from Day -6 until Visit 2 / Day 
1.  For analysis purposes, randomization strata information will be taken from the Case 
Report Form (CRF).
3.5. Safety Endpoints
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.  Endpoints will be assessed as:

Incidence of treatment emergent adverse events.

Incidence of SAEs and AEs leading to discontinuation.

Incidence of clinical abnormalities and change from baseline in selected clinical 
laboratory values, ECG measurements, and vital signs.
The safety endpoints will be defined in accordance with Clinical Data Interchange Standards 
Consortium (CDISC) aligned Pfizer Standards (CaPS).
3.5.1. Adverse Events
An adverse event will be considered a Treatment-Emergent Adverse Event (TEAE) if the 
event started during the effective duration of treatment. All events that start on or after the 
first dosing day and time / start time, if collected, but before the last dose plus the lag time 
(28 days) will be flagged as TEAEs. The algorithm will not consider any events that started 
prior to the first dose date.
A 3-tier approach will be used to summarize AEs.  Under this approach, AEs are classified 
into one of 3 tiers.  Different analyses will be performed for different tiers (See Section 
6.9.1).
Tier-1 events: These are pre-specified events of clinical importance and are maintained in a 
list in the product’s Safety Review Plan.  Herpes zoster and serious infections have been 
identified as Tier-1 events. No other Tier-1 events have been identified so far and the study 
team will continue monitoring all safety events.
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 subjects with an event in any 
treatment group.
Tier-3 events: These are events that are neither Tier-1 nor Tier-2 events.
3.5.2. Laboratory Data
Below is a list of hematology and serum chemistry test parameters.
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
Hematology: hemoglobin, hematocrit, red blood cell count, reticulocyte count, 
platelet count, white blood cell count with differential, total neutrophils, eosinophils, 
monocytes, basophils, lymphocytes, coagulation panel.

Serum chemistry: blood urea nitrogen, creatinine, creatine phosphokinase, glucose, 
sodium, potassium, chloride, calcium, total bicarbonate, aspartate aminotransferase, 
alanine aminotransferase, gamma-glutamyl transferase, bilirubin, alkaline 
phosphatase, lactate dehydrogenase, uric acid, albumin, total protein, total 
cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), 
triglycerides.
3.5.3. Vital Signs, including Height and Weight
Vital sign measurements are oral or tympanic temperature, respiratory rate, pulse rate and 
blood pressures.
Height and weight are collected at pre- and post-treatment.
3.5.4. Physical Examinations
Complete physical examinations consist of assessments of general appearance; skin; head, 
eyes, ears, nose and throat; mouth, heart; lungs; breast (optional); abdomen; external 
genitalia (optional); extremities; neurologic function; and lymph nodes.
4. ANALYSIS SETS
Data for all subjects will be assessed to determine if subjects meet the criteria for inclusion in 
each analysis population described below prior to unblinding and releasing the database and 
classifications will be documented per standard operating procedures.
4.1. Full Analysis Set
The Full Analysis Set (FAS) is defined as all subjects who have been randomized and who 
have received at least one dose of treatment. Subject is assigned to the randomized treatment 
group regardless of actual treatment received.  Analyses for endpoints that are defined based 
on a threshold of change from baseline (eg, NRS4) will also require the baseline value to be 
equal to or greater than that threshold (eg, for NRS4, the baseline value needs to be ≥4).
It is expected that the FAS as defined here will be identical to an ITT analysis set 
(randomized and dispensed study medication) because the first dose is administered in-clinic. 
The number of subjects randomized and dispensed study medication but did not receive 
treatment will be reported.
4.2. Per Protocol Analysis Set
The Per Protocol Analysis Set (PPAS) is defined as a subset of FAS who had no major 
protocol violations.  The subjects excluded from the PPAS will be determined and 
documented before the study is unblinded.  The primary and key secondary endpoints will be 
analyzed for the PPAS.  This set will include subjects who:  
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
Were eligible for the study by way of meeting key inclusion criteria and none of the 
key exclusion criteria.

Had valid and non-missing baseline efficacy data (IGA and EASI score).

Had actual, observed IGA and EASI scores at Visit 8 / Week 12.

Did not take a protocol-prohibited medication for the primary diagnosis prior to 
completion of the study dosing period (Visit 8 / Week 12).

Took the correct randomized treatment for at least 80% and at most 120% of the 
assigned amount until completion of the study dosing period (Visit 8 / Week 12).

Had no other major protocol violations as determined by the clinical team prior to 
database lock.  A major protocol violation in this context is one that is likely to affect 
materially the efficacy responses of the patient and will be defined by the clinical 
team before database is locked and any analysis is performed for this study.
These items will either be assessed by programmed checks of the data or be determined by 
clinical review prior to unblinding of study treatment.
4.3. Safety Analysis Set
The Safety Analysis Set (SAF) will be defined as all subjects who receive at least one dose of 
study medication classified according to actual study treatment received.  The safety analysis 
set is the primary population for treatment administration / compliance and safety.  A 
randomized but not treated subject will be excluded from the safety analyses.  
5. GENERAL METHODOLOGY AND CONVENTIONS
The final analysis and reporting of results will be performed after the completion of the study 
and the database is locked.
5.1. Hypotheses and Decision Rules
PF-04965842 200 mg QD will be declared superior to placebo if the null hypothesis of no 
difference between PF-04965842 200 mg QD versus placebo for both co-primary endpoints 
is rejected at the 5% significance level.  Similarly, PF-04965842 100 mg QD will be declared 
superior to placebo if the null hypothesis of no difference between PF-04965842 100 mg QD 
versus placebo for both co-primary endpoints is rejected at the significance level specified
below.
A sequential Bonferroni-based iterative multiple testing procedure to strongly control the 
familywise Type 1 error at 5% will be used for testing each of the two PF-04965842 doses 
(200 mg QD and 100 mg QD) versus placebo on the primary and key secondary endpoints.  
The procedure belongs to a class of consonant multiple test procedures (Hommel et al. 2007)
which are a subclass of the closed test procedures (Marcus et al. 1976).
The procedure will first test the Week 12 co-primary endpoints (IGA and EASI-75) for 
200 mg QD vs placebo at a 5% significant level.  If this hypothesis is not rejected, then no 
further testing will be conducted.  If this hypothesis is rejected, then testing may continue on 
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Protocol B7451012 (PF-04965842)
two paths depending on the te
at a 2.5% significance level:

If the hypothesis for t
rejected, then the unu
Sequence A (see Figu
sequence is not reject

If the hypothesis for t
rejected, then the serie
at a 2.5% significance
the procedure stops.  I
alpha level of 2.5% w
2 NRS4 for severity (
Figure 2
Schematic for M
Hypotheses for all other endp
significant level, without mak
) Statistical Analysis Plan
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esting for Week 2 NRS4 for severity for 200 mg
the Week 2 NRS4 for severity for 200 mg QD vs
used alpha level of 2.5% will be passed on to a se
ure 2 below) at a 5% significance level.  If any h
ted, then the procedure stops.
the Week 2 NRS4 for severity for 200 mg QD vs
es of testing in Sequence A (see Figure 2 below
e level.  If any hypothesis in this sequence is not
If all hypotheses in this sequence are rejected, th
will be passed on to the testing of hypotheses for 
(200 mg QD vs placebo) at a 5% significance lev
Multiple Testing Procedure
points not described here are to be tested at the n
king adjustments for multiple comparisons.
g QD vs placebo 
s placebo is 
eries of testing in 
hypothesis in this 
s placebo is not 
) will be tested 
t rejected, then 
hen the unused 
Week 
vel.
nominal 5% 
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5.2. General Methods
In general, for descriptive analyses, number and percent will be presented for binary 
endpoints. Number, median, Q1 and Q3 will be presented for descriptive analyses of 
continuous efficacy endpoints. 
5.2.1. Analyses of Binary Data
Binary data at each scheduled visit will be analyzed by two approaches: (1) the test of 
hypothesis (and the p-value) between the PF-04965842 treatment groups versus the placebo 
group will be conducted by the Cochran-Mantel-Haenszel (CMH) statistic adjusting for the 
effect of randomization strata; p-values from the CMH statistic will be used to establish the 
superiority of each dose of PF-04965842 to placebo in binary responses; and (2) the
proportion of responders in the PF-04965842 treatment groups versus the placebo group will 
be summarized by the difference and its 95% confidence interval obtained by normal 
approximation.  The difference in proportions will be calculated within each randomization 
stratum.  The final estimate of the difference in proportions will be a weighted average of 
these stratum-specific estimates using CMH weights.  The CMH weight ݓ௞for stratum 
݇(݇= 1, 2, 3, 4) is given by,
ݓ௞=
݊௜௞݊௖௞
݊௜௞+ ݊௖௞
∑
݊௜௝݊௖௝
݊௜௝+ ݊௖௝
ସ
௝ୀଵ
where ݊refers to sample size, the subscript ܿrefers to a comparator group (e.g., placebo) and 
the subscript ݅refers to a test group (e.g., either the low or high doses; so that two test 
statistics are calculated, one for each dose versus placebo).  The difference is estimated 
as ݀መ= ∑
ݓ௞(݌̂௜௞−݌̂௖௞)
ସ
௞ୀଵ
, where ݌̂ refers to the estimated relative frequency. An estimate 
for ݌̂ is obtained as ݔ/݊, where ݔis the number of responders.
Two-sided 95% confidence intervals for the difference (based on a normal approximation) 
are formed by:
݀መ± 1.96ඩ෍ݓ௞
ଶ
ସ
௞ୀଵ
൬݌̂௜௞(1 −݌̂௜௞)
݊௜௞
+ ݌̂௖௞(1 −݌̂௖௞)
݊௖௞
൰
In the above formula for the variance of ݀መ(under the square-root sign), when the number of 
responders is zero (ݔ= 0), then ݌̂ will be replaced by 0.5/(݊+ 1). This change will be 
made only for calculating the variance of ݀መand not anywhere else. Estimates of the 
difference in proportions along with the two-sided 95% confidence interval will also be 
provided for the PF-04965842 200 mg QD group versus the PF-04965842 100 mg QD group. 
No hypotheses will be tested. 
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5.2.2. Analyses of Non-Longitudinal Continuous Data
The non-longitudinal continuous data will be analyzed by Analysis of Covariance 
(ANCOVA) with treatment as the factor and randomization strata (baseline disease severity 
and age category) as covariates.  When modeling the change from baseline values, the 
variable for visit will start with the first post-baseline visit, and the actual baseline value will 
be included as a covariate.  At each visit, estimates of least square mean (LSM) values and 
the LSM differences between the PF-04965842 treated groups and the placebo group will be 
derived from the model.  The corresponding p-values and 95% confidence intervals will also 
be derived from the model.  Estimates of the difference in LSMs along with the two-sided 
95% confidence interval will also be provided for the PF-04965842 200 mg QD group versus 
the PF-04965842 100 mg QD group.  No hypotheses will be tested.
5.2.3. Analyses of Longitudinal Continuous Data
Mixed-effect, repeated measures (MMRM) models will be used.  The fixed effects of 
treatment (PF-04965842 200 mg QD and 100 mg QD and the placebo group), visit (Weeks 2, 
4, 8 and 12), treatment-by-visit interaction and randomization stratification factors will be 
included.  Visit will be modeled as a categorical covariate.  Unstructured covariance matrix 
will be assumed for the model errors. Compound symmetry covariance matrix will be used if 
the model with unstructured covariance doesn’t converge.
When modeling the change from baseline values, the variable for visit will start with the first 
post-baseline visit, and the actual baseline value will be included as a covariate.  At each 
visit, estimates of least square mean (LSM) values and the LSM differences between the 
PF-04965842 treated groups and the placebo group will be derived from the model.  The 
corresponding p-values and 95% confidence intervals will also be derived from the model.
Estimates of the difference in LSMs along with the two-sided 95% confidence interval will 
also be provided for the PF-04965842 200 mg QD group versus the PF-04965842 100 mg 
QD dose group. No hypotheses will be tested.
5.2.4. Analyses of Categorical Data
The frequency and percentage of subjects in each category will be presented.
5.2.5. Analyses of Time to Event Data
For a subject who experiences the event, the time to event will be the study day 
corresponding to the actual date of the event or the earliest visit date at which the subject has 
already experienced the event.  For all subjects who have not experienced the event, their 
time to event will be right censored at the last available measurement time (or visit) used to 
define whether the subject experienced the associated event.
Time-to-event endpoints will be summarized using the Kaplan-Meier method and estimated 
survival curves will be displayed graphically.  Graphs will describe the number of patients at 
risk over time.  The median and quartiles will be estimated by the Kaplan-Meier method and
95% CIs for the median and quartiles will also be provided.
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The log-rank test (stratified using randomization strata) p-value will be used for comparing 
time to event data between each active group and the placebo group.
5.2.6. Analyses of Tier-1 and Tier-2 Events
Number and percentage of subjects with AEs over the duration of treatment will be provided 
for each treatment group.  Tier-1 and Tier-2 events will be analyzed using methods proposed 
by Chan and Zhang (1999). Exact methods will be used for Tier-1 events while an 
asymptotic method will be used for Tier-2 events. Risk differences (each PF-04965842 dose 
group compared to placebo) and 2-sided 95% CIs will be reported.  P-values will be reported 
only for Tier-1 events.
5.3. Methods to Manage Missing Data
In general, for analyses using descriptive statistics, missing values will not be imputed.  In 
addition, for safety endpoints, missing values will not be imputed.  Other methods for 
handling missing values are discussed below.
5.3.1. Binary Endpoints
For binary endpoints analyzed at each scheduled visit separately, visit windows (see 
Appendix 2) will be used to map all observed data into nominal visits. After mapping, for 
subjects who drop out for any reason or require a rescue medication, any missing data will be 
defined as “non-responsive” from that point on at all subsequent visits; for other subjects, 
any observations missing intermittently (including baseline values) will be considered 
missing completely at random (MCAR) and will remain missing in the analysis.
Additional analyses that are based on statistical considerations will utilize the longitudinal 
nature of the binary endpoint. A Generalized Linear Mixed Model (GLMM) will be fit to the 
observed data (i.e., without defining missing data due to dropout as “non-response”). The 
binary outcome will be modeled using a logistic-normal distribution.  Fixed factors will 
include treatment (PF-04965842 200 mg QD and 100 mg QD and the placebo group), visit 
(Weeks 2, 4, 8 and 12) and treatment-by-visit interaction.  Visit will be modeled as a 
categorical covariate.  A subject-specific random intercept will be used to model the 
correlation within a subject over time (see Appendix 3).  Missing observations for the active 
groups will be imputed multiply using a tipping point analysis to estimate the treatment effect 
under the assumption that the missing data mechanism is missing at random (MAR) or more 
generally, is missing not at random (MNAR). Using the estimated posterior predictive 
distribution of the GLMM model parameters obtained using Markov Chain Monte Carlo 
(MCMC) methods, estimates of the posterior predictive probability of response will be 
calculated for each treatment group. For subjects with missing data at a visit, the posterior 
predictive response probability in each PF-04965842 dose group will be re-defined as a 
weighted linear combination of the posterior predictive response probability from this group 
and the posterior predictive response probability from the placebo group, where the missing 
observations in placebo group are assumed to be missing at random (MAR) (see 
Appendix 3). These weights are fixed MNAR quantities for the active groups. A single 
imputation of the missing value will be sampled from a Bernoulli distribution with this
corresponding shifted / re-defined probability of response for the PF-04965842 dose groups. 
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This imputation will be repeated multiple times with different MCMC samples to obtain 
multiple completed datasets. For each such completed dataset, the estimates of the 
proportions and CMH-weighted difference of proportions between each PF-04965842 dose 
group and placebo will be obtained along with the associated standard errors using the 
methods in Section 5.2.1. Rubin’s rule (Rubin, 1987) will be used to combine the multiple 
estimates and standard errors across the imputed datasets and provide p-values.  
The above analysis can be repeated for different combinations of MNAR quantities which 
will be applied to the probability of response to assess when the conclusion might change 
(i.e., tipping). Two important scenarios are included in the tipping point analysis framework.
When the MNAR quantities are zero and the posterior predictive probabilities in the 
PF-04965842 dose groups are not shifted, results are obtained under an assumption of MAR 
for the missing data mechanism. Alternatively, at the other extreme, when the MNAR 
quantities are 1.0 for each PF-04965842 dose group, results are obtained under an 
assumption that the distribution of the missing responses after discontinuation of either dose 
of PF-04965842 is the same as that of the missing responses on the placebo arm. More 
detailed descriptions are provided in Appendix 3.
Due to a technical error in the process of transmission and collection of electronic data with 
the device, the data on the pruritus NRS scale was not collected from several subjects at the 
scheduled visits of Week 2 (Day 15) and after. This was not restricted to a particular site or 
country and was not indicative of being related to the missing value of pruritus endpoint or 
any other endpoints. As such, the missing data mechanism may be reasonably assumed to be 
missing completely at random or missing at random.
For the binary endpoints derived from the pruritus NRS, a hybrid approach will be used 
which is partially based on the multiple imputation method described in the previous 
paragraph. For this analysis, all data missing due to dropouts will be defined as “non-
responsive” as described in the first paragraph, but any other data which remains missing at 
any intermittent visits will be handled using multiple imputation under the MAR assumption
(which may be obtained by substituting the MNAR quantities as zero in the analysis 
described in the previous paragraph; see also, Appendix 3). At any particular visit, if there 
are 5 or fewer subjects with missing data in each treatment group after applying the non-
responder definition, no imputations will be performed, and the data will remain missing. 
Note that, as described in the previous paragraphs, the GLMM will be fit to the observed data 
(i.e., without defining missing data due to dropout as “non-response”).
5.3.2. Continuous Endpoints
For non-PRO continuous endpoints measured longitudinally, missing values post-baseline 
will not be imputed explicitly.  For such endpoints, assuming that the missing data 
mechanism is missing at random (MAR), the data will be analyzed based on a restricted 
maximum likelihood (REML) using a linear mixed-effect model with repeated measures for 
these continuous variables (see Section 5.2.3). This model will yield valid inferences in the 
presence of a missing data mechanism that is MAR.  
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For the continuous PRO variables such as pruritus NRS, DLQI / CDLQI, POEM, PSAAD, 
HADS, EQ-5D-5L / EQ-5D-Y, SF-36v2 and FACIT-F, rules suggested by the developers of 
these instruments will be followed in calculating the missing values.  If these rules are not 
enough for imputing a value, then the missing values will be handled in the same way as 
non-PRO variables.
5.3.3. Time to Event Endpoints
For time-to-event endpoints, subjects who complete the study without the event of interest or 
those who withdraw before experiencing the event of interest will have their event times right 
censored at the last available measurement time (or visit) used to define whether the subject 
experienced the associated event (ie, the event of interest is presumed to have occurred
beyond this time point).
6. ANALYSES AND SUMMARIES
Analysis will be done pairwise between each of the PF-04965842 QD treated groups (200 mg 
and 100 mg) and placebo (two separate tests of hypotheses).  An analysis with point 
estimates of the difference and the associated 95% confidence intervals will also be done for 
PF-04965842 200 mg QD versus PF-04965842 100 mg QD without testing any hypotheses.
A summary of analyses for clinical efficacy endpoints is provided in Appendix 1.  Visit 
windows to be used for all efficacy analyses and some relevant safety analyses are detailed in 
Appendix 2.
Data collected at Week 16 will be displayed in listings only, and will not be part of any 
analyses, unless specifically noted otherwise.
6.1. Co-primary Endpoint - Week 12 IGA Response
6.1.1. Primary Analysis

Summary: Proportion of subjects achieving IGA response at Week 12;

Population: FAS;

Statistical Method: CMH and normal approximation in Section 5.2.1;

Missing Data: Missing data arising due to subject dropout are considered 
“non-response” (see Section 5.3.1).
6.1.2. Additional/Supportive Analysis
Additional analyses of the Week 12 IGA response are:

The proportion of subjects achieving IGA response at Week 12 will be analyzed using 
the CMH and normal approximation method in Section 5.2.1 for the PPAS 
population.
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
Results of proportion of subjects achieving the EASI-75 at Week 12 will be obtained 
from the FAS population using a tipping point analysis where all missing responses 
will be multiply imputed (which will consider analyses under MAR as well as MNAR 
as described in Section 5.3.1 and Appendix 3). 
6.2. Co-primary Endpoint - Week 12 EASI-75 Response
6.2.1. Primary Analysis

Summary: Proportion of subjects achieving EASI-75 response at Week 12;

Population: FAS;

Statistical Method: CMH and normal approximation in Section 5.2.1;

Missing Data: Missing data arising due to subject dropout are considered 
“non-response” (see Section 5.3.1).
6.2.2. Additional/Supportive Analyses
Additional analyses of the Week 12 EASI-75 response are:

The proportion of subjects achieving EASI-75 response at Week 12 will be analyzed 
using the CMH and normal approximation method in Section 5.2.1 for the PPAS 
population.

Results of proportion of subjects achieving the EASI-75 at Week 12 will be obtained 
from the FAS population using a tipping point analysis where all missing responses
will be multiply imputed (which will consider analyses under MAR as well as MNAR 
as described in Section 5.3.1 and Appendix 3).    
6.3. Key Secondary Endpoints
6.3.1. Weeks 2, 4 and 12 NRS4 for severity Response

Summary: Proportion of subjects with NRS4 for severity response at Weeks 2, 4 and 
12;

Population: Subjects from the (FAS, PPAS) with a baseline NRS score for severity 
≥4;

Statistical Method: CMH and normal approximation in Section 5.2.1. Visit windows 
will be used as described in Appendix 2;

Missing Data: Two analyses will be performed:

Primary Analysis: Missing data arising due to subject dropout are considered 
“non-response”. For any other missing observations, a multiple imputation 
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approach based on a GLMM will be used. (see the last two paragraphs within
Section 5.3.1). This analysis will be based on both the FAS and the PPAS.

Sensitivity Analysis: All missing data will be considered as “non-response”. This 
analysis will be based on the FAS only.
6.3.2. Week 12 Change from Baseline in PSAAD

Summary: Change from baseline at Week 12;

Population: FAS, PPAS;

Statistical Method: MMRM in Section 5.2.3. As PSAAD is collected daily, data will 
be summarized weekly using a simple average of the values recorded within a week
(see Appendix 8). In the implementation of the MMRM models, data from all weekly 
visits will be used;

Missing Data: Observed Data.
6.4. Secondary Efficacy Endpoints
6.4.1. Week 8 NRS4 for severity Response

Summary: Proportion of subjects with NRS4 for severity response at Week 8;

Population: Subjects from the FAS with a baseline NRS score for severity ≥4;

Statistical Method: CMH and normal approximation in Section 5.2.1. Visit windows 
will be used as described in Appendix 2;

Missing Data: Two analyses will be performed:

Primary Analysis: Missing data arising due to subject dropout are considered 
“non-response”. For any other missing observations, a multiple imputation 
approach based on a GLMM will be used. (see the last two paragraphs within 
Section 5.3.1). This analysis will be based on both the FAS and the PPAS.

Sensitivity Analysis: All missing data will be considered as “non-response”. This 
analysis will be based on the FAS only.
6.4.2. Time to Achieve NRS4 for severity 

Summary: Time to achieve a ≥4-point improvement in the pruritus NRS for severity 
from baseline;

Population: Subjects from the FAS with a baseline NRS score for severity ≥4;

Statistical Method: Analyses for Time to Event Data in Section 5.2.5;
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
Missing Data: See Section 5.3.3.
6.4.3. Weeks 2, 4, 8 and 12 IGA Response

Summaries: 

Proportion of subjects with Weeks 2, 4 and 8 IGA response based on achieving 
clear (0) or almost clear (1) and 2 points reduction from baseline;

Proportion of subjects with Weeks 2, 4, 8 and 12 IGA response based on 
achieving clear (0);

Population: FAS;

Statistical Method: CMH and normal approximation in Section 5.2.1;

Missing Data: Missing data arising due to subject dropout are considered 
“non-response” (see Section 5.3.1).
6.4.4. Weeks 2, 4, 8 and 12 EASI-50, EASI-90, EASI-100, SCORAD50,
SCORAD75 Response

Summary: Proportion of subjects with Weeks 2, 4, 8 and 12 EASI-50, EASI-90,
EASI-100, SCORAD50, SCORAD75 response;

Population: FAS;

Statistical Method: CMH and normal approximation in Section 5.2.1;

Missing Data: Missing data arising due to subject dropout are considered 
“non-response” (see Section 5.3.1).
6.4.5. Weeks 2, 4 and 8 EASI-75 Response

Summary: Proportion of subjects with Weeks 2, 4 and 8 EASI-75 response;

Population: FAS;

Statistical Method: CMH and normal approximation in Section 5.2.1;

Missing Data: Missing data arising due to subject dropout are considered 
“non-response” (see Section 5.3.1).
6.4.6. Weeks 2, 4, 8 and 12 Change from Baseline in Total EASI Score, Total SCORAD 
Score, Severity of Pruritus NRS, %BSA, SCORAD (VAS) of Sleep Loss

Summary: Change from baseline in Total EASI Score, Total SCORAD Score, 
Severity of Pruritus NRS, %BSA, SCORAD (VAS) of Sleep Loss at Weeks 2, 4, 8
and 12;
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
Population: FAS;

Statistical Method: MMRM in Section 5.2.3;

Missing Data: Observed Data.
6.4.7. Weeks 2, 4, 8 and 12 Response based on %BSA

Summary: Proportion of subjects with %BSA < 5% at Weeks 2, 4, 8 and 12;

Population: FAS;

Statistical Method: CMH and normal approximation in Section 5.2.1;  

Missing Data: Missing data arising due to subject dropout are considered 
“non-response” (see Section 5.3.1).
6.5. Additional PRO Endpoints
6.5.1. Weeks 2, 4, 8 and 12 Change from Baseline in PRO Endpoints

Summary: Change from Baseline at Weeks 2, 4, 8 and 12 in PSAAD, DLQI /
CDLQI, HADS (anxiety and depression), POEM, PtGA and EQ-5D-5L / EQ-5D-Y;

Population: FAS;

Statistical Method: MMRM in Section 5.2.3. For implementing the MMRM for 
PSAAD score, data from all weekly visits will be used;

Missing Data: Observed Data.
6.5.2. Weeks 2, 4, 8 and 12 PSAAD Response

Summary: Proportion of subjects with Weeks 2, 4, 8 and 12 PSAAD response (≥1-
point improvement from baseline);

Population: Subjects from the FAS with a baseline PSAAD score ≥1;

Statistical Method: CMH and normal approximation in Section 5.2.1;

Missing Data: Missing data arising due to subject dropout are considered 
“non-response” (see Section 5.3.1).
6.5.3. Weeks 2, 4, 8 and 12 PtGA Response

Summary: Proportion of subjects with Weeks 2, 4, 8 and 12 PtGA response;

Population: Subjects from the FAS with a baseline PtGA value ≥2;

Statistical Method: CMH and normal approximation in Section 5.2.1;
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
Missing Data: Missing data arising due to subject dropout are considered 
“non-response” (see Section 5.3.1).
6.5.4. Weeks 2, 4, 8 and 12 HADS Response in Adults

Summaries: 

Proportion of adult subjects achieving a score < 8 in each of the components 
(anxiety and depression) of the HADS score at Weeks 2, 4, 8 and 12 (among adult 
subjects with a score ≥8 at baseline);

Proportion of adult subjects achieving a score < 11 in each of the components 
(anxiety and depression) of the HADS score at Weeks 2, 4, 8 and 12 (among adult 
subjects with a score ≥11 at baseline);

Populations: 

Adult subjects from the FAS with a baseline corresponding component score ≥8;

Adult subjects from the FAS with a baseline corresponding component score ≥11;

Statistical Method: CMH and normal approximation in Section 5.2.1;

Missing Data: Missing data arising due to subject dropout are considered 
“non-response” (see Section 5.3.1).
6.5.5. Weeks 2, 4, 8 and 12 DLQI Response in Adults

Summaries: 

Proportion of adult subjects with ≥4-point improvement from baseline in the 
DLQI score at Weeks 2, 4, 8 and 12 (among adult subjects with a score ≥4 at 
baseline);

Proportion of adult subjects with a DLQI score < 2 at Weeks 2, 4, 8 and 
12 (among adult subjects with a score ≥2 at baseline);

Populations: 

Adult subjects from the FAS with a baseline DLQI score ≥4;

Adult subjects from the FAS with a baseline DLQI score ≥2;

Statistical Method: CMH and normal approximation in Section 5.2.1;

Missing Data: Missing data arising due to subject dropout are considered 
“non-response” (see Section 5.3.1).
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6.5.6. Weeks 2, 4, 8 and 12 CDLQI Response in Adolescents

Summaries: 

Proportion of adolescent subjects with ≥2.5-point improvement from baseline in 
the CDLQI score at Weeks 2, 4, 8 and 12 (among adolescent subjects with a score 
≥2.5 at baseline);

Proportion of adolescent subjects with a CDLQI score < 2 at Weeks 2, 4, 8 and 
12 (among adolescent subjects with a score ≥2 at baseline);

Populations: 

Adolescent subjects from the FAS with a baseline CDLQI score ≥2.5;

Adolescent subjects from the FAS with a baseline CDLQI score ≥2;

Statistical Method: CMH and normal approximation in Section 5.2.1;
Missing Data: Missing data arising due to subject dropout are considered 
“non-response” (see Section 5.3.1).
6.5.7. Week 12 PRO Endpoints

Summary: Change from Baseline at Week 12 in FACIT-F, Peds-FACIT-F, and 
physical and mental component scores of SF-36v2 acute;

Population: FAS;

Statistical Method: ANCOVA in Section 5.2.2;

Missing Data: Observed Data.
6.6. PK Endpoints
Population PK data for PF-04965842 will be summarized through appropriate data 
tabulations, descriptive statistics, and graphical presentation.  A population PK model will be 
developed for the purpose of estimating PK parameters.  Additional details of the 
methodology will be captured in a separate modeling plan and the results will also be 
reported separately.
6.7. Subset Analyses
Summary statistics for co-primary endpoints will be presented by subgroups below.

Age (years) group (<18, ≥18; <40, ≥40; <65, ≥65);

Sex (Male, Female);
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
Race (White, Black or African-American, Asian, Other2);

Region of enrollment (US/Canada/Australia, Europe);

AD Duration (years) group (<26, ≥26);

Baseline disease severity (moderate, severe);

Baseline EASI group (16-25, >25);

Baseline % BSA group (10-30, >30-50, >50);

Previous use of systemic immunosuppressant for AD (Yes, No).
Estimates of the difference between the active dose groups and placebo, along with the 95% 
confidence interval (no p-value), will be presented for each defined category of each 
subgroup.  Analyses will be performed using the normal approximation to the binomial 
distribution, without any adjustments for randomization strata.
The primary purpose of the subgroup analyses is to check for consistency of results across 
subgroups, to make sure overall results are not being driven by some subset of subjects.
Graphical display (e.g., forest plots) of the differences between treatment groups will be
presented.  There is no intention to have any specific inference within subgroups.
6.8. Baseline and Other Summaries and Analyses
6.8.1. Baseline Summaries
Demographics, medical history, primary diagnosis, history of prior AD treatments and 
disease characteristics including variables defined in Section 3.4 will be summarized by
treatment group according to CaPS.
6.8.2. Study Conduct and Subject Disposition
Subjects’ evaluation, disposition and discontinuation will be summarized according to CaPS.
6.8.3. Study Treatment Exposure
A summary of dosing compliance by treatment group will be provided.
The exposure to study drug will be summarized by the total number of days of dosing, mean / 
median number of days of exposure and number and percent of subjects in exposure duration 
categories.
                                                
2 For purposes of analysis, Other will comprise the categories of American Indian or Alaska Native, 
Hawaiian or Other Pacific Islander, Multi-Racial and any other category reported on the CRF.
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6.8.4. Concomitant Medications and Non-drug Treatments
Prior drug and non-drug treatment, concomitant drug and non-drug treatment will be 
summarized according to CaPS.
6.9. Safety Summaries and Analyses
Safety analyses will be based on the SAF analysis set.
All clinical AEs, SAEs, TEAEs, withdrawal due to AEs, ECGs, vital signs and safety 
laboratory data will be reviewed and summarized on an ongoing basis during the study to 
evaluate the safety of subjects.
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate.  All safety endpoints will be listed and summarized in 
accordance with CaPS.  Categorical outcomes (e.g., AEs) will be summarized by subject 
counts and percentage.  Continuous outcome (e.g., blood pressure, pulse rate, etc.) will be 
summarized using N, mean, median, standard deviation, etc.  Change from baseline in 
laboratory data, ECGs and vital signs will also be summarized.  Subject listings will be 
produced for these safety endpoints accordingly.
6.9.1. Adverse Events
The safety data will be summarized in accordance with CaPS.  All safety data will be 
summarized descriptively through appropriate data tabulations, descriptive statistics, 
categorical summaries, and graphical presentations.  Safety endpoints for the study include:
•
Treatment-emergent AEs and SAEs;
•
Withdrawals from active treatment due to AEs;
•
Serious infections, defined as any infection (viral, bacterial, and fungal) requiring 
hospitalization or parenteral antimicrobials.
Treatment-emergent AEs will also be analyzed using a 3-tier approach.  Risk differences 
between the active treatments and placebo will be used to summarize the results. 
For Tier-1 events, point estimates, 95% confidence intervals and p-values will be presented 
graphically comparing each active dose group with placebo.  No multiplicity adjustments 
will be made.  For Tier-2 events, only point estimates and 95% confidence intervals will be 
presented graphically (see Section 5.2.6).  Tier-3 events will be summarized as part of the 
overall AE summaries, AEs will be displayed by MedDRA system organ class (SOC).
It should be recognized that most studies are not designed to reliably demonstrate a causal 
relationship between the use of a pharmaceutical product and an adverse event or a group of 
adverse events.  Except for select events in unique situations, studies do not employ formal 
adjudication procedures for the purpose of event classification. 
 
 
CCI
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6.9.2. Laboratory Data
Laboratory data will be listed and summarized in accordance with the CaPS reporting 
standards.  Summaries of subjects meeting pre-specified monitoring and discontinuation 
criteria will be created using methods for categorical data (see Section 5.2.4).
6.9.3. Vital Signs, including Height and Weight
Vital signs will be summarized at baseline, Weeks 2, 4, 8, and 12/End of Treatment visits.  
Height and weight will be summarized at baseline and End of Treatment visits.
6.9.4. Electrocardiogram
ECG parameters, if applicable, will be summarized at baseline and End of Treatment visits.
6.9.5. Physical Examination
Physical examinations will be summarized at baseline and all-available post-baseline visits.
7. INTERIM ANALYSES
There will be no interim analyses for this study.
This study uses an External Data Monitoring Committee (E-DMC). The E-DMC will be 
responsible for ongoing monitoring of the efficacy, safety and PKs of subjects in the study 
according to the charter.  Pharmacokinetic data from the first 20 adolescent subjects will be 
analyzed and reviewed by the E-DMC.  The recommendations made by the E-DMC to alter 
the conduct of the study will be forwarded to Pfizer for final decision.  Pfizer will forward 
such decisions, which may include summaries of aggregate analyses of endpoint events and 
of safety data that are not endpoints, to regulatory authorities, as appropriate.  Composition 
of the E-DMC and processes under which the E-DMC operates will be documented in the 
E-DMC charter.
8. REFERENCES
1.
Hommel G, Bretz F, Maurer W. Powerful short-cuts for multiple testing procedures 
with special reference to gatekeeping strategies. Statistics in Medicine, 2007, 26:4063–
4073.
2.
Marcus R, Peritz E, Gabriel KR. On closed testing procedure with special reference to 
ordered analysis of variance. Biometrika, 1976, 63:655–660.
3.
Chan ISF and Zhang Z. Test based exact confidence intervals for the difference of two 
binomial proportions. Biometrics, 1999, 55:1201–1209.
4.
Rubin DB (1987). Multiple imputation for nonresponse in surveys. New York: Wiley.
5.
Basra MKA, Salek MS, Camilleri L, Sturkey R and Finlay AY. Determining the 
Minimal Clinically Important Difference and Responsiveness of the Dermatology Life 
Quality Index (DLQI): Further Data. Dermatology, 2015, 230:27–33.
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6.
Zigmond AS and Snaith RP. The Hospital Anxiety and Depression Scale. Acta 
Psychiatr Scand, 1983, 67: 361–70.
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9. APPENDICES
Appendix 1. Summary of Clinical Efficacy Analyses
Efficacy Endpoints
Population
Analysis 
Method
Missing
Data Imputation
Primary Analysis for
Co-primary
Endpoints
Week 12 IGA Response
FAS
CMH
NR
Yes
PPAS
CMH
NR
No
FAS
CMH
TP (MAR)
No
FAS
CMH
TP (MNAR)
No
Week 12 EASI-75 Response
FAS
CMH
NR
Yes
PPAS
CMH
NR
No
FAS
CMH
TP (MAR)
No
FAS
CMH
TP (MNAR)
No
Weeks 2, 4, 8 and 12 NRS4 for severity 
Response
FAS
CMH
NR+MI
PPAS
CMH
NR+MI
FAS
CMH
NR
Week 12 CFBL in PSAAD
FAS
MMRM
OD
PPAS
MMRM
OD
Time to NRS4 for severity
FAS
Kaplan-Meier
OD
Weeks 2, 4 and 8 IGA Response
FAS
CMH
NR
Weeks 2, 4, 8 and 12 EASI-50 / EASI-90 / 
EASI-100 Response
FAS
CMH
NR
Weeks 2, 4 and 8 EASI-75 Response
FAS
CMH
NR
Weeks 2, 4, 8 and 12 CFBL in Total EASI 
Score
FAS
MMRM
OD
Weeks 2, 4, 8 and 12 CFBL in NRS for 
severity
FAS
MMRM
OD
Weeks 2, 4, 8 and 12 CFBL in %BSA
FAS
MMRM
OD
Weeks 2, 4, 8 and 12 CFBL in SCORAD 
Total Score
FAS
MMRM
OD
Weeks 2, 4, 8 and 12 SCORAD50 / 
SCORAD75 Response
FAS
CMH
NR
Weeks 2, 4, 8 and 12 CFBL in SCORAD 
subjective VAS assessments of sleep loss
FAS
MMRM
OD
CFBL=Change from baseline; CMH=Cochran-Mantel-Haenszel; ANCOVA=Analysis of Covariance; 
MMRM=Mixed-effect Model Repeated Measures; NR=Non-Responder; TP=Tipping Point; OD=Observed Data; 
MI=Multiple Imputation; MAR=Missing At Random; MNAR=Missinng Not At Random
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Appendix 2. Definition and Use of Visit Windows in Reporting
Visit windows will be used for efficacy variables, and for any safety data that display or 
summarize by study visit.  For other endpoints (e.g., ECG, vital signs), visit windows will be 
applied for summary statistics by study visits if required.
Visit Label
Target Day
Definition [Day window]
Screening
Days -28 to Day -1
Baseline
Day 1 (Day of first 
dose)
Last observation prior to and 
including day of first dose
Week 2
15
Days 2 to 22
Week 4
29
Days 23 to 43
Week 8
57
Days 44 to 71
Week 12
85
Days 72 to 99
Follow Up/End of Study
Week 16
-
Days 100 to -
For the lab values, if the calculated study day for the labelled baseline visit is not study Day 
1, but falls within 28 days before the start of the study dosing, then that data should be used 
for the baseline instead of leaving baseline missing.
For the other values, if the calculated study day for the labelled baseline visit is not study 
Day 1, but falls before the start of the study dosing, then that data should be used for the 
baseline instead of leaving baseline missing.
If two or more visits fall into the same window, keep the one closest to the Target Day.  If 
two visits are equaled distant from the Target Day in absolute value, the later visit should be 
used.
Safety analysis may follow CaPS standards.
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Appendix 3. A Logit-Normal GLMM for Longitudinal Binary Data and Tipping Point 
Analysis
A Logit-Normal Model
Let ܻ௜௝be the binary outcome for subject ݅(݅= 1, 2, … , ܰ) and visit ݆(݆= 1, 2, 3, 4).  We 
assume ܻ௜௝= 1 for a response and ܻ௜௝= 0 for a non-response.  Then we model as
ܲ൫ܻ௜௝= 1 หݔ௜௝, ݑ௜) =
݁ఉᇲ௫೔ೕା௨೔
1 + ݁ఉᇲ௫೔ೕା௨೔≡ߨ௜௝(ߚ; ݑ௜)
Here, ߚis a vector of unknown parameters corresponding to the vector of fixed effects ݔ௜௝
and ݑ௜is a subject-specific random effect which is assumed to be normally distributed with 
mean 0 and variance ߪଶ.  Note that conditional on ݑ௜, ܻ௜௝is independent of ܻ௜௞, when ݆≠݇.
The full marginal likelihood of the data is then,
ܮ(ߚ, ߪଶ) = ෑනෑߨ௜௝(ߚ; ݑ௜)௒೔ೕ(1 −ߨ௜௝(ߚ; ݑ௜))(ଵି௒೔ೕ) × ܰ(ݑ௜; 0, ߪଶ)
ସ
௝ୀଵ
ஶ
ିஶ
ே
௜ୀଵ
݀ݑ௜
There is no closed analytical form for this likelihood.
For the present study, the primary endpoint is evaluated at Visit 8 / Week 12 (݆= 4).  There 
are three treatment groups, so the model term ߚᇱݔ௜௝when written out looks like,
ߚ଴+ ෍ߚଵ௞
ଷ
௞ୀଵ
× 1(்೔ୀ௞) + ߚଶ௝+ ෍ߚଷ௝௞
ଷ
௞ୀଵ
× 1(்೔ୀ௞)
Here, ܶ௜represents treatment for subject ݅.  The third term in the expression is the effect for 
visit ݆and the fourth term in the expression is the interaction effect between treatment and 
visit.  With an overall intercept term, the model is over-parameterized as written and so to fit 
the model, some restrictions on ߚare required.  The default option (this can be changed using 
programming syntax) in standard statistical software is to assume ߚଵଷ= 0, ߚଶସ= 0, thereby 
interpreting ߚଵଵ, ߚଵଶas the difference in treatment effect relative to ܶ= 3 and ߚଶଵ, ߚଶଶ, ߚଶଷas 
the difference in visit effect relative to ܸ= 4.  Consequently, ߚଷ௝௞= 0 when ݆= 4 or ݇= 3.  
So, for example, for a subject taking PF-04965842 100 mg QD at Week 12, the expression 
would be ߚ଴+ ߚଵଵ.  For a subject taking PF-04965842 200 mg QD at Week 12, the 
expression would be ߚ଴+ ߚଵଶ.  For a subject on placebo at Week 12, the expression would 
be ߚ଴.
Tipping Point Analysis
A method to analyze the longitudinal data of a binary endpoint measured during the placebo-
controlled period (eg, IGA and EASI-75 response rates at Weeks 2, 4, 8 and 12) under the 
MNAR assumption is called the tipping point analysis.  This tipping point analysis includes 
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two popular scenarios as special cases: (1) the Jump-to-Reference (JTR) analysis in which 
the response rate for a missing subject assessment in the active treatment group takes on (ie, 
jumps to) the rate for the reference or control treatment group and (2) the MAR analysis in 
which the response rate for a missing subject assessment in each treatment group is based on 
the posterior predictive response rate for that treatment group alone.
The saturated logit-normal GLMM as described above will be used as the imputation model.  
Estimation of the model parameters will be performed under the Bayesian framework using 
Markov Chain Monte Carlo (MCMC) methods.  We assign a non-informative prior for each 
component of ߚto be independent and identically distributed as ~ܰ(0, 10000)  and assign a 
weakly informative prior for ߪଶas an Inverse-Gamma distribution with shape=1 and scale=1.  
With this prior distribution, the 90th percentile for ߪଶis approximately 9. 
Let ߚ௕, ݑ௜
௕, ܾ= 1, 2, … , ܤbe a sample from the posterior distribution.  A single imputation 
ܻప,ఫ௕
෪of missing ܻ௜௝is based on the posterior predictive distribution of the response 
probabilities estimated from the GLMM.  For example, if subject ݅is randomized to 
PF-04965842 100 mg QD (ܶ௜= 1), then at Week 12 (ܸ= 4),
݈݋݃݅ݐ(ߨ௜,ଵ,ସ
௕
) = ݈݋݃݅ݐቀܲ(ܻప,ସ
௕
෪= 1|ܶ௜= 1, ܸ= 4)ቁ= ߚ଴
௕+ ߚଵଵ
௕+ ݑ௜
௕.
If subject ݅is randomized to PF-04965842 200 mg QD (ܶ௜= 2), then at Week 12 (ܸ= 4),
݈݋݃݅ݐ(ߨ௜,ଶ,ସ
௕
) = ݈݋݃݅ݐቀܲ(ܻప,ସ
௕
෪= 1|ܶ௜= 2, ܸ= 4)ቁ= ߚ଴
௕+ ߚଵଶ
௕+ ݑ௜
௕.
If subject ݅is randomized to placebo (ܶ௜= 3), then at Week 12 (ܸ= 4),
݈݋݃݅ݐ(ߨ௜,ଷ,ସ
௕
) = ݈݋݃݅ݐቀܲ(ܻప,ସ
௕
෪= 1|ܶ௜= 3, ܸ= 4)ቁ= ߚ଴
௕+ ݑ௜
௕.
In the tipping analysis, we apply a series of fixed quantities ߜ= (ߜଵ, ߜଶ)′ to account for 
MNAR. We define,
ߨ௜,ଷ,ସ
∗௕
= ߨ௜,ଷ,ସ
௕
,
ߨ௜,ଵ,ସ
∗௕
= ߜଵߨ௜,ଷ,ସ
௕
+ (1 −ߜଵ)ߨ௜,ଵ,ସ
௕
,
ߨ௜,ଶ,ସ
∗௕
= ߜଶߨ௜,ଷ,ସ
௕
+ (1 −ߜଶ)ߨ௜,ଶ,ସ
௕
We then sample the single imputed value ܻప,ఫ௕
෪from a Bernoulli distribution with probability 
of success ߨ௜,்೔,ସ
∗௕
. For the present analysis, the responses from the placebo arm are not 
shifted.
Analysis of an imputed data set will produce an estimate as well as standard error of the 
treatment difference using CMH and normal approximation in Section 5.2.1.  For a given 
value of MNAR parameter ߜ, this is repeated for B (typically, B=500) times to generate B
complete imputed data sets and these B sets of estimates are combined using the Rubin’s 
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Method (Rubin, 1987).  This can then be repeated for different values of MNAR parameter ߜ
to evaluate the impact of missing data. Note that ߜ= (0, 0)′ corresponds to an MAR analysis
and ߜ= (1, 1)′corresponds to an analysis commonly known as Jump-To-Reference (JTR).
As a special case, we will consider ߜଵ= ߜଶfor our analyses.
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Appendix 4. Investigator’s Global Assessment (IGA)
The Investigator’s Global Assessment of atopic dermatitis is scored on a 5-point scale (0-4), 
reflecting a global consideration of the erythema, induration and scaling.  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 the table below.  The 
assessment will be a static evaluation without regard to the score at a previous visit.
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 soles from the assessment/scoring.
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Appendix 5. 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 the table below.
Clinical Sign Severity Scoring Criteria for the 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.
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%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 (see table below).  When measuring, the handprint unit refers 
to the size of each individual subject’s hand with fingers in a closed position.
Handprint Determination of %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.
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 (see table below).
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
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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 below.
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.
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Appendix 6. 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 score 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 score of 100%.
Severity (B, maximum score 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)/papulation;

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 score of 18).
Subjective Symptoms (C, maximum score of 20): Subjective symptoms (i.e., itch and sleep 
loss) are each scored by the subject using a visual analog scale (VAS) where “0” is no itch 
(or no sleep loss) and “10” is the worst imaginable itch (or sleep loss).  The value for each 
should reflect the average on a 10 point scale for the last 3 days/nights.  These scores are 
added to give 'C' (maximum score of 20).
SCORAD Total Score: The SCORAD for an individual is calculated by the formula: A/5 + 
7B/2 + C (can range from 0 to 103).
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Appendix 7. Pruritus Severity and Frequency (Pruritus NRS)
Severity of Pruritus
The severity of itch (pruritus) due to atopic dermatitis will be assessed using the Pruritus 
Numerical Rating Scale, a validated horizontal NRS.  Subjects will be asked to assess their 
worst itching due to atopic dermatitis over the past 24 hours on an NRS anchored by the 
terms “no itch” (0) and “worst itch imaginable” (10).  This item will be administered to all 
subjects.  Subjects will enter pruritus NRS assessment into an eDiary.
On a scale of 0 to 10, with 0 being “no itch” and 10 being “worst itch imaginable”, how 
would you rate your itch at the worst moment during the previous 24 hours?
Frequency of Pruritus
The frequency of itch (pruritus) due to atopic dermatitis will be assessed using a horizontal 
NRS.  Subjects will be asked to assess frequency of itching due to atopic dermatitis over the 
past 24 hours on an NRS anchored by the terms “never/no itching” (0) and “always/constant 
itching” (10).  This item will be administered to all subjects.  Subjects will enter pruritus 
NRS assessment into an eDiary.
Select the number that best describes frequency of itching due to Atopic Dermatitis over the 
past 24 hours (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 
itch
Worst 
itch 
imaginable
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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Appendix 8. Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD) 
(e-Diary)
The PSAAD is a daily patient-reported symptom diary.  The preliminary version is a 15-item 
questionnaire that includes 11 items developed to measure symptoms of atopic dermatitis, 
capturing those identified by patients to be most important, based on a 24-hour recall.  
Analysis of the PSAAD will be based solely on these 11 items.  
 
 
 
The PSAAD total score will be calculated as the simple arithmetic mean of items 1-11 as 
listed below.  Items 12, 13, 14, and 15 will be only used to further validate PSAAD and they 
are not the part of the PSAAD scale itself.
For analyses included in this SAP, weekly averages of the PSAAD score will be used. For 
example, the baseline value is defined as a simple average of all observed values from Day -6 
until Day 1, the Week 1 value is defined as a simple average of all observed values from Day 
2 until Day 8, the Week 2 value is defined as a simple average of all observed values from 
Day 9 until Day 15, and so on and so forth up to Week 12.
Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD)
Please answer each question by thinking about your skin condition (most often called atopic 
eczema or atopic dermatitis) over the past 24 hours.  This includes today and last night. 
For each question, think about all the areas of your body affected by your skin condition and 
choose the number that best describes your experience.
1) How itchy was your skin over the past 24 hours?
0
1
2
3
4
5
6
7
8
9
10
Not 
itchy
Extremely 
itchy
2) How painful was your skin over the past 24 hours?
0
1
2
3
4
5
6
7
8
9
10
Not 
painful
Extremely 
painful
3) How dry was your skin over the past 24 hours?
0
1
2
3
4
5
6
7
8
9
10
CCI
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Not dry
Extremely 
dry
4) How flaky was your skin over the past 24 hours?
0
1
2
3
4
5
6
7
8
9
10
Not 
flaky
Extremely 
flaky
5) How cracked was your skin over the past 24 hours?
0
1
2
3
4
5
6
7
8
9
10
Not 
cracked
Extremely 
cracked
6) How bumpy was your skin over the past 24 hours?
0
1
2
3
4
5
6
7
8
9
10
Not 
bumpy
Extremely 
bumpy
7) How red was your skin over the past 24 hours?
0
1
2
3
4
5
6
7
8
9
10
Not red
Extremely 
red
8) How discolored (darker or lighter) was your skin over the past 24 hours?
0
1
2
3
4
5
6
7
8
9
10
Not 
discolored
Extremely 
discolored 
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9) How much did your skin bleed over the past 24 hours?
0
1
2
3
4
5
6
7
8
9
10
No 
bleeding 
Extreme 
bleeding
10) How much did your skin seep or ooze fluid (other than blood) over the past 24 hours?
0
1
2
3
4
5
6
7
8
9
10
No 
seeping 
or 
oozing 
Extreme 
seeping 
or oozing
11) How swollen was your skin over the past 24 hours?
0
1
2
3
4
5
6
7
8
9
10
Not 
swollen
Extremely 
swollen 
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Appendix 9. Schedule of Activities
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the STUDY PROCEDURES 
and ASSESSMENTS sections of the protocol for detailed information on each procedure and assessment required for compliance 
with the protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities table, in order to 
conduct evaluations or assessments required to protect the well-being of the subject.
Visit Identifiera
Day -28
Screening
Day 1
Week 0
Baseline
Day 8
Week 1
Call
Day 15
Week 2
Day 29
Week 4
Day 43
Week 6
Call
Day 57
Week 8
Day 85
Week 
12 (EOT/ET) 
EOS, 
Follow- up
Week 16
(4 Weeks after 
EOT or ET)
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit Window
None
None
1 Day
1 Days
2 Days 3 Days 3 Days
3 Days
3 Days
Enrollment Procedure
Informed consent
X
Register subject using IRT system
X
Inclusion/Exclusion Criteria
X
X
Demographics, Medical History, Tobacco 
and Alcohol History, Atopic Dermatitis 
Disease Historyb
X
Review Prior/Concomitant Medications & 
Treatments
X
X
X
X
X
X
X
X
X
Dispense e-Diary and instruct subjects on 
use
X
Medical Procedures
Complete Physical Examc
X
X
X
Targeted Physical Examc
X
X
X
X
Vital Signsd
X
X
X
X
X
X
X
Additional Blood Pressure and Pulse Rate 
(post dose)d
X
X
Weight
X
X
X
Height
X
X
Chest X-raye
X
ECG (12-lead)
Xx
X
X
X
X
X
X
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Visit Identifiera
Day -28
Screening
Day 1
Week 0
Baseline
Day 8
Week 1
Call
Day 15
Week 2
Day 29
Week 4
Day 43
Week 6
Call
Day 57
Week 8
Day 85
Week 
12 (EOT/ET) 
EOS, 
Follow- up
Week 16
(4 Weeks after 
EOT or ET)
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit Window
None
None
1 Day
1 Days
2 Days 3 Days 3 Days
3 Days
3 Days
Laboratory Assessments 
Serum chemistry and hematology (including 
coagulation panel)f
X
X
X
X
X
X
X
Lipid Panelf
X
X
X
X
Urinalysis
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
HIV Testing (per local regulations)i
X
Hepatitis B Surface Antigen (HBsAg), 
Hepatitis B Surface Antibody (HBsAb), 
Hepatitis B Core Antibody (HBcAb), 
Hepatitis C Antibody (HCV Ab), Hepatitis 
C Viral RNA (HCV RNA)j
X
Varicella Zoster Virus (VZV IgG Ab) 
(adolescents only, if applicable)k
X
Tuberculosis Testl
X
Pharmacokinetic 
Pharmacokinetic Blood Sampling 
(Pre-dose)m
X
Pharmacokinetic Blood Sampling 
(Post-dose)n
X
X
Trial Treatment 
Randomization 
X
Drug Dispensing
X
X
X
Investigational Product Accountability  
X
X
X
X
Investigational Treatment Administrationo
X---------------------------------------------------------------------------------------------X
Review eDiary to assess completion
X
X
X
X
X
X
Assess eligibility for B7451015v
X
Clinical Assessments 
Fitzpatrick Skin Type Assessment
X
Investigator’s Global Assessment (IGA) 
X
X
X
X
X
X
X
SCORing Atopic Dermatitis (SCORAD)
X
X
X
X
X
X
X
Eczema Area and Severity Index (EASI)
X
X
X
X
X
X
X
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Visit Identifiera
Day -28
Screening
Day 1
Week 0
Baseline
Day 8
Week 1
Call
Day 15
Week 2
Day 29
Week 4
Day 43
Week 6
Call
Day 57
Week 8
Day 85
Week 
12 (EOT/ET) 
EOS, 
Follow- up
Week 16
(4 Weeks after 
EOT or ET)
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit Window
None
None
1 Day
1 Days
2 Days 3 Days 3 Days
3 Days
3 Days
Body Surface Area (BSA from EASI) 
X
X
X
X
X
X
X
C-SSRSp
X
SBQ-Rp
X
PHQ-8p
X
Patient-reported Outcome 
Pruritus Numerical Rating Scale (NRS)q
X------------------X
X-----------------------------------------X
X
X
X
X
Patient Global Assessment (PtGA)
X
X
X
X
X
X
Dermatology Life Quality Index (DLQI or 
CDLQI)y
X
X
X
X
X
X
Patient-Oriented Eczema Measure (POEM)
X
X
X
X
X
X
Pruritus and Symptoms Assessment for 
Atopic Dermatitis (PSAAD)r
X ------------------X
X---------------------------------------------------------------------------------------------------------------------X
Hospital Anxiety and Depression Scale 
(HADS)
X
X
X
X
X
X
EQ-5D-5L (adults) or EQ-5D-Y (ages 
12-17 years)
X
X
X
X
X
X
SF-36v2, Acutet
X
X
X
FACIT-F or Peds-FACIT-Fw
X
X
X
Safety
Serious and non-serious adverse event 
monitoring
X
X
X
X
X
X
X
X
X
Contraception Checks
X
X
X
X
X
X
X
X
X
Serum Sample for Baseline Viral Screenu
X
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Abbreviations: BSA =  body surface area; CDLQI = Children’s Dermatology Life Quality Index; C-SSRS = Columbia Suicide Severity Rating Scale; 
DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; ECG = electrocardiogram; EOS=End of Study; EOT = End of 
Treatment; ET= early termination; EQ-5D-5L = EuroQol Quality of Life 5-Dimension 5-Level Scale; EQ-5D-Y = EuroQol Quality of Life 5-Dimension, 
Youth Scale; FACIT-F = Functional Assessment of Chronic Illness Therapy Fatigue Scale;  FSH = follicle stimulating hormone; GGT= gamma-glutamyl 
transferase; HADS= Hospital Anxiety and Depression Scale; HBsAg = hepatitis B surface antigen; HBsAb = hepatitis B surface antibody; HBcAb = 
hepatitis B core antibody; HCVAb = hepatitis C antibody; HCV RNA = Hepatitis C Viral RNA; Hep B = Hepatitis B; HIV = human immunodeficiency 
virus; HSV-1 = herpes simplex virus type 1; HSV2 = herpes simplex virus type 2; IGA = Investigator’s Global Assessment; IgE = Immunoglobulin E; IRT = 
Interactive Response System; LDH = Lactate dehydrogenase; NRS = numerical rating scale; Peds-FACIT-F = Pediatric Functional Assessment of Chronic 
Illness Therapy Fatigue Scale; PHQ-8 = Patient Health Questionnaire 8 items;  POEM= Patient-Oriented Eczema Measure; PSAAD=Pruritus and Symptoms 
Assessment for Atopic Dermatitis; PtGA = Patient Global Assessment; RNA = Ribonucleic acid; SBQ-R = Suicide Behaviors Questionnaire-Revised; 
SCORAD = SCORing Atopic Dermatitis; SF-36v2 = Short Form-36 Health Survey Version 2;VZV = varicella zoster virus; VZV IgG Ab = varicella zoster 
virus immunoglobulin G antibody; 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 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, lungs, and abdomen 
and examination of body systems where there are symptom complaints by the subject.
d.
Vital Signs include sitting blood pressure, pulse rate, respiratory rate, and temperature measured after at least 5 minutes of rest.  All vital signs at 
baseline and Week 12 must be performed prior to administration of investigational product and additional blood pressure and pulse rate assessments 
must be performed at least 1 hour following administration of investigational product.  All vital signs at all other on-site visits must be performed at 
least 1 hour following administration of investigational product. 
e.
Chest X-ray or other appropriate diagnostic image (i.e., CT or MRI) may be performed up to 12 weeks prior to Day 1.  Chest X-rays (posterior-anterior 
and lateral views) are required for adults and recommended for adolescents as per local guidelines and standard of care.  Official reading must be 
located and available in the source documentation.
f.
Serum chemistry includes: blood urea nitrogen (BUN), serum creatinine, creatine phosphokinase, glucose, Ca++, Na+, K+, Cl-, total CO2, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), total, indirect and direct bilirubin, alkaline phosphatase, 
lactate dehydrogenase, uric acid, albumin and total protein.  The 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, Week 4, Week 12 and 
EOS visits. Hematology includes: Hemoglobin, hematocrit, red blood cell count and indices (MCH, MCHC, MCV, RBC Morphology), white blood 
cells, neutrophils (%, absolute), lymphocytes (%, absolute), monocytes (%, absolute), eosinophils (%, absolute), basophils (%, absolute), platelets, 
reticulocyte count and coagulation panel.  Coagulation panel includes: Activated Partial Thromboplastin Time (APTT), Prothrombin Time/International 
Normalized Ratio (PT/INR).  Laboratory tests with abnormal results (per Section 6.1 and Section 7.5.2) 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, including adolescents aged 12 years and older, regardless of 
whether they have experienced menarche.  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.
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h.
Urine pregnancy test must be performed prior to dosing with the investigational product for female subjects of childbearing potential, including 
adolescents aged 12 years and older, regardless of whether they have experienced menarche. 
i.
Subjects who are positive for HIV will be screen-failed. 
j.
HBsAb reflex testing will be performed only if HBsAg negative but HBcAb positive.  Subjects who are positive for HCVAb and HCV RNA will be 
screen-failed.
k.
VZV IgG antibody testing is required to confirm eligibility in adolescent subjects who have not received at least one dose of a varicella vaccine.
l.
A documented TB test performed within 12 weeks prior to Day 1 is acceptable.  Subjects with a history of tuberculosis may not require TB testing as 
per the protocol exclusion criteria in Section 4.2.  Perform TB test procedure using the QuantiFERON-TB Gold In Tube Test (or Purified Protein 
Derivative).  A negative PPD test can be substituted for the QuantiFERON-TB Gold In-Tube test only if the central laboratory is unable to perform the 
QuantiFERON-TB Gold In-Tube test or cannot determine the results to be positive or negative and the Pfizer Medical Monitor approves it on a 
case-by-case basis.  In addition to protocol required TB testing, sites should follow their local standards for TB status determination, which may include 
chest X-ray.  See Section 7.2.3.
m. A pharmacokinetic (PK) blood sample will be collected prior to dosing at the study site on Week 4. 
n.
PK blood samples will be collected at 0.5 hours (15 min) postdose at the Week 4 visit and at 0.5 hours (15 min) and 4.0 hours (30 min) postdose at 
the Week 12 visit (EOT/ET).  For ET visits, if the subject discontinues before Week 4 do not collect PK samples.  If the ET visit occurs after Week 4, 
collect PK samples only if the subject takes the investigational product at the site visit. 
o.
Subjects should take the medication from study Days 1 to 85.  Subjects will be encouraged to take the medication in the morning whenever 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.
p.
Site staff is to administer the C-SSRS, SBQ-R and PHQ-8 to all subjects at screening and score immediately.  Subjects who have recent or active 
suicidal ideation or behavior or clinically significant depression will be excluded from the study or discontinued from the study per Section 4.2, Section 
7.4.1, Section 7.4.2 and Section 7.4.3.
q.
Pruritus Numerical Rating Scale (NRS) will be assessed using an eDiary, daily during the screening period and from Day 1 to 15.  After Day 15, the 
pruritus NRS will be completed only on study visit days in the eDiary.  At the Screening visit, site staff will dispense the ePRO device and review 
instructions for completion of the subject eDiary for the NRS.  At every visit, the study coordinator will review the eDiary for completeness and counsel 
the subject on how to complete the items in the daily eDiary, if needed. 
r.
Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD) will be conducted to assess the severity and frequency of pruritus, symptoms and 
sleep collected daily in a subject e-diary during the screening period and from Day 1 through the End of Study visit in selected countries (See Section 
7.7.7).  At the Screening visit, site staff will dispense the ePRO device and review instructions for completion of the subject eDiary for the PSAAD 
questionnaire.  Subjects will be asked to record their assessment in their eDiary once a day before taking the investigational product.  At every visit, the 
study coordinator will review the eDiary for completeness and counsel the subject on how to complete the items in the daily eDiary, if needed. 
s.
The contraception check is an opportunity to confirm that contraception, if assigned, is used consistently and correctly.  It also facilitates continual 
reassessment of child-bearing potential in women.  This allows for implementing necessary changes to contraception; for example, investigators may 
need to ensure alternative contraceptive methods if new concomitant disease contraindicates a selected method of contraception, or if a subject is 
demonstrably no longer of child-bearing status (as per protocol) then they will no longer require contraception.  Continual reassessment of contraceptive 
needs is imperative.
t.
SF-36v2 will be completed by adult subjects only.  Adolescents 12-17 years of age will not complete this assessment.
u.
A serum sample will be collected at baseline but analyzed only if the subject has suspected varicella or herpes zoster.  In that event, the sample would be 
analyzed for HSV1, HSV2 and VZV. 
v.
Subjects who complete EOT will be assessed for eligibility for participation in long-term extension study B7451015 as noted in Section 6.2.7.
w.
FACIT-F will be completed by adult subjects only.  Adolescents 12-17 years of age will complete the Peds-FACIT-F instead. 
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x.
A single 12-lead ECG will be performed at screening and all other on-site visits and interpreted by a central reader.  Clinically significant or 
exclusionary ECG findings at the screening or baseline visits will require screen failure. 
y.
DLQI will be completed by adult subjects only.  Adolescents 12-17 years of age will complete the CDLQI instead. 
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