Clinical trial NCT03720470
Conditions: Dermatitis Dermatitis, Atopic Eczema Skin Diseases Skin Diseases, Genetic Genetic Diseases, Inborn Skin Diseases, Eczematous Hypersensitivity Hypersensitivity, Immediate Immune System Diseases
Keywords: atopic dermatitis atopic eczema eczema JAK janus kinase
Sponsor: Pfizer
Start date: 2018-10-29; Completion date: 2020-03-06
Enrollment: 838 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
B7451029 is a Phase 3 study to investigate PF-04965842 in adult patients who have moderate to severe atopic dermatitis and use background topical therapy. The efficacy 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. The efficacy of the two dosage strengths of PF-04965842 will be compared with dupilumab in terms of pruritus relief at 2 weeks. The two dosage strengths of PF-04965842 and dupilumab 300 mg injected subcutaneously once every two weeks (with a loading dose of 600 mg injected on the first day) will also be evaluated relative to placebo over 16 weeks. The safety of the investigational products will be evaluated over the duration of the study. Subjects will use non-medicated emollient at least twice a day and medicated topical therapy such as corticosteroids, calcineurin inhibitors or PDE4 inhibitors, as per protocol guidance, to treat active lesions during the study. Subjects who are randomized to receive one of the two dosage strengths of PF-04965842 will also receive placebo injectable study drug every two weeks until Week 16 and then will continue on receiving only the oral study drug for 4 weeks. Subjects who are randomized to receive dupilumab injections every two weeks will also receive oral placebo to be taken once daily until Week 16 and will then continue to receive only the oral placebo for 4 weeks. Subjects who are randomized to the placebo arms, will receive both daily oral placebo and injectable placebo every two weeks until Week 16, after which they will receive either 100 mg or 200 mg of PF-04965842 taken orally once daily for 4 weeks, dependent upon which arm they have been allocated to. Eligible subjects will have an option to enter a long-term extension study after completing 20 weeks of treatment.

Detailed description:

Arms: arm 1: Once-daily oral PF-04965842 100 mg + Placebo injected subcutaneously once every 2 weeks from Day 1 until Week 16 followed by once-daily oral PF-04965842 100 mg from Week 16 to Week 20 arm 2: Once-daily oral PF-04965842 200 mg + Placebo injected subcutaneously once every 2 weeks from Day 1 until Week 16 followed by once-daily oral PF-04965842 200 mg from Week 16 to Week 20 arm 3: Dupilumab injected subcutaneously once every 2 weeks + once-daily oral Placebo from Day 1 until Week 16 followed by once-daily oral Placebo from Week 16 to Week 20 arm 4: Once-daily oral Placebo + Placebo injected subcutaneously once every 2 weeks from Day 1 until Week 16 followed by once-daily oral 100 mg PF-04965842 from Week 16 to Week 20 arm 5: Once-daily oral Placebo + Placebo injected subcutaneously once every 2 weeks from Day 1 until Week 16 followed by once-daily oral 200 mg PF-04965842 from Week 16 to Week 20
Interventions: intervention 1: PF-04965842 100 mg intervention 2: PF-04965842 200 mg intervention 3: Dupilumab intervention 4: Oral Placebo intervention 5: Injectable Placebo
Intervention descriptions: intervention 1: PF-04965842 100 mg, administered as two tablets to be taken orally once daily as follows:

1. In the arm "PF-04965842 100 mg + Injectable Placebo followed by PF-04965842 100 mg," PF-04965842 100 mg is taken together with Injectable Placebo from Day 1 until Week 16, then by itself from Week 16 to Week 20;
2. In the arm "Oral Placebo + Injectable Placebo followed by 100 mg PF-04965842" subjects take PF-04965842 100 mg from Week 16 to Week 20. intervention 2: PF-04965842 200 mg, administered as two tablets to be taken orally once daily as follows:

1. In the arm "PF-04965842 200 mg + Injectable Placebo followed by PF-04965842 100 mg," PF-04965842 200 mg is taken together with Injectable Placebo from Day 1 until Week 16, then by itself from Week 16 to Week 20;
2. In the arm "Oral Placebo + Injectable Placebo followed by 200 mg PF-04965842" subjects take PF-04965842 200 mg from Week 16 to Week 20. intervention 3: Two subcutaneous injections of Dupilumab 300 mg as a loading dose administered on Day 1 (for a total of 600 mg) followed by one injection once every two weeks (q2w) until Week 16. intervention 4: Oral placebo (for PF-04965842) administered as two tablets to be taken orally once daily as follows:

1. In the arm "Dupilumab Injection + Oral Placebo followed by Oral Placebo," the Oral Placebo is taken together with Dupilumab from Day 1 until Week 16, then by itself to Week 20;
2. In the arms "Oral Placebo + Injectable Placebo followed by 100 mg PF-04965842" and "Oral Placebo + Injectable Placebo followed by 200 mg PF-04965842," subjects, take Oral Placebo from Day 1 until Week 16. intervention 5: Two subcutaneous injections of Placebo (for Dupilumab) administered as a loading dose on Day 1 followed by one injection every other week (q2w) until Week 16.

Protocol documents:
Prot_000.pdf: 
PF-04965842
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Final Protocol Amendment 5, 29 May 2019
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A PHASE 3 RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY, 
PLACEBO-CONTROLLED, PARALLEL GROUP, MULTI-CENTER STUDY 
INVESTIGATING THE EFFICACY AND SAFETY OF PF-04965842 AND 
DUPILUMAB IN COMPARISON WITH PLACEBO IN ADULT SUBJECTS ON 
BACKGROUND TOPICAL THERAPY, 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:
European Clinical Trials Database 
(EudraCT) Number:
2018-002573-21
Protocol Number:
B7451029
Phase:
3
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Document History
Document
Version Date
Summary of Changes and Rationale
Amendment 5
29 May 2019
To address the recommendations made by 
the Food and Drug Administration (FDA) 
following review of the protocol (ordered 
as they first appear in the protocol): 
1. Details of the randomization plan have 
been added in Section 4.3 
Randomization Criteria to clarify that 
the randomization will be administered 
using center-based permuted blocks.
2. In Section 9.2.1, the definition of Full 
Analysis Set (FAS) was clarified and 
details were added on major protocol 
violations that would preclude 
inclusion in the Per Protocol Analysis 
Set (PPAS).
3. Added a summary of the proposed 
sensitivity analyses for the co-primary 
endpoints in Section 9.2.3.
The protocol changes specified in Protocol 
Administrative Change Letter 
20 December 2018 have been incorporated 
as follows: 
1. Since atopic dermatitis has a natural 
history of chronic remissions and 
flares, subjects may be inappropriately
disqualified during periods of 
remission, and may become eligible 
when re-screened during a flare 
episode.  For subjects who are 
screen-failure due to not meeting the 
disease severity inclusion criteria, 
re-screening may be considered.  This 
re-screening should only occur after 
discussion with Pfizer Medical Monitor 
(or designee). The following sections 
of the protocol are affected: Protocol 
Summary, Study Design and Section 3, 


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Study Design.
2. Medical Device Incidents Reporting:
Pre-filled syringes used to administer 
dupilumab or matching placebo are 
combination products and considered 
medical devices.  For clarification, the 
following sections describing the 
medical devices used in study 
B7451029, medical device incidents 
definition and medical device 
incidents reporting are added in the 
protocol. The following sections of 
the protocol are affected: Section 5.6. 
Medical Devices, Section 8.4.5 
Medical Device Incidents (Including 
Malfunctions) and Appendix 17: 
Medical Device Incidents: Definition 
and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.
The protocol changes specified in Protocol 
Administrative Change Letter - France 
20 February 2019, which is applicable to 
site in France only, have been incorporated 
in Appendix 18, adding operational items 
not included in the mandatory contract 
format for France, which Pfizer includes in 
standard contract language for other 
countries. The information being added 
relates to requirements for:
1. GCP Training.
2. Investigational Product.
3. Suspected Unexpected Serious 
Adverse Reactions (SUSARs).
4. Collection of ethnic origin 
information.
The protocol changes specified in Protocol 
Administrative Change Letter 08 March 
2019 have been incorporated as follows:
1. The intent of the criterion “Subjects 
who have received prior treatment with 


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any JAK inhibitors” is clarified to 
specify that only systemic JAK 
inhibitors are excluded.  Prior treatment 
with topical JAK inhibitors is not 
exclusionary.  Changes were made 
Section 4.2 Exclusion Criteria, 
Criterion 7, and Section 5.9.2 
Prohibited Medications and 
Treatments.
2. In Section 4.2 Exclusion Criteria, 
Criterion 18, it is clarified that the 
definition of “acceptable alternative 
regimen” refers to acceptability as 
described by local standards of care.
3. In Appendix 3 Prohibited Concomitant 
Medications, the following medications 
are deleted form the CYP2C19 
inhibitors list, as they are not inhibitors 
of CYP2C19 and were included 
inadvertently: Amitriptyline (Elavil), 
Clomipramine (Anafranil), Imipramine 
(Tofranil).
In addition, protocol inconsistencies and
clarifications have been corrected as 
follows (ordered as they first appear in the 
protocol):
The number of sites was updated in the 
Study Design sections.
Clarified in the Schedule of Activities 
footnote q and in Section 7.3.4 that if the 
results of the TB test procedure using the 
QuantiFERON®-TB Gold In-Tube Test are 
indeterminate, the test should be repeated.
In Section 4.2 Exclusion Criteria 10, and in 
Note 2 of Appendix 3 Prohibited 
Concomitant Medications, the number of 
days included in the calculation of the 
washout period for CYP2C9 and CYP2C19 
inducer drugs has been corrected from 


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28 days to 14 days.
In section 4.2 Exclusion Criterion 10 and 
in Appendix 3, “28 days” was corrected to 
“14 days”: Use of CYP2C9 and CYP2C19 
inducers within 5 half-lives of the inducer 
plus 14 days of first dose of investigational 
product.
A note has been added in Section 4.2 
Exclusion Criterion 10 and in Appendix 3
to clarify that the half-life refers to half-life 
of the parent drug and its metabolites 
which are inhibitors or inducers. The 
longest half-life should be used to calculate 
the period necessary to washout a 
medication prior to the first dose of
investigational product.
It was clarified in Section 4.4.1 
Contraception, that male subjects are not 
required to use contraception.
In Section 4.2 Exclusion Criteria, 
Criterion 19, the absolute lymphocyte 
count in the parenthesis was corrected from 
<500/mm3 to <750/mm3.
A clarification to the criteria for screening 
ECG findings has been added in 
Section 7.3.5, as the intent is that the 
subject’s screening ECG must not have 
clinically significant adverse findings.
Additional minor edits were made in 
Section 9.2.4 Analysis of Secondary 
Endpoints to improve clarity.
Section 9.6 Week 16 Analysis and End of 
Study Analysis was added outlining details 
of performing two planned analyses. The 
Week 16 Analysis was added to accelerate 
the final reporting timeline.  
Abbreviations were added to Appendix 1.  
Country/region specific changes from 


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Amendments 2, 3 and 4 were incorporated 
into Amendment 5.
Amendment 4
24 January 2019
For Republic of Korea and Taiwan only:
Similar to China, other countries in Asia,
such as Republic of Korea and Taiwan, 
have a high prevalence of hepatitis B 
surface antigen (HBsAg) negative, 
hepatitis B core antibody (HBcAb) 
positive, and hepatitis B surface antibody 
(HBsAb) positive serology. Therefore, 
Republic of Korea and Taiwan will adopt
the same changes as those proposed for 
China in Amendment 2 to monitor the risk 
of hepatitis B reactivation.  The following 
sections of the protocol are affected:
Schedule of Activities, Sections 4.2, 6.1, 
6.2.6, 6.2.9, 7.6.2, and 7.6.2.1.
Amendment 3
05 December 2018
For Japan only:
Similar to China, other countries in Asia,
such as Japan, have a high prevalence of 
hepatitis B surface antigen (HBsAg) 
negative, hepatitis B core antibody 
(HBcAb) positive, and hepatitis B surface 
antibody (HBsAb) positive serology.  
Therefore, Japan will adopt similar
changes as those proposed for China in 
Amendment 2 to monitor the risk of 
hepatitis B reactivation.  The following 
sections of the protocol are affected:
Schedule of Activities, Sections 4.2, 6.1, 
6.2.6, 6.2.9, 7.6.2, 7.6.2.1 and Appendix 1.
Based on local request, HBsAg, HBcAb 
and HBsAb testing will be performed 
concurrently at Screening for all subjects 
rather than performing HBsAb as a reflex 
test only.  
Based on local practices for tuberculosis 
testing in Japan, if QuantiFERON- TB 
Gold In-Tube (QTF-G) testing is not 
possible, the T-SPOT.TB test performed 


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at a local laboratory is acceptable as the 
screening TB test. The following sections 
of the protocol are affected:  Schedule of 
Activities, Sections 4.2, 6.1, 7.3.4, and 
7.6.2.
Amendment 2
12 September 2018
The following changes, requested by an 
Ethics Committee in China for study 
B7451013, are being applied to the 
PF-04965842 program. 
These changes are in effect for China only.
Subjects who are hepatitis B surface 
antigen (HBsAg) negative, hepatitis B core 
antibody (HBcAb) positive, and hepatitis B 
surface antibody (HBsAb) positive at 
Screening will have reflex testing for 
Hepatitis B Virus Deoxyribonucleic Acid
(HBV DNA). Subjects who have HBV 
DNA above the lower limit of 
quantification (LLQ) are excluded.
Subjects who have HBV DNA negative or 
below LLQ may be randomized, but will 
have HBV DNA testing repeated at 
Week 12 and Week 20 End of Treatment 
(EOT) visit, or Early Termination (ET) 
visit, whichever is sooner.
A single HBV DNA test result above the 
LLQ for a subject requires immediate and 
permanent discontinuation from treatment.
The following sections of the protocol are 
affected:

Schedule of Activities;

Section 4.2. Exclusion Criteria;

Section 6.1. Visit 1, Screening;

Section 6.2.6. Visit 7, Day 85/Week 12 
(3 days);

Section 6.2.9. Visit 10, Day 141/Week 


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20 (±3 Days) End of Treatment or 
Early Termination Visit;
•
Section 7.6.2. Laboratory Tests;
•
Section 7.6.2.1. Hepatitis Testing.
Amendment 1
09 August 2018
Added European Clinical Trials Database 
(EudraCT) Number on the cover page.
Added 100% improvement in EASI total 
score (EASI-100) secondary efficacy 
endpoint in the Protocol Summary and in 
Section 2 to ascertain the proportion of 
patients achieving complete EASI 
clearance. 
 
 
 
 
 
 
 
 
 
 
 
Added two secondary efficacy endpoints
related to SCORing Atopic Dermatitis 
(SCORAD) in the Protocol Summary and 
in Section 2, corresponding to the 
respective PRO. 
 
 
 
 
 
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In Section 9.2.4 Analysis of Secondary 
Endpoints, removed “and frequency” from 
the analysis, as this is no longer a 
secondary endpoint.
 
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Corrections of typographical errors and 
administrative edits were made.
Original Protocol
25 June 2018
Not applicable (N/A)
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...................................................................................................................16
LIST OF FIGURES .................................................................................................................16
APPENDICES .........................................................................................................................16
PROTOCOL SUMMARY.......................................................................................................18
SCHEDULE OF ACTIVITIES................................................................................................27
1. INTRODUCTION ...............................................................................................................34
1.1. Mechanism of Action/Indication.............................................................................34
1.2. Background and Rationale ......................................................................................35
1.2.1. Drug Development and Rationale ..............................................................35
1.2.2. Atopic Dermatitis........................................................................................35
1.2.3. Non-Clinical and Phase 1 Data...................................................................37
1.2.4. Phase 2b in AD (B7451006).......................................................................38
1.3. Summary of PF-04965842 Clinical Pharmacokinetics...........................................39
1.3.1. Population Pharmacokinetics......................................................................40
1.4. Summary of Benefits and Risks..............................................................................40
1.5. Dose Selection Rationale ........................................................................................40
41
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................41
3. STUDY DESIGN.................................................................................................................45
4. SUBJECT ELIGIBILITY CRITERIA.................................................................................47
4.1. Inclusion Criteria.....................................................................................................47
4.2. Exclusion Criteria....................................................................................................49
4.3. Randomization Criteria ...........................................................................................55
4.4. Lifestyle Requirements ...........................................................................................55
4.4.1. Contraception..............................................................................................56
4.4.2. Vaccine and Exposure to Infections Guidelines.........................................58
4.4.2.1. Subject Specific Recommendations..........................................58
4.4.2.2. Guidance Regarding Household Contact Vaccine-Related 
Exposure............................................................................................58
4.4.3. Surgery........................................................................................................58
4.5. Sponsor’s Qualified Medical Personnel..................................................................59
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5. STUDY TREATMENTS.....................................................................................................59
5.1. Allocation to Treatment ..........................................................................................60
5.2. Breaking the Blind ..................................................................................................60
5.3. Subject Compliance.................................................................................................61
5.4. Investigational Product Supplies.............................................................................63
5.4.1. Dosage Form(s) and Packaging..................................................................63
5.4.2. Preparation and Dispensing........................................................................63
5.5. Administration.........................................................................................................63
5.6. Medical Devices......................................................................................................64
5.7. Investigational Product Storage ..............................................................................65
5.8. Investigational Product Accountability...................................................................66
5.8.1. Destruction of Investigational Product Supplies ........................................66
5.9. Concomitant Treatment(s).......................................................................................66
5.9.1. Permitted Concomitant Medications ..........................................................67
5.9.2. Prohibited Medications and Treatments .....................................................69
6. STUDY PROCEDURES .....................................................................................................69
6.1. Visit 1, Screening ....................................................................................................70
6.2. Treatment Period.....................................................................................................73
6.2.1. Visit 2, Day 1/Week 0 (Baseline)...............................................................73
6.2.2. Visit 3 (Phone call visit), Day 8/Week 1 (1 day) .....................................75
6.2.3. Visit 4, Day 15/Week 2 (1 day)................................................................75
6.2.4. Visit 5, Day 29/Week 4 (2 days) ..............................................................76
6.2.5. Visit 6, Day 57/Week 8 (3 days) ..............................................................77
6.2.6. Visit 7, Day 85/Week 12 (3 days) ............................................................79
6.2.7. Visit 8, Day 113/Week 16 (3 days) ..........................................................80
6.2.8. Visit 9, Day 127/Week 18 (3 Days) .........................................................81
6.2.9. Visit 10, Day 141/Week 20 (3 Days) End of Treatment or Early 
Termination Visit.............................................................................................82
6.3. Follow-up Visits......................................................................................................83
6.3.1. Visit 11, Day 169/Week 24 (3 Days) .......................................................83
6.4. Subject Withdrawal.................................................................................................84
7. ASSESSMENTS..................................................................................................................85


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7.1. Pregnancy Testing...................................................................................................86
86
87
7.3. Safety Assessments .................................................................................................88
7.3.1. Vitals Signs.................................................................................................88
7.3.2. Medical History, Physical Examination, Height, and Weight....................88
7.3.3. Chest X-Ray................................................................................................89
7.3.4. Tuberculosis Testing...................................................................................89
7.3.5. Electrocardiogram.......................................................................................90
7.3.6. Special Safety Assessment .........................................................................91
7.4. Skin Type Assessment ............................................................................................91
7.5. Assessment of Suicidal Ideation and Behavior.......................................................91
7.5.1. Columbia Suicide Severity Rating Scale (C-SSRS)...................................91
7.5.2. Patient Health Questionnaire - 8 items (PHQ-8) ........................................91
7.6. Clinical Laboratory Tests........................................................................................91
7.6.1. Blood Volume.............................................................................................91
7.6.2. Laboratory Tests .........................................................................................92
7.6.2.1. Hepatitis Testing .......................................................................94
7.6.2.2. Baseline Viral Screen................................................................95
7.7. Pharmacodynamics..................................................................................................95
7.8. Efficacy Assessments..............................................................................................95
7.8.1. Rater Qualifications....................................................................................95
7.8.2. Investigator’s Global Assessment (IGA)....................................................96
7.8.3. SCORAD....................................................................................................96
7.8.4. Eczema Area and Severity Index (EASI) ...................................................97
7.8.4.1. Body Surface Area – Efficacy (BSA Efficacy).......................100
100
7.10. Patient-Reported Outcomes (PROs)....................................................................101
7.10.1. Pruritus Numerical Rating Scale (NRS).................................................101
102
7.10.3. Patient Global Assessment (PtGA).........................................................102
7.10.4. EuroQol Quality of Life 5-Dimension 5-Level Scale (EQ-5D-5L)........102
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7.10.5. Dermatology Life Quality Index (DLQI) ...............................................103
7.10.6. Patient-Oriented Eczema Measure (POEM)...........................................103
7.10.7. Hospital Anxiety and Depression Scale (HADS)...................................103
7.10.8. Pruritus and Symptoms Assessment for Atopic Dermatitis 
(PSAAD)........................................................................................................103
104
8. ADVERSE EVENT REPORTING....................................................................................104
8.1. Requirements.........................................................................................................104
8.1.1. Additional Details on Recording Adverse Events on the CRF.................105
8.1.2. Eliciting Adverse Event Information........................................................105
8.1.3. Withdrawal from the Study Due to Adverse Events (see also the 
Subject Withdrawal section)..........................................................................105
8.1.4. Time Period for Collecting AE/SAE Information....................................106
8.1.4.1. Reporting SAEs to Pfizer Safety.............................................106
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF ...............106
8.1.5. Causality Assessment ...............................................................................106
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ................107
8.2. Definitions.............................................................................................................107
8.2.1. Adverse Events.........................................................................................107
8.2.2. Abnormal Test Findings ...........................................................................108
8.2.3. Serious Adverse Events ............................................................................108
8.2.4. Hospitalization..........................................................................................109
8.3. Severity Assessment..............................................................................................110
8.4. Special Situations ..................................................................................................110
8.4.1. Protocol-Specified Serious Adverse Events.............................................110
8.4.2. Potential Cases of Drug-Induced Liver Injury..........................................110
8.4.3. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure...................................................112
8.4.3.1. Exposure During Pregnancy....................................................112
8.4.3.2. Exposure During Breastfeeding ..............................................113
8.4.3.3. Occupational Exposure ...........................................................114
8.4.4. Medication Errors .....................................................................................114
8.4.4.1. Medication Errors....................................................................114
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8.4.5. Medical Device Incidents (Including Malfunctions)................................115
8.4.5.1. Time Period for Detecting Medical Device Incidents.............115
8.4.5.2. Follow-up of Medical Device Incidents..................................115
8.4.5.3. Prompt Reporting of Medical Device Incidents to Sponsor ...115
8.4.5.4. Regulatory Reporting Requirements for Medical Device 
Incidents ..........................................................................................116
9. DATA ANALYSIS/STATISTICAL METHODS.............................................................116
9.1. Sample Size Determination...................................................................................116
9.2. Efficacy Analysis ..................................................................................................117
9.2.1. Analysis Sets.............................................................................................117
9.2.2. Testing Procedure for Multiple Comparisons...........................................117
9.2.3. Analysis of the Primary Endpoints...........................................................118
9.2.4. Analysis of Secondary Endpoints.............................................................119
9.3. Safety Analysis......................................................................................................119
9.4. External Data Monitoring Committee...................................................................120
9.5. Safety Adjudication Committees ..........................................................................120
9.6. Week 16 Analysis and End of Study Analysis......................................................120
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................121
11. DATA HANDLING AND RECORD KEEPING ...........................................................121
11.1. Case Report Forms/Electronic Data Record .......................................................121
11.2. Record Retention.................................................................................................122
12. ETHICS............................................................................................................................123
12.1. Institutional Review Board/Ethics Committee....................................................123
12.2. Ethical Conduct of the Study ..............................................................................123
12.3. Subject Information and Consent........................................................................123
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................124
13. DEFINITION OF END OF TRIAL.................................................................................124
13.1. End of Trial in All Participating Countries .........................................................124
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................124
15. PUBLICATION OF STUDY RESULTS........................................................................125
15.1. Communication of Results by Pfizer ..................................................................125
15.2. Publications by Investigators ..............................................................................125


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16. REFERENCES ................................................................................................................127
LIST OF TABLES
Table 1.
Objectives and Endpoints:........................................................................42
Table 2.
Investigator’s Global Assessment (IGA) Score........................................96
Table 3.
Clinical Sign Severity Scoring Criteria for the Eczema Area and 
Severity Index (EASI) ..............................................................................98
Table 4.
Handprint Determination of Body Surface Area (BSA)...........................99
Table 5.
Eczema Area and Severity Index (EASI) Area Score Criteria.................99
Table 6.
Eczema Area and Severity Index (EASI) Body Region Weighting.........99
LIST OF FIGURES
Figure 1.
Study Design Schematic...........................................................................45
Figure 2.
Schematic for Multiple Testing Procedure.............................................118
APPENDICES
Appendix 1. Abbreviations....................................................................................................130
Appendix 2. Diagnostic Criteria for Atopic Dermatitis.........................................................135
Appendix 3. Prohibited Concomitant Medications................................................................136
Appendix 4. Monitoring and Discontinuation Criteria..........................................................137
Appendix 5. Fitzpatrick Skin Type........................................................................................140
Appendix 6. Pruritus Severity and Frequency (Pruritus NRS)..............................................141
142
Appendix 8. Patient Global Assessment (PtGA)...................................................................143
Appendix 9. European Quality of Life 5-Dimension 5-Level Scale (EQ-5D-5L) ................144
Appendix 10. Dermatology Life Quality Index (DLQI)........................................................146
Appendix 11. Patient-Oriented Eczema Measure (POEM)...................................................147
Appendix 12. Hospital Anxiety and Depression Scale (HADS) ...........................................148
Appendix 13. Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD) 
Symptom Diary.......................................................................................150
154
Appendix 15. C SSRS - Columbia Suicide Severity Rating Scale........................................156
Appendix 16. Patient Health Questionnaire – 8 items...........................................................159
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Appendix 17. Medical Device Incidents: Definition and Procedures for Recording, 
Evaluating, Follow-up, and Reporting....................................................160
Appendix 18. France Appendix.............................................................................................162


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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 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  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%.3  Earlier reports indicated that, in up to 70% of 
cases, the disease greatly improves or resolves by 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 life and likely longer.4  At every age, more 
than 80% of PEER study subjects had symptoms of AD and/or were using medication to treat 
their AD.
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
Non-medicated topical therapies include emollients.  Medicated topical therapy for moderate 
to severe AD include topical corticosteroids (TCS) (eg, betamethasone, clobetasol,
fluocinonide), topical calcineurin inhibitors (TCI) (eg, pimecrolimus, tacrolimus), and coal 
tar preparations.  TCS are limited in terms of the treatment duration (eg, corticosteroid use is 
limited to 2 to 4 weeks) and the body region of treatment, due to consistent skin toxicities, as 
well as having risks associated with their broad immunosuppressive actions.  TCI have a 
limited role as a second-line treatment, due to their limitations in the duration and the body 
region of treatment, inhibition of tumor surveillance in the skin, and safety concerns with 
malignancies.  Crisaborole was approved as a medicated topical therapy 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-), mycophenolate mofetil, methotrexate [MTX], azathioprine, intravenous
immunoglobulin).7
There are a limited number of approved systemic treatments for moderate to severe AD and 
in the USA, the only approved systemic drugs are corticosteroids and dupilumab.  
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, for the treatment of moderate to severe AD.  Treatment with systemic 
corticosteroids has known and well documented adverse effects.  Treatment with dupilumab 
has the risk of injection site reactions, allergic reactions, eye and eyelid inflammations and 
cold sores.  Another potential limitation of dupilumab is the possibility for the development 


PF-04965842
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Final Protocol Amendment 5, 29 May 2019
Page 19
of antidrug antibodies, which may result in loss of efficacy over time and the development of 
safety concerns such as serum sickness-like reactions.  Furthermore, dupilumab is delivered 
via subcutaneous injection, which may not be a method of administration tolerated well by 
all patients.  During a 1-year, randomized, double-blinded study with dupilumab, in the 
dupilumab 300 mg every 2 weeks (marketed maintenance dose) plus TCS group, the 
estimated difference from placebo of the Investigator's Global Assessment (IGA) response 
rate and Eczema Area and Severity Index (EASI)-75 response rate were 26% and 46%, 
respectively.  The placebo response rate for IGA and EASI-75 was 12% and 23%, 
respectively.8  The development of potential treatments with further improvements in
efficacy remains desirable.  In Europe, cyclosporine is approved for use in patients with 
severe AD when systemic therapy is required.  Cyclosporine use is associated with several 
undesirable side effects and due to its narrow therapeutic index, occasional therapeutic drug 
monitoring is recommended.  Known adverse effects include infections, renal toxicity, 
hepatotoxicity, skin malignancies, lymphoma and other malignancies. 
The predominant unmet medical need is for an oral therapy with an acceptable safety profile, 
for long-term use, which is effective for moderate to severe AD.  Patients with moderate to 
severe AD require other systemic treatment options beyond those which are currently 
approved. PF-04965842 is an oral tablet, providing a more convenient route of 
administration compared with the subcutaneous injection required for dupilumab and so it 
does not have the potential risk of injection site reactions.  Unlike dupilumab, PF-04965842 
is a small molecule and there is no anticipated immunogenicity for PF-04965842, and so it is 
unlikely to generate antidrug antibodies.
Key cytokines implicated in the pathophysiology of AD include IL-4, IL-5, IL-13, IL-31,
and IFN-, and 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.8
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 in vitro 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 
multiple cytokine pathways involved in the pathophysiology of AD, including
IL-4, IL-5, IL-13, IL-31 and IFN-.  Data from a Phase 2b proof of concept (POC) study 
(B7451006) that evaluated subjects with 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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Objectives and Endpoints
Primary Objective
Primary Endpoints
To compare the efficacy 
of 100 mg and 200 mg 
once daily (QD) of 
PF-04965842 versus 
placebo in adult 
subjects on background 
topical therapy with 
moderate to severe 
atopic dermatitis (AD).
The following co-primary endpoints will be tested:

Response based on achieving the Investigator's Global Assessment (IGA) of clear (0) or 
almost clear (1) (on a 5-point scale) and a reduction from baseline (pre-dose Day 1) of 
2 points at Week 12;

Response based on achieving the Eczema Area and Severity Index (EASI)-75 
(75% improvement from baseline) at Week 12.
Secondary Objectives
Secondary Endpoints
To compare the efficacy 
of PF-04965842 versus 
dupilumab in terms of 
attaining a clinically 
significant 
improvement in the 
severity of pruritus for 
adult subjects on 
background topical 
therapy with moderate 
to severe AD.
Key Secondary Endpoints:

Response based on achieving at least 4 points improvement in the severity of Pruritus 
Numerical Rating Scale (NRS) from baseline at Week 2.
To estimate the 
difference in efficacy 
measures between two 
doses of PF-04965842 
and dupilumab for adult 
subjects on background 
topical therapy with 
moderate to severe AD.

Response based on achieving the IGA of clear (0) or almost clear (1) (on a 5-point scale) 
and a reduction from baseline of 2 points at Week 16; 

Response based on achieving EASI-75 (75% improvement from baseline) at Week 16.
To estimate the effect of 
PF-04965842 on 
additional efficacy 
endpoints and 
patient-reported 
outcomes over time in 
adult subjects on 
background topical 
therapy with moderate 
to severe AD.
Secondary Efficacy Endpoints:

Response based on achieving the IGA of clear (0) or almost clear (1) (on a 5-point scale) 
and 2 point reduction from baseline at all scheduled time points except Week 12 and 
Week 16;

Response based on achieving a 75% improvement in the EASI total score (EASI-75) at 
all scheduled time points except Week 12 and Week 16;

Response based on achieving a 50%, 90%, and 100% improvement in the EASI total 
score (EASI-50, EASI-90, and EASI-100) at all scheduled time points;

Response based on achieving at least 4 points improvement in the severity of Pruritus 
NRS from baseline at all scheduled time points except Week 2;

Time from baseline to achieve at least 4 points improvement in the severity of Pruritus 
NRS scale;

Change from baseline in the percentage Body Surface Area (BSA) affected at all 
scheduled time points;

Change from baseline of Patient Global Assessment (PtGA) at all scheduled time points;

Change from baseline in Dermatology Life Quality Index (DLQI) at all scheduled time 
points;


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Final Protocol Amendment 5, 29 May 2019
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•
Change from baseline in EuroQol Quality of Life 5-Dimension 5-Level Scale 
(EQ-5D-5L) at all scheduled time points;
•
Change from baseline in Hospital Anxiety and Depression Scale (HADS) at all 
scheduled time points;
•
Change from baseline in Patient-Oriented Eczema Measure (POEM) at all scheduled 
time points;
•
Change from baseline in Pruritus and Symptoms Assessment for Atopic Dermatitis 
(PSAAD) total score 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;
•
Steroid-free days at Week 16.
Safety Objectives
Safety Endpoints
To compare the safety 
and tolerability of 
100 mg and 200 mg QD 
of PF-04965842 and 
dupilumab versus 
placebo in adult 
subjects on background 
topical therapy with 
moderate to severe AD.
To estimate the safety 
and tolerability of the 
two doses of 
PF-04965842 versus 
dupilumab, for adult 
subjects on background 
topical therapy with 
moderate to severe AD.
•
Incidence of treatment-emergent adverse event (AE)s;
•
Incidence of serious adverse event (SAE)s and AEs leading to discontinuation;
•
Incidence of clinical abnormalities and change from baseline in clinical laboratory 
values, electrocardiogram (ECG) measurements, and vital signs.
 
 
 
 
 
 
 
 
 
 
 
CCI


PF-04965842
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Final Protocol Amendment 5, 29 May 2019
Page 22
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AD = Atopic dermatitis; AE = Adverse Event; BSA = Body Surface Area; DLQI = Dermatology Life Quality Index; 
EASI = Eczema Area and Severity Index; ECG = Electrocardiogram; EQ-5D-5L = EuroQol Quality of Life 5-Dimension 
5-Level Scale; HADS = Hospital Anxiety and Depression Scale; 
; 
IGA = Investigator’s Global Assessment; NRS = numerical rating scale; POEM = Patient-Oriented Eczema Measure; 
PSAAD = Pruritus and Symptoms Assessment for Atopic Dermatitis; PtGA = Patient Global Assessment; 
SAE = Serious Adverse Event; SCORAD = Scoring Atopic Dermatitis;
CCI
CCI
CCI
CCI
CCI


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Final Protocol Amendment 5, 29 May 2019
Page 23
Study Design
This is a randomized, double-blind, double-dummy, placebo-controlled, parallel-group, 
multi-center study to assess the efficacy and safety of PF-04965842 100 mg or 200 mg QD 
and dupilumab (as per label) compared with placebo in adult subjects on background topical 
therapy, with moderate to severe AD.  This study will provide a direct comparison of both 
doses of PF-04965842 with dupilumab in terms of pruritus relief.  This study will also 
provide data, which will estimate the relative efficacy of both doses of PF-04965842 and 
dupilumab.  The treatment duration is 20 weeks.  A total of approximately 700 subjects will 
be enrolled from approximately 270 sites globally.  There is a primary efficacy assessment at 
Week 12, and key secondary efficacy assessments at Week 2 and Week 16.  Efficacy and 
safety endpoints will be assessed throughout the entire study.
After providing informed consent, subjects will be assessed for study eligibility at the 
screening visit.  Subjects will undergo screening within 28 days prior to randomization.  
During the screening period, systemic treatments and medicated topical therapy for AD will 
be washed out, as applicable, according to eligibility requirements.  Eligible subjects must 
have a documented history, within 6 months of the screening visit, of inadequate response to 
treatment with medicated topical therapy for at least 4 weeks, or must have required systemic 
therapies for control of their disease.  Eligible subjects must meet the eligibility criteria at 
both screening and baseline.  In addition, subjects are required to use non-medicated topical 
therapy (ie, emollients) at least twice daily for the last 7 days prior to Day 1 and must also be 
willing and able to use standardized background topical therapy, as per protocol guidelines, 
throughout the duration of the study.  Subjects may be re-screened once if they fail the 
screening evaluation for reasons related to incidental transitory conditions.  Subjects for 
whom screen failure is related to failing the disease severity (including extent of disease) 
inclusion criterion and who subsequently experience worsening AD, which in the 
investigator’s judgement would make them eligible for participation, may be considered for 
re-screening. Such cases should be discussed with the Pfizer Medical Monitor (or designee)
to determine if re-screening is appropriate.
Subjects who continue to meet eligibility criteria at baseline will undergo Day 1 assessments 
and be randomized in a 4:4:4:1:1 ratio to receive 100 mg or 200 mg of PF-04965842 QD 
with dupilumab-matching placebo administered every other week, dupilumab 300 mg 
administered every other week (with a loading dose of 600 mg at baseline) with 
PF-04965842-matching placebo administered QD, or one of 2 sequences of 
PF-04965842-matching placebo administered QD with dupilumab-matching placebo 
administered every other week from Day 1, for 16 weeks followed by either 100 mg or 
200 mg of PF-04965842 QD.  Investigators, subjects, and the sponsor study team will be 
blinded as to treatment group.
The total treatment period is 20 weeks.  The first part of this treatment period consists of a 
16-week randomized, double-blind, placebo-controlled, double-dummy treatment period with 
subjects receiving both injectable and oral investigational product.  The randomization and 
double-blind will be maintained during the final 4 weeks of the treatment period, but subjects 
will only receive oral investigational product.  At Week 16 in the treatment period, all 


PF-04965842
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Final Protocol Amendment 5, 29 May 2019
Page 24
subjects will cease injectable dupilumab or its matching placebo.  This is to facilitate the 
washout of dupilumab (for a total of 6 weeks; as the final dose of dupilumab or its matching 
placebo is administered at Week 14) prior to eligible subjects entering the long-term 
extension study, in which all subjects will receive PF-04965842 active treatment.  As, 
following Week 16, data for the primary and key secondary efficacy assessments will have 
already been obtained, subjects previously receiving only placebo will receive PF-04965842 
100 mg or 200 mg QD as per their randomized allocation.  Subjects previously receiving 
PF-04965842 100 mg or 200 mg QD will continue on their respective dose.  Subjects 
previously receiving dupilumab will continue to take oral placebo.  These alterations to study 
treatment will all be conducted while maintaining the blind when re-issuing oral 
investigational product to all subjects at the Week 16 time point. 
Eligible subjects completing the entire 20-week treatment period of the study will have the 
option to enter a long-term extension (LTE) study, B7451015, in which all subjects will 
receive PF-04965842 active treatment.  Subjects discontinuing early from treatment, or who 
are otherwise ineligible for the LTE study, will undergo a 4-week follow-up period in study 
B7451029.
Study Treatments

Orally administered 100 mg of PF-04965842 QD with dupilumab-matching placebo 
administered by subcutaneous injection every other week (two injections at baseline; 
to dummy the loading dose) from Day 1 to Week 16, followed by orally administered 
100 mg of PF-04965842 QD until Week 20.

Orally administered 200 mg of PF-04965842 QD with dupilumab-matching placebo 
administered by subcutaneous injection every other week (two injections at baseline; 
to dummy the loading dose) from Day 1 to Week 16, followed by orally administered 
200 mg of PF-04965842 QD until Week 20.

Dupilumab 300 mg administered every other week (with a loading dose of 600 mg at 
baseline) with PF-04965842-matching orally administered placebo QD from Day 1 to 
Week 16, followed by PF-04965842-matching orally administered placebo QD until 
Week 20.

PF-04965842-matching orally administered placebo QD with dupilumab-matching 
subcutaneously injected placebo administered every other week (two injections at 
baseline; to dummy the loading dose) from Day 1 to Week 16 followed by orally 
administered 100 mg of PF-04965842 QD until Week 20.

PF-04965842-matching orally administered placebo QD with dupilumab-matching 
subcutaneously injected placebo administered every other week (two injections at 
baseline; to dummy the loading dose) from Day 1 to Week 16 followed by orally 
administered 200 mg of PF-04965842 QD until Week 20.

Treatment duration will be 20 weeks (with the blind maintained throughout).


PF-04965842
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Final Protocol Amendment 5, 29 May 2019
Page 25

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 700 subjects, with 200 randomized to PF-04965842 200 mg QD, 
200 subjects randomized to PF-04965842 100 mg QD, 200 subjects randomized to 
dupilumab and 50 subjects each randomized to two sequences of matching placebo for 
16 weeks followed by (a) PF-04965842 100 mg QD and by (b) PF-04965842 200 mg QD 
(4:4:4:1:1 randomization) is planned.  The two placebo sequences will be combined for 
purposes of analyses at all visits up to and including Week 16, which will result in a 
2:2:2:1 randomization ratio.  This will provide at least 96% power to detect a difference of at 
least 20% in IGA response rate between either dose of PF-04965842 and placebo, assuming 
the placebo response rate is 12% at Week 12.  This will also provide at least 99% power to 
detect a difference of at least 30% in EASI-75 response rate between either dose of 
PF-04965842 and placebo, assuming the placebo response rate is 23% at Week 12.
Both co-primary endpoints must achieve statistical significance to meet the primary 
objective.
In addition, this sample size will also provide at least 92% power to detect a difference of at 
least 15% in the proportion of subjects with a 4 points improvement in the severity of 
Pruritus Numerical Rating Scale (NRS) between PF-04965842 and dupilumab, assuming the 
dupilumab response rate is 18% at Week 2.
The Type-I error rate is set at 5% (two-sided).  The familywise Type-I error rate (for testing 
the co-primary and key secondary endpoints) will be strongly controlled at 5% using a 
closed-testing method based on a sequential, iterative Bonferroni-type approach.  This is 
described in further detail in Section 9.2.2 of the protocol and in the statistical analysis plan 
(SAP).
The study has been sized to help gain sufficient safety data to be able to effectively evaluate 
the benefit-risk of PF-04965842 in conjunction with the other studies in the clinical 
development program, therefore the power for the co-primary endpoints is relatively high.  
This sample size will also help ensure adequate power is maintained for testing all the 
co-primary and key secondary endpoints for both doses of PF-04965842 via the multiple 
testing procedure.
For analysis of the co-primary endpoints, the (Cochran-Mantel-Haenszel) test adjusted by 
baseline disease severity group (moderate and severe) will be used.  If a subject withdraws 
from the study, then this subject will be counted as a non-responder for endpoints after 
withdrawal. 


PF-04965842
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Final Protocol Amendment 5, 29 May 2019
Page 26
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, disease severity 
group, visit, treatment-by-visit interaction, and relevant baseline value.  Within the 
framework of MMRM, the treatment at each time point will be derived 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.


PF-04965842
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Final Protocol Amendment 5, 29 May 2019
Page 27
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 57
Week 8
Day 85
Week 12
Day 113
Week 16
Day 127
Week 18
Day 141 
Week 20
EOT or ET 
Visit
Day 169
Week 24
(4 Weeks after EOT 
or ET)
EOS, Follow-up Visit
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10
Visit 11
Visit Window
None
None
1 Day 1 Day
2 Days 3 Days 3 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
X
X
Dispense eDiary and instruct 
subjects on use
X
Train on washout of 
medicated topical therapy and 
use of non-medicated topical 
therapy pre-baseline and daily 
recording in eDiaryc
X
Train/check understanding of 
subjects on protocol guidance 
for background topical
medication and daily 
recording in eDiaryd
X
X
X
X
X
X
X
X
X


PF-04965842
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Final Protocol Amendment 5, 29 May 2019
Page 28
Visit Identifiera
Day -28
Screening
Day 1
Week 0
Baseline
Day 8
Week 1
Call
Day 15
Week 2
Day 29
Week 4
Day 57
Week 8
Day 85
Week 12
Day 113
Week 16
Day 127
Week 18
Day 141 
Week 20
EOT or ET 
Visit
Day 169
Week 24
(4 Weeks after EOT 
or ET)
EOS, Follow-up Visit
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10
Visit 11
Visit Window
None
None
±1 Day ±1 Day
±2 Days ±3 Days ±3 Days
±3 Days
±3 Days
±3 Days
±3 Days
Provide Patient Emergency 
Contact Card
X
Medical Procedures
Complete Physical Exame
X
X
X
X
Targeted Physical Exame
X
X
X
X
X
X
Vital Signsf
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
Height
X
Chest X-rayg
X
ECG (12-lead)
Xh
X
X
X
X
X
X
X
X
X
Laboratory Assessments 
Serum Chemistry and 
Hematology (including 
Coagulation Panel)i
X
X
X
X
X
X
X
X
X
X
Lipid Paneli
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
Serum FSH (WONCBP only) 
or Pregnancy Testl
X
Urine Pregnancy Test 
(conducted at study site)m
X
X
X
X
X
X
X
X
X
HIV Testingo
X
CCI
CCI


PF-04965842
B7451029
Final Protocol Amendment 5, 29 May 2019
Page 29
Visit Identifiera
Day -28
Screening
Day 1
Week 0
Baseline
Day 8
Week 1
Call
Day 15
Week 2
Day 29
Week 4
Day 57
Week 8
Day 85
Week 12
Day 113
Week 16
Day 127
Week 18
Day 141 
Week 20
EOT or ET 
Visit
Day 169
Week 24
(4 Weeks after EOT 
or ET)
EOS, Follow-up Visit
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10
Visit 11
Visit Window
None
None
1 Day 1 Day
2 Days 3 Days 3 Days
3 Days
3 Days
3 Days
3 Days
Hepatitis B Surface Antigen 
(HBsAg), Hepatitis B 
Surface Antibody (HBsAb), 
Hepatitis B Core Antibody 
(HBcAb), Hepatitis C 
Antibody (HCVAb), 
Hepatitis C Viral RNA 
(HCV RNA)p
X
HBV DNA testing for China, 
Japan, Republic of Korea, 
and Taiwan onlyaa
X
X
X
Tuberculosis Testq
X
Trial Treatment 
Randomization 
X
Oral Drug Dispensing
X
X
X
X
X
Injectable Drug Dispensing
X
X
X
X
X
Investigational Product 
Accountability  
X
X
X
X
X
X
X
Subject Injection Trainingr
X
Observed Investigational 
Product Administrations
X
X
X
X
X
X
X
X
Reallocation to new treatment 
regimens
X
Review eDiary to assess 
completion
X
X
X
X
X
X
X
X
X
Assess eligibility for 
B7451015t
X
Clinical Assessments 
Fitzpatrick Skin Type 
Assessment
X
Investigator’s Global 
Assessment (IGA) 
X
X
X
X
X
X
X
X
X
X
SCORing Atopic Dermatitis 
(SCORAD)
X
X
X
X
X
X
X
X
X
X


PF-04965842
B7451029
Final Protocol Amendment 5, 29 May 2019
Page 30
Visit Identifiera
Day -28
Screening
Day 1
Week 0
Baseline
Day 8
Week 1
Call
Day 15
Week 2
Day 29
Week 4
Day 57
Week 8
Day 85
Week 12
Day 113
Week 16
Day 127
Week 18
Day 141 
Week 20
EOT or ET 
Visit
Day 169
Week 24
(4 Weeks after EOT 
or ET)
EOS, Follow-up Visit
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10
Visit 11
Visit Window
None
None
±1 Day ±1 Day
±2 Days ±3 Days ±3 Days
±3 Days
±3 Days
±3 Days
±3 Days
Eczema Area and Severity 
Index (EASI)
X
X
X
X
X
X
X
X
X
X
Body Surface Area (BSA 
from EASI) 
X
X
X
X
X
X
X
X
X
X
C-SSRSu
X
PHQ-8u
X
Patient-reported Outcomes
Pruritus Numerical Rating 
Scale (NRS)v
X---------X
X-------------------------X
X
X
X
X
X
X
X
Patient Global Assessment 
(PtGA)
X
X
X
X
X
X
X
X
X
Dermatology Life Quality 
Index (DLQI)
X
X
X
X
X
X
Pruritus and Symptoms 
Assessment for Atopic 
Dermatitis (PSAAD)w
X---------X        X------------------------------------------------------------------------------------------------------------------------------------------X
EQ-5D-5L
X
X
X
X
X
Hospital Anxiety and 
Depression Scale (HADS)
X
X
X
X
Patient-Oriented Eczema 
Measure (POEM)
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 57
Week 8
Day 85
Week 12
Day 113
Week 16
Day 127
Week 18
Day 141 
Week 20
EOT or ET 
Visit
Day 169
Week 24
(4 Weeks after EOT 
or ET)
EOS, Follow-up Visit
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10
Visit 11
Visit Window
None
None
±1 Day ±1 Day
±2 Days ±3 Days ±3 Days
±3 Days
±3 Days
±3 Days
±3 Days
Safety
Serious and non-serious 
adverse event monitoring
X
X
X
X
X
X
X
X
X
X
X
Contraception Checky
X
X
X
X
X
X
X
X
X
X
X
Ensure subject adherence to 
background topical therapy 
requirementsd
X
X
X
X
X
X
X
X
X
X
X
Serum Sample for Baseline 
Viral Screenz
X
Abbreviations: BSA = body surface area; 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; FSH = follicle stimulating hormone; HADS= Hospital Anxiety and Depression Scale; HBsAg = hepatitis B surface antigen; 
HBsAb = hepatitis B surface antibody; HBcAb = hepatitis B core antibody; HBV DNA = hepatitis B virus deoxyribonucleic acid;
 
; HCVAb = hepatitis C antibody; HCV RNA = Hepatitis C Viral RNA; HIV = human immunodeficiency virus; 
 
; IGA = Investigator’s Global Assessment; IRT = Interactive Response System; LLQ = lower limit quantification; NRS = numerical rating 
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; SCORAD = SCORing Atopic Dermatitis; WONCBP = women of non-childbearing 
potential.
a.
Day relative to start of study treatment (Day 1).
b.
Any previous history of intolerance/allergy to any drug, regardless of indication.  Atopic Dermatitis Disease History includes collection of details of AD: AD 
diagnosis and duration, the use of topical treatments, systemic treatments and other treatments for AD. 
c.
Train the subject on washout of medicated topical therapy (Exclusion criterion 10, Section 4.2) and use of non-medicated topical therapy pre-baseline 
(Inclusion criterion 4, Section 4.1) Train and explain to the subject that their daily use of non-medicated topical therapy is recorded in the e-Diary.
d.
For background topical therapy guidelines see Section 5.9.1.
e.
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.
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f.
Vital Signs include sitting blood pressure, pulse rate, respiratory rate, and temperature (oral or tympanic) measured (pre-dose, if applicable) after at least 
5 minutes of rest. 
g.
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.  Official reading must be located and available in the source documentation.
h.
A single 12-lead ECG will be performed at screening and all other on-site visits after the subject has rested quietly for at least 10 minutes in the supine 
position.  ECG will be interpreted by a central reader.  Clinically significant or exclusionary ECG findings at the screening visits will require screen failure. 
i.
Serum chemistry includes: blood urea nitrogen (BUN), serum creatinine, creatine phosphokinase, glucose, Ca++, Na+, K+, Cl-, P, 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 16, 
Week 20 and EOS visits.  Hematology includes: Hemoglobin, hematocrit, red blood cell count and indices (MCH, MCHC, MCV, RBC Morphology), WBC 
count with differential, total 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 7.6.2) may be repeated once during the 
screening period; the last value will be used to determine eligibility. 
l.
Serum pregnancy testing at screening is required for female subjects of childbearing potential.  Follicle stimulating hormone (FSH) test to be performed at 
Screening to confirm postmenopausal status in female subjects who have been amenorrheic for at least 12 consecutive months.
m. Urine pregnancy test must be performed prior to dosing with the investigational product for female subjects of childbearing potential. 
 
o.
HIV testing will be performed for all subjects.  Subjects who are positive for HIV will be screen-failed. 
p.
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.
q.
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).  If 
the test results are indeterminate, the test should be repeated.  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, a chest X-ray is required, unless previously performed and 
documented within 12 weeks prior to Study Day 1.  See Section 7.3.3. For Japan only: While QuantiFERON® is the preferred testing method, the 
T-SPOT®.TB test is acceptable as the screening TB test. T-SPOT®.TB testing will be performed at the site’s local laboratory.  Borderline results from the 
T-SPOT®.TB test should be considered exclusionary. If the test results are indeterminate, the test should be repeated.  If the result of the repeat test is 
indeterminate, subjects may be screened using the Mantoux/PPD skin test with Pfizer Medical Monitor approval.  See Section 7.3.4.
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r.
The first injection will be administered by an unblinded administrator/trainer and used to train the subject on correct injection technique.  The second 
injection will be administered by the subject (or caregiver, if applicable) under observation of the unblinded administrator/trainer.
s.
When not at the site, subjects (and caregiver, if applicable) will be encouraged to administer investigational product in the morning whenever possible; 
however, on study visit days, subjects (and caregiver, if applicable) are to be instructed to refrain from dosing at home, and are to administer investigational 
product in the clinic under observation.  If any issues with injection technique are observed, the unblinded administrator/trainer must retrain the subject (or 
caregiver, if applicable) appropriately.
t.
Subjects who complete EOT will be assessed for eligibility for participation in long-term extension study B7451015 as noted in Section 6.2.9. 
u.
Site staff is to administer the C-SSRS 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 7.5.1, and Section 7.5.2.  
For subjects meeting exclusionary results on the C-SSRS or 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.
 
 
 
w.
Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD) will be conducted to assess the severity and frequency of pruritus, symptoms and sleep 
and collected daily in a subject eDiary during the screening period and from Day 1 through the End of Study visit in selected countries (See Section 7.10.8).  
At the Screening visit, site staff will dispense the eDiary 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.
 
y.
The contraception check is an opportunity to confirm that contraception, if required, is used consistently and correctly.
z.
A serum sample will be collected at baseline but analyzed only if the subject has a suspected viral reactivation. 
aa. For China, Republic of Korea, and Taiwan only: Subjects who are HBsAg negative, HBcAb positive, and HBsAb positive at Screening will have reflex 
testing for Hepatitis B Virus (HBV) DNA.  Subjects who have HBV DNA above the lower limit of quantification (LLQ) are excluded. Subjects who have 
HBV DNA negative or below LLQ may be randomized, but will have HBV DNA testing repeated at Week 12 and Week 20 End of Treatment (EOT) visit, 
or Early Termination (ET) visit, whichever is sooner (See Section 7.6.2.1).  A single HBV DNA test result above the LLQ for a subject requires immediate 
and permanent discontinuation from treatment.  Refer to Section 6.4.  For Japan only: In addition to HBsAg and HBcAb, HBsAb testing will be performed at 
Screening for all subjects rather than as a reflex test. Subjects with negative results for HBsAg, HBcAb and HBsAb may be eligible. Subjects who are 
HBsAg negative, HBcAb negative and HBsAb positive and provide documentation of prior HBV vaccination may be eligible and will not require HBV 
DNA monitoring during the study. Subjects who are HBsAg negative, HBcAb negative and HBsAb positive without documentation of prior HBV 
vaccination AND subjects who are HBsAg negative, HBcAb positive, and HBsAb positive at screening will have reflex testing for HBV DNA.  Subjects 
who are HBV DNA negative or below LLQ may be randomized but will have HBV DNA repeated at Week 12 and Week 20 End of Treatment (EOT) visit, 
or Early Termination (ET) visit, whichever is sooner (See Section 7.6.2.1).  A single HBV DNA test result above the LLQ for a subject requires immediate 
and permanent discontinuation from treatment.  Refer to Section 6.4.
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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 -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-), and interferon alpha (IFN-).  JAK2 homodimers are 
critical for the signaling of hematopoietic cytokines and hormones including erythropoietin 
(EPO), thrombopoietin (TPO), IL-3, granulocyte-macrophage colony-stimulating factor 
(GM-CSF) and prolactin.
Key cytokines implicated in the pathophysiology of AD include IL-4, IL-5, IL-13, IL-31,
and IFN-, and require 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.9
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.
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 in vitro against 
other kinases: 28-fold selectivity over JAK2, >340-fold over JAK3 and 43-fold over TYK2, 
as well as a good selectivity profile over the broader range of human kinases. The selective 
inhibition of JAK1 will lead to modulation of multiple cytokine pathways involved in the 
pathophysiology of AD, including IL-4, IL-5, IL-13, IL-31 and IFN-.  Data from a Phase 2b 
proof of concept (POC) study (B7451006) that evaluated subjects with moderate to severe 
AD have shown positive efficacy, as well as an acceptable safety profile, sufficient to support 
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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).
The SRSD for dupilumab is the United States Package Insert (USPI).
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%.3  Earlier reports indicated that, in up to 70% of cases, the 
disease greatly improves or resolves by 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 life and likely longer.4  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.10
The majority of studies conducted across multiple age groups suggest a continued decrease in 
prevalence with older age.11  Adult-onset AD does also occur, though it is less common.  The 
prevalence of AD in adults is estimated to be 10%.12 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.13
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 


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pro-inflammatory cytokines and chemokines.  This amplification cycle sustains the 
inflammatory responses characteristic of the AD lesions.14
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.8,14,15 Recent research showed that a 
small increase of Type 1 helper T cell (TH1)-associated genes has been also detected in acute 
phase.16
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--producing TH1 
cells or TH1 dominance.14  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.8,15
Non-medicated topical therapies include emollients.  Medicated topical therapies for 
moderate to severe AD include TCS (eg, betamethasone, clobetasol, fluocinonide), TCI 
(eg, pimecrolimus, tacrolimus), and coal tar preparations.  TCS are limited in terms of the 
treatment duration (eg, corticosteroid use is limited to 2 to 4 weeks) and the body region of 
treatment, due to consistent skin toxicities, as well as having risks associated with their broad 
immunosuppressive actions. TCI have a limited role as a second line treatment, due to their 
limitations in terms of the duration of treatment and the body region of treatment, inhibition 
of tumor surveillance in the skin, and safety concerns with malignancies.  Crisaborole was 
approved as a medicated topical therapy 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-, 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
There are a limited number of approved systemic treatments for moderate to severe AD, and 
in the USA, the only approved systemic drugs are corticosteroids and dupilumab. 
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, for the treatment of moderate to severe AD. Treatment with systemic 
corticosteroids has known and well documented adverse effects. Treatment with dupilumab 
has the risk of injection site reactions, allergic reactions, eye and eyelid inflammations and 
cold sores.  Another potential limitation of dupilumab is the possibility for development of 
antidrug antibodies, which may result in loss of efficacy over time and the development of
safety concerns such as serum sickness-like reactions. Furthermore, dupilumab is delivered 
via subcutaneous injection, which may not be a method of administration tolerated well by 
all patients.  During a 1-year, randomized, double-blinded study with dupilumab, in the 
dupilumab 300 mg every 2 weeks (marketed maintenance dose) plus TCS group, the 
estimated difference from placebo of the IGA response rate and EASI-75 response rate were 


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26% and 46%, respectively.  The placebo response rate for IGA and EASI-75 was 12% and 
23%, respectively.8  The development of potential treatments with further improvements to 
efficacy remains desirable.  In Europe, cyclosporine is approved for use in patients with 
severe AD when systemic therapy is required.  Cyclosporine use is associated with several 
undesirable side effects and due to its narrow therapeutic index, occasional therapeutic drug 
monitoring is recommended.  Known adverse effects include infections, renal toxicity, 
hepatotoxicity, skin malignancies, lymphoma and other malignancies.
The predominant unmet medical need is for an oral therapy with an acceptable safety profile, 
for long-term use, which is effective for moderate to severe AD.  Patients with moderate to 
severe AD require other systemic treatment options beyond those which are currently 
approved.
Currently available therapies for the treatment of AD have multiple limitations.  The 
medicated 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 medicated topical 
therapies and phototherapy, on- and off-label use of systemic agents, which include oral 
corticosteroids or 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.
PF-04965842 is an oral tablet, a more convenient route of administration compared with 
subcutaneous injection required for dupilumab and so it does not have the potential risk of 
injection site reactions.  Unlike dupilumab, PF-04965842 is a small molecule and there is no 
anticipated immunogenicity for PF-04965842, and so it is unlikely to generate antidrug 
antibodies.
As mentioned above, a variety of pro-inflammatory cytokines such as IL-4, IL-5, IL-13, 
IL-31 and IFN-, have been suggested to have a role in the pathogenesis of AD.  Many of 
these pathogenic cytokines use the JAK1 for signaling.  Therefore, JAK1 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 IB.


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1.2.4. Phase 2b in AD (B7451006)
B7451006 was a Phase 2b proof-of-concept trial in adults (ages 18-75) with moderate to 
severe AD investigating doses of 10, 30, 100, and 200 mg PF-04965842 or placebo taken 
once daily 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%, respectively.  The IGA 
response rate in the placebo group was 6.3% and the estimated differences from placebo in 
the 200 mg and 100 mg groups were 38.2% (P=0.0032) and 21.5% (P=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.  The estimated percent 
change from baseline in EASI score was -35.2% in the placebo group, -82.6% in the 200 mg 
group and -59.0% in the 100 mg group.  At Week 12, the proportion of subjects achieving 
EASI-75 response was 15.6% in the placebo group, 63.7% in the 200 mg group and 41.6% in 
the 100 mg group.  The difference from placebo was 41.8% (P<0.0001) for the 200 mg group 
and 26.0% (P=0.0043) in the 100 mg group.  At Day 15, the proportion of response based on 
achieving at least 4 points improvement in the severity of Pruritus NRS from baseline 
(Pruritus NRS4) of PF-04965842 100 mg and 200 mg dose groups was greater than placebo.  
The estimated proportion of Pruritus NRS4 responses at Day 15 were 69.8%, 41.1% and 
15.7% for 200 mg, 100 mg and placebo groups, 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.  Overall, adverse 
events (AE)s and Serious Adverse Events (SAE)s 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.  Further 
details of the clinical Phase 2 development program can be found in the 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). 
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.


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1.3.1. Population Pharmacokinetics
Population pharmacokinetics (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.
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 JAK inhibitors and 
include viral reactivation, serious and opportunistic infections, hematopoietic effects 
(including reduced platelet count), and malignancy and immunoproliferative disorders 
Further information is available in the IB.  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 mg and 200 mg dose.
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 as a monotherapy is expected 
to provide efficacy similar to that of currently approved systemic treatments (eg cyclosporine, 
systemic corticosteroids and dupilumab) 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.  Additionally, a dose of 100 mg QD was selected for 
Phase 3 evaluation.  The 100 mg dose is expected to differentiate from the higher dose in 
terms of efficacy, safety and systemic exposure.  In this study, the efficacy and safety of the 
100 mg dose will be evaluated in combination with background topical therapy.  Both 
100 mg and 200 mg QD doses demonstrated acceptable safety and tolerability in the Phase 2 
study.  Further details are available in the IB.  The dosing regimen of dupilumab used in the 
study will be based on the approved USPI (reference).


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This study will assess the efficacy and safety of PF-04965842 100 mg or 200 mg QD and 
dupilumab compared with placebo in adult subjects on background topical therapy, with 
moderate to severe AD.  The data generated will also estimate the efficacy of PF-04965842 
and dupilumab. This study will also provide a direct comparison of both doses of 
PF-04965842 with dupilumab in terms of pruritus relief.
2. STUDY OBJECTIVES AND ENDPOINTS
Study objectives and corresponding endpoints are provided in Table 1.
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Table 1.
Objectives and Endpoints:
Primary Objective
Primary Endpoints
To compare the efficacy 
of 100 mg and 200 mg 
once daily (QD) of 
PF-04965842 versus
placebo in adult 
subjects on background 
topical therapy with 
moderate to severe 
atopic dermatitis (AD).
The following co-primary endpoints will be tested:

Response based on achieving the Investigator's Global Assessment (IGA) of clear (0) or 
almost clear (1) (on a 5-point scale) and a reduction from baseline (pre-dose Day 1) of 
2 points at Week 12;

Response based on achieving the Eczema Area and Severity Index (EASI)-75 
(75% improvement from baseline) at Week 12.
Secondary Objectives
Secondary Endpoints
To compare the efficacy
of PF-04965842 versus 
dupilumab in terms of 
attaining a clinically 
significant 
improvement in the 
severity of pruritus for 
adult subjects on 
background topical 
therapy with moderate 
to severe AD.
Key Secondary Endpoints:

Response based on achieving at least 4 points improvement in the severity of Pruritus 
Numerical Rating Scale (NRS) from baseline at Week 2.
To estimate the 
difference in efficacy 
measures between two 
doses of PF-04965842 
and dupilumab for adult 
subjects on background 
topical therapy with 
moderate to severe AD.

Response based on achieving the IGA of clear (0) or almost clear (1) (on a 5-point scale) 
and a reduction from baseline of 2 points at Week 16; 

Response based on achieving EASI-75 (75% improvement from baseline) at Week 16.
To estimate the effect of 
PF-04965842 on 
additional efficacy 
endpoints and 
patient-reported 
outcomes over time in 
adult subjects on 
background topical 
therapy with moderate 
to severe AD.
Secondary Efficacy Endpoints:

Response based on achieving the IGA of clear (0) or almost clear (1) (on a 5-point scale) 
and 2 point reduction from baseline at all scheduled time points except Week 12 and 
Week 16;

Response based on achieving a 75% improvement in the EASI total score (EASI-75) at 
all scheduled time points except Week 12 and Week 16;

Response based on achieving a 50%, 90%, and 100% improvement in the EASI total 
score (EASI-50, EASI-90, and EASI-100) at all scheduled time points;

Response based on achieving at least 4 points improvement in the severity of Pruritus 
NRS from baseline at all scheduled time points except Week 2;

Time from baseline to achieve at least 4 points improvement in the severity of Pruritus 
NRS scale;

Change from baseline in the percentage Body Surface Area (BSA) affected at all 
scheduled time points;

Change from baseline of Patient Global Assessment (PtGA) at all scheduled time points;

Change from baseline in Dermatology Life Quality Index (DLQI) at all scheduled time 
points;

Change from baseline in EuroQol Quality of Life 5-Dimension 5-Level Scale 
(EQ-5D-5L) at all scheduled time points;


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•
Change from baseline in Hospital Anxiety and Depression Scale (HADS) at all 
scheduled time points;
•
Change from baseline in Patient-Oriented Eczema Measure (POEM) at all scheduled 
time points;
•
Change from baseline in Pruritus and Symptoms Assessment for Atopic Dermatitis 
(PSAAD) total score 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;
•
Steroid-free days at Week 16.
Safety Objectives
Safety Endpoints
To compare the safety 
and tolerability of 
100 mg and 200 mg QD 
of PF-04965842 and 
dupilumab versus
placebo in adult 
subjects on background 
topical therapy with 
moderate to severe AD.
To estimate the safety 
and tolerability of the 
two doses of 
PF-04965842 versus 
dupilumab, for adult 
subjects on background 
topical therapy with 
moderate to severe AD.
•
Incidence of treatment-emergent adverse event (AE)s;
•
Incidence of serious adverse event (SAE)s and AEs leading to discontinuation;
•
Incidence of clinical abnormalities and change from baseline in clinical laboratory 
values, electrocardiogram (ECG) measurements, and vital signs.
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AD = Atopic dermatitis; AE = Adverse Event; BSA = Body Surface Area; DLQI = Dermatology Life Quality Index; 
EASI = Eczema Area and Severity Index; ECG = Electrocardiogram; EQ-5D-5L = EuroQol Quality of Life 5-Dimension 
5-Level Scale; HADS = Hospital Anxiety and Depression Scale; 
 
IGA = Investigator’s Global Assessment; NRS = numerical rating scale; POEM = Patient-Oriented Eczema Measure; 
PSAAD = Pruritus and Symptoms Assessment for Atopic Dermatitis; PtGA = Patient Global Assessment; 
SAE = Serious Adverse Event; SCORAD = Scoring Atopic Dermatitis;
.
CCI
CCI
CCI
CCI
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3. STUDY DESIGN
This is a randomized, double-blind, double-dummy, placebo-controlled, parallel-group, 
multi-center study to assess the efficacy and safety of PF-04965842 100 mg or 200 mg QD 
and dupilumab (as per label) compared with placebo in adult subjects on background topical 
therapy, with moderate to severe AD.  This study will provide a direct comparison of both 
doses of PF-04965842 with dupilumab in terms of pruritus relief.  This study will also 
provide data which will estimate the relative efficacy of both doses of PF-04965842 and 
dupilumab.  The treatment duration is 20 weeks.  A total of approximately 700 subjects will 
be enrolled from approximately 270 sites globally.  There is a primary efficacy assessment at 
Week 12, and key secondary efficacy assessments at Week 2 and Week 16.  Efficacy and 
safety endpoints will be assessed throughout the entire study. A study design schematic is 
presented in Figure 1.
Figure 1.
Study Design Schematic
a At Week 2 and Week 16, key secondary endpoints are measured.
b At Week 12, primary endpoints are measured.
c At Week 20, eligible subjects will enter the B7451015 long-term extension study; ineligible subjects will 
instead enter the 4-week off-treatment follow-up period in B7451029. 
Note: Standardized background topical therapy must be used as per protocol guidelines throughout the study.
After providing informed consent, subjects will be assessed for study eligibility at the 
screening visit.  Subjects will undergo screening within 28 days prior to randomization.  
During the screening period, systemic treatments and medicated topical therapy for AD will 
be washed out, as applicable, according to eligibility requirements.  Eligible subjects must 
have a documented history, within 6 months of the screening visit, of inadequate response to 
treatment with medicated topical therapy for at least 4 weeks, or must have required systemic 
therapies for control of their disease.  Eligible subjects must meet the eligibility criteria at 
both screening and baseline. In addition, subjects are required to use non-medicated topical 
therapy (ie, emollients) at least twice daily for the last 7 days prior to Day 1 and must also be 


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willing and able to use standardized background topical therapy, as per protocol guidelines, 
throughout the duration of the study.  Subjects may be re-screened once if they fail the 
screening evaluation for reasons related to incidental transitory conditions.  Subjects for 
whom screen failure is related to failing the disease severity (including extent of disease) 
inclusion criterion 3 and who subsequently experience worsening AD, which in the 
investigator’s judgement would make them eligible for participation, may be considered for 
re-screening. Such cases should be discussed with the Pfizer Medical Monitor (or designee) 
to determine if re-screening is appropriate.
Subjects who continue to meet eligibility criteria at baseline will undergo Day 1 assessments 
and be randomized in a 4:4:4:1:1 ratio to receive 100 mg or 200 mg of PF-04965842 QD 
with dupilumab-matching placebo administered every other week , dupilumab 300 mg 
administered every other week (with a loading dose of 600 mg at baseline) with 
PF-04965842-matching placebo administered QD, or one of two sequences of 
PF-04965842-matching placebo administered QD with dupilumab-matching placebo 
administered every other week from Day 1, for 16 weeks followed by either 100 mg or 
200 mg of PF-04965842 QD.  Investigators, subjects, and the sponsor study team will be 
blinded as to treatment group.
The total treatment period is 20 weeks.  The first part of this treatment period consists of a 
16-week randomized, double-blind, placebo-controlled, double-dummy treatment period with 
subjects receiving both injectable and oral investigational product.  The randomization and 
double-blind will be maintained during the final 4 weeks of the treatment period, but subjects 
will only receive oral investigational product.  At Week 16 in the treatment period, all 
subjects will cease injectable dupilumab or its matching placebo.  This is to facilitate the 
washout of dupilumab (for a total of 6 weeks; as the final dose of dupilumab or its matching 
placebo is administered at Week 14) prior to eligible subjects entering the long-term 
extension study, in which all subjects will receive PF-04965842 active treatment.  As, 
following Week 16, data for the primary and key secondary efficacy assessments will have 
already been obtained, subjects previously receiving only placebo will receive PF-04965842 
100 mg or 200 mg QD as per their randomized allocation.  Subjects previously receiving 
PF-04965842 100 mg or 200 mg QD will continue on their respective dose.  Subjects 
previously receiving dupilumab will continue to take oral placebo.  These alterations to study 
treatment will all be conducted while maintaining the blind when re-issuing oral 
investigational product to all subjects at the Week 16 time point.
Eligible subjects completing the entire 20-week treatment period of the study will have the 
option to enter a long-term extension (LTE) study, B7451015.  In which all subjects will 
receive PF-04965842 active treatment. Subjects discontinuing early from treatment, or who 
are otherwise ineligible for the LTE study, will undergo a 4-week follow-up period in study 
B7451029.


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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 has been informed of all pertinent aspects of the study.
2. Male or female subjects aged 18 years or older at the time of informed consent.
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 at the screening 
and baseline visits according to Hanifin and Rajka criteria for AD17
(see Appendix 2).

Documented recent history (within 6 months before the screening visit) of 
inadequate response to treatment with medicated topical therapy for AD for at 
least 4 weeks, or who have required systemic therapies for control of their 
disease.
NOTE: Medicated topical therapy is defined as a topical product that contains an 
active pharmaceutical ingredient indicated for the treatment of AD (irrespective of 
whether it is an over-the-counter [OTC] or prescribed product).

Moderate to severe AD (affected body surface area (BSA) 10%, IGA 3, 
EASI 16, and Pruritus NRS severity score 4 on the day of the baseline visit).
4. During the last 7 days prior to Day 1, for the treatment of AD, the subject must have 
used only non-medicated topical therapy (ie, emollient) without other active 
ingredients indicated to treat AD, or other additives which could affect AD 
(eg, hyaluronic acid, urea, ceramide or filaggrin degradation products) at least twice 
daily, with response to treatment remaining inadequate at baseline.  The subject must 
also be willing and able to comply with standardized background topical therapy, as 
per protocol guidelines (Section 5.9.1), throughout the remainder of the study.


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5. Willing and able to comply with scheduled visits, treatment plan, laboratory tests and 
other study procedures.
6. Female subjects who are of childbearing potential 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.
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.
7. 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.
8. 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.
9. 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.


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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;

Clinically significant depression: patient health questionnaire – 8 items (PHQ-8) 
total score 15 (Appendix 16);

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.


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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. Subjects who have received prior treatment with any systemic JAK inhibitors.  Prior 
treatment with topical JAK inhibitors is not exclusionary.  
8. Previous treatment with dupilumab and/or a history of hypersensitivity, intolerance, 
adverse event, or allergic reaction associated with prior exposure to dupilumab’s 
excipients.
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.
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 4 weeks of first dose of investigational product:

Use of oral immunosuppressive drugs (eg, cyclosporine A [CsA], azathioprine, 
methotrexate, systemic corticosteroids, mycophenolate-mofetil, IFN-) within 
4 weeks of first dose of investigational product or within 5 half-lives (if known), 
whichever is longer.


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NOTE: Corticosteroid inhalers and intranasal sprays are permissible for subjects
receiving a stable dose.
NOTE: Ophthalmic corticosteroids are permissible for subjects receiving a stable 
dose.

Use of CYP2C9 and CYP2C19 inducers within 5 half-lives of the inducer plus 
14 days of first dose of investigational product.  For example, the average half-life 
of Carbamazepine after repeat dosing is 15 hours.  The washout period is 
calculated as the sum of 5 half-lives (approximately 3 days) and an additional 
14 days for a total of 17 days prior to the first dose of investigational product.

Phototherapy narrowband UVB (NB-UVB) or broadband 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:

Medicated topical therapy that could affect atopic dermatitis (eg, corticosteroids, 
calcineurin inhibitors, tars, antibiotic creams, topical antihistamines).
NOTE: Non-medicated topical therapy (ie, emollients), as detailed in Section 5.9.1
are permitted.
Within 1 week of first dose of investigational product:

Use of CYP2C9 and CYP2C19 inhibitors within 1 week of first dose of 
investigational product or within 5 half-lives (if known) of the inhibitor, 
whichever is longer.  NOTE: Half-life refers to the half-life of the parent drug and 
its metabolites, which are inhibitors, as detailed in Appendix 3.

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.
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 a known helminth infection;


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c.
Have active chronic or acute skin infection requiring treatment with systemic 
antimicrobials within 2 weeks prior to Day 1, or superficial skin infections within 
1 week prior to Day 1;
d. A subject known to be infected with Human Immunodeficiency Virus (HIV), 
Hepatitis B, or Hepatitis C (Section 7.6.2);
For China, Republic of Korea, and Taiwan only:
Subjects who are hepatitis B surface antigen (HBsAg) negative, hepatitis B core 
antibody (HBcAb) positive, and hepatitis B surface antibody (HBsAb) positive at 
Screening will have reflex testing for Hepatitis B Virus (HBV) DNA.  Subjects 
who have HBV DNA above the lower limit of quantification (LLQ) are excluded.
Subjects who have HBV DNA negative or below LLQ may be randomized, but 
will have HBV DNA testing repeated at Week 12 and Week 20 End of Treatment 
(EOT) visit, or Early Termination (ET) visit, whichever is sooner.
For Japan only:
Subjects with negative results for HBsAg, HBcAb and HBsAb may be eligible. 
Subjects who are HBsAg negative, HBcAb negative and HBsAb positive and 
provide documentation of prior HBV vaccination may be eligible and will not 
require HBV DNA monitoring during the study. Subjects who are HBsAg 
negative, HBcAb negative and HBsAb positive without documentation of prior 
HBV vaccination AND subjects who are HBsAg negative, HBcAb positive, and 
HBsAb positive at screening will have reflex testing for HBV DNA.  Subjects 
who are HBV DNA negative or below LLQ may be randomized but will have 
repeat HBV DNA testing at Week 12 and Week 20 End of Treatment (EOT) visit, 
or Early Termination (ET) visit, whichever is sooner.
e.
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:
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:


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
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.
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 5.9.2 and
Appendix 3) or have received a prohibited concomitant medication within the 
specified timeframe prior to the first dose of investigational product.
18. Have evidence of active or latent or inadequately treated infection with 
Mycobacterium tuberculosis (TB) as evidenced by any of the following:

A positive QuantiFERON-TB Gold (QFT-G) In-Tube test or positive 
Mantoux/Purified Protein Derivative (PPD) tuberculin skin test performed at or 
within the 12 weeks prior to Day 1. 
NOTE: A negative QFT-G, a Mantoux/PPD tuberculin skin test, or a 
T-SPOT®.TB test (Japan only) is required unless the subject has previously 
received a documented adequate course of therapy for either latent (9 months of 
isoniazid in a locale where rates of primary multi-drug TB resistance are <5% or 
an acceptable alternative regimen per local standards of care) or active 
(acceptable multi-drug regimen) TB infection.  If the current incidence rates of 
multi-drug resistant TB infection in the locale are unavailable, an adequate 
treatment regimen should be defined as the regimen recommended by the health 
ministry or expert panel in the locale.

It is recommended that subjects with a history of Bacille Calmette Guérin (BCG) 
vaccination be tested with the QFT-G test since the Mantoux/PPD tuberculin skin 
test may be positive due to vaccination.  See Section 7.3.4 for requirements for 
Mantoux/PPD tuberculin skin testing. 

For Japan only: While QuantiFERON® is the preferred testing method, the 
T-SPOT®.TB test is also acceptable as the screening TB test.  Borderline results 
from the T-SPOT.TB test should be considered exclusionary.  If the 
T-SPOT®.TB test results are indeterminate, the test should be repeated.  If the 


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result of the repeat test is indeterminate, subjects may be screened using the 
Mantoux/PPD skin test with Pfizer Medical Monitor approval.  See Section 7.3.4.

Chest radiograph (or chest Computed Tomography (CT) scan, if available) taken 
at screening with changes suggestive of active tuberculosis (TB) infection as 
determined by a qualified radiologist.  A chest X-ray is required, unless 
previously performed and documented within 12 weeks prior to Study Day 1.

A history of either untreated or inadequately treated latent or active TB infection.

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%;

Platelet count of <150 x 109/L (<150,000/mm3);

Absolute lymphocyte count of <0.50 x 109 /L (<500/mm3);
NOTE: In the Czech Republic only an Absolute lymphocyte count of <0.75 x 109 /L 
(<750/mm3) is exclusionary.

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.


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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 have signed an informed consent 
document to participate in the study, have undergone all screening procedures, meet all 
inclusion and none of the exclusion criteria for participation in the study, and meet the 
randomization criterion listed above at Day 1.  A computer-generated randomization 
schedule will be used to assign subjects to the treatment groups using an Interactive 
Response Technology (IRT).  Randomization will be administered using center-based 
randomly permuted blocks. Center-based randomization was chosen based on drug 
management considerations. Randomization will not be stratified by baseline disease 
severity or age.
NOTE: the maximum screening period length is 28 days.  Subjects who cannot be screened 
within this timeframe must be screen failed.
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.

Prior to the Day 1, Week 4, Week 16, Week 20 and End of Study (EOS) visits, 
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 5.9.1).

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 administer 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.

On study visit days, topical therapy (ie, non-medicated topical therapy and medicated 
topical therapy, if applicable as per protocol guidelines as described in Section 5.9.1)
are not permitted to be applied prior to attending the study visit.  Topical therapies are 
permitted to be applied after the visit (if applicable as per protocol guidelines as 
described in Section 5.9.1).

Agree to use one highly effective method of contraception (as specified in 
Section 4.4.1, as applicable).


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4.4.1. Contraception
Male subjects are not required to use contraception.
All female subjects of childbearing potential who are, in the opinion of the investigator, 
sexually active and at risk for pregnancy with their partner(s) must agree to use a highly 
effective method of contraception consistently and correctly for the duration of the active 
treatment period and for at least 28 days after the last dose of 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.
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.
NOTE: Vasectomized partner is a highly effective birth control method provided that 
partner is the sole sexual partner of the woman of childbearing potential (WOCBP)
trial participant and that the vasectomized partner has received medical assessment of 
the surgical success.


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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 childbearing 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 childbearing 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.
2. Correctly placed copper-containing intrauterine device (IUD).
3. Male sterilization with absence of sperm in the post-vasectomy ejaculate.
NOTE: Vasectomized partner is a highly effective birth control method provided that 
partner is the sole sexual partner of the WOCBP trial participant and that the 
vasectomized partner has received medical assessment of the surgical success.
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.


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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 attenuated vaccines is prohibited within the 6 weeks prior to first dose of 
investigational product, for the duration of the study, and for 6 weeks following completion 
of the study.
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 attenuated vaccines 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(intranasal flu vaccine) for 1 week following vaccination;
Subjects should avoid exposure to recently vaccinated or infected persons and contact the 
investigator promptly should they develop signs or symptoms of infections.
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.


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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 calls that number, he 
or she will be directed back to the investigator site.
5. STUDY TREATMENTS 
The study treatments are as follows:

Orally administered 100 mg of PF-04965842 QD with dupilumab-matching placebo 
administered by subcutaneous injection every other week (two injections at baseline; 
to dummy the loading dose) from Day 1 to Week 16, followed by orally administered 
100 mg of PF-04965842 QD until Week 20.

Orally administered 200 mg of PF-04965842 QD with dupilumab-matching placebo 
administered by subcutaneous injection every other week (two injections at baseline; 
to dummy the loading dose) from Day 1 to Week 16, followed by orally administered 
200 mg of PF-04965842 QD until Week 20.

Dupilumab 300 mg administered every other week (with a loading dose of 600 mg at 
baseline) with PF-04965842-matching orally administered placebo QD from Day 1 to 
Week 16, followed by PF-04965842-matching orally administered placebo QD until 
Week 20.

PF-04965842-matching orally administered placebo QD with dupilumab-matching 
subcutaneously injected placebo administered every other week (two injections at 
baseline; to dummy the loading dose) from Day 1 to Week 16 followed by orally 
administered 100 mg of PF-04965842 QD until Week 20.


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
PF-04965842-matching orally administered placebo QD with dupilumab-matching 
subcutaneously injected placebo administered every other week (two injections at 
baseline; to dummy the loading dose) from Day 1 to Week 16 followed by orally 
administered 200 mg of PF-04965842 QD until Week 20.

Treatment duration will be 20 weeks (with the blind maintained throughout).

Subjects who do not enroll into the long-term extension study, B7451015, will enter a 
4-week follow-up post-treatment period.
For the purposes of this study, and per International Council for 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).
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. At 
each site, an unblinded administrator/trainer will administer the first dose of dupilumab or its 
matching placebo to train the subject (or caregiver, if applicable) in proper injection 
technique.  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.


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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 investigator is responsible for, and may break the blind for safety reasons, where 
the knowledge of actual treatment is essential for the further management of the subject.  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
There are viscosity differences between dupilumab and the matched placebo, and as such 
there is a potential for functional unblinding of the administrator/trainer; who may notice the 
difference in viscosity and/or may have previous experience administering dupilumab.
Although no administrator/trainer will know the treatment allocation of subjects, as a risk 
mitigation against functional unblinding affecting study integrity this administrator/trainer 
will only administer injectable investigational product (IP), or observe/train subjects 
administering injectable IP, will be isolated from all other study activities, and will be treated 
as if unblind. Throughout the protocol, these individuals will be referred to as "unblinded 
administrator/trainer" in order to make this clear distinction from other site personnel.
When investigational product is administered at the research facility, it will be administered 
under the supervision of the unblinded administrator/trainer only. From the Day 1 visit 
onward, subjects will be dispensed PF-04965842 or PF-04965842-matching placebo to take 
home with them for self-administration on non-study visit days. Subjects will be dispensed 
dupilumab or dupilumab-matching placebo at the Day 1, Week 2, Week 4, Week 8 and 
Week 12 visits for self-administration (or administration by a caregiver, if applicable) at the 
site.  Subjects will also be dispensed dupilumab or dupilumab-matching placebo at Week 4, 
Week 8, and Week 12 visits to take home with them for self-administration (or 
administration by a caregiver, if applicable) at Week 6, Week 10, and Week 14, respectively.  
If the subject is unwilling/unable to self-administer the injectable investigational product or 
arrange for a caregiver to administer the injectable investigational product, then it is 
permissible for site to arrange for the subject to return to the site for administration by the 
unblinded trainer/administrator.  Subjects will be directed to bring any used and unused 
syringe cartons to visits following administration at home. Study sites will provide subjects 
with a sharps container for disposal of used syringes. Subjects will return this sharps 
container to the study site at the final visit for disposal.
Subjects will be issued an electronic dosing diary (eDiary) and will be educated to record the 
time of their dosing, once they have taken the investigational product.  Subjects will also use 
the eDiary to record their daily use of standardized background topical therapy for the 
treatment of AD, as required and as per protocol guidelines in Section 5.9.1, beginning at 
screening through the EOS visit.


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Compliance with the dosing of investigational product will be monitored and verified by 
delegated site personnel through a combination of observed investigational product 
administration at study visits, 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.
Investigational product should be administered in the morning.  Subjects should be instructed 
that if an oral dose is inadvertently missed then it should be taken as soon as remembered, 
but not within 12 hours of the next scheduled dose.  If an injectable dose is missed, subjects 
(or caregivers, if applicable) should be instructed to administer the injection within 7 days 
from the missed dose and then resume the subject’s original schedule.  If the missed dose is 
not administered within 7 days, subjects (or caregivers, if applicable) should be instructed to 
wait until the next dose on the original schedule.
Investigational product may be temporarily withheld for a maximum of 14 days at 
investigator's discretion due to abnormal laboratory tests or adverse event. See Appendix 4
for further guidance on temporary withholding of investigational product. Doses not taken 
for the reasons mentioned above do not constitute protocol deviations or medication errors 
and should not be considered dosing errors, but should be noted in the dosing log with the 
reason for reduced drug consumption.
Other than for the above reasons, the following compliance cases will be considered 
medication errors and will be discussed with the sponsor for possible withdrawal from the 
study:

Subjects interrupting oral 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;

Missed dose of injectable investigational product is not administered within 7 days of 
the originally scheduled dose; 

Subjects administering >1 prefilled syringe every 2 weeks, with the exception of the 
initial loading dose of two prefilled syringes on Day 1;

Subjects who have an overall compliance of <80% or >120% between visits.
Compliance with background topical therapy guidelines in Section 5.9.1 will be monitored 
and verified by delegated site personnel through a combination of review of the electronic 
diary, and discussion with the subject, which will be documented in the source documents.


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Any deviation from protocol specified dosing of investigational product or protocol specified 
guideline concerning background topical medication should be recorded as a protocol 
deviation and the investigator or designee is to counsel the subject 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).
Blinded active comparator (dupilumab) will be provided as 300 mg/2 mL prefilled syringes 
for subcutaneous injection.  Dupilumab-matching placebo will also be provided as prefilled 
syringes for subcutaneous injection.  The dupilumab and matching placebo syringes will be 
labeled according to local regulatory requirements, and when received by the pharmacy will 
be in containers that will sufficiently blind all site staff to content within the syringes.
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 quantities appropriate for the study visit schedule.  The subject 
(or caregiver, if applicable) should be instructed to maintain the product in the containers 
provided throughout the course of dosing and return the containers to the site at the next 
study visit.
5.5. Administration
The treatment period is 20 weeks.
Oral investigational product, PF-04965842 or its matching placebo, will be administered for 
20 weeks.  Subjects will be dispensed two (2) bottles of oral investigational product at the 
Day 1, Week 4, Week 8, Week 12, and Week 16 visits.  Subjects will be given clear dosing 
instructions to take one tablet from each bottle, once daily, preferably in the morning
whenever possible, at approximately the same time of day.  On study visit days, subjects (and 
caregivers, if applicable) are to be instructed to refrain from dosing at home, and are to 
administer investigational product in the clinic under observation.
Subjects will swallow the oral investigational product whole, and will not manipulate or 
chew the medication prior to swallowing.  Oral investigational product may be taken with or 
without food, other than on study visit days where fasting is required. Injectable 
investigational product, dupilumab or its matching placebo, will be administered for 
16 weeks with the final injection planned for Week 14.  Subjects will be dispensed prefilled 
syringes containing injectable investigational product at the Day 1, Week 2, Week 4, Week 8, 


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and Week 12 visits.  Injectable investigational product will be administered at the site on 
Day 1, Week 2, Week 4, Week 8 and Week 12 under the observation of the unblinded 
administrator/trainer, and at home by the subject (or caregiver, if applicable) at Week 6, 
Week 10, and Week 14.  The unblinded administrator/trainer will instruct the subject (or 
caregiver, if applicable) on the proper aseptic technique to administer a subcutaneous 
injection when using the prefilled syringes.  The first injection at the Day 1 visit will be 
administered by an unblinded administrator/trainer and used to train the subject (or caregiver, 
if applicable) on correct injection technique.  The second injection will be administered by 
the subject (or caregiver, if applicable) immediately following the first injection, under the 
observation of the unblinded administrator/trainer.  If any issues with technique are observed, 
the unblinded observer must retrain the subject appropriately.  All injections should be 
administered in accordance with the dupilumab drug label.
The investigator should assign the responsibility of unblinded administrator/trainer to a 
member of the study site staff who will not participate in any other study-related activities, 
ensuring that all other site staff do not risk becoming functionally unblinded. Contact 
between the unblinded administrator/trainer and study subjects should be kept to a minimum.  
The unblinded administrator/trainer must not take any action that may potentially reveal 
treatment assignment to the subject or site staff. The investigator, site staff, and any study 
participants other than the unblinded administrator/trainer must not be allowed to know the 
investigational product assigned to any study subject and must not be allowed to see the 
treatment records.
At Week 16, subjects previously receiving only placebo will receive PF-04965842 
100 mg QD or 200 mg QD as per randomized allocation.  Subjects previously receiving 
PF-04965842 100 mg QD or 200 mg QD will continue on this dose.  Subjects previously 
receiving dupilumab will continue to take oral placebo.  These alterations to study treatment 
will all be conducted while maintaining the blind, when re-issuing oral investigational 
product to all subjects at the Week 16 time point.
A guidance document with detailed dosing instructions will also be provided to subjects to 
support at-home dosing.
5.6. Medical Devices
1. The devices manufactured for Pfizer by a third party provided for use in this study 
are: 
a.
pre-filled syringes for subcutaneous injection of dupilumab (manufactured by 
Sanofi-Regeneron followed by relabeling and repackaging for Pfizer by a third 
party); 
b. pre-filled syringes for subcutaneous injection of matching placebo. 
2. Instructions for medical device use are provided in the Dosing Instructions.


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3. Pre-filled syringe medical device incidents, including those resulting from 
malfunctions of the device, must be detected, documented, and reported by the 
investigator throughout the study (see Section 8.4.5).
5.7. 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.
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.


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5.8. 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 oral investigational product must be brought back to the site at every visit for 
inspection by the site staff and all bottles/unused oral investigational product must be 
returned to the investigator by the subject at the relevant visit(s).
Subjects will be directed to bring any used and unused syringe cartons to all visits for 
inspection by the site staff.  Study sites will provide subjects with a sharps container for 
disposal of used syringes.  Subjects will return this sharps container to the study site at the 
final visit for disposal.
5.8.1. 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.
5.9. 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 
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.


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5.9.1. Permitted Concomitant Medications
Background Topical Therapy
Subjects must comply with standardized background topical therapy guidance throughout the 
study. Background topical therapy will not be provided by the sponsor. Standardized 
background topical therapy refers to the below, in accordance with the local standard of care 
and according to the Investigator’s usual practice: 
Non-medicated Topical Therapy

Non-medicated topical emollient without other active ingredients indicated to treat 
AD, or other additives which could affect AD (eg, hyaluronic acid, urea, ceramide or 
filaggrin degradation products): must be applied at least twice daily to all body areas 
affected with AD, throughout at least the final 7 days prior to Day 1 and throughout 
the remainder of the study.
Medicated Topical Therapy

Topical Corticosteroids (TCS) must be applied once daily to areas with active lesions, 
starting on Day 1 (Baseline) and throughout the study, according to the guidance 
below:

Medium potency TCS (eg, Triamcinolone acetonide 0.1% cream or fluocinolone 
acetonide 0.025% ointment) must be applied to body areas with active lesions that 
are suitable for the use of medium potency TCS.  Subjects must be clinically 
monitored for toxicity to topical steroids and stepped down as needed.

After lesions are under control (clear or almost clear), treat once daily for a 
further 7 days, then stop;

If lesions return then resume treatment with medium potency TCS, but use the 
approach described above upon lesion resolution.

Low potency TCS (ie, hydrocortisone 1% cream) must be applied to body areas of 
thin skin (face, neck, intertriginous, and genital areas, areas of skin atrophy, etc.) 
with active lesions instead of medium potency TCS or to body areas where 
continued treatment with medium potency TCS is considered unsafe.  Subjects 
must be clinically monitored for toxicity to topical steroids and stepped down as 
needed. 

After lesions are under control (clear or almost clear), treat once daily for a 
further 7 days, then stop;

If lesions return then resume treatment with low potency TCS, but use the 
approach described above upon lesion resolution.


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
Topical calcineurin inhibitors (eg, tacrolimus, pimecrolimus) or a PDE4 inhibitor 
(eg, crisaborole) may be used instead of corticosteroids in body areas of thin skin 
(face, neck, intertriginous, and genital areas, areas of skin atrophy, etc.) with active 
lesions or if continued treatment with TCS of any potency is considered unsafe, and 
according to locally approved label at the investigator’s discretion and considering 
prior response or intolerance to these medications. 
NOTE: Background topical therapy must not be applied prior to attending a study visit, on 
the day of the study visit.  Background topical therapy instead should be applied after the 
visit, on study visit days.
Other Concomitant AD Therapies
The following other concomitant AD therapies are permitted during the study and will not be 
provided by the sponsor:

Oral antihistamines.
The following concomitant medications are permitted during the study:

Corticosteroid inhalers and intranasal sprays are permissible for subjects receiving a 
stable dose;

Ophthalmic corticosteroids are permissible for subjects receiving a stable dose;

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;

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.


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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.
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.
5.9.2. Prohibited Medications and Treatments
Subjects are required to discontinue and avoid using certain medications and treatments (see
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. Medicated topical therapy for AD must be washed out one week 
prior to Day 1 (Baseline).  Starting on Day 1, standardized background topical therapy will 
be used as per protocol guidance in Section 5.9.1.
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 systemic JAK inhibitors are to be excluded from 
the study.  Prior treatment with topical JAK inhibitors is not exclusionary.
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 4.2.
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.


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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 16, Week 20 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 through to the EOS visit.
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 in accordance with the procedures described in 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;

Register subject using the IRT system;

Collect demography;

Administer C-SSRS and PHQ-8.  Subjects meeting any of the criteria specified in 
Exclusion Criterion 2 as described in Section 4.2 on the C-SSRS or 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;

Obtain weight;

Obtain height;


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
Obtain vital signs including pulse rate, sitting blood pressure, respiratory rate and oral 
or tympanic temperature (after at least 5 minutes of rest);

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;

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 
and other treatments (excluding systemic);

Lifetime history of previous systemic treatment for AD and reason for stopping 
any systemic treatment for AD;

Lifetime history of intolerance/allergy to any drug, regardless of indication;

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;

Train subject on protocol guidance for the use of background topical therapy as 
described in Section 5.9.1;

Conduct complete physical examination;

Conduct clinical evaluations including IGA, SCORing Atopic Dermatitis (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;

Perform a single 12-lead electrocardiogram (ECG).  Clinically significant or 
exclusionary ECG findings require screen failure;

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;


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•
Tuberculosis Test QuantiFERON® – TB Gold In-Tube test or locally analyzed 
T-SPOT®.TB test (Japan only) (unless performed within 12 weeks of Day 1).  If 
Mantoux PPD tuberculin skin test is required to be performed instead, per 
Section 7.3.4, the subject must return between 48-72 hours post-injection for 
evaluation of induration (see Section 7.3.4 for further details on TB testing);
•
Chest X-ray (posterior-anterior and lateral views) or other appropriate diagnostic 
image (ie, computerized tomography [CT] or magnetic resonance imaging [MRI]) are 
required.  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 (female subjects of childbearing potential) or serum pregnancy test 
(female subjects of childbearing potential), 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 7.6.2.1);  
•
For China, Republic of Korea, and Taiwan only: Collect sample for HBV DNA reflex 
test (see Section 7.6.2.1);
•
For Japan only: In addition to HBsAg and HBcAb, HBsAb testing will be performed
at Screening for all subjects rather than as a reflex test. Subjects with negative results 
for HBsAg, HBcAb and HBsAb may be eligible.  Subjects who are HBsAg negative, 
HBcAb negative and HBsAb positive and provide documentation of prior HBV 
vaccination may be eligible and will not require HBV DNA monitoring during the 
study. Subjects who are HBsAg negative, HBcAb negative and HBsAb positive 
without documentation of prior HBV vaccination AND subjects who are HBsAg 
negative, HBcAb positive, and HBsAb positive at screening will have reflex testing 
for HBV DNA. Subjects who are HBV DNA negative or below LLQ may be 
randomized but will have HBV DNA repeated at Week 12 and Week 20 End of 
Treatment (EOT) visit, or Early Termination (ET) visit, whichever is sooner;
•
Dispense eDiary and instruct subject in how to use the device.  Instruct the subject to 
begin daily completion of the Pruritus and Symptoms Assessment for Atopic 
Dermatitis (PSAAD) (in selected countries), Pruritus NRS, 
 
; 
•
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; 
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Instruct the subject to keep a daily record of use of standardized background topical 
therapy.  Standardized background topical therapy use and adherence with guidelines 
will be recorded daily in the subject eDiary during the screening period and through 
the End of Study visit;
•
 
 
 
 
 
 
 
 
 
•
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 Patient Global Assessment 
(PtGA), Dermatology Life Quality Index (DLQI), EuroQol Quality of Life 
5-Dimension 5-Level Scale (EQ-5D-5L), 
 
Hospital Anxiety and Depression Scale (HADS), and Patient-Oriented Eczema 
Measure (POEM); 
•
Obtain weight;
•
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);
•
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;
•
Check subject’s understanding of protocol guidance for the use of background topical 
therapy as described in Section 5.9.1, ensure subject adherence to background topical 
therapy requirements and re-educate as required;
•
Conduct complete physical examination; 
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Conduct clinical evaluations including Fitzpatrick Skin Type Assessment, IGA, 
SCORAD, EASI and BSA (calculated in the EASI);
•
Perform a single 12-lead electrocardiogram (ECG).  Clinically significant or 
exclusionary ECG findings require screen failure; 
•
Obtain samples for laboratory testing: serum chemistry, hematology (including 
coagulation panel), lipid profile (fasting), 
,
and urinalysis; 
•
 
•
Collect sample for viral surveillance: Herpes simplex virus (eg, Herpes simplex virus 
(HSV) HSV-1, HSV-2 and varicella zoster virus (VZV), etc);
•
Urine pregnancy test (female subjects of childbearing potential).  A negative urine 
pregnancy test must be obtained prior to dosing with the 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 of Inclusion/Exclusion Criteria;
•
If subject continues to meet all Inclusion/Exclusion criteria, officially randomize 
subject into the study;
•
Dispense oral investigational product to the subject;
•
Administer oral investigational product and observe dosing;
•
Dispense injectable investigational product to the subject;
•
Unblinded administrator/trainer: administer the first dose of injectable investigational 
product, using this injection to train the subject and/or caregiver in the proper 
injection technique;
•
Unblinded administrator/trainer: observe the administration of the second dose of 
injectable investigational product performed by the subject or his/her caregiver;
 
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•
 
 
 
 
 
•
Assess and record any Adverse Events since the last visit. 
6.2.2. Visit 3 (Phone call visit), 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;
•
Check subject understanding of protocol guidance for the use of background topical 
therapy as described in Section 5.9.1 and re-educate as required;
•
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.
6.2.3. Visit 4, Day 15/Week 2 (±1 day)
•
Administer PROs including PtGA and DLQI;
•
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);
•
Review Pruritus NRS, 
, and PSAAD completion (in selected 
countries) and review eDiary procedures with subject as necessary.  Instruct subject 
that Pruritus NRS and 
 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;
•
Review any changes in the subject’s concomitant medications and treatments 
information;
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•
Check subject understanding of protocol guidance for the use of background topical 
therapy as described in Section 5.9.1, ensure subject adherence to background topical 
therapy requirements and re-educate as required;
•
Conduct targeted physical examination;
•
Conduct clinical evaluations including IGA, SCORAD, EASI and BSA (calculated in 
the EASI);
•
Perform a single 12-lead electrocardiogram (ECG);
•
Obtain samples for laboratory testing: serum chemistry, hematology (including 
coagulation panel), 
 and urinalysis; 
•
Urine pregnancy test (female subjects of childbearing potential).  A negative urine 
pregnancy test must be obtained prior to dosing with the 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 eDiary to assess completion;
•
Perform drug accountability procedures;
•
Dispense injectable investigational product to the subject;
•
Unblinded administrator/trainer: observe the administration of injectable 
investigational product performed by the subject or his/her caregiver;
•
Administer oral investigational product and observe dosing;
•
Assess and record any Adverse Events since the last visit.
6.2.4. Visit 5, Day 29/Week 4 (±2 days)
•
Administer PROs including PtGA;
•
Review any changes in the subject’s concomitant medications and treatments 
information;
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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);
•
Review PSAAD daily completion (in selected countries), 
, and 
Pruritus NRS completion for this visit in the eDiary; 
•
Check subject understanding of protocol guidance for the use of background topical 
therapy as described in Section 5.9.1, ensure subject adherence to background topical 
therapy requirements and re-educate as required;
•
Conduct targeted physical examination;
•
Conduct clinical evaluations including IGA, SCORAD, EASI and BSA (calculated in 
the EASI);
•
Perform a single 12-lead electrocardiogram (ECG);
•
Obtain samples for laboratory testing: serum chemistry, hematology (including 
coagulation panel), lipid profile (fasting),
and urinalysis; 
•
Urine pregnancy test (female subjects of childbearing potential).  A negative urine 
pregnancy test must be obtained prior to dosing with the 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 eDiary to assess completion;
•
Perform drug accountability procedures;
•
Dispense oral investigational product to the subject;
•
Administer oral investigational product and observe dosing;
•
Dispense injectable investigational product to the subject;
•
Unblinded administrator/trainer: observe the administration of injectable 
investigational product performed by the subject or his/her caregiver; 
•
Assess and record any Adverse Events since the last visit.
6.2.5. Visit 6, Day 57/Week 8 (±3 days)
•
Administer PROs including PtGA;
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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);
•
Review PSAAD daily completion (in selected countries), 
, and 
Pruritus NRS completion for this visit in the eDiary; 
•
Review any changes in the subject’s concomitant medications and treatment 
information;
•
Check subject understanding of protocol guidance for the use of background topical 
therapy as described in Section 5.9.1, ensure subject adherence to background topical 
therapy requirements and re-educate as required;
•
Conduct targeted physical examination;
•
Conduct clinical evaluations including IGA, SCORAD, EASI and BSA (calculated in 
the EASI);
•
Perform a single 12-lead electrocardiogram (ECG);
•
Obtain samples for laboratory testing: serum chemistry, hematology (including 
coagulation panel), 
, and urinalysis; 
•
Urine pregnancy test (female subjects of childbearing potential).  A negative urine 
pregnancy test must be obtained prior to dosing with the 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 eDiary to assess completion;
•
Perform drug accountability procedures;
•
Dispense oral investigational product to the subject;
•
Administer oral investigational product and observe dosing;
•
Dispense injectable investigational product to the subject;
•
Unblinded administrator/trainer: observe the administration of injectable 
investigational product performed by the subject or his/her caregiver; 
•
Assess and record any Adverse Events since the last visit.
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6.2.6. Visit 7, Day 85/Week 12 (±3 days)
•
Administer PROs including PtGA, DLQI, EQ-5D-5L, HADS, and POEM;
•
Obtain weight;
•
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);
•
Review PSAAD daily completion (in selected countries),
, and 
Pruritus NRS completion for this visit in the eDiary; 
•
Review any changes in the subject’s concomitant medications and treatments 
information;
•
Check subject understanding of protocol guidance for the use of background topical 
therapy as described in Section 5.9.1, ensure subject adherence to background topical 
therapy requirements and re-educate as required;
•
Conduct targeted physical examination;
•
Conduct clinical evaluations including IGA, SCORAD, EASI and BSA (calculated in 
the EASI);
•
Perform a single 12-lead electrocardiogram (ECG);
•
Obtain samples for laboratory testing: serum chemistry, hematology (including 
coagulation panel), 
, and urinalysis; 
•
For China, Republic of Korea, Taiwan, and Japan only: For subjects who had HBV 
DNA testing at Screening, collect blood sample for repeat HBV DNA testing, as 
appropriate;
•
Urine pregnancy test (female subjects of childbearing potential).  A negative urine 
pregnancy test must be obtained prior to dosing with the 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 eDiary to assess completion;
•
Perform drug accountability procedures;
•
Dispense oral investigational product to the subject;
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Administer oral investigational product and observe dosing;
•
Dispense injectable investigational product to the subject;
•
Unblinded administrator/trainer: observe the administration of injectable 
investigational product performed by the subject or his/her caregiver;
•
Assess and record any Adverse Events since the last visit.
6.2.7. Visit 8, Day 113/Week 16 (±3 days) 
•
Administer PROs including PtGA, DLQI, EQ-5D-5L, 
 HADS, and POEM;
•
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);
•
Review PSAAD daily completion (in selected countries), 
, and 
Pruritus NRS completion for this visit in the eDiary; 
•
Review any changes in the subject’s concomitant medication and treatments 
information;
•
Check subject understanding of protocol guidance for the use of background topical 
therapy as described in Section 5.9.1, ensure subject adherence to background topical 
therapy requirements and re-educate as required;
•
Conduct targeted physical examination;
•
Conduct clinical evaluations including IGA, SCORAD, EASI and BSA (calculated in 
the EASI);
•
Perform a single 12-lead electrocardiogram (ECG);
•
Obtain samples for laboratory testing: serum chemistry, hematology (including 
coagulation panel), lipid profile (fasting), 
,
and urinalysis; 
•
Urine pregnancy test (female subjects of childbearing potential).  A negative urine 
pregnancy test must be obtained prior to dosing with the 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 eDiary to assess completion;
•
Perform drug accountability procedures;
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Reallocate subject to new treatment regimen;
•
Dispense oral investigational product to the subject;
•
Administer oral investigational product and observe dosing;
•
Assess and record any Adverse Events since the last visit.
6.2.8. Visit 9, Day 127/Week 18 (±3 Days)
•
Administer PROs including PtGA;
•
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);
•
Review PSAAD daily completion (in selected countries), 
, and 
Pruritus NRS completion for this visit in the eDiary; 
•
Review any changes in the subject’s concomitant medication and treatments 
information;
•
Check subject understanding of protocol guidance for the use of background topical 
therapy as described in Section 5.9.1, ensure subject adherence to background topical 
therapy requirements and re-educate as required;
•
Conduct targeted physical examination;
•
Conduct clinical evaluations including IGA, SCORAD, EASI and BSA (calculated in 
the EASI);
•
Perform a single 12-lead electrocardiogram (ECG);
•
Obtain samples for laboratory testing: serum chemistry, hematology (including 
coagulation panel), 
and urinalysis; 
•
Urine pregnancy test (female subjects of childbearing potential).  A negative urine 
pregnancy test must be obtained prior to dosing with the 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 eDiary to assess completion;
•
Perform drug accountability procedures;
•
Administer oral investigational product and observe dosing;
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•
Assess and record any Adverse Events since the last visit.
6.2.9. Visit 10, Day 141/Week 20 (±3 Days) End of Treatment or Early Termination 
Visit
•
Administer PROs including PtGA, DLQI, EQ-5D-5L, HADS, and POEM;
•
Obtain weight;
•
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);
•
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;
•
Check subject understanding of protocol guidance for the use of background topical 
therapy as described in Section 5.9.1, ensure subject adherence to background topical 
therapy requirements and re-educate as required;
•
Conduct complete physical examination; 
•
Conduct clinical evaluations including, IGA, SCORAD, EASI and BSA (calculated 
in the EASI);
•
Perform a single 12-lead electrocardiogram (ECG);
•
Obtain samples for laboratory testing: serum chemistry, hematology (including 
coagulation panel), lipid profile (fasting), 
,
and urinalysis; 
•
For China, Republic of Korea, Taiwan, and Japan only: For subjects who had HBV 
DNA testing at Screening, collect blood sample for repeat HBV DNA testing, as 
appropriate;
•
Urine pregnancy test (female subjects of childbearing potential).  A negative urine 
pregnancy test must be obtained prior to dosing with the 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 eDiary to assess completion;
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•
Perform drug accountability procedures;
•
Administer oral investigational product and observe dosing;
•
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 11 (see Section 6.3.1).
6.3. Follow-up Visits
6.3.1. Visit 11, Day 169/Week 24 (±3 Days) 
•
Administer PROs including: PtGA, DLQI, and EQ-5D-5L; 
•
Review eDiary Pruritus NRS, 
, and PSAAD completion (in 
selected countries) and review eDiary procedures with subject as necessary;
•
Obtain vital signs including pulse rate, sitting blood pressure, respiratory rate and oral 
or tympanic temperature (after at least 5 minutes of rest);
•
Review any changes in the subject’s prior and concomitant medications and treatment 
information;
•
Review subject use of background topical therapy as described in Section 5.9.1;
•
Conduct complete physical examination; 
•
Conduct clinical evaluations including IGA, SCORAD, EASI and BSA (calculated in 
the EASI);
•
Perform a single 12-lead electrocardiogram (ECG);
•
Obtain samples for laboratory testing: serum chemistry, hematology (including 
coagulation panel), lipid profile (fasting), 
,
and urinalysis; 
•
Urine pregnancy test (female subjects of childbearing potential).  A negative urine 
pregnancy test must be obtained prior to dosing with the 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;
•
Assess and record any Adverse Events since the last visit.
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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 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. 
The only exception to this is when a subject specifically withdraws consent for any further 
contact with him or her or persons previously authorized by the subject to provide this 
information.  Subjects should notify the investigator in writing of the decision to withdraw 
consent from future follow-up, whenever possible.  The withdrawal of consent should be 
explained in detail in the medical records by the investigator, as to whether the withdrawal is 
only from further receipt of investigational product or also from study procedures and/or 
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 informed consent, 
then the investigator may use a sponsor-retained third-party representative to assist site staff 
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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.
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 
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7.1. Pregnancy Testing
For female subjects of childbearing potential, 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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7.3. 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.
7.3.1. Vitals Signs
Vital signs (sitting blood pressure, pulse rate, respiratory rates and temperature) will be 
measured (pre-dose, if applicable) 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.
7.3.2. 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) 
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visit.  Weight (lb or kg) will continue to be measured and recorded at various time points, 
see Schedules of Activities.
Complete physical examinations must be performed by the investigator, sub-investigator or a 
qualified health professional per local guidelines.  Complete physical examinations consist of 
assessments of general appearance; skin; head, eyes, ears, nose and throat (HEENT); mouth, 
heart; lungs; breast (optional); abdomen; external genitalia (optional); extremities; neurologic 
function; and lymph nodes.
Targeted physical examinations must be performed by the investigator, sub-investigator or a 
qualified health professional per local guidelines and should include skin, heart, 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.
7.3.3. Chest X-Ray
Chest radiograph (posterior-anterior and lateral views) 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, are required.  Documentation of the official 
reading must be located and available in the source documentation.
7.3.4. 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 test results are indeterminate, the test should be repeated.  If the 
QuantiFERON-TB Gold In-Tube test cannot be performed, or if the results of the repeat test 
are indeterminate, 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. 
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 
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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.
Japan only: While QuantiFERON® is the preferred testing method, the T-SPOT®.TB test is 
also acceptable as the screening TB test.  Like QuantiFERON®, the T-SPOT®.TB test is an in 
vitro diagnostic test for M. tuberculosis infection; however, it differs in that it uses a peptide 
cocktail of ESAT-6 and CFP-10 proteins to stimulate peripheral blood mononuclear cells. 
T-SPOT®.TB testing will be performed at the site’s local laboratory.  Borderline results from 
the T-SPOT®.TB test should be considered exclusionary.  If the T-SPOT.TB test results are 
indeterminate, the test should be repeated.  If the result of the repeat test is indeterminate, 
subjects may be screened using the Mantoux/PPD skin test with Pfizer Medical Monitor 
approval.
Purified Protein Derivative (PPD) Test
If the QuantiFERON-TB Gold In-Tube test or the T-SPOT®.TB test (Japan only) 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.
7.3.5. Electrocardiogram
A single 12-lead ECG will be performed at screening and all other on-site visits as specified 
in the Schedule of Activities.  ECGs reading will be interpreted 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 not demonstrate clinically significant abnormalities prior to 
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7.3.6. 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. 
7.4. 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).
7.5. Assessment of Suicidal Ideation and Behavior 
Subjects meeting exclusionary results as described in Section 4.2 on the C-SSRS or 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.
7.5.1. 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).18  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, score immediately
and assess the subject’s eligibility based on the answers.
7.5.2. Patient Health Questionnaire - 8 items (PHQ-8)
The Patient Health Questionnaire – 8 items (Appendix 16) 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.19 Site staff is to administer the 
PHQ-8 to all subjects at screening and score immediately.
7.6. Clinical Laboratory Tests
7.6.1. Blood Volume
Total blood sampling volume planned for this study is approximately 166 mL.  Further 
details regarding the collection, processing, storage, and shipping of the blood samples will 
be provided in the lab manual.


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7.6.2. 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.
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 16, Week 20 and EOS.  For all other lab tests, fasting is not required.


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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++, P
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
Serum FSH (WONCBP only) or
Pregnancy Testa, c
Urine pregnancy testc
QFT-G or PPD (if applicable) or 
T-SPOT®.TB test (Japan only)e
Viral Screen (if applicable)
HBV DNA
a.
At Screening only.  HIV testing will be performed for all subjects.  Subjects who are positive for HIV will be 
screen-failed.
b.
HBsAb reflex testing only if HBsAg negative but HBcAb positive.  For Japan only: In addition to HBsAg and HBcAb, 
HBsAb testing will be performed at Screening for all subjects rather than as a reflex test. HCV RNA is reflex testing 
only if HCVAb is positive.  Subjects who are positive for HCVAb and HCV RNA will be screen-failed.
c.
Pregnancy testing for females of childbearing potential; serum FSH for postmenopausal female subjects 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. For Japan only: QFT-G is preferred but T-SPOT®.TB test may be 
performed instead through the site’s local laboratory.
f.
Lipid Profile Panel requires at least an 8 hour fast.  Lipid profile panel will be completed at Day 1, Week 4, Week 16, 
Week 20, and EOS, and will include total cholesterol, LDL, HDL, and triglycerides. 
h.
For China, Republic of Korea and Taiwan only: Subjects who are HBsAg negative, HBcAb positive, and HBsAb 
positive at Screening will have reflex testing for Hepatitis B Virus (HBV) DNA. Subjects who have HBV DNA above 
the lower limit of quantification (LLQ) are excluded. Subjects who have HBV DNA negative or below LLQ may be 
randomized, but will have HBV DNA testing repeated at Week 12 and Week 20 End of Treatment (EOT) visit, or Early 
Termination (ET) visit, whichever is sooner.  For Japan only: Subjects with negative results for HBsAg, HBcAb and 
HBsAb tests may be eligible. Subjects who are HBsAg negative, HBcAb negative and HBsAb positive and provide 
documentation of prior HBV vaccination may be eligible and will not require HBV DNA monitoring during the study.
Subjects who are HBsAg negative, HBcAb negative and HBsAb positive without documentation of prior HBV 
vaccination AND subjects who are HBsAg negative, HBcAb positive, and HBsAb positive at Screening will have 
reflex testing for HBV DNA.  Subjects who are HBV DNA negative or below LLQ may be randomized but will have
HBV DNA repeated at Week 12 and Week 20 End of Treatment (EOT) visit, or Early Termination (ET) visit, 
whichever is sooner.
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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.
7.6.2.1. Hepatitis Testing 
Hepatitis B testing: HB surface antigen (HBsAg), HB core antibody (HBcAb), HB surface 
antibody (HBsAb).
Subjects will be screened for hepatitis B virus infection.  Subjects with hepatitis B surface 
antigen (HBsAg) negative testing but who test positive for hepatitis B core antibody 
(HBcAb) must have further testing for hepatitis B 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;

For China, Republic of Korea, and Taiwan only: Subjects who are HBsAg 
negative, HBcAb positive, and HBsAb positive at Screening will have reflex testing 
for Hepatitis B Virus (HBV) DNA.  Subjects who have HBV DNA above the lower 
limit of quantification (LLQ) are excluded.  Subjects who have HBV DNA negative 
or below LLQ may be randomized, but will have HBV DNA testing repeated at 
Week 12 and Week 20 End of Treatment (EOT) visit, or Early Termination (ET) 
visit, whichever is sooner;

For Japan only: In addition to HBsAg and HBcAb, HBsAb testing will be 
performed at Screening for all subjects rather than as a reflex test. Subjects with 
negative results for HBsAg, HBcAb and HBsAb may be eligible. Subjects who are 
HBsAg negative, HBcAb negative and HBsAb positive and provide documentation of 
prior HBV vaccination may be eligible and will not require HBV DNA monitoring 
during the study. Subjects who are HBsAg negative, HBcAb negative and HBsAb 
positive without documentation of prior HBV vaccination AND subjects who are 
HBsAg negative, HBcAb positive, and HBsAb positive at screening will have reflex 
testing for HBV DNA.  Subjects who are HBV DNA negative or below LLQ may be 
randomized but will have HBV DNA repeated at Week 12 and Week 20 End of 
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•
A single HBV DNA test result above the LLQ for a subject requires immediate and 
permanent discontinuation from treatment, and the Medical Monitor (or designee) 
must be notified. The subject must be scheduled for an End of Treatment visit/Early 
Termination visit, enters the end of treatment follow up period, and must be 
scheduled for an End of Study visit.  No further scheduled HBV DNA tests will be 
required for a subject once a result above the LLQ is established for that subject 
during any study in the program.  Follow up by the investigator is required as detailed 
in Section 6.4.
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. 
7.6.2.2. Baseline Viral Screen 
A serum sample will be collected at baseline but analyzed only if the subject has suspected 
viral reactivation.  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. 
7.8. Efficacy Assessments
7.8.1. 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 
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.
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7.8.2. 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 2.  The assessment
will be a static evaluation without regard to the score at a previous visit.
Table 2.
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.
7.8.3. 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 
using a visual analog scale (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; 


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
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, ie, itch and sleep loss, are each scored by the subject or caregiver 
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).
7.8.4. 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, 
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adjustment for the percent of BSA involved for each body region and for the proportion of 
the body region to the whole body.
Lesion Severity by Clinical Signs: The basic characteristics of atopic dermatitis 
lesions-erythema, induration/papulation, excoriation, and lichenification-provide a means for 
assessing the severity of lesions.  Assessment of these four main clinical signs is performed 
separately for four body regions: head and neck, upper limbs, trunk (including axillae and 
groin) and lower limbs (including buttocks).  Average erythema, induration/papulation, 
excoriation, and lichenification are scored for each body region according to a 4-point scale: 
0 = absent; 1 = mild; 2 = moderate; 3 = severe.  Morphologic descriptors for each clinical 
sign severity score are shown in Table 3.
Table 3.
Clinical Sign Severity Scoring Criteria for the Eczema Area and Severity 
Index (EASI)
Score
Description*
Erythema (E)
0
Absent
None; may have residual discoloration (post-inflammatory hyperpigmentation 
and/or hypopigmentation)
1
Mild
Light pink to light red
2
Moderate
Red
3
Severe
Deep, dark red
Induration/Papulation (I)
0
Absent
None
1
Mild
Barely palpable to slight, but definite hard thickened skin and/or papules
2
Moderate
Easily palpable moderate hard thickened skin and/or papules
3
Severe
Severe hard thickened skin and/or papules
Excoriation (Ex)
0
Absent
None
1
Mild
Slight, but definite linear or picked scratch marks or penetrating surface injury
2
Moderate
Moderate linear or picked scratch marks or penetrating surface injury
3
Severe
Severe linear or picked scratch marks or penetrating surface injury
Lichenification (L)
0
Absent
None
1
Mild
Barely perceptible to slight, but definite thickened skin, fine skin markings, 
and lichenoid scale
2
Moderate
Moderate thickened skin, coarse skin markings, and coarse lichenoid scale
3
Severe
Severe thickened skin with very coarse skin markings and lichenoid scale
The EASI will exclude scalp, palms, and soles from the assessment/scoring.
Percent BSA with Atopic Dermatitis: The number of handprints of skin afflicted with 
atopic dermatitis in a body region can be used to determine the extent (%) to which a body 
region is involved with atopic dermatitis (Table 4).  When measuring, the handprint unit 
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Table 4.
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 5).
Table 5.
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 6).
Table 6.
Eczema Area and Severity Index (EASI) Body Region Weighting
Body Region
Body Region Weighting
Head and Neck
0.1
Upper Limbs
0.2
Trunk (including axillae and groin/genitals)
0.3
Lower Limbs (including buttocks)
0.4
* No adjustment for body regions excluded for assessment.
In each body region, the sum of the Clinical Signs Severity Scores for erythema, 
induration/papulation, excoriation, and lichenification is multiplied by the Area Score and by 
the Body Region Weighting to provide a body region value, which is then summed across all 
four body regions resulting in an EASI score as described in Equation 3.


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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.
7.8.4.1. 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 4).  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%.
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7.10. Patient-Reported Outcomes (PROs)
In selected countries, 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, 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. 
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.
7.10.1. 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).20  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).  Subjects will enter the 
Pruritus NRS assessment into an eDiary.  Severity of pruritus score as it is assessed at the 
screening visit and on the day of the baseline visit will be included in the evaluation of 
Inclusion Criteria 3 (See Section 4.1). 
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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).  Subjects will enter Pruritus NRS assessment into an 
eDiary.  Frequency of pruritus will not be included in the evaluation of Inclusion Criteria 3
(See Section 4.1). 
The Pruritus NRS should be completed as per Schedule of Activities. 
 
 
 
 
 
 
 
 
 
 
7.10.3. 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 8).  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.
7.10.4. EuroQol Quality of Life 5-Dimension 5-Level Scale (EQ-5D-5L)
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 9).21-24  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.21,23,24-27
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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.22,23,25,26 Both the EuroQol 
EQ-5D-3L and EQ-5D-5L versions are well-established instruments used to measure health 
states and utilities in various diseases areas and assess mobility, self-care, usual activities, 
pain/discomfort, anxiety/depression and health status using a VAS.24,28 The EQ-5D-3L was 
used previously in AD studies, including the dupilumab trials, to measure utilities.29-32
7.10.5. Dermatology Life Quality Index (DLQI)
The DLQI is a validated general dermatology questionnaire that consists of 10 items to assess 
subject-reported health-related quality of life (daily activities, personal relationships, 
symptoms and feelings, leisure, work and school, and treatment) (Appendix 10).33 It has 
been extensively used in clinical trials for AD.  The DLQI is a psychometrically valid and 
reliable instrument that has been translated into several languages, and the DLQI total scores 
have been shown to be responsive to change.  The minimally important difference for the 
DLQI has been estimated as a 3 to 5 point change from baseline.34 The DLQI should be 
completed as per Schedule of Activities.
7.10.6. Patient-Oriented Eczema Measure (POEM) 
The POEM is a validated 7-item PRO measure used to assess the impact of AD recalled over 
the past week (Appendix 11).  This instrument is appropriate for use by subjects aged 12 and 
older.35,36  The POEM should be completed as per Schedule of Activities.
7.10.7. Hospital Anxiety and Depression Scale (HADS)
The HADS is a validated 14-item PRO measure used to assess states of anxiety and 
depression over the past week37 (Appendix 12). The instrument has been validated for use by 
adolescents aged 12 and older.37 The HADS should be completed as per Schedule of 
Activities.
7.10.8. Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD)
The PSAAD is a daily patient reported symptom diary.  The preliminary version 
(Appendix 13) 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 is an electronic PRO
that was developed through concept elicitation and cognitive debriefing in AD patients 
ages 12 to 67;
 
 
  All technical documents describing measurement 
properties of the PSAAD will be submitted as required to the Regulatory Agencies upon 
finalization.  The PSAAD should be completed by subjects as per Schedule of Activities on 
an eDiary. 
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8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; 
(2) non-serious adverse events (AEs); and (3) exposure to the investigational product under 
study during pregnancy or breastfeeding, and occupational exposure. 
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the 
investigational product 
under study during 
pregnancy or 
breastfeeding, and 
occupational exposure
All (regardless of whether 
associated with an AE), 
except occupational 
exposure
Exposure during pregnancy, 
exposure via breastfeeding, 
occupational exposure 
(regardless of whether 
associated with an AE)
All observed or volunteered events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
paragraphs.
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 timeframe 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.
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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.
8.1.2. Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study subject.  In addition, each study subject will be questioned about the 
occurrence of AEs in a non-leading manner.
8.1.3. Withdrawal from the Study Due to Adverse Events (see also 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 
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8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each subject begins from the time the subject provides informed consent, which 
is obtained before the subject’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving investigational product), through and including a 
minimum of 28 calendar days; 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.
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 
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In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study subject administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage.  Examples of AEs include, but are not limited to: 

Abnormal test findings;

Clinically significant signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease; 

Drug abuse;

Drug dependency.
Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;


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
Occupational exposure.
8.2.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
recording as an AE.
8.2.3. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Or that is considered to be:

An important medical event.
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 
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Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.2.4. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility, or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit is assessed for medical importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical 
AE is not in itself an SAE.  Examples include:

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of a persistent pretreatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;


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
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 
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).  


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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. 
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), 


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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).

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 


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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.
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.


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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.
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. 


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Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.4.5. Medical Device Incidents (Including Malfunctions)
Medical devices are being provided for use in this study for the purposes of subcutaneous 
injection of dupilumab or injectable placebo.  In order to fulfill regulatory reporting 
obligations worldwide, the investigator is responsible for the detection and documentation of 
events meeting the definitions of incident or malfunction that occur during the study with 
such devices.
The definition of a medical device incident can be found in Appendix 17.
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 8 of the protocol.
8.4.5.1. Time Period for Detecting Medical Device Incidents
Medical device incidents or malfunctions of the device that result in an incident will be 
detected, documented, and reported during all periods of the study in which the medical 
device is used.
If the investigator learns of any incident at any time after a participant has been discharged 
from the study, and such incident is considered reasonably related to a medical device 
provided for the study, the investigator will promptly notify the sponsor.
The method of documenting medical device incidents is provided in Appendix 17.
8.4.5.2. Follow-up of Medical Device Incidents
All medical device incidents involving an AE will be followed and reported in the same 
manner as other AEs (see Section 8).  This applies to all participants, including those who 
discontinue study intervention.
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the incident.
New or updated information will be recorded on the originally completed form with all 
changes signed and dated by the investigator.
8.4.5.3. Prompt Reporting of Medical Device Incidents to Sponsor
Medical device incidents will be reported to the sponsor within 24 hours after the investigator 
determines that the event meets the protocol definition of a medical device incident.
The Investigational Drug Product and Medical Device Complaint Submission Form will be 
completed.


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8.4.5.4. Regulatory Reporting Requirements for Medical Device Incidents
The investigator will promptly report all incidents occurring with any medical device 
provided for use in the study in order for the sponsor to fulfill the legal responsibility to 
notify appropriate regulatory authorities and other entities about certain safety information 
relating to medical devices being used in clinical studies.
The investigator, or responsible person according to local requirements (eg, the head of the 
medical institution), will comply with the applicable local regulatory requirements relating to 
the reporting of incidents to the IRB/EC.
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
A total sample of 700 subjects, with 200 subjects randomized to PF-04965842 200 mg QD, 
200 subjects randomized to PF-04965842 100 mg QD, 200 subjects randomized to 
dupilumab and 50 subjects each randomized to two sequences of matching placebo for 
16 weeks followed by (a) PF-04965842 100 mg QD and by (b) PF-04965842 200 mg QD 
(4:4:4:1:1 randomization) is planned. The two placebo sequences will be combined for 
purposes of analyses at all visits up to and including Week 16, which would essentially result 
in a 2:2:2:1 randomization ratio. This would provide at least 96% power to detect a 
difference of at least 20% in IGA response rate between either dose of PF-04965842 and 
placebo, assuming the placebo response rate is 12% at Week 12.  This will also provide at 
least 99% power to detect a difference of at least 30% in EASI-75 response rate between 
either dose of PF-04965842 and placebo, assuming the placebo response rate is 23% at 
Week 12.
For a given dose (PF-04965842 200 mg QD or 100 mg QD), both co-primary endpoints must 
achieve statistical significance to meet the primary objective.
In addition, this sample size will also provide at least 92% power to detect a difference of at 
least 15% in the proportion of subjects with a 4 points improvement in the severity of 
pruritus NRS between PF-04965842 and dupilumab, assuming the dupilumab response rate is 
18% at Week 2.
The Type-I error rate is set at 5% (two-sided). The familywise Type-I error rate (for testing 
the co-primary and key secondary endpoints) will be strongly controlled at 5% using a 
closed-testing method based on a sequential, iterative Bonferroni-type approach as outlined 
below.


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The study has been sized to help gain sufficient safety data to be able to effectively evaluate 
the benefit-risk of PF-04965842 in conjunction with the other studies in the clinical 
development program, therefore the power for the co-primary endpoints is relatively high.  
This sample size will also help ensure adequate power is maintained for testing all the 
co-primary and key secondary endpoints for both doses of PF-04965842 via the multiple 
testing procedure.
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 investigational product.  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.  Major protocol violations would consist of not meeting inclusion criteria or 
meeting exclusion criteria or not having taken the correct randomized treatment for at least 
80% of the assigned amount or not having adhered to standardized background topical 
therapy guidelines or having taken a protocol-prohibited concomitant medication or any 
other major protocol violation as determined by the clinical team or medical monitor prior to 
database lock.  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. 
It is expected that the FAS as defined here will be identical to a true intent to treat (ITT) 
analysis set (randomized and dispensed study medication) because the first dose is 
administered in-clinic. Nevertheless, any differences from ITT in terms of the number of 
subjects will be noted and summarized.
9.2.2. Testing Procedure for Multiple Comparisons
The familywise Type-I error rate for testing the co-primary and key secondary endpoints 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 EASI-75 at Week 12 for 
200 mg QD vs placebo) at the 5% level.  If this hypothesis is not rejected, then all subsequent 
hypotheses will not be considered statistically significant.  If this hypothesis is rejected, then 
testing for statistical significance will continue for the co-primary endpoints (IGA and 
EASI-75 at Week 12) for the 100 mg QD vs placebo comparison. If this hypothesis is not 
rejected, then all subsequent hypotheses will not be considered statistically significant.  If 
this hypothesis is rejected, then testing may continue as follows:

A series of hypotheses related to the severity of pruritus at Week 2 will be tested at 
the 2.5% level in the order specified in Sequence A.  If all hypotheses in Sequence A 
are rejected, then the unused alpha level of 2.5% will be passed on to the testing for 
the Week 16 endpoints in the order specified in Sequence B at a 5% significance level 


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(see figure below).  All subsequent hypotheses from any point where a hypothesis 
cannot be rejected will not be considered statistically significant.

If any hypothesis in Sequence A cannot be rejected at the 2.5% level, then testing for 
statistical significance will stop along this sequence but will continue for the 
hypotheses related to the Week 16 endpoints in the order specified in Sequence B at 
the 2.5% level.  If all hypotheses in Sequence B are rejected, then the unused alpha 
level of 2.5% will be passed back for testing the hypotheses in Sequence A at the 
5% level.  All subsequent hypotheses from any point where a hypothesis cannot be 
rejected will not be considered statistically significant.
Figure 2.
Schematic for Multiple Testing Procedure
The figure above illustrates the procedure showing the sequence of the tests.
9.2.3. Analysis of the Primary Endpoints 
The co-primary endpoints will be analyzed using the (Cochran-Mantel-Haenszel) test 
adjusted by baseline disease severity group (moderate and severe) and for a given dose both 
must achieve statistical significance to meet the primary objective.  The difference between 
each active group and the placebo group in the proportion of subjects achieving IGA 
response (similarly for EASI-75) along with its 95% confidence interval (using the normal 
approximation for the difference in binomial proportions) will be reported.  If a subject 
withdraws from the study, then this subject will be counted as non-responder for endpoints 
after withdrawal.  


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Additional secondary analyses will utilize missing at random (MAR) and missing not at 
random (MNAR) approaches.  Missing observations will be multiply imputed using a tipping 
point analysis to estimate the treatment effect under the assumption that the missing data 
mechanism is MAR or more generally, is MNAR. A longitudinal logit-normal mixed model 
will be fit using only the observed data. Under the MAR framework, imputations will be 
based on the posterior predictive probability of response obtained from the posterior 
distribution under the mixed model. Under an MNAR framework, imputations for the active 
treatment groups will be based on a linear combination of the posterior predictive probability 
of response for the active group and the placebo group. For each such completed dataset, the 
estimates of the proportions and Cochran-Mantel-Haenszel (CMH)-weighted difference of 
proportions between each active dose group and placebo will be obtained and Rubin’s rule 
will be used to combine the multiple estimates and standard errors across the imputed 
datasets and provide p-values.
9.2.4. Analysis of Secondary Endpoints
The key secondary endpoints which are summarized as proportions such as EASI-75, and the 
proportion of subjects achieving a 4-point improvement from baseline in the severity of 
Pruritus NRS measure will be analyzed using the same method as for the co-primary 
endpoints.  This would also apply to any other binary endpoint in the study, such as the 
response based on subjects reported with PtGA of AD of clear (0) or almost clear (1) and 
2 point improvement from baseline over 12 weeks. 
For continuous endpoints, and change from baseline in the pruritus severity 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, disease 
severity group, 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;


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
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.
9.4. 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 safety of subjects in the study according to the 
charter.  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.
9.5. 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.
9.6. Week 16 Analysis and End of Study Analysis
There will be a total of two planned analyses conducted for the study. The Week 16 Analysis 
will be performed after the last subject in the study has the opportunity to complete the 
Week 16 visit.  The Week 16 Analysis will constitute as the final analysis for the co-primary 
and key secondary endpoints, and the overall family-wise Type 1 error will be controlled as 
specified in Section 9.2.2. The conclusions with regards to the co-primary endpoints and the 
secondary endpoints will be based on this analysis, and hence the overall family-wise Type 1 
error for this study is maintained. The results from the Week 16 Analysis will not be used to 
make decisions for modifying the study design or for stopping the study.  Access to the 
database containing individual treatment group assignments will be restricted to the sponsor 
study team at the time of Week 16 Analysis.  Study sites, investigators and subjects will not 
be unblinded.  


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The purpose of the Week 16 Analysis is to accelerate final reporting timeline. The final 
clinical study report (CSR) for the study will be based on the results from the Week 16 
Analysis.  
The End of Study Analysis will contain additional data after the final database release and 
the results will be reported in a supplemental CSR.
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.
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 shall ensure that the 
CRFs/DCTs are securely stored at the study site in encrypted electronic and/or paper form 


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and will be password protected or secured in a locked room to prevent access by 
unauthorized third parties.
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 documents, copies of all CRFs, safety reporting forms, source 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.  The 
investigator must ensure that the records continue to be stored securely for so long as they are 
retained.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations. 
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.


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12. ETHICS
12.1. Institutional Review Board/Ethics Committee
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, legal and regulatory 
requirements, and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
Helsinki.
12.3. Subject Information and Consent
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of subject personal data.  Such 
measures will include omitting subject names or other directly identifiable data in any 
reports, publications, or other disclosures, except where required by applicable law. 
The personal data will be stored at the study site in encrypted electronic and/or paper form 
and will be password protected or secured in a locked room to ensure that only authorized 
study staff have access.  The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster.  In the event of a potential personal data breach, the study site shall be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, when study data are compiled for transfer to Pfizer and other authorized 
parties, subject names will be removed and will be replaced by a single, specific numerical 
code, based on a numbering system defined by Pfizer.  All other identifiable data transferred 
to Pfizer or other authorized parties will be identified by this single, subject-specific code.  
The investigator site will maintain a confidential list of subjects who participated in the 
study, linking each subject’s numerical code to his or her actual identity.  In case of data 
transfer, Pfizer will maintain high standards of confidentiality and protection of subjects’ 
personal data consistent with the Clinical Study Agreement and applicable privacy laws.


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The informed consent documents and any subject recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws.
The informed consent documents used during the informed consent process and any subject 
recruitment materials must be reviewed and approved by Pfizer, approved by the IRB/EC 
before use, and available for inspection. 
The investigator must ensure that each study subject is fully informed about the nature and 
objectives of the study, the sharing of data relating to the study and possible risks associated 
with participation, including the risks associated with the processing of the subject’s personal 
data.  The investigator further must ensure that each study subject is fully informed about his 
or her right to access and correct his or her personal data and to withdraw consent for the 
processing of his or her personal data. 
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject before any study-specific activity is performed.  The investigator 
will retain the original of each subject's signed consent document.
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in 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.


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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.
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 


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publication or other type of disclosure of the results of the study (collectively, “publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before it is submitted 
for publication or otherwise disclosed.  If any patent action is required to protect intellectual 
property rights, the investigator agrees to delay the disclosure for a period not to exceed an 
additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all investigator sites, and that any subsequent publications 
by the PI will reference that primary publication.  However, if a joint manuscript has not 
been submitted for publication within 12 months of completion or termination of the study at 
all participating sites, the investigator is free to publish separately, subject to the other 
requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.


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16. REFERENCES
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Slater NA, Morrell DS. Systemic therapy of childhood atopic dermatitis. Clin Dermatol 
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Blauvelt A, de Bruin-Weller M, Gooderham M, et al.  Long-term management of 
moderate-to-severe atopic dermatitis with dupilimab and concomitant topical 
corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomized, double-blind, 
placebo-controlled, phase 3 trial. Lancet 2017; 389: 2207-303.
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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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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 
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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 
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Silverberg JI, Hanifin JM. Adult eczema prevalence and associations with asthma and 
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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 
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skin inflammation.J Allergy Clin Immunol 2006;118(1):178-89.
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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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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.
17.
Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol 
1980;92(suppl):44-7.
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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.
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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. 
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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.
21.
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.  
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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.  
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health states using a hybrid approach. Medical care 2017;55(7):e51-8.  
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Yang Y, Brazier J, Longworth L. EQ-5D in skin conditions: an assessment of validity 
and responsiveness. Eur J Health Econ. 2015;16(9):927-39.
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compared to the EQ-5D-3L across eight patient groups: a multi-country study. Quality 
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Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new 
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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;12:74.
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EuroQol Group. EuroQolea new facility for the measurement of health-related quality
of life. The EuroQol Group. Health Policy 1990;16:199-208.
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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.
30.
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.
31.
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.
32.
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Ann Dermatol. 2015;27(3):298-305. 
33.
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.
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Basra MK, Salek MS, Camilleri L, et al. Determining the minimal clinically important 
difference and responsiveness of the Dermatology Life Quality Index (DLQI): further 
data. Dermatology. 2015;230(1):27-33.
35.
Ersser SJ, Cowdell F, Latter S, et al. Psychological and educational interventions for 
atopic eczema in children. Cochrane Database Syst Rev 2014; (1):CD004054. 
36.
Schmitt J, Langan S, Williams H, et al. What are the best outcome measurements for 
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Scale for use with adolescents. Br J Psychiatry 1999;175(5):452-4. 


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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
peak plasma concentration 
CD
cluster of differentiation
CFB
change from baseline
CFR
Code of Federal Regulations
CI
confidence interval
CL/F
clearance/fraction of dose absorbed
CO2
carbon dioxide
CK
creatine kinase
CMH
Cochran-Mantel-Haenszel
CNIL
French Data Protection Authority
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
DCT
Data Collection Tool
DILI
drug-induced liver injury
DLQI
Dermatology Life Quality Index
DMC
data monitoring committee


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Abbreviation
Term
DNA
deoxyribonucleic acid
DU
dispensable unit
EASI
Eczema Area and Severity Index
EBV
Epstein Barr virus
EC
ethics committee
ECG
electrocardiogram
eCRF
electronic Case Report Form
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
EQ-5D-5L
EuroQol Quality of Life 5-Dimension 5-Level Scale
ET
early termination 
EU
European Union
EudraCT
European Clinical Trials Database
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
HADS
Hospital Anxiety and Depression Scale
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
HBcAb 
hepatitis B core antibody
HBV
hepatitis B virus
HBV DNA
hepatitis B virus deoxyribonucleic acid
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
HSV
herpes simplex virus
CCI
CCI


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Abbreviation
Term
HTA
health technologies assessment 
IB
Investigator’s Brochure
ICH
International Council for Harmonisation
ID
identification
IFN
interferon
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
ITT
intent to treat
IUD
intrauterine device
IWR
interactive web response
JAK
Janus kinase
JAK1
Janus kinase 1
LDL
low-density lipoprotein
LFT
liver function test
LLQ
lower limit of quantification
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
OTC
over the counter
CCI


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Abbreviation
Term
Pruritus NRS4
improvement in the severity of Pruritus NRS from baseline by at 
least 4 points
NRS 
numerical rating scale
PCD
primary completion date
PCP
primary care physician
PD
Pharmacodynamics
PEER Study
Pediatric Eczema Elective Registry Study
PFS
prefilled syringe
PGIC
Patient Global Impression of Change
PGIS
Patient Global Impression of Severity
PGx
Pharmacogenomics
PHQ-8
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
Fridericia corrected Q wave interval
Rac
accumulation ratio 
RBC
red blood cell
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SCORAD
SCORing atopic dermatitis
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
TARC
thymus and activation regulated chemokine
TB
tuberculosis
TBili
total bilirubin
TCI
topical calcineurin inhibitors


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Abbreviation
Term
TCS
topical corticosteroids
TdP
Torsade de Pointes
TH1
type 1 helper T cell
TH2
type 2 helper T cell
Tmax
time to maximum absorption
TPO
Thrombopoietin
TYK2
tyrosine kinase 2
ULN
upper limit of normal
US
United States
USPI
United States Package Insert
UVA
ultraviolet A light
UVB
ultraviolet B light
VAS
visual analog scale
V/F
volume of distribution/fraction absorbed
VZV 
varicella zoster virus
WBC
white blood cell
WOCBP
woman of childbearing potential
WONCBP 
women of non-childbearing potential
CCI


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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.17
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
CYP2C19 Inhibitors 
CYP2C19 Inducers
Fluconazole (Diflucan)
Enzalutamide (Xtandi)
Fluvoxamine (Luvox)
Rifampin
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)
Note 1: All CYP2C9 and CYP2C19 inhibitors require at least 1 week or at least 5 half-lives 
(whichever is longer) washout period prior to the first dose of investigational product.
Note 2: All CYP2C9 and CYP2C19 inducers require a period of washout of at least 
5 half-lives plus 14 days prior to the first dose of investigational product.  For example, the 
average half-life of Carbamazepine after repeat dosing is 15 hours.  The washout period is 
calculated as the sum of 5 half-lives (approximately 3 days) and an additional 14 days for a 
total of 17 days prior to the first dose of investigational product.
Note 3: Half-life refers to the half-life of the parent drug and its metabolites, which are 
inhibitors or inducers. The longest half-life should be used to calculate the period necessary 
to washout a medication prior to the first dose of investigational product. For example, 
fluoxetine and its metabolite norfluoxetine are both inhibitors of CYP2C19. The terminal 
half-life of fluoxetine is up to 6 days. However, norfluoxetine has a longer half-life, up to 
16 days. Therefore, the washout period should be calculated based on the 5 times the 
half-life of norfluoxetine, for a total of approximately 80 days prior to the first dose of 
investigational product.
This is not an all-inclusive list.  Study personnel should stay current and consult with their
pharmacy to exclude all concomitant medications that are CYP2C9 or CYP2C19 inhibitors 
or inducers.


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Appendix 4. Monitoring and Discontinuation Criteria
Monitoring Criteria 
The following laboratory abnormalities require prompt retesting:

Neutrophil counts <1000 neutrophils/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.
Temporary Interruption to Dosing
An investigator can temporarily interrupt dosing for up to a maximum of 14 consecutive days 
for a subject, for safety reasons or while monitoring abnormal laboratory tests if the 
investigator judges that this is necessary.  In the case of investigational product being 
withheld, all investigational products that the subject is receiving should be withheld (ie, both 
oral and injected investigational product, as applicable). The investigator should use their 
judgement with regard to unscheduled visits/laboratory/clinical assessments required to 
monitor the subject during this timeframe. If within this timeframe the investigator judges 
that it is safe to restart dosing, then the subject may restart investigational product. If the 
investigator judges that it is not safe to restart dosing within this timeframe then the subject 
must be permanently discontinued from treatment, have an End of Treatment visit and enter 
the 4-week follow-up period.  Doses not taken for the reasons mentioned above do not 
constitute protocol deviations or medication errors and should not be considered dosing 
errors, but should be noted in the dosing log with the reason for reduced drug consumption
clearly described.
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.

Serious infection (see definition for Serious Adverse Events in Section 8.2.3).


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
Any bleeding event thought to be associated with a platelet count reduction per the 
judgement of the investigator (or, if necessary/desired, following discussion with 
sponsor).

Adverse event, per judgment of the investigator, requiring discontinuation from 
treatment (or, if necessary/desired, following discussion with sponsor).

Any adverse event or laboratory abnormality, that per the investigator’s judgement 
requires withholding of investigational product for >14 days.
NOTE: any initial lab value below must be retested within 48 hours.

Two sequential platelet counts <50,000/mm3.  If the subject has a platelet count 
<25,000/mm3, investigational product should be temporarily withheld pending the 
confirmatory retest.

Two sequential neutrophil counts <500/mm3.

Two sequential lymphocyte counts <500/mm3.

Two sequential hemoglobin assessments <8.0 g/dL or <30% from baseline value.

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.
NOTE: 

Any of the above findings should prompt review of “The Potential Cases 
of Drug-Induced Liver Injury,” Section 8.4.2 for which additional 
investigations must be conducted.


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
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 subject 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.
Having met Discontinuation Criteria, the subject must be permanently withdrawn from 
treatment, have their end of treatment visit, and will then enter the 4-week follow-up period. 
Additional individual subject safety monitoring, including laboratory testing or unscheduled 
study visits, in addition to these guidelines is at the discretion of the investigator and 
dependent on any perceived safety concerns.  Unscheduled laboratory testing through the 
central laboratory may be obtained at any time during the study to assess such concerns. 
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.


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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
Never /No 
itching
Always/constant 
itching
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


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Appendix 8. 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 9. European Quality of Life 5-Dimension 5-Level Scale (EQ-5D-5L) 
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

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


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Appendix 10. Dermatology Life Quality Index (DLQI) 
DERMATOLOGY LIFE QUALITY INDEX
The aim of this questionnaire is to measure how much your skin problem has affected 
your life OVER THE LAST WEEK.  Please tick one box for each question
1.
Over the last week, how itchy, sore, painful or stinging has your 
skin been?
Very much 
A lot
A little 
Not at all
2.
Over the last week, how embarrassed or self conscious have you been 
because of your skin?
Very much 
A lot
A little 
Not at all
3.
Over the last week, how much has your skin interfered with you going
shopping or looking after your home or garden?
Very much 
A lot
A little 
Not at all
Not relevant 4.
Over the last week, how much has your skin influenced the clothes
you wear?
Very much 
A lot
A little 
Not at all
Not relevant 5.
Over the last week, how much has your skin affected any social or
leisure activities?
Very much 
A lot
A little 
Not at all
Not relevant 6.
Over the last week, how much has your skin made it difficult for you to 
do any sport?
Very much 
A lot
A little 
Not at all
Not relevant 7.
Over the last week, has your skin prevented you from working or
studying?
yes 
no
Not relevant If "No", over the last week how much has your skin been a problem at
work or studying?
A lot 
A 
little
Not at all
8.
Over the last week, how much has your skin created problems with your
partner or any of your close friends or relatives?
Very much 
A lot
A little 
Not at all
Not relevant 9.
Over the last week, how much has your skin caused any 
sexual difficulties?
Very much 
A lot
A little 
Not at all
Not relevant 10. Over the last week, how much of a problem has the treatment for your 
skin been, for example by making your home messy, or by taking up 
time?
Very much 
A lot
A little 
Not at all
Not relevant Please check you have answered EVERY question.  Thank you.
AY Finlay, GK Khan, April 1992. This must not be copied without the permission of the authors.


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Appendix 11. Patient-Oriented Eczema Measure (POEM)


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Appendix 12. Hospital Anxiety and Depression Scale (HADS)


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Appendix 13. Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD) 
Symptom Diary 


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Appendix 15. C SSRS - Columbia Suicide Severity Rating Scale


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Appendix 16. Patient Health Questionnaire – 8 items


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Appendix 17. Medical Device Incidents: Definition and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Definitions of a Medical Device Incident
The detection and documentation procedures described in this protocol apply to all sponsor 
medical devices provided for use in the study (see Section 5.6) for the list of sponsor medical 
devices).
Medical Device Incident Definition

A medical device incident is any malfunction or deterioration in the characteristics 
and/or performance of a device as well as any inadequacy in the labeling or the 
instructions for use which, directly or indirectly, might lead to or might have led to 
the death of a participant/user/other person or to a serious deterioration in his/her 
state of health.

Not all incidents lead to death or serious deterioration in health.  The 
nonoccurrence of such a result might have been due to other fortunate 
circumstances or to the intervention of healthcare personnel.
It is sufficient that:

An incident associated with a device happened.
AND

The incident was such that, if it occurred again, might lead to death or a serious 
deterioration in health.
A serious deterioration in state of health can include any of the following:

Life-threatening illness;

Permanent impairment of body function or permanent damage to body structure;

Condition necessitating medical or surgical intervention to prevent one of the above;

Fetal distress, fetal death, or any congenital abnormality or birth defects.


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Examples of Incidents

A participant, user, caregiver, or healthcare professional is injured as a result of 
a medical device failure or its misuse.

A participant’s study intervention is interrupted or compromised by a medical 
device failure.

A misdiagnosis due to medical device failure leads to inappropriate treatment.

A participant’s health deteriorates due to medical device failure.
Documenting Medical Device Incidents
Medical Device Incident Documentation

Any medical device incident occurring during the study will be documented in the 
participant’s medical records, in accordance with the investigator’s normal clinical 
practice, and on the appropriate form of the CRF.

For incidents fulfilling the definition of an AE or an SAE, the appropriate AE/SAE 
CRF page will be completed as described in Section 8.

It is very important that the investigator provides his/her assessment of causality 
(relationship to the medical device provided by the sponsor) at the time of the initial 
AE or SAE report and describes any corrective or remedial actions taken to prevent 
recurrence of the incident.

A remedial action is any action other than routine maintenance or servicing of a 
medical device where such action is necessary to prevent recurrence of an incident.  
This includes any amendment to the device design to prevent recurrence.


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Appendix 18. France Appendix
This appendix applies to study sites located in France.
1. GCP Training
Prior to enrollment of any subjects, the investigator and any sub-investigators will 
complete the Pfizer-provided Good Clinical Practice training course (“Pfizer GCP 
Training”) or training deemed equivalent by Pfizer.  Any investigators who later join 
the study will complete the Pfizer GCP Training or equivalent before performing 
study-related duties.  For studies of applicable duration, the investigator and 
sub-investigators will complete Pfizer GCP Training or equivalent every three years 
during the term of the study, or more often if there are significant changes to the ICH 
GCP guidelines or course materials.
2. Investigational Product
No subjects or third-party payers will be charged for investigational product.
3. Suspected Unexpected Serious Adverse Reactions (SUSARs)
Pursuant to a sponsor’s safety reporting obligations under 21 CFR 312.32(c)(1), 
Pfizer will report to the Investigator all SUSARs.  Investigator will receive and 
review SUSAR reports and report SUSARs to the responsible IRB/IEC according to 
institution’s guidelines. 
4. Collection of ethnic origin information
Information regarding ethnic origin will be collected in this study in compliance with 
the French Data Protection Authority (CNIL): Deliberation no. 2016-262 of 21 July 
2016 amending the reference methodology for the processing of personal data 
conducted in connection with biomedical research (MR-001), § 2.2.3 Nature of the 
data.
Individuals participating in this study will consent that this information can be 
collected in the study before they enter the study.
The electronic Case Report Form (eCRF) will be used as the source file for ethnic 
origin in France. This information will not be recorded in the patient’s medical 
records.

SAP_001.pdf: 
Protocol B7451029 (PF-04965842) Statistical Analysis Plan
Page 1
PROTOCOL B7451029
A PHASE 3 RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY, 
PLACEBO-CONTROLLED, PARALLEL GROUP, MULTI-CENTER STUDY 
INVESTIGATING THE EFFICACY AND SAFETY OF PF-04965842 AND 
DUPILUMAB IN COMPARISON WITH PLACEBO IN ADULT SUBJECTS ON 
BACKGROUND TOPICAL THERAPY, WITH MODERATE TO SEVERE ATOPIC 
DERMATITIS
STATISTICAL ANALYSIS PLAN
(SAP)
Version:
2.0
Date:
23 Jan 2020
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TABLE OF CONTENTS
LIST OF TABLES...........................................................................................................4
LIST OF FIGURES .........................................................................................................4
1. VERSION HISTORY..................................................................................................6
2. INTRODUCTION .......................................................................................................7
2.1. Study Objectives .............................................................................................7
2.2. Study Design .................................................................................................10
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS .................................................................................................13
3.1. Primary Endpoints.........................................................................................13
3.2. Secondary Endpoints.....................................................................................13
3.2.1. Key Secondary Efficacy Endpoints..................................................13
3.2.2. Secondary Efficacy Endpoints..........................................................14
3.3. Other Endpoints.............................................................................................14
3.3.1. Patient-Reported Outcomes (PRO)...................................................14
15
3.4. Baseline Variables.........................................................................................15
3.5. Safety Endpoints ...........................................................................................15
3.5.1. Adverse Events .................................................................................16
3.5.2. Laboratory Data................................................................................16
3.5.3. Vital Signs, including Height and Weight........................................16
3.5.4. Physical Examinations......................................................................16
4. ANALYSIS SETS .....................................................................................................17
4.1. Full Analysis Set ...........................................................................................17
4.2. Per Protocol Analysis Set..............................................................................17
4.3. Safety Analysis Set........................................................................................18
5. GENERAL METHODOLOGY AND CONVENTIONS..........................................18
5.1. Hypotheses and Decision Rules ....................................................................18
5.2. General Methods ...........................................................................................21
5.2.1. Analyses for Binary Data..................................................................22
5.2.2. Analyses of Non-Longitudinal Continuous Data .............................23
5.2.3. Analyses of Longitudinal Continuous Data......................................23
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5.2.4. Analyses for Categorical Data..........................................................23
5.2.5. Analyses for Time to Event Data......................................................23
5.2.6. Analyses of Tier-1 and Tier-2 Events...............................................24
5.3. Methods to Manage Missing Data ................................................................24
5.3.1. Binary Endpoints ..............................................................................24
5.3.2. Continuous Endpoints.......................................................................25
5.3.3. Time to Event Endpoints ..................................................................25
6. ANALYSES AND SUMMARIES ............................................................................25
6.1. Co-primary Endpoint - Week 12 IGA Response...........................................26
6.1.1. Primary Analysis ..............................................................................26
6.1.2. Additional/Supportive Analysis........................................................26
6.2. Co-primary Endpoint - Week 12 EASI-75 Response ...................................26
6.2.1. Primary Analysis ..............................................................................26
6.2.2. Additional/Supportive Analyses.......................................................27
6.3. Key Secondary Efficacy Endpoints...............................................................27
6.3.1. Week 2 NRS4 for severity Response................................................27
6.3.2. Week 16 IGA Response....................................................................27
6.3.3. Week 16 EASI-75 Response ............................................................27
6.4. Secondary Efficacy Endpoints ......................................................................28
6.4.1. Binary Endpoints ..............................................................................28
6.4.2. Time to Achieve NRS4 for severity .................................................28
6.4.3. Continuous Endpoints.......................................................................28
6.4.4. Week 16 Corticosteroid-free days ....................................................29
6.5. PRO Endpoints..............................................................................................29
6.5.1. Continuous Endpoints.......................................................................29
30
6.7. Subset Analyses.............................................................................................30
6.8. Baseline and Other Summaries and Analyses...............................................30
6.8.1. Baseline Summaries..........................................................................30
6.8.2. Study Conduct and Subject Disposition ...........................................30
6.8.3. Study Treatment Exposure ...............................................................31
6.8.3.1. Oral Dosing .....................................................................31
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6.8.3.2. Injection Dosing ..............................................................31
6.8.4. Concomitant/Background Medications and Non-Drug Treatments.32
6.8.4.1. Background Topical Therapy (Medicated and Non-
Medicated) .....................................................................32
6.8.4.2. Protocol Prohibited Therapy for Primary Diagnosis.......33
6.9. Safety Summaries and Analyses ...................................................................33
6.9.1. Adverse Events.................................................................................33
6.9.2. Laboratory Data................................................................................34
6.9.3. Vital Signs, including Height and Weight........................................34
6.9.4. Electrocardiogram.............................................................................34
6.9.5. Physical Examination .......................................................................34
6.10. End of Study analysis..................................................................................34
6.10.1. Weeks 18 and 20 Efficacy Endpoints.............................................34
6.10.2. End of Study Safety Summaries and Analyses...............................34
7. INTERIM ANALYSES.............................................................................................35
8. REFERENCES ..........................................................................................................35
9. APPENDICES ...........................................................................................................36
LIST OF TABLES
Table 1
Summary of Major Changes in SAP Amendments ......................................6
Table 2
Study Objectives and Endpoints...................................................................7
LIST OF FIGURES
Figure 1
Study Design Schematic.............................................................................11
Figure 2
Schematic for Multiple Testing Procedure.................................................20
APPENDICES
Appendix 1. Summary of Clinical Efficacy Analyses...................................................36
Appendix 2. Definition and Use of Data Cut and Visit Windows in Reporting............37
Appendix 3. A Logistic-Normal GLMM for Longitudinal Binary Data and Tipping 
Point Analysis.............................................................................................39
Appendix 4. Investigator’s Global Assessment (IGA) ..................................................42
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Appendix 5. Eczema Area and Severity Index (EASI)..................................................43
Appendix 6. Scoring Atopic Dermatitis (SCORAD)....................................................46
Appendix 7. Pruritus Severity and Frequency (Pruritus NRS)......................................47
Appendix 8. Schedule of Activities ...............................................................................48
Appendix 9. Abbreviations ..........................................................................................55
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1. VERSION HISTORY
Table 1
Summary of Major Changes in SAP Amendments
Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Changes
1
25 Jul 2018
N/A
N/A
N/A
2
23 Jan 2020
Protocol 
Amendment 5
Align with changes 
in study protocol 
amendment 5
•
Added responder analyses based on 
SCORAD and change from baseline 
analysis in SCORAD assessment of sleep 
loss in Section 2, Section 3.2.2 and Section 
6.4.
 
 
•
Added endpoints percent change from 
baseline in total EASI score, Severity of 
Pruritus NRS and percentage body surface
area in Section 3.2.2 and Section 6.4.
•
Deleted endpoints response based on PtGA, 
DLQI, HADS and POEM in Section 3.3.1 
and Section 6.5.
 
 
•
Updated the definition of baseline variables
in Section 3.4.
•
Updated the definition of a treatment 
emergent adverse event (TEAE) in Section 
3.5.1, in alignment with the latest CaPS 
algorithm.
•
Updated the criteria for inclusion into the 
PPAS in Section 4.2.
•
Provided descriptions and scopes of the 
Week 16 Analysis and End of Study 
Analysis in Section 5 and Section 6. 
Updated the visit windows in Appendix 2 to 
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remove any gaps in the study period and 
provide the data cut definition of the Week 
16 Analysis.

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 and Appendix 3.

Updated study treatment exposure 
definitions and summaries in Section 6.8.3.

Updated concomitant/background 
medications and non-drug treatment 
summaries in Section 6.8.4.

Additional minor changes to improve clarity 
and alignment with the protocol.
2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study B7451029.  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.
2.1. Study Objectives
Study objectives and corresponding endpoints are provided in Table 2 below.
Table 2
Study Objectives and Endpoints
Primary Objective
Primary Endpoints
To compare the efficacy 
of 100 mg and 200 mg 
once daily (QD) of 
PF-04965842 versus 
placebo in adult subjects 
on background topical 
therapy with moderate to 
severe atopic dermatitis 
(AD).
The following co-primary endpoints will be tested:

Response based on achieving the Investigator's Global Assessment (IGA) of clear (0) or 
almost clear (1) (on a 5-point scale) and a reduction from baseline (pre-dose Day 1) of
2 points at Week 12;

Response based on achieving the Eczema Area and Severity Index (EASI)-75 (75% 
improvement from baseline) at Week 12.
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Secondary Objectives
Secondary Endpoints
To compare the efficacy 
of PF-04965842 versus 
dupilumab in terms of 
attaining a clinically 
significant improvement 
in the severity of pruritus 
for adult subjects on 
background topical 
therapy with moderate to 
severe AD;
Key Secondary Endpoints:

Response based on achieving at least 4 points improvement in the severity of Pruritus 
Numerical Rating Scale (NRS) from baseline at Week 2.
To estimate the 
difference in efficacy 
measures between two 
doses of PF-04965842 
and dupilumab for adult 
subjects on background 
topical therapy with 
moderate to severe AD;

Response based on achieving the IGA of clear (0) or almost clear (1) (on a 5-point 
scale) and a reduction from baseline of 2 points at Week 16; 

Response based on achieving EASI-75 (75% improvement from baseline) at Week 16.
To estimate the effect of 
PF-04965842 on 
additional efficacy 
endpoints and 
patient-reported 
outcomes over time in 
adult subjects on 
background topical 
therapy with moderate to 
severe AD.
Secondary Efficacy Endpoints:

Response based on achieving the IGA of clear (0) or almost clear (1) (on a 5-point 
scale) and 2-point reduction from baseline at all scheduled time points except Week 
12 and Week 16;

Response based on achieving a 75% improvement in the EASI total score (EASI-75) 
at all scheduled time points except Week 12 and Week 16;

Response based on achieving a 50% and 90% improvement in the EASI total score 
(EASI-50 and EASI-90) at all scheduled time points;

Response based on achieving at least 4 points improvement in the severity of Pruritus 
NRS from baseline at all scheduled time points except Week 2;

Time from baseline to achieve at least 4 points improvement in the severity of Pruritus 
NRS scale;

Change from baseline in the percentage Body Surface Area (BSA) affected at all 
scheduled time points;

Change from baseline of Patient Global Assessment (PtGA) at all scheduled time 
points;

Change from baseline in Dermatology Life Quality Index (DLQI) at all scheduled time 
points;

Change from baseline in EuroQol Quality of Life 5-Dimension 5-Level Scale 
(EQ-5D-5L) at all scheduled time points;

Change from baseline in Hospital Anxiety and Depression Scale (HADS) at all 
scheduled time points;

Change from baseline in Patient-Oriented Eczema Measure (POEM) at all scheduled 
time points;
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•
Change from baseline in Pruritus and Symptoms Assessment for Atopic Dermatitis 
(PSAAD) total score 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 Visual 
Analogue Scale (VAS) assessments of sleep loss;
•
Steroid-free days by Week 16.
Safety Objectives
Safety Endpoints
To compare the safety 
and tolerability of 100 
mg and 200 mg QD of 
PF-04965842 and 
dupilumab versus
placebo in adult subjects 
on background topical 
therapy with moderate to 
severe AD;
To estimate the safety 
and tolerability of the 
two doses of 
PF-04965842 versus 
dupilumab, for adult 
subjects on background 
topical therapy with 
moderate to severe AD.
•
Incidence of treatment-emergent adverse event (AE)s;
•
Incidence of serious adverse event (SAE)s and AEs leading to discontinuation;
•
Incidence of clinical abnormalities and change from baseline in clinical laboratory 
values, electrocardiogram (ECG) measurements, and vital signs.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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AD = Atopic dermatitis; AE = Adverse Event; BSA = Body Surface Area; DLQI = Dermatology Life Quality Index; 
EASI = Eczema Area and Severity Index; ECG = Electrocardiogram; EQ-5D-5L = EuroQol Quality of Life 5-Dimension 
5-Level Scale; HADS = Hospital Anxiety and Depression Scale; 
; IGA 
= Investigator’s Global Assessment; NRS = numerical rating scale; POEM = Patient-Oriented Eczema Measure; 
PSAAD = Pruritus and Symptoms Assessment for Atopic Dermatitis; PtGA = Patient Global Assessment; SAE 
= Serious Adverse Event,
2.2. Study Design
This is a randomized, double-blind, double-dummy, placebo-controlled, parallel-group, 
multi-center study to assess the efficacy and safety of PF-04965842 100 mg or 200 mg QD 
and dupilumab (as per label) compared with placebo in adult subjects on background topical 
therapy, with moderate to severe AD.  This study will provide a direct comparison of both 
doses of PF-04965842 with dupilumab in terms of pruritus relief.  This study will also 
provide data which will estimate the relative efficacy of both doses of PF-04965842 and 
dupilumab.  The treatment duration is 20 weeks. A total of approximately 700 subjects will 
be enrolled from approximately 180 sites globally. A study design schematic is presented in
Figure 1.
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Figure 1
Study Design Schematic
At Week 2 and Week 16, key secondary endpoints are measured.
At Week 12, primary endpoints are measured.
At Week 20, eligible subjects will enter the B7451015 long-term extension study; ineligible subjects will 
instead enter the 4-week off-treatment follow-up period in B7451029. 
Note: Standardized background topical therapy must be used as per protocol guidelines throughout the study.
Subjects who continue to meet eligibility criteria at baseline will undergo Day 1 assessments 
and be randomized in a 4:4:4:1:1 ratio to receive 100 mg or 200 mg of PF-04965842 QD 
with dupilumab-matching placebo administered every other week, dupilumab 300 mg 
administered every other week (with a loading dose of 600 mg at baseline) with 
PF-04965842-matching placebo administered QD, or one of two sequences of 
PF-04965842-matching placebo administered QD with dupilumab-matching placebo 
administered every other week from Day 1, for 16 weeks followed by either 100 mg or 
200 mg of PF-04965842 QD.  Randomization will be administered using center-based 
permuted blocks. Investigators, subjects, and the sponsor study team will be blinded as to 
treatment group.
The total treatment period is 20 weeks. The first part of this treatment period consists of a 
16-week randomized, double-blind, placebo-controlled, double-dummy treatment period with 
subjects receiving both injectable and oral investigational product. The randomization and 
double-blind will be maintained during the final 4 weeks of the treatment period, but subjects 
will only receive oral investigational product.  At Week 16 in the treatment period, all 
subjects will cease injectable dupilumab or its matching placebo.  Following Week 16, 
subjects previously receiving only placebo will receive PF-04965842 100 mg or 200 mg QD 
as per their randomized allocation.  Subjects previously receiving PF-04965842 100 mg or 
200 mg QD will continue their respective dose.  Subjects previously receiving dupilumab 
will continue to take oral placebo.  
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Eligible subjects completing the entire 20-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 study B7451029.
A full schedule of activities for the study is provided in Appendix 8.
Study Treatments

Orally administered 100 mg of PF-04965842 QD with dupilumab-matching placebo 
administered by subcutaneous injection every other week (two injections at baseline; 
to dummy the loading dose) from Day 1 to Week 16, followed by orally administered 
100 mg of PF-04965842 QD until Week 20.

Orally administered 200 mg of PF-04965842 QD with dupilumab-matching placebo 
administered by subcutaneous injection every other week (two injections at baseline; 
to dummy the loading dose) from Day 1 to Week 16, followed by orally administered 
200 mg of PF-04965842 QD until Week 20.

Dupilumab 300 mg administered every other week (with a loading dose of 600 mg 
at baseline) with PF-04965842-matching orally administered placebo QD from 
Day 1 to Week 16, followed by PF-04965842-matching orally administered 
placebo QD until Week 20.

PF-04965842-matching orally administered placebo QD with dupilumab-matching 
subcutaneously injected placebo administered every other week (two injections at 
baseline; to dummy the loading dose) from Day 1 to Week 16 followed by orally 
administered 100 mg of PF-04965842 QD until Week 20.

PF-04965842-matching orally administered placebo QD with dupilumab-matching 
subcutaneously injected placebo administered every other week (two injections at 
baseline; to dummy the loading dose) from Day 1 to Week 16 followed by orally 
administered 200 mg of PF-04965842 QD until Week 20.
Sample Size Determination
A total sample of 700 subjects, with 200 randomized to PF-04965842 200 mg QD, 
200 subjects randomized to PF-04965842 100 mg QD, 200 subjects randomized to 
dupilumab and 50 subjects each randomized to two sequences of matching placebo for 
16 weeks followed by (a) PF-04965842 100 mg QD and by (b) PF-04965842 200 mg QD 
(4:4:4:1:1 randomization) is planned.  The two placebo sequences will be combined for 
purposes of analyses at all visits up to and including Week 16, which will result in a 2:2:2:1 
randomization ratio. This will provide at least 96% power to detect a difference of at least 
20% in IGA response rate between either dose of PF-04965842 and placebo, assuming the 
placebo response rate is 12% at Week 12.  This will also provide at least 99% power to detect 
a difference of at least 30% in EASI-75 response rate between either dose of PF-04965842 
and placebo, assuming the placebo response rate is 23% at Week 12.
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Both co-primary endpoints must achieve statistical significance to meet the primary 
objective.
In addition, this sample size will also provide at least 92% power to detect a difference of at 
least 15% in the proportion of subjects with a ≥4 points improvement in the severity of 
Pruritus NRS between PF-04965842 and dupilumab, assuming the dupilumab response rate 
is 18% at Week 2.
The Type-I error rate is set at 5% (two-sided).  The familywise Type-I error rate (for testing 
the co-primary and key secondary endpoints) will be strongly controlled at 5% using a 
closed-testing method based on a sequential, iterative Bonferroni-type approach.  This is 
described in further detail in Section 5.1.
The study has been sized to help gain sufficient safety data to be able to effectively evaluate 
the benefit-risk of PF-04965842 in conjunction with the other studies in the clinical 
development program, therefore the power for the co-primary endpoints is relatively 
high. This sample size will also help ensure adequate power is maintained for testing all the 
co-primary and key secondary endpoints for both doses of PF-04965842 via the multiple
testing procedure.
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. Secondary Endpoints
3.2.1. Key Secondary Efficacy Endpoints
The key secondary efficacy endpoints are:

Response based on ≥4 points improvement from baseline in the pruritus NRS (NRS4) 
for severity at Week 2;

Response based on achieving the IGA of clear (0) or almost clear (1) (on a 5-point 
scale) and a reduction from baseline of 2 points at Week 16;
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
Response based on achieving EASI-75 (75% improvement from baseline) at Week 
16.
Detailed descriptions of how the severity of Pruritus NRS is derived is provided in 
Appendix 7.
3.2.2. Secondary Efficacy Endpoints

Response based on achieving the IGA of clear (0) or almost clear (1) (on a 5-point 
scale) and 2 point reduction from baseline at all scheduled time points except Week 
12 and Week 16;

Response based on achieving a 75% improvement in the EASI total score (EASI-75) 
at all scheduled time points except Week 12 and Week 16;

Response based on achieving a 50%, 90% and 100% improvement in the EASI 
total score (EASI-50, EASI-90 and EASI-100) at all scheduled time points;

Percent change from baseline in total EASI score;

Response based on achieving NRS4 at all scheduled time points except Week 2;

Time from baseline to achieve NRS4;

Percent Change from Baseline in Severity of Pruritus NRS each day from Days 2-15, 
Weeks 4, 8, 12 and 16;

Change from baseline and Percent change from baseline in the percentage Body 
Surface Area (%BSA) affected at all scheduled time points;

Steroid-free days by Week 16;

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;

Percent change from baseline and change from baseline at all scheduled time points 
in the SCORAD total score;

Percent change from baseline and change from baseline at all scheduled time points 
in SCORAD subjective assessments of sleep loss.
3.3. Other Endpoints
3.3.1. Patient-Reported Outcomes (PRO)

Change from baseline of Patient Global Assessment (PtGA) at all scheduled time 
points;
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•
Change from baseline in Dermatology Life Quality Index (DLQI) at all scheduled 
time points;
•
Change from baseline in EuroQol Quality of Life 5-Dimension 5-Level Scale 
(EQ-5D-5L) at all scheduled time points;
•
Change from baseline in each component (anxiety and depression) of the Hospital 
Anxiety and Depression Scale (HADS) at all scheduled time points;
•
Change from baseline in Patient-Oriented Eczema Measure (POEM) at all scheduled 
time points;
•
Change from baseline in Pruritus and Symptoms Assessment for Atopic Dermatitis 
(PSAAD) total score at all scheduled time points.
3.4. Baseline Variables
In general, for all analyses, baseline will be defined based on observations collected prior to 
first dose.  For DLQI, EQ-5D-5L, FACIT-F, HADS, POEM, PtGA, baseline will be defined 
based on observations collected on or prior to the day of 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, baseline will be defined as the average of 
all values recorded from Day -6 until Visit 2 / Day 1.
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 CaPS (CaPS).
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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. 
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.
•
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, phosphate, total bicarbonate, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl 
transferase (GGT), 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 is collected at screening and weight is 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.
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4. ANALYSIS SETS
Data for all subjects will be assessed to determine if subjects meet the criteria for inclusion in 
each analysis population 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 binary 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). For continuous endpoint change from baseline and percent change from baseline, 
subjects must have baseline value to be included in the analysis.
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 prior to Week 12 (timepoint of the primary endpoints).  The subjects 
excluded from the PPAS will be determined and documented before the study is unblinded.  
The primary endpoints will be analyzed for the PPAS. This set will include subjects who:  
•
Had valid and non-missing baseline efficacy data (IGA, EASI).
•
Met inclusion criteria 3 of documented prior qualifying treatment for AD.
•
Did not permanently discontinue assigned study oral treatment prior to Week 12.
•
Had actual, observed IGA and EASI scores at Week 12. 
•
Did not take a protocol-prohibited therapy for the primary diagnosis (high potency 
TCS or systemic medication or phototherapy) prior to Week 12.
•
Did not take a protocol-prohibited (CYP2C19/CYP2C9 inhibitor and/or inducer 
drugs) concomitant medication prior to Week 12.
•
Have an overall compliance of ≥80% but ≤120% with randomized oral treatment at
Week 12.
•
Adhered to standardized background topical therapy guidelines for ≥80% of days at
Week 12.
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
Had no other major protocol violations that is likely to affect materially the clinical 
observations, or the responses of the patient determined by the clinical team before 
the Week 16 Analysis is conducted (Section 5).
Prior to the unblinding of the study, the clinical team may update or remove any criteria, and 
the final items will either be assessed by programmed checks of the data or be determined by 
clinical review.
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
There will be a total of two planned analyses conducted for the study. The Week 16 Analysis 
will be performed after the last subject in the study has the opportunity to complete the Week 
16 visit.  The Week 16 Analysis will be the final analysis for the co-primary and key 
secondary endpoints, and the overall family-wise Type 1 error will be controlled as specified 
in Section 5.1. The conclusions with regards to the co-primary endpoints and the secondary 
endpoints will be based on this analysis. The results from the Week 16 Analysis will not be 
used to make decisions for modifying the study design or for stopping the study.  At the time 
of Week 16 Analysis, access to the database containing individual treatment group 
assignments will be restricted to the sponsor study team, while study sites, investigators and 
subjects will not be unblinded.  
The final clinical study report (CSR) for the study will be based on the results from the Week 
16 Analysis.  
The End of Study Analysis will contain additional data after the final database release and 
the results will be reported in a supplemental CSR.
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 assessing 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).
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The procedure will first assess the co-primary endpoints (IGA and EASI-75 at Week 12 for 
200 mg QD vs placebo) at the 5% level.  If this hypothesis is not rejected, then statistical 
significance will not be claimed for any subsequent hypotheses.  If this hypothesis is rejected, 
then assessing for statistical significance will continue for the co-primary endpoints (IGA and 
EASI75 at Week 12) for the 100 mg QD vs placebo comparison. If this hypothesis is not 
rejected, then no statistical significance will be claimed for any subsequent hypotheses.  If 
this hypothesis is rejected, then continue as follows:

A series of hypotheses related to the severity of pruritus at Week 2 will be assessed at 
the 2.5% level in the order specified in Sequence A.  

If all hypotheses in Sequence A are rejected, then the unused alpha level of 2.5% will 
be passed on to the assessing for the Week 16 endpoints in the order specified in 
Sequence B at a 5% significance level (see figure below).  The statistical significance 
for each hypothesis in Sequence B cannot be claimed unless the prior hypothesis in 
the sequence is statistically significant. In Sequence B, if one hypothesis is not 
rejected at alpha level of 5% then no statistically significant will be claimed for any 
subsequent hypotheses in the sequence.

In Sequence A, if one hypothesis is not rejected at alpha level of 2.5% then no 
statistically significant will be claimed for any subsequent hypotheses in the 
sequence. In this case, the assessing for statistical significance in Sequence B will be 
at the 2.5% level.  If all hypotheses in Sequence B are rejected, then the unused alpha 
level of 2.5% will be passed back for assessing the hypotheses in Sequence A at the 
5% level.  In Sequence B, if one hypothesis is not rejected at alpha level of 2.5 % 
then no statistically significant will be claimed for any subsequent hypotheses in the 
sequence.
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Figure 2
Schematic for Multiple Testing Procedure
The figure above illustrates the procedure showing the sequence of the tests.
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In order to be more rigorous about the onset of relief of severity of pruritus, a step-down 
approach with the NRS4 endpoint from Week 2 to earlier time points will be utilized as an 
additional family of hypothesis tests separate from Figure 2 once statistical significance is 
demonstrated at Week 2. Rejection of each hypothesis of no difference in NRS4 at Week 2 
within Sequence A will enable further assessing at earlier time points. Specifically, further 
hypotheses of no difference in NRS4 will be assessed along the following four sequences:

If hypothesis of no difference in NRS4 at Week 2 between 200 mg QD and placebo is 
rejected in Sequence A, compare 200 mg QD versus placebo at Day 15, Day 14, Day 
13, Day 12, …, Day 2, in that order. Any hypotheses after the last time point (or Day) 
for which the comparison 200 mg QD versus placebo is significant will not be 
considered statistically significant.

If hypothesis of no difference in NRS4 at Week 2 between 100 mg QD and placebo is 
rejected in Sequence A, compare 100 mg QD versus placebo at Day 15, Day 14, Day 
13, Day 12, …, Day 2, in that order. In this sequence, any hypotheses after the last 
time point (or Day) for which both comparisons (200 mg QD versus placebo and 100 
mg QD versus placebo) are significant will not be considered significant.

If hypothesis of no difference in NRS4 at Week 2 between 200 mg QD and 
dupilumab is rejected in Sequence A, compare 200 mg QD versus dupilumab at Day 
15, Day 14, Day 13, Day 12, …, Day 2, in that order. For this sequence, any 
hypotheses after the last time point (or Day) for which both comparisons (200 mg QD 
versus placebo and 200 mg QD versus dupilumab) are significant will not be 
considered significant.

If hypothesis of no difference in NRS4 at Week 2 between 100 mg QD and 
dupilumab is rejected in Sequence A, compare 100 mg QD versus dupilumab at Day 
15, Day 14, Day 13, Day 12, …, Day 2, in that order. For this sequence, any 
hypotheses after the last time point (or Day) for which all four comparisons (200 mg 
QD versus placebo, 200 mg QD versus dupilumab 100 mg QD versus placebo and 
100 mg QD versus dupilumab) are significant will not be considered significant.
All hypotheses in each of the four sequences will be assessed at the 5% level of significance. 
Although this testing procedure will not protect the Type-I error for the family of all possible 
comparisons, it will provide Type-I error protection for the family of NRS4 time points 
within each treatment group and treatment groups within each time point.
Hypotheses corresponding to all secondary and other endpoints will be tested at the 5% level 
of significance without any adjustment for multiplicity.
5.2. General Methods 
In general, for descriptive analyses, number and percent will be presented for binary 
variables. Number, mean, standard deviation, median, first and third quartiles will be 
presented for continuous variables.
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Estimates of the pairwise differences along with its two-sided 95% confidence interval will 
be provided among the treatment groups, PF-04965842 200 mg QD, PF-04965842 100 mg 
QD, dupilumab and placebo. No statistical significance will be claimed unless an exception 
is noted in Section 5.1 or Section 6 or any of its subsections.
5.2.1. Analyses for Binary Data
Binary data at each scheduled visit will be analyzed by two approaches: (1) the test of 
hypothesis (and the p-value) of no difference between two treatment groups will be 
conducted by the Cochran-Mantel-Haenszel (CMH) statistic adjusting for baseline disease 
severity (moderate or severe); p-values from the CMH statistic will be used to test the 
hypothesis of no difference in binary responses between two treatment groups; and (2) the 
proportion of responders in each treatment group will be reported and differences between 
two treatment groups will be summarized by the weighted 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 ݇ሺ݇ൌ1, 2ሻis given by,
ݓ௞ൌ
݊௜௞݊௖௞
݊௜௞൅݊௖௞
∑
݊௜௝݊௖௝
݊௜௝൅݊௖௝
ଶ
௝ୀଵ
where ݊refers to sample size, the subscript ܿrefers to a comparator group (eg, placebo) and 
the subscript ݅refers to a test group (eg, an active treatment group). The difference is 
estimated as ݀መൌ∑
ݓ௞ሺ݌̂௜௞െ݌̂௖௞ሻ
ଶ
௞ୀଵ
, where ݌̂ refers to the estimated proportion. 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:
݀መേ1.96ඩ෍ݓ௞
ଶ
ଶ
௞ୀଵ
൬݌̂௜௞ሺ1 െ݌̂௜௞ሻ
݊௜௞
൅݌̂௖௞ሺ1 െ݌̂௖௞ሻ
݊௖௞
൰
In the above formula, the standard error is ට∑
ݓ௞
ଶ
ଶ
௞ୀଵ
ቀ
௣ො೔ೖሺଵି௣ො೔ೖሻ
௡೔ೖ
൅
௣ො೎ೖሺଵି௣ො೎ೖሻ
௡೎ೖ
ቁ. When the 
number of responders is zero ሺݔൌ0ሻ, then ݌̂ will be replaced by 0.5/ሺ݊൅1ሻ. 
The 95% confidence interval for the response rate in each treatment group will also be 
provided using Wald normal approximation (or the Clopper-Pearson exact method when 
there are no or all responders in one group).
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Protocol B7451029 (PF-04965842) Statistical Analysis Plan
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5.2.2. Analyses of Non-Longitudinal Continuous Data
The non-longitudinal continuous data will be analyzed by ANCOVA with treatment as the 
factor and baseline disease severity 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 treatment groups will be derived from the model. 
The corresponding p-values and 95% confidence intervals will also be derived from the 
model.
5.2.3. Analyses of Longitudinal Continuous Data
Mixed-effect, repeated measures (MMRM) models will be used. The fixed effects of 
treatment, visit, treatment-by-visit interaction and baseline disease severity 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 
treatment groups will be derived from the model. The corresponding p-values and 95% 
confidence intervals will also be derived from the model. In the model all patients with 
baseline data are used for estimating baseline covariate effects and adjusting LS means.
5.2.4. Analyses for Categorical Data
The frequency and percentage for each category will be presented.
5.2.5. Analyses for 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.  
95% CIs for the median and quartiles will also be provided.
The log-rank test (stratified using baseline disease severity) p-value will be used for 
comparing time to event data between treatment groups.
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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 events will be analyzed using methods proposed by Chan 
and Zhang (1999). Tier-2 events will be analyzed using asymptotic methods proposed by 
Miettinen and Nurminen (1985). Risk differences (each PF-04965842 dose group compared 
to placebo, and each PF-04965842 dose group compared to dupilumab) and 2-sided 95% 
confidence intervals will be reported.  P-values will also be reported for Tier-1 events. Tier-
3 events will not be summarized separately but included within the summary of all AEs.
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, any data will be defined as “non-responsive” at all 
subsequent visits after the last observed value; 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 will utilize the longitudinal nature of the binary endpoint. A
Generalized Linear Mixed Model (GLMM) will be fit to the observed data (ie, 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, dupilumab and the placebo group), visit (Weeks
2, 4, 8, 12 and 16) 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 
(PF-04965842 200 mg QD and 100 mg QD, dupilumab) 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 
active 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 active 
groups. 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 
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proportions and CMH-weighted difference of proportions between each active 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 (ie, 
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 active 
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 active dose group, results are obtained under an assumption that the distribution of the 
missing responses after discontinuation of each active group is the same as that of the 
missing responses on the placebo arm.  More detailed descriptions are provided in
Appendix 3.
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.
For the continuous PRO variables such as pruritus NRS, DLQI, POEM, PSAAD, HADS, and 
EQ-5D-5L, 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
Unless specifically noted otherwise, the analyses specified in Section 6 will be included in 
the Week 16 Analysis. The Week 16 Analysis contains data up to and including Week 16
Visit Date. The definition of data cut for the analysis is detailed in Appendix 2. For all 
endpoints, comparisons will be done pairwise between each active treatment group 
(PF-04965842 200 mg QD, PF-04965842 100 mg QD and dupilumab) and placebo (three
separate tests of hypotheses). For the Week 16 Analysis, the two placebo sequences will be 
combined into one group. Pairwise analyses with point estimates of the difference and the 
associated 95% confidence intervals will also be done among the active treatment groups
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PF-04965842 200 mg QD, PF-04965842 100 mg QD and dupilumab. P-value will only be 
presented for the PF-04965842 doses vs. placebo (except for NRS4 at Week 2 and Days 2-15
where p-value for PF-04965842 doses vs. dupilumab will also be presented, see Section 5.1).
For the End of Study Analysis which contains additional data after the final database release, 
the two placebo sequences will not be combined. 
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.
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.

Results of proportion of subjects achieving the IGA response 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 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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6.2.2. 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 response 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 Efficacy Endpoints
6.3.1. Week 2 NRS4 for severity Response

Summary: Proportion of subjects with NRS4 for severity response at Week 2; Week 2 
NRS value is based on visit window (Appendix 2);

Population: Subjects from the FAS with a baseline NRS score for severity 4;

Statistical Method: CMH and normal approximation in Section 5.2.1. In addition to 
comparisons versus placebo, tests of hypotheses will also be performed (with p-
values reported) for comparing this endpoint between PF-04965842 200 mg QD and 
dupilumab as well as between PF-04965842 100 mg QD and dupilumab;

Missing Data: Missing data arising due to subject dropout are considered “non-
response” (see Section 5.3.1).
6.3.2. Week 16 IGA Response

Summary: Proportion of subjects achieving IGA response at Week 16;

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).
6.3.3. Week 16 EASI-75 Response

Summary: Proportion of subjects achieving EASI-75 response at Week 16;

Population: FAS;

Statistical Method: CMH 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).
6.4. Secondary Efficacy Endpoints
6.4.1. Binary Endpoints

Endpoints: 

Weeks 2, 4 and 8 IGA, EASI-75 Response; 

NRS4 for Severity Response each day from Days 2-15, Weeks 4, 8, 12 and 16;

Weeks 2, 4, 8, 12 and 16 EASI-50, EASI-90, EASI-100, SCORAD50, 
SCORAD75.

Summary: Proportion of subjects with response at each specified time points;

Population: FAS; Subjects from the FAS with a baseline NRS score for severity ≥4
will be used for NRS4 analysis;

Statistical Method: CMH and normal approximation in Section 5.2.1. P-value for 
PF-04965842 doses vs. dupilumab will also be presented for Days 2-15 NRS4;

Missing Data: Missing data arising due to subject dropout are considered 
“non-response” (see Section 5.3.1).
6.4.2. Time to Achieve NRS4 for severity

Summary: Time to achieve NRS4 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;  

Missing Data: See Section 5.3.3.
6.4.3. Continuous Endpoints

Endpoints: 

Weeks 2, 4, 8, 12 and 16 Change from Baseline and Percent Change from 
Baseline in % BSA, Total SCORAD score, SCORAD subjective assessments of 
sleep loss (VAS);

Weeks 2, 4, 8, 12 and 16 Percent Change from Baseline in Total EASI Score;

Percent Change from Baseline in Severity of Pruritus NRS each day from Days 
2-15, Weeks 4, 8, 12 and 16;
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
Summary: Change from baseline and/or percent change from baseline at each 
specified time points;

Population: FAS;

Statistical Method: MMRM in Section 5.2.3;  

Missing Data: Observed Data.
6.4.4. Week 16 Corticosteroid-free days

Summary: Number of days when neither topical or systemic corticosteroids1 was 
taken (from Day 1 up to Week 16/Day 116 during the study treatment exposure 
period);

Population: FAS;

Statistical Method: ANCOVA in Section 5.2.2;

Missing Data: Observed Data.
6.5. PRO Endpoints
6.5.1. Continuous Endpoints

Endpoints: 

Weekly Change from Baseline (up to Week 16) in Total PSAAD Score; 

Weeks 2, 4, 8, 12, and 16 Change from Baseline in PtGA;

Weeks 2, 12 and 16 Change from Baseline in DLQI; 

Weeks 12 and 16 Change from Baseline in HADS (separate for anxiety and 
depression), POEM, EQ-5D-5L;

Summary: Change from Baseline for each specified time points;

Population: FAS;

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;

Missing Data: Observed Data.
                                                
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6.7. Subset Analyses 
Summary statistics for co-primary endpoints will be presented by subgroups below.
•
Age (years) group (<40, ≥40; <65, ≥65);
•
Sex (Male, Female);
•
Race (White, Black or African-American, Asian, Other2);
•
Region of enrollment (US/Canada/Australia, Europe, Asia, Latin America);
•
Weight (kg) (less than or equal to the median value in FAS, above the median value);
•
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 response of and all pairwise difference between the PF-04965842 200 mg 
QD, PF-04965842 100 mg QD and placebo, along with the 95% confidence interval (no 
p-value), will be presented for each defined category of each subgroup. For the binary 
endpoints, analyses will be performed using normal approximation without any adjustments 
for baseline disease severity.
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 (eg, 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. Baseline disease severity based on IGA and baseline 
EASI score will also be summarized by gender.
6.8.2. Study Conduct and Subject Disposition
Subjects evaluation, disposition, discontinuation will be summarized according to CaPS.
                                                
2 For purposes of analysis, Other will comprise the categories of American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Multi-Racial and any other category reported on the CRF.
CCI
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6.8.3. Study Treatment Exposure
6.8.3.1. Oral Dosing

Duration of Treatment is defined as the total number of dosing days on which study 
drug was actually administered; if N doses missed on unknown dates, it reduces the 
Duration of Treatment by N/2 (when N is an even number) or (N-1)/2 (when N is an 
odd number);

Exposure Time is defined as the total number of days from first to and including last 
day of study oral dosing (Last Oral Dosing Date - First Oral Dosing Date + 1);

Dose Compliance is defined as the number of doses of study drug the subject took out 
of the expected total number of doses of study drug.

Expected Number of Doses = 2*(Exposure Time);

Dose Compliance = (Total Actual Oral Pills/ Expected Number of Doses) * 
100%.
Investigational product may be temporarily withheld for a maximum of 14 days at 
investigator's discretion due to abnormal laboratory tests or adverse event (Protocol Section 
5.3). The Dose Compliance does not consider whether missed doses were due to protocol-
allowed temporary withholding.
Number, mean, standard deviation, median, minimum and maximum will be presented for 
those variables: Duration of Treatment, Exposure Time and Dose Compliance. Number and 
percent will be reported for subjects in Duration of Treatment categories, and Dose 
Compliance <80% and Dose Compliance >120%.
6.8.3.2. Injection Dosing
Dupilumab or its matching placebo is administered every other week from Day 1 to Week 
14, with two loading doses at baseline and then one dose each time. 

Exposure Time of Injection = (Last Injection Date - First Injection Date + 14); Eg, for 
subject receiving only the loading doses at baseline, the Exposure Time of Injection
should be 14 days;
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
Expected Number of Injections (Cumulative) will be based on Last Injection Date 
relative to Day 1/Baseline, using the following table:
Injection Schedule
Target Day
Window
Expected Number of 
Injections 
(Cumulative)
Baseline
Day 1
Days 1 to 7
2
Week 2
Day 15
Days 8 to 21
3
Week 4
Day 29
Days 22 to 35
4
Week 6
Day 43
Days 36 to 49
5
Week 8
Day 57
Days 50 to 63
6
Week 10
Day 71
Days 64 to 77
7
Week 12
Day 85
Days 78 to 91
8
Week 14
Day 99
Days 92 to -
9

Eg, if a subject receives his/her last injection on Day 76, the Expected Number of 
Injections (Cumulative) should be 7.

Injection Dose Compliance = (Number of Injections Received / Expected Number of 
Injections) * 100%.
Number, mean, standard deviation, median, minimum and maximum will be presented for
those variables: Exposure Time of Injection, Number of Injections Received, Injection Dose 
Compliance. Number and percent will be reported for with Injection Dose Compliance 
<80% and Injection Dose Compliance >120%.
6.8.4. Concomitant/Background Medications and Non-Drug Treatments
Prior drug and non-drug treatment, concomitant drug and non-drug treatment will be 
summarized according to CaPS.
6.8.4.1. Background Topical Therapy (Medicated and Non-Medicated)
Number and percent of subjects used non-medicated emollient, medicated topical therapy, 
topical corticosteroids (TCS), topical calcineurin inhibitors (TCI), topical PDE4 inhibitors
will be reported during the study treatment exposure period.
Subjects must comply with standardized background topical therapy guidance throughout the 
study (Protocol Section 5.9.1). “Did the subject conform to background therapy per protocol”
is ‘No’ when medication should have been used per protocol and was not used OR if 
medication was used but did not meet protocol requirements.

Exposure Time (of study treatment) is defined as the total number of days from first 
to and including last day of study dosing (Last Dosing Date - First Dosing Date + 1);
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
During the period of first dosing date to last dosing date, if any use of TCS, TCI or 
PDE4 inhibitor is non-compliance with protocol (ie, “No” is entered for “Did the 
subject conform to background therapy per protocol”), the compliance for that day is 
“No”;

Medicated Topical Therapy Compliance = 1 - (Days non-compliant with background 
topical/ Exposure Time) * 100%.
Number, mean, standard deviation, median, minimum and maximum will be presented for 
Medicated Topical Therapy Compliance. Number and percent will be reported for subjects 
with compliance of medicated topical therapy< 80%.
6.8.4.2. Protocol Prohibited Therapy for Primary Diagnosis
Number and percent will be reported for subjects used protocol prohibited therapy for AD: 
high potency TCS, systemic medication for AD, phototherapy during the period of first 
dosing date to last dosing date.
6.9. Safety Summaries and Analyses
Safety analysis will be based on the SAF analysis set.
All clinical AEs, SAEs, treatment-emergent signs and symptoms (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 (eg, AEs) will be summarized by subject 
counts and percentage.  Continuous outcome (eg, blood pressure, pulse rate, etc.) will be 
summarized using N, mean, median, standard deviation, etc.  Change from baseline in 
laboratory data, ECGs, physical exams 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. 
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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 selected events in unique situations, studies do not employ formal 
adjudication procedures for event classification. 
 
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 and at Weeks 2, 4, 8, 12 and 16. Height will be 
reported at baseline only and weight will be summarized at baseline and Week 12.
6.9.4. Electrocardiogram
ECG parameters, if applicable, will be summarized at baseline.
6.9.5. Physical Examination
Physical examinations will be summarized at baseline and all-available post-baseline visits.
6.10. End of Study analysis
The Week 16 Analysis contains data up to and including Week 16. The definition of data cut 
for the analysis is detailed in Appendix 2. The End of Study Analysis which contains
additional data after the final database release, the two placebo sequences will not be 
combined. Data collected at Week 24 will be displayed in listings only, and will not be part 
of any analyses, unless specifically noted otherwise.
6.10.1. Weeks 18 and 20 Efficacy Endpoints 
Only descriptive summaries will be provided. 
6.10.2. End of Study Safety Summaries and Analyses 
Selected subset of safety summaries will be produced.
CCI
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7. INTERIM ANALYSES
This study uses an External Data Monitoring Committee (E-DMC). The E-DMC will be 
responsible for ongoing monitoring of the efficacy and safety of subjects in the study 
according to the charter. 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. (2007) Powerful short-cuts for multiple testing
procedures with special reference to gatekeeping strategies. Statistics in Medicine,
26:4063–4073.
2.
Marcus R, Peritz E, Gabriel KR. (1976) On closed testing procedure with special
reference to ordered analysis of variance. Biometrika, 63:655–660.
3.
Miettinen O and Nurminen M. Comparative analysis of two rates. Statistics in 
Medicine, 1985, 4: 213-226.
4.
Rubin DB (1987). Multiple imputation for nonresponse in surveys. New York: Wiley.
5.
Chan ISF and Zhang Z. Test based exact confidence intervals for the difference of two 
binomial proportions. Biometrics, 1999, 55:1201–1209.
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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
Week 12 IGA Response
PPAS
CMH
NR
No
Week 12 IGA Response
FAS
CMH
TP
No
Week 12 EASI-75 Response
FAS
CMH
NR
Yes
Week 12 EASI-75 Response
PPAS
CMH
NR
No
Week 12 EASI-75 Response
FAS
CMH
TP
No
Week 2 NRS4 for severity Response
FAS
CMH
NR
Week 16 IGA Response
FAS
CMH
NR
Week 16 EASI-75 Response
FAS
CMH
NR
Days 2-15, Weeks 4, 8, 12 and 16 NRS4 for 
Severity Response
FAS
CMH
NR
Time to NRS4 for severity
FAS
Time to Event
Weeks 2, 4 and 8 IGA Response
FAS
CMH
NR
Weeks 2, 4, 8, 12 and 16 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, 12 and 16 Percent CFBL in 
Total EASI Score
FAS
MMRM
OD
Days 2-15, Weeks 2, 4, 8, 12 and 16 Percent 
CFBL in NRS for severity
FAS
MMRM
OD
Weeks 2, 4, 8, 12 and 16 Percent CFBL in 
%BSA
FAS
MMRM
OD
Weeks 2, 4, 8, 12 and 16 CFBL and Percent 
CFBL in SCORAD Total Score
FAS
MMRM
OD
Weeks 2, 4, 8, 12 and 16 SCORAD50 
Response
FAS
CMH
NR
Weeks 2, 4, 8, 12 and 16 SCORAD75 
Response
FAS
CMH
NR
Weeks 2, 4, 8, 12 and 16 CFBL and Percent 
CFBL in SCORAD (VAS) for 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; OD=Observed Data; TP=Tipping Point
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Appendix 2. Definition and Use of Data Cut and Visit Windows in Reporting
For both the Week 16 Analysis and End of Study Analysis, a data cut at Week 16 drug 
dispensing visit will apply to each subject before the windowing. Only data from up to and 
including the Data Cut will be used for the Week 16 Analysis. Only data from after the Data 
Cut will be used for the End of Study Analysis. If a subject withdrew from the study and no 
drug was dispensed at Week 16, all available data for that subject will be included in the
Week 16 Analysis. 
Week 16 Analysis: 
Visit Label
Target Day
Definition [Day window]
Screening
Days -28 to Day -1
Baseline
Day 1, Baseline
Day 1
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
Week 16
113
Days 100 to 120
End of Study Analysis: 
Visit Label
Target Day
Definition [Day window]
Week 18
127
Days 121 to 134
Week 20
141
Days 135 to 155
Follow Up/End of Study
Week 24
-
Days 156 to -
Visit windows will be used for efficacy variables, and for any safety data that display or 
summarize by study visit.  For other endpoints (eg, ECG, vital signs), visit windows will be 
applied for summary statistics by study visits if required.
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.
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Observations on the actual day will be used to analyze Days 2-15 Pruritus NRS. Weeks 2, 4, 
8, 16 Pruritus NRS will be based on the windowing method.
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.
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Appendix 3. A Logistic-Normal GLMM for Longitudinal Binary Data and Tipping Point 
Analysis
Let ܻ௜௝be the binary outcome for subject ݅ሺ݅ൌ1, 2, … , ܰሻand visit ݆ሺ݆ൌ1, 2, 3, 4, 5ሻ. We 
assume ܻ௜௝ൌ1 for a response and ܻ௜௝ൌ0 for a non-response. Then we model as
ܲ൫ܻ௜௝ൌ1 หݔ௜௝, ݑ௜ሻൌ
݁ఉᇲ௫೔ೕା௨೔
1 ൅݁ఉᇲ௫೔ೕା௨೔≡ߨ௜௝ሺߚ; ݑ௜ሻ
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,
ܮሺߚ, ߪଶሻൌෑනෑߨ௜௝ሺߚ; ݑ௜ሻ௒೔ೕሺ1 െߨ௜௝ሺߚ; ݑ௜ሻሻሺଵି௒೔ೕሻൈܰሺݑ௜; 0, ߪଶሻ
ହ
௝ୀଵ
ஶ
ିஶ
ே
௜ୀଵ
݀ݑ௜
There is no closed analytical form for this likelihood.
For the present study, the primary endpoint is evaluated at Week 12 ሺ݆ൌ4ሻ. There are four
treatment groups, so the model term ߚᇱݔ௜௝when written out looks like,
ߚ଴൅෍ߚଵ௞
ସ
௞ୀଵ
ൈ1ሺ்೔ୀ௞ሻ൅ߚଶ௝൅෍ߚଷ௝௞
ସ
௞ୀଵ
ൈ1ሺ்೔ୀ௞ሻ
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 in many standard 
statistical software is to assume ߚଵସൌ0, ߚଶହൌ0, thereby interpreting ߚଵଵ, ߚଵଶas the 
difference in treatment effect relative to ܶൌ4 and ߚଶଵ, ߚଶଶ, ߚଶଷas the difference in visit 
effect relative to ܸൌ5. Consequently, ߚଷ௝௞ൌ0 when ݆ൌ5 or ݇ൌ4. So, for example, for a 
subject taking PF-04965842 100 mg QD at Week 12, the expression would be ߚ଴൅ߚଵଵ൅
ߚଶସ൅ߚଷସଵ. For a subject taking PF-04965842 200 mg QD at Week 12, the expression would 
be ߚ଴൅ߚଵଶ൅ߚଶସ൅ߚଷସଶ. For a subject taking dupilumab at Week 12, the expression would 
be ߚ଴൅ߚଵଷ൅ߚଶସ൅ߚଷସଷ. For a subject on placebo at Week 12, the expression would 
be ߚ଴൅ߚଶସ.
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, 12 and 16) under 
the MNAR assumption is called the tipping point analysis.  This tipping point analysis 
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includes 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 ~ܰሺ0, 10000ሻand 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 ሺܶ௜ൌ1ሻ, then at Week 12 ሺܸൌ4ሻ,
݈݋݃݅ݐ൫ߨ௜,ଵ,ସ
௕
൯ൌ݈݋݃݅ݐ൬ܲቀܻప,ସ
௕
෪ൌ1ቚܶ௜ൌ1, ܸൌ4ቁ൰ൌߚ଴
௕൅ߚଵଵ
௕൅ߚଶସ
௕൅ߚଷସଵ
௕
൅ݑ௜
௕.
If subject ݅is randomized to PF-04965842 200 mg QD ሺܶ௜ൌ2ሻ, then at Week 12 ሺܸൌ4ሻ,
݈݋݃݅ݐሺߨ௜,ଶ,ସ
௕
ሻൌ݈݋݃݅ݐ൬ܲቀܻప,ସ
௕
෪ൌ1ቚܶ௜ൌ2, ܸൌ4ቁ൰ൌߚ଴
௕൅ߚଵଶ
௕൅ߚଶସ
௕൅ߚଷସଶ
௕
൅ݑ௜
௕.
If subject ݅is randomized to dupilumabሺܶ௜ൌ3ሻ, then at Week 12 ሺܸൌ4ሻ,
݈݋݃݅ݐ൫ߨ௜,ଷ,ସ
௕
൯ൌ݈݋݃݅ݐ൬ܲቀܻప,ସ
௕
෪ൌ1ቚܶ௜ൌ3, ܸൌ4ቁ൰ൌߚ଴
௕൅ߚଵଷ
௕൅ߚଶସ
௕൅ߚଷସଷ
௕
൅ݑ௜
௕.
If subject ݅is randomized to placebo ሺܶ௜ൌ4ሻ, then at Week 12 ሺܸൌ4ሻ,
݈݋݃݅ݐ൫ߨ௜,ସ,ସ
௕
൯ൌ݈݋݃݅ݐ൬ܲቀܻప,ସ
௕
෪ൌ1ቚܶ௜ൌ4, ܸൌ4ቁ൰ൌߚ଴
௕൅ߚଶସ
௕൅ݑ௜
௕.
In the tipping analysis, we apply a series of fixed quantities ߜൌሺߜଵ, ߜଶ, ߜଷሻ′ to account for 
MNAR. We define,
ߨ௜,ସ,ସ
∗௕
ൌߨ௜,ସ,ସ
௕
,
ߨ௜,ଵ,ସ
∗௕
ൌߜଵߨ௜,ସ,ସ
௕
൅ሺ1 െߜଵሻߨ௜,ଵ,ସ
௕
,
ߨ௜,ଶ,ସ
∗௕
ൌߜଶߨ௜,ସ,ସ
௕
൅ሺ1 െߜଶሻߨ௜,ଶ,ସ
௕
,
ߨ௜,ଷ,ସ
∗௕
ൌߜଷߨ௜,ସ,ସ
௕
൅ሺ1 െߜଷሻߨ௜,ଷ,ସ
௕
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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 
Method (Rubin, 1987).  This can then be repeated for different values of MNAR parameter ߜ
to evaluate the impact of missing data. Note that ߜൌሺ0, 0,0ሻ′ corresponds to an MAR 
analysis and ߜൌሺ1, 1,1ሻ′ corresponds to an analysis commonly known as Jump-To-
Reference (JTR). As a special case, we will consider ߜଵൌߜଶൌߜଷfor our analyses.
The multiple imputations will be done for all treatment groups. Only PF-04965842 200 mg 
QD, PF-04965842 100 mg QD and placebo results will be presented in Tipping Point 
Analysis to support the family-wise type one error controlled comparisons of the primary 
endpoints.
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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.
%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.
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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
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)
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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 (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).
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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
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. 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 57
Week 8
Day 85
Week 12 
Day 113
Week 16
Day 127
Week 18
Day 141 
Week 20
EOT or ET 
Visit
Day 169
Week 24
(4 Weeks after EOT 
or ET)
EOS, Follow-up Visit
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10
Visit 11
Visit Window
None
None
1 Day 1 Day
2 Days 3 Days 3 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
X
X
Dispense eDiary and instruct 
subjects on use
X
Train on washout of 
medicated topical therapy and 
use of non-medicated topical 
therapy pre-baseline and daily 
recording in eDiaryc
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 57
Week 8
Day 85
Week 12 
Day 113
Week 16
Day 127
Week 18
Day 141 
Week 20
EOT or ET 
Visit
Day 169
Week 24
(4 Weeks after EOT 
or ET)
EOS, Follow-up Visit
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10
Visit 11
Visit Window
None
None
±1 Day ±1 Day
±2 Days ±3 Days ±3 Days
±3 Days
±3 Days
±3 Days
±3 Days
Train/check understanding of 
subjects on protocol guidance 
for background topical 
medication and daily 
recording in eDiaryd
X
X
X
X
X
X
X
X
X
Provide Patient Emergency 
Contact Card
X
Medical Procedures
Complete Physical Exame
X
X
X
X
Targeted Physical Exame
X
X
X
X
X
X
Vital Signsf
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
Height
X
Chest X-rayg
X
ECG (12-lead)
Xh
X
X
X
X
X
X
X
X
X
Laboratory Assessments 
Serum Chemistry and 
Hematology (including 
Coagulation Panel)i
X
X
X
X
X
X
X
X
X
X
Lipid Paneli
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
Serum FSH (WONCBP only) 
or Pregnancy Testk
X
Urine Pregnancy Test 
(conducted at study site) l
X
X
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 57
Week 8
Day 85
Week 12 
Day 113
Week 16
Day 127
Week 18
Day 141 
Week 20
EOT or ET 
Visit
Day 169
Week 24
(4 Weeks after EOT 
or ET)
EOS, Follow-up Visit
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10
Visit 11
Visit Window
None
None
±1 Day ±1 Day
±2 Days ±3 Days ±3 Days
±3 Days
±3 Days
±3 Days
±3 Days
HIV Testingn
X
Hepatitis B Surface Antigen 
(HBsAg), Hepatitis B 
Surface Antibody (HBsAb), 
Hepatitis B Core Antibody 
(HBcAb), Hepatitis C 
Antibody (HCVAb), 
Hepatitis C Viral RNA 
(HCV RNA)o
X
Tuberculosis Testp
X
Trial Treatment 
Randomization 
X
Oral Drug Dispensing
X
X
X
X
X
Injectable Drug Dispensing
X
X
X
X
X
Investigational Product 
Accountability  
X
X
X
X
X
X
X
Subject Injection Trainingq
X
Observed Investigational 
Product Administrationr
X
X
X
X
X
X
X
X
Reallocation to new treatment 
regimens
X
Review eDiary to assess 
completion
X
X
X
X
X
X
X
X
X
Assess eligibility for 
B7451015s
X
Clinical Assessments 
Fitzpatrick Skin Type 
Assessment
X
Investigator’s Global 
Assessment (IGA) 
X
X
X
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 57
Week 8
Day 85
Week 12 
Day 113
Week 16
Day 127
Week 18
Day 141 
Week 20
EOT or ET 
Visit
Day 169
Week 24
(4 Weeks after EOT 
or ET)
EOS, Follow-up Visit
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10
Visit 11
Visit Window
None
None
±1 Day ±1 Day
±2 Days ±3 Days ±3 Days
±3 Days
±3 Days
±3 Days
±3 Days
SCORing Atopic Dermatitis 
(SCORAD)
X
X
X
X
X
X
X
X
X
X
Eczema Area and Severity 
Index (EASI)
X
X
X
X
X
X
X
X
X
X
Body Surface Area (BSA 
from EASI) 
X
X
X
X
X
X
X
X
X
X
C-SSRSt
X
PHQ-8t
X
Patient reported Outcomes
Pruritus Numerical Rating 
Scale (NRS)u
X----------X
X------------------------X
X
X
X
X
X
X
X
Patient Global Assessment 
(PtGA)
X
X
X
X
X
X
X
X
X
Dermatology Life Quality 
Index (DLQI)
X
X
X
X
X
X
Pruritus and Symptoms 
Assessment for Atopic 
Dermatitis (PSAAD)v
X----------X        X------------------------------------------------------------------------------------------------------------------------------------------X
EQ-5D-5L
X
X
X
X
X
Hospital Anxiety and 
Depression Scale (HADS)
X
X
X
X
Patient-Oriented Eczema 
Measure (POEM)
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 57
Week 8
Day 85
Week 12 
Day 113
Week 16
Day 127
Week 18
Day 141 
Week 20
EOT or ET 
Visit
Day 169
Week 24
(4 Weeks after EOT 
or ET)
EOS, Follow-up Visit
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10
Visit 11
Visit Window
None
None
±1 Day ±1 Day
±2 Days ±3 Days ±3 Days
±3 Days
±3 Days
±3 Days
±3 Days
Safety
Serious and non-serious 
adverse event monitoring
X
X
X
X
X
X
X
X
X
X
X
Contraception Checkx
X
X
X
X
X
X
X
X
X
X
X
Ensure subject adherence to 
background topical therapy 
requirementsd
X
X
X
X
X
X
X
X
X
X
X
Serum Sample for Baseline 
Viral Screeny
X
Abbreviations: BSA =  body surface area; 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; FSH = follicle stimulating hormone; 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; IGA = Investigator’s Global Assessment; IRT = Interactive Response System; NRS = numerical 
rating 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; SCORAD = SCORing Atopic Dermatitis; WONCBP = women of 
non-childbearing potential.
a.
Day relative to start of study treatment (Day 1).
b.
Any previous history of intolerance/allergy to any drug, regardless of indication.  Atopic Dermatitis Disease History includes collection of details of AD: AD 
diagnosis and duration, the use of topical treatments, systemic treatments and other treatments for AD. 
c.
Train the subject on washout of medicated topical therapy (Exclusion criterion 10, Section 4.2) and use of non-medicated topical therapy pre-baseline 
(Inclusion criterion 4, Section 4.1) Train and explain to the subject that their daily use of non-medicated topical therapy is recorded in the e-Diary.
d.
For background topical therapy guidelines see Section 5.8.1.
e.
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.
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f.
Vital Signs include sitting blood pressure, pulse rate, respiratory rate, and temperature (oral or tympanic) measured (pre-dose, if applicable) after at least 
5 minutes of rest. 
g.
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.  Official reading must be located and available in the source documentation.
h.
A single 12-lead ECG will be performed at screening and all other on-site visits after the subject has rested quietly for at least 10 minutes in the supine 
position.  ECG will be interpreted by a central reader.  Clinically significant or exclusionary ECG findings at the screening visits will require screen failure.  
i.
Serum chemistry includes: blood urea nitrogen (BUN), serum creatinine, creatine phosphokinase, glucose, Ca++, Na+, K+, Cl-, P, 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 16, Week 
20 and EOS visits.  Hematology includes: Hemoglobin, hematocrit, red blood cell count and indices (MCH, MCHC, MCV, RBC Morphology), WBC count 
with differential, total 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 7.6.2) may be repeated once during the 
screening period; the last value will be used to determine eligibility. 
 
k.
Serum pregnancy testing at screening is required for female subjects of childbearing potential.  Follicle stimulating hormone (FSH) test to be performed at 
Screening to confirm postmenopausal status in female subjects who have been amenorrheic for at least 12 consecutive months.
l.
Urine pregnancy test must be performed prior to dosing with the investigational product for female subjects of childbearing potential. 
 
n.
HIV testing will be performed for all subjects.  Subjects who are positive for HIV will be screen-failed. 
o.
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.
p.
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 7.3.3. 
q.
The first injection will be administered by an unblinded administrator/trainer and used to train the subject on correct injection technique.  The second 
injection will be administered by the subject (or caregiver, if applicable) under observation of the unblinded administrator/trainer.
r.
When not at the site, subjects (or caregiver, if applicable) will be encouraged to administer investigational product in the morning whenever possible; 
however, on study visit days, subjects (or caregiver, if applicable) are to be instructed to refrain from dosing at home, and are to administer investigational 
product in the clinic under observation.  If any issues with injection technique are observed, the unblinded administrator/trainer must retrain the subject (or 
caregiver, if applicable) appropriately.
s.
Subjects who complete EOT will be assessed for eligibility for participation in long-term extension study B7451015 as noted in Section 6.2.9. 
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t.
Site staff is to administer the C-SSRS 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 7.5.1, and Section 7.5.2.  
For subjects meeting exclusionary results on the C-SSRS or 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.
 
 
 
v.
Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD) will be conducted to assess the severity and frequency of pruritus, symptoms and sleep 
and collected daily in a subject eDiary during the screening period and from Day 1 through the End of Study visit in selected countries (See Section 7.9.8).  
At the Screening visit, site staff will dispense the eDiary 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. 
 
 
x.
The contraception check is an opportunity to confirm that contraception, if required, is used consistently and correctly.
y.
A serum sample will be collected at baseline but analyzed only if the subject has a suspected viral reactivation. 
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Appendix 9. Abbreviations
Abbreviation
Term
AD
atopic dermatitis
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
Analysis of Covariance
AST
aspartate aminotransferase
BSA
body surface area
CaPS
CDISC and Pfizer Standards
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CMH
Cochran-Mantel-Haenszel
CO2
carbon dioxide
CsA
cyclosporine A
CSR
clinical study report
C-SSRS
Columbia Suicide Severity Rating Scale
DLQI
Dermatology Life Quality Index
DMC
data monitoring committee
EASI
Eczema Area and Severity Index
EASI-100
Response based on achieving 100% 
improvement from baseline in Eczema Area and 
Severity Index 
EASI-50 
Response based on achieving ≥50% 
improvement from baseline in Eczema Area and 
Severity Index 
EASI-75 
Response based on achieving ≥75% 
improvement from baseline in Eczema Area and 
Severity Index 
EASI-90
Response based on achieving ≥90% 
improvement from baseline in Eczema Area and 
Severity Index 
ECG
electrocardiogram
ED
early discontinuation
e-Diary
electronic diary
E-DMC
external data monitoring committee
EOS
End of Study
EOT
End of Treatment
EQ-5D-5L
EuroQol Quality of Life 5-Dimension 5-Level 
Scale
EU
European Union
FAS
full analysis set
FDA
Food and Drug Administration
GGT
gamma-glutamyl transferase
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Abbreviation
Term
GLMM
Generalized Linear Mixed Model 
HADS
Hospital Anxiety and Depression Scale
ID
identification
IGA
Investigator’s Global Assessment
LDH
lactate dehydrogenase
LDL
low-density lipoprotein
LFT
liver function test
LLQ
lower limit of quantification
LSM
Least squares mean
LTE
long-term extension
MAR
missing at random
MCAR
Missing completely at random
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCMC
Markov Chain Monte Carlo
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed-effect model with repeated measures
MNAR
missing not at random
MTX
methotrexate
N/A
not applicable
NB-UVB
narrowband ultraviolet B light
NRS
numerical rating scale
NRS4
improvement in the severity of Pruritus NRS 
from baseline by at least 4 points
PCD
primary completion date
PDE4
phosphodiesterase 4
PFS
prefilled syringe
PHQ-8
Patient Health Questionnaire - 8 items
PK
Pharmacokinetic(s)
POEM
Patient-Oriented Eczema Measure
PPAS
per-protocol analysis set
PRO
patient reported outcome
Pruritus NRS4
improvement in the severity of Pruritus NRS 
from baseline by at least 4 points
PtGA
Patient Global Assessment
Q2W
every two weeks
QD
once daily
QoL
quality of life
RBC
red blood cell
REML
restricted maximum likelihood 
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Abbreviation
Term
SAE
serious adverse event
SAP
statistical analysis plan
SCORAD
SCORing atopic dermatitis
SCORAD50
Response based on achieving ≥50% 
improvement in SCORAD
SCORAD75
Response based on achieving ≥75% 
improvement in SCORAD
SoA
schedule of activities
SOC
system organ class
TB
Tuberculosis
TCI
topical calcineurin inhibitors
TCS
topical corticosteroids
TEAE
Treatment-Emergent Adverse Event
TP
Tipping Point 
US
United States
UVA
ultraviolet A light
UVB
ultraviolet B light
VAS
Visual Analogue Scale
WBC 
white blood cell
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