Clinical trial NCT03796676
Conditions: Atopic Dermatitis
Keywords: Atopic Dermatitis, JAK1 inhibitor
Sponsor: Pfizer
Start date: 2019-02-18; Completion date: 2020-04-08
Enrollment: 287 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, double blind, placebo controlled, parallel group, Phase 3 study to evaluate the efficacy and safety of PF 04965842 in adolescent participants 12 to \<18 years of age with moderate to severe AD.

Detailed description:
This is a randomized, double blind, placebo controlled, parallel group, Phase 3 study to evaluate the efficacy and safety of PF 04965842 in adolescent participants 12 to \<18 years of age with moderate to severe AD. Participants will be screened within 28 days prior to the first dose of study intervention to confirm study eligibility. Subjects must have moderate-severe AD involving at least 10% Body Surface Area (BSA); an Investigator Global Assessment (IGA) score of at least 3; an Eczema Area Severity Index (EASI) of at least 16 and Peak Pruritus Numerical Rating Score (NRS) of at least 4 on baseline/Day 1. Eligible subjects will be randomized at the Baseline/Day 1 visit. Approximately 225 participants will be randomized in a 1:1:1 ratio to receive once daily PF 04965842 at 200 mg, 100 mg, or placebo for 12 weeks. Randomization will be stratified by baseline disease severity (moderate \[IGA = 3\] vs. severe \[IGA = 4\] AD). The investigational products will be administered QD for 12 weeks. Background therapy (medicated and non-medicated topical therapy) must be applied BID for the duration of the treatment period. The co-primary efficacy endpoints are an IGA score of clear (0) or almost clear (1) with a reduction from baseline of greater than 2 points at Week 12 AND an at least 75% improvement of the EASI score (EASI-75) at week 12. Safety and efficacy assessments will be conducted at the investigator site by a clinical assessor blinded to treatment assignment. Scheduled clinic or telephone study visits for all subjects will occur at Screening, Baseline/Day 1, Day 8 (by phone), Day 15, Day 29, Day 43 (by phone), Day 57, Day 85 (End of treatment/Early termination), Day 113 (End of Study). Participants discontinuing early from the study will undergo a 4 week follow up period.

This study includes an immunogenicity sub study integrated into the last 4 weeks of the main study treatment period. At Week 8, up to approximately 90 participants (up to approximately 30 in each treatment arm) who have completed 8 weeks of treatment with study intervention will receive a tetanus, diphtheria and acellular pertussis combination vaccine (Tdap), and collection of blood samples for the evaluation of immunogenicity at Weeks 8 and 12. Participants of this sub study will complete all other protocol specified procedures in the main study.

At the end of the 12 week study treatment, qualified participants completing the study will have the option to enter the long term extension (LTE) study B7451015.

Arms: arm 1: Placebo arm 2: active arm 3: active
Interventions: intervention 1: Placebo intervention 2: PF-04965842 intervention 3: PF04965842
Intervention descriptions: intervention 1: Placebo intervention 2: 100 mg QD intervention 3: 200 mg QD

Protocol documents:
Prot_000.pdf: 
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SAP_001.pdf: 
Protocol B7451036 (PF-04965842) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 1
Protocol B7451036
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
MULTI-CENTER STUDY INVESTIGATING THE EFFICACY AND SAFETY OF 
PF-04965842 CO-ADMINISTERED WITH BACKGROUND MEDICATED TOPICAL 
THERAPY IN ADOLESCENT PARTICIPANTS 12 TO <18 YEARS OF AGE WITH 
MODERATE-TO-SEVERE ATOPIC DERMATITIS
Statistical Analysis Plan 
(SAP)
Version:
2.0
Date: 16 April 2020 
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Protocol B7451036 (PF-04965842) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 3
5.2.1. Analyses for Binary Endpoints...................................................................22
5.2.2. Analyses of Non-Longitudinal Continuous Data .......................................23
5.2.3. Analyses of Longitudinal Continuous Data................................................23
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 ......................................................................................26
6.1. Primary Endpoint(s) ................................................................................................26
6.1.1. Week 12 IGA Response..............................................................................26
6.1.1.1. Main Analysis ...........................................................................26
6.1.1.2. Sensitivity/Supplementary Analyses.........................................26
6.1.2. Week 12 EASI-75 Response ......................................................................27
6.1.2.1. Main Analysis ...........................................................................27
6.1.2.2. Sensitivity/Supplementary Analyses.........................................27
6.2. Secondary Endpoint(s) ............................................................................................28
6.2.1. Key Secondary Endpoint - Weeks 2, 4, and 12 Peak Pruritus NRS4 
Response ..........................................................................................................28
6.2.2. Key Secondary Endpoint - Change from Baseline in PSAAD at 
Week 12 ...........................................................................................................28
6.2.3. Secondary Efficacy Endpoints....................................................................29
6.2.3.1. Binary Endpoints.......................................................................29
6.2.3.2. Time to Achieve at Least 4 Points Improvement in the 
Peak Pruritus NRS from Baseline .....................................................29
6.2.3.3. Continuous Endpoints ...............................................................30
6.2.3.4. Week 12 Corticosteroid-free Days............................................31
6.2.4. Patient Reported Outcomes ........................................................................31
6.2.4.1. Continuous Endpoints ...............................................................31
6.2.4.2. Change from Baseline at Week 12 in Peds FACIT-F ...............32
6.2.4.3. Binary Endpoints.......................................................................32
090177e19618b8f5\Approved\Approved On: 25-Jan-2021 08:47 (GMT)


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090177e19618b8f5\Approved\Approved On: 25-Jan-2021 08:47 (GMT)


Protocol B7451036 (PF-04965842) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 5
APPENDICES
Appendix 1. Summary of Efficacy Analyses...........................................................................40
Appendix 2. Definition and Use of Visit Windows in Reporting............................................42
Appendix 3. A Logistic-normal GLMM for Longitudinal Binary Data and Tipping 
Point Analysis.......................................................................................................43
Appendix 4. Investigators Global Assessment ........................................................................46
Appendix 5. Eczema Area and Severity Index (EASI)............................................................47
Appendix 6. Peak Pruritus Numerical Rating Scale (NRS).....................................................50
Appendix 7. Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD) 
Symptom Diary.....................................................................................................51
Appendix 8. Scoring Atopic Dermatitis (SCORAD)...............................................................55
Appendix 9. Abbreviation List ................................................................................................56
090177e19618b8f5\Approved\Approved On: 25-Jan-2021 08:47 (GMT)


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090177e19618b8f5\Approved\Approved On: 25-Jan-2021 08:47 (GMT)


Protocol B7451036 (PF-04965842) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 7
•
Updated method to manage missing data for 
binary endpoints. See sections 5.3.1 and 
Appendix 3.
•
Updated study treatment exposure definitions 
and summaries in Section 6.5.3.
•
Updated concomitant/background 
medications and non-drug treatment 
summaries in Section 6.5.4.
•
Additional minor changes to improve clarity 
and alignment with the protocol.
2. INTRODUCTION
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study B7451036.  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, Endpoints, and Estimands
Study objectives and corresponding endpoints are provided in the Table 2 below.
Table 2.
Study Objectives and Endpoints
Objectives
Endpoints
Primary
•
To assess the efficacy of 
PF-04965842 compared with 
placebo when co-administered with 
background medicated topical 
therapy in adolescent participants 
12 to <18 years of age with 
moderate-to-severe AD.
Co-primary endpoints
•
Response based on the Investigator's 
Global Assessment (IGA) score of 
clear (0) or almost clear (1) (on a 
5 point scale) and a reduction from 
baseline of ≥2 points at Week 12;
•
Response based on the Eczema Area 
and Severity Index 
≥75% improvement from baseline 
(EASI-75) response at Week 12.
Secondary
•
To evaluate the effect of 
PF-04965842 co-administered with 
background medicated topical 
therapy on additional efficacy 
endpoints and patient reported 
outcomes over time in adolescent 
Key Secondary Endpoints
•
Response based on at least 4 points 
improvement in the Peak Pruritus 
Numerical Rating Scale (PP-NRS)
from baseline at Weeks 2, 4, and 12;
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Protocol B7451036 (PF-04965842) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 8
participants 12 to <18 years of age 
with moderate-to-severe AD.
•
Change from baseline in Pruritus 
and Symptoms Assessment for 
Atopic Dermatitis (PSAAD) total 
score at Week 12. 
Secondary Efficacy Endpoints
•
Response based on at least 4 points 
improvement in the Peak Pruritus 
NRS from baseline at all scheduled 
time points other than Weeks 2, 4 
and 12;
•
Time to achieve at least 4 points 
improvement in the Peak Pruritus 
NRS from baseline;
•
Response based on the EASI-75 at 
all scheduled time points except 
Week 12; 
•
Response based on the IGA of clear 
(0) or almost clear (1) and 2 point 
reduction from baseline at all 
scheduled time points except 
Week 12.
Other Efficacy Endpoints
•
Response based on a ≥50%, ≥90% 
and 100% improvement in the EASI 
total score (EASI-50, EASI-90 and 
EASI-100) at all scheduled time 
points;
•
Change from baseline and Percent 
change from baseline in the 
percentage Body Surface Area 
(BSA) affected at all scheduled time 
points;
•
Response based on affected BSA 
<5% at Week 12; 
•
Response based on a ≥50% and 
≥75% improvement in Scoring 
Atopic Dermatitis (SCORAD50, 
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Protocol B7451036 (PF-04965842) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 9
SCORAD75) from baseline at all 
scheduled time points;
•
Percent Change from Baseline in
EASI at all scheduled time points;
•
Change from baseline and Percent 
change from baseline at all 
scheduled time points in Scoring 
Atopic Dermatitis (SCORAD) total 
score and subjective assessments of 
sleep loss;
•
Percent Change from Baseline in 
PP-NRS at all scheduled time 
points;
•
Week 12 Corticosteroid-free days.
Patient-Reported Outcomes
•
Change from baseline at Week 12 in 
Children's Dermatology Life 
Quality Index (CDLQI) and at all
other scheduled time points;
•
Change from baseline at Week 12 in 
Hospital Anxiety and Depression 
Scale (HADS) and at all other 
scheduled time points;
•
Change from baseline at Week 12 in 
Patient Oriented Eczema Measure 
(POEM) and at all other scheduled 
time points; 
•
Change from baseline at Week 12 in 
Dermatitis Family Impact (DFI) 
questionnaire;
•
Change from baseline of Patient 
Global Assessment (PtGA) at 
Week 12 and at all other scheduled 
time points; 
•
Change from baseline of EuroQol 
Quality of Life 5 Dimension Youth 
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Protocol B7451036 (PF-04965842) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 10
Scale (EQ-5D-Y) at Week 12 and at 
all other scheduled time points;
•
Change from baseline of Pediatric 
Functional Assessment of Chronic 
Illness Therapy Fatigue Scale (Peds 
FACIT-F) at Week 12 and at all 
other scheduled time points;
•
Response based on Achieving 
≥2.5-point Improvement from 
Baseline in the CDLQI Score at all 
scheduled time points;
•
Response based on the PtGA of 
clear (0) or almost clear (1) (on a 
5 point scale) and a reduction from 
baseline of ≥2 points at all 
scheduled time points.
Immunogenicity Sub-Study Objective
Immunogenicity sub-study endpoint
•
To evaluate the effect of 
PF-04965842 on the 
immunogenicity to Tdap vaccine in 
adolescent participants 
12 to <18 years of age with 
moderate-to-severe AD.
•
Fold increase from baseline at 4 weeks 
post-vaccination in concentrations of 
IgG against:
•
Tetanus toxoid;
•
Diphtheria toxoid;
•
Pertussis toxoid;
•
Pertactin (PRN);
•
Filamentous hemagglutinin (FHA);
•
Fimbriae types 2 and 3 (FIM).
Safety Objective 
Safety Endpoints
•
To evaluate the safety and 
tolerability of PF-04965842 
co-administered with background 
medicated topical therapy in 
adolescent participants 
12 to <18 years of age with 
moderate-to-severe AD.
•
Incidence of treatment emergent 
adverse events;
•
Incidence of SAEs;
•
Incidence of AEs leading to 
discontinuation;
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•
Population: Participants with moderate-to-severe AD as defined by the inclusion 
criteria to reflect the targeted participant population;
•
Variable: Change from baseline in Pruritus and Symptoms Assessment for Atopic 
Dermatitis (PSAAD) total score at Week 12;
•
Intercurrent event: All data collected will be utilized;
•
Population-level summary: Difference in least-square means between each 
PF-04965842 dose and placebo.
Change from baseline or Percent change from baseline to each specific post baseline 
scheduled time points in a continuous outcome measure such as total scores obtained from 
EASI, NRS, SCORAD, %BSA, PtGA, HADS, POEM, CDLQI, EQ-5D-Y, DFI, Peds 
FACIT-F will follow the same structure as defined for PSAAD.
2.1.3. Additional Estimand(s)
2.1.3.1. Treatment Policy Estimand (Estimand 3)
A supplemental analysis of the co-primary endpoints will be based on the treatment policy 
estimand as described below: 
•
Population: Participants with moderate-to-severe AD as defined by the inclusion 
criteria to reflect the targeted participant population;
•
Variable: Response based on IGA at Week 12;
•
Intercurrent event: All data collected will be utilized;
•
Population-level summary: Proportion of participants who are responders in each 
treatment group and differences in proportions of responders between each 
PF-04965842 dose and placebo.
Response based on EASI-75 at Week 12 will follow the same structure as defined for IGA.
2.2. Study Design
This is a randomized, double blind, placebo controlled, parallel group, Phase 3 study to 
evaluate the efficacy and safety of PF-04965842 in adolescent participants 12 to <18 years of 
age with moderate-to-severe AD co administered with background topical therapy.  A total of 
approximately 225 participants will be enrolled from approximately 100 sites located 
globally.  Participants will be randomized in a 1:1:1 ratio to receive 200 mg PF-04965842 
(N=75) or 100 mg PF-04965842 QD (N=75) or matching placebo (N=75) from Day 1.
Randomization will be stratified by baseline disease severity (moderate [IGA = 3] vs. severe 
[IGA = 4] AD).  The treatment period is 12 weeks.  
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In a sub-study, up to approximately 90 participants (up to 30 in each respective study group) 
who have completed 8 weeks of treatment with study intervention will receive a tetanus, 
diphtheria and pertussis combination vaccine (Tdap) at Week 8, and will have blood samples 
collected for the evaluation of immunogenicity to the vaccine at Weeks 8 and 12.  The 
participants in the immunogenicity sub-study will complete all other protocol-specified 
procedures in the main study.  A study design schematic is presented in Figure 1.
Qualified participants completing 12-week treatment with study intervention will have the 
option to enter the long-term extension (LTE) study B7451015.  Participants discontinuing 
early from the study will undergo a 4 week follow up.
Figure 1.
Study Design
Intervention Groups and Duration:
Eligible participants will be randomized into 3 intervention groups in the main study:
Group 1 (N=75): 200 mg PF-04965842 once daily (QD) for 12 weeks (Sub-study: N=up 
to 30, Tdap vaccination at Week 8).
Group 2 (N=75): 100 mg PF-04965842 QD for 12 weeks (Sub-study: N=up to 30, Tdap 
vaccination at Week 8).
Group 3 (N=75): placebo QD for 12 weeks (Sub-study: N=up to 30, Tdap vaccination at 
Week 8).
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Sample Size Determination
A total sample of 225 participants, with 75 participants randomized to PF-04965842
200 mg QD, 75 participants randomized to PF-04965842 100 mg QD, 75 participants 
randomized to matching placebo (1:1:1 randomization) is planned. This would provide at 
least 80% 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 96% 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.
The familywise Type I error rate (for testing the co-primary and key secondary endpoints) 
will be strongly controlled at 5% (2-sided) using a closed-testing method based on a 
sequential, iterative Bonferroni type approach as outlined in Section 5.1.
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint(s)
The co-primary efficacy endpoints are:
•
IGA response: Response based on the IGA score of clear (0) or almost clear (1); and a 
reduction from baseline of ≥2 points at Week 12.
•
EASI-75 response: 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 Endpoint(s)
3.2.1. Key Secondary Efficacy Endpoints
The key secondary efficacy endpoints are:
•
Response based on ≥4 points improvement from baseline in the Peak Pruritus 
Numerical Rating Scale (NRS) from baseline at Weeks 2, 4, and 12.
•
Change from baseline in Pruritus and Symptoms Assessment for Atopic Dermatitis 
(PSAAD) total score at Week 12.
Detailed descriptions of how the Peak Pruritus NRS and PSAAD are derived are provided in 
Appendix 6 and Appendix 7, respectively. 
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Protocol B7451036 (PF-04965842) Statistical Analysis Plan
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3.2.2. Secondary Efficacy Endpoints
•
Response based on at least 4 points improvement in the Peak Pruritus NRS from 
baseline at all scheduled time points other than Weeks 2, 4 and 12.
•
Time to achieve at least 4 points improvement in the Peak Pruritus NRS from 
baseline.
•
Response based on the EASI-75 at all scheduled time points except Week 12.
•
Response based on the IGA of clear (0) or almost clear (1) and 2 point reduction from 
baseline at all scheduled time points except Week 12.
•
Response based on a ≥50%, ≥90% and 100% improvement in the EASI total score 
(EASI-50, EASI-90 and EASI-100) at all scheduled time points.
•
Change from baseline and Percent Change from Baseline in the percentage Body 
Surface Area (BSA) affected at all scheduled time points.
•
Response based on BSA <5% at Week 12.
•
Percent Change from Baseline in EASI at all scheduled time points.
•
Response based on a ≥50% and ≥75% improvement in Scoring Atopic Dermatitis 
(SCORAD50, SCORAD75) from baseline at all scheduled time points.
•
Change from baseline and Percent Change from Baseline at all scheduled time points 
in Scoring Atopic Dermatitis (SCORAD) total score and subjective assessments sleep 
loss.
•
Percent Change from Baseline in Peak Pruritus numerical rating scale (PP-NRS) from 
Days 2-15, Weeks 4, 8 and 12.
•
Week 12 Corticosteroid-free days.
•
Detailed descriptions of how the BSA and SCORAD are derived are provided in 
Appendix 5 and Appendix 8 respectively.
3.3. Other Endpoint(s)
3.3.1. Patient-Reported Outcomes
•
Change from baseline at Week 12 in Children's Dermatology Life Quality Index 
(CDLQI) and at all other scheduled time points.
•
Change from baseline at Week 12 in Hospital Anxiety and Depression Scale (HADS) 
and at all other scheduled time points.
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Tier-2 events: These are events that are not tier 1 but are “common”. A Medical Dictionary 
for Regulatory Activities (MedDRA) preferred term (PT) is defined as a Tier-2 event if there 
are at least 4 in any treatment group.
Tier-3 events: These are events that are neither Tier-1 nor Tier-2 events.
3.5.2. Laboratory Data
Below is a list of hematology and serum chemistry test parameters.
•
Hematology: hemoglobin, hematocrit, red blood cell count and indices, reticulocyte 
count, platelet count, white blood cell count with differential, total neutrophils, 
eosinophils, monocytes, basophils, lymphocytes, lymphocyte subsets (markers), 
coagulation panel.
•
Serum chemistry: blood urea nitrogen, creatinine, creatine phosphokinase, glucose
(non-fasting), sodium, potassium, chloride, calcium, 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.
Detailed descriptions of the laboratory data and other tests are in the B7451036 Protocol 
Appendix 2.
3.5.3. Vital Signs, including Height and Weight
Vital sign measurements are pulse rate and blood pressures.
Height and weight are collected at pre- and post-treatment.
3.5.4. Physical Examinations
Complete physical examinations consist of assessments of general appearance; skin; head, 
eyes, ears, nose and throat; mouth, heart; lungs; breast (optional); abdomen; external 
genitalia (optional); extremities; neurologic function; and lymph nodes.
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
Data for all participants will be assessed to determine if participants 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.
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Protocol B7451036 (PF-04965842) Statistical Analysis Plan
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Population
Description
Full Analysis Set (FAS)
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention.  Participants will 
be analysed according to the intervention they are randomized 
to. 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.
Per-Protocol Analysis Set 
(PPAS)
The Per Protocol Analysis Set (PPAS) is defined as a subset of 
FAS who had no major protocol violations.  The subjects 
excluded from the PPAS will be determined and documented 
before the study is unblinded.  This set will include subjects 
who:
•
Met inclusion criteria 1: be 12 to <18 years of age, 
inclusive, at the time of signing the informed consent.
•
Had valid and non-missing baseline efficacy data (IGA, 
EASI).
•
Met inclusion criteria 2 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).
•
Did not take a protocol prohibited (CYP2C19/CYP2C9 
inhibitor and/or inducer drugs) concomitant 
medication.
•
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 treatment days and had used at 
least one medicated background topical therapy during 
treatment period.
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Population
Description
•
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.
Safety Analysis Set (SAF) All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention. Participants will 
be analysed according to the intervention they actually 
received.
Immunogenicity 
Sub-study Analysis Set
All eligible participants participating in the sub-study. The 
sub-study participants will remain in their treatment groups as 
previously randomized in the main study.
FAS is the analysis set for all the estimands defined in Section 2.1.
5. GENERAL METHODOLOGY AND CONVENTIONS
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.
The familywise Type‑I error rate for assessing the co‑primary and key secondary endpoints 
will be strongly controlled at 5% (2-sided) using a sequential, Bonferroni‑based iterative 
multiple testing procedure.
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 all subsequent 
hypotheses will not be considered statistically significant.  If this hypothesis is rejected, then 
assessing for statistical significance will continue as follows:
•
The hypothesis for severity of pruritus (Peak Pruritus NRS4) 200 mg QD vs placebo 
at Week 2 will be assessed at the 2.5% level.  If this hypothesis is rejected, then the 
unused alpha level of 2.5% will be passed on to the assessment for the key secondary 
endpoints and the co-primary endpoints for 100 mg QD vs placebo, in the order 
specified in Sequence A at a 5% significance level (see figure below).  All subsequent 
hypotheses from any point where a hypothesis cannot be rejected will not be 
considered statistically significant.
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•
If the hypothesis for severity of pruritus (Peak Pruritus NRS4) 200 mg QD vs placebo 
at Week 2) is not rejected at the 2.5% level, then the hypotheses for the key secondary 
endpoints and the co-primary endpoints for 100 mg QD vs placebo, in the order 
specified in Sequence A will be assessed at a 2.5% significance level (see figure 
below).  If all hypotheses in this sequence are rejected, then the unused alpha level of 
2.5% will be passed on to the assessment of the hypothesis for severity of pruritus 
(200 mg QD vs placebo) at Week 2 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 (Figure 2) illustrates the procedure showing the sequence of the tests.  
Hypotheses for all other endpoints not described here are to be tested at the nominal
5% (2-sided) significant level, without adjusting for multiple comparisons.
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 active treatment groups, PF-04965842 200 mg QD, PF-04965842 
100 mg QD and placebo. 
5.2.1. Analyses for Binary Endpoints
Binary data at each scheduled visit will generally 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 (IGA = 3 or IGA = 4); 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.
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).
For the Immunogenicity Sub study, the Clopper-Pearson exact method will be used to 
compute the associated 95% confidence interval for each treatment, while unconditional 
exact method proposed by Chan and Zhang will be used to compute the difference in 
proportions.
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5.2.2. Analyses of Non-Longitudinal Continuous Data
The non-longitudinal continuous data will generally 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. The model will be used in the analysis of Change from Baseline 
at Week 12 in Peds FACIT-F.
For the Immunogenicity Sub-Study, natural logarithm of the IgG concentration data will be 
used for analysis. For the fold increase 4 weeks post-vaccination the ratio (post: pre) of 
concentration values will be calculated.  Ratio values will be logarithmically transformed for 
analysis purposes.  The geometric mean fold rise (GMFR) and geometric standard deviation 
of these fold rises will be calculated for each treatment arm.  A 95% CI for this GMFR and 
the GMFR ratio will be constructed by back transformation of the CI for the logarithmically 
transformed GMFRs and the difference computed using the Student’s t distribution.
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 variance 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 participant 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 participant
has already experienced the event. For all participants 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 participant experienced the associated event.
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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, quartiles and probabilities of an event at particular points in time 
will be estimated by the Kaplan-Meier method. Ninety five percent CIs for median and 
quartiles will 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.
5.2.6. Analyses of Tier-1 and Tier-2 Events
Number and percentage of participants 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).5 Tier-2 events will be analyzed using asymptotic methods 
proposed by Miettinen and Nurminen (1985).3 Risk differences (each PF-04965842 dose 
compared to placebo) 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 and the placebo group), visit (Weeks 2, 4, 8
and 12) and treatment by visit interaction. Visit will be modeled as a categorical covariate. 
A subject specific random intercept will be used to model the correlation within a subject 
over time (see Appendix 3). Missing observations for the active groups (PF-04965842
200 mg QD and 100 mg QD) 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 
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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 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)4 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 CDLQI, HADS, POEM, DFI, PtGA, EQ-5D-Y 
and Peds FACIT-F, rules suggested by the developers of these instruments will be followed 
in calculating the missing values. If these rules are not enough for imputing a value, then the 
missing values will be handled in the same way as non-PRO variables.
Only available measurements will be used when taking a simple average for the analysis for 
a time point (eg, Week 12 PSAAD).
5.3.3. Time to Event Endpoints
For time-to-event endpoints, participants 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 participant experienced the associated event (ie, the event of interest is presumed to have 
occurred beyond this time point).
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6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint(s)
6.1.1. Week 12 IGA Response
6.1.1.1. Main Analysis
•
Estimand strategy: Composite, Estimand 1(Section 2.1.1).
•
Analysis set: FAS (Section 4). 
•
Analysis methodology: CMH and normal approximation in Section 5.2.1.
•
Intercurrent events and missing data: The intercurrent event is captured through the 
variable definition; for participants who drop out for any reason, the response will be 
defined as “non-responsive” after that point.
•
The number of participants, number and percent of response at Week 12 along with 
the 95% confidence interval by normal approximation will be presented for each 
treatment arm.
•
The CMH test p-value, the estimate of the difference in proportions of response at 
Week 12 along with the corresponding 95% confidence interval by CMH normal 
approximation will be presented for each PF-04965842 dose group versus placebo.
6.1.1.2. Sensitivity/Supplementary Analyses
6.1.1.2.1. Supplementary Analysis - PPAS 
An analysis that assesses the primary endpoint on the analysis set PPAS (Section 4).  It will 
use the same methodology and summary as the main analysis. 
6.1.1.2.2. Supplementary Analysis – Treatment Policy Estimand 
•
Estimand strategy: Treatment Policy, Estimand 3 (Section 2.1.3).
•
Analysis set: FAS (Section 4). 
•
Analysis methodology: IGA response will be analyzed using a tipping point analysis 
in Section 5.3.1 including data from Weeks 2, 4, 8 and 12.
•
Intercurrent events and missing data: All data collected will be utilized; missing 
values will be handled through multiple imputations as described by Tipping Point 
Analysis (Section 5.3.1 and Appendix 3).
•
The number of participants, the number and percent of participants with missing 
response, and the estimate of response percentage at Week 12 along with the 
corresponding 95% confidence interval will be presented for each treatment arm.
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•
The estimate of the difference in proportions of response at Week 12 along with the 
corresponding p value and 95% confidence interval will be presented will be 
presented for each PF-04965842 dose group versus placebo. 
6.1.2. Week 12 EASI-75 Response
6.1.2.1. Main Analysis
•
Estimand strategy: Composite, Estimand 1 (Section 2.1.1).
•
Analysis set: FAS (Section 4). 
•
Analysis methodology: CMH and normal approximation in Section 5.2.1.
•
Intercurrent events and missing data: The intercurrent event is captured through the 
variable definition; for participants who drop out for any reason, the response will be 
defined as “non-responsive” after that point.
•
The number of participants, number and percent of response at Week 12 along with 
the 95% confidence interval by normal approximation will be presented for each 
treatment arm.
•
The CMH test p-value, the estimate of the difference in proportions of response at 
Week 12 along with the corresponding 95% confidence interval by CMH normal 
approximation will be presented for each PF-04965842 dose group versus placebo.
6.1.2.2. Sensitivity/Supplementary Analyses
6.1.2.2.1. Supplementary Analysis - PPAS 
An analysis that assesses the primary endpoint on the analysis set PPAS (Section 4).  It will 
use the same methodology and summary as the main analysis. 
6.1.2.2.2. Supplementary Analysis – Treatment Policy Estimand
•
Estimand strategy: Treatment Policy, Estimand 3 (Section 2.1.3).
•
Analysis set: FAS (Section 4). 
•
Analysis methodology: EASI-75 Response will be analyzed using a tipping point 
analysis in Section 5.3.1 including data from Weeks 2, 4, 8 and 12.
•
Intercurrent events and missing data: All data collected will be utilized; missing 
values will be handled through multiple imputations as described by Tipping Point 
Analysis (Section 5.3.1 and Appendix 3). 
•
The number of participants, the number and percent of participants with missing 
response, and the estimate of response percentage at Week 12 along with the 
corresponding 95% confidence interval will be presented for each treatment arm.
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•
The estimate of the difference in proportions of response at Week 12 along with the 
corresponding p value and 95% confidence interval will be presented will be 
presented for each PF-04965842 dose group versus placebo. 
6.2. Secondary Endpoint(s)
6.2.1. Key Secondary Endpoint - Weeks 2, 4, and 12 Peak Pruritus NRS4 Response
•
Estimand strategy: Composite, Estimand 1 (Section 2.1.1).
•
Analysis set: FAS (Section 4). 
•
Analysis methodology: CMH and normal approximation in Section 5.2.1.
Participants must have baseline PP-NRS ≥4 to be included in the analysis.
•
Intercurrent events and missing data: The intercurrent event is captured through the 
variable definition; for participants who drop out for any reason, the response will be 
defined as “non-responsive” after that point.
•
The number of participants, number and percent of response at each specified 
timepoints along with the 95% confidence interval by normal approximation will be 
presented for each treatment arm.
•
The CMH test p-value, the estimate of the difference in proportions of response at 
each specified timepoints along with the corresponding 95% confidence interval by 
CMH normal approximation will be presented for each PF-04965842 dose group 
versus placebo.
6.2.2. Key Secondary Endpoint - Change from Baseline in PSAAD at Week 12
•
Estimand strategy: Hypothetical, Estimand 2 (Section 2.1.2).
•
Analysis set: FAS (Section 4). Participants must have observed baseline measure to 
be included in the analysis.
•
Analysis methodology: MMRM in Section 5.2.3 including change from baseline data 
for each Week from Weeks 1 – 12.
•
Intercurrent events and missing data: All data collected will be utilized; a simple 
average of the available values recorded within a week will be used for the analysis as 
a weekly measure; if there’s no available values recorded within a week, PSAAD for 
the week is missing and will not be used for analysis.
•
Number of participants included in the analysis will be presented for each treatment 
arm.
•
The least square mean (LSM) of change from baseline in PSAAD along with the 
corresponding 95% confidence interval will be presented for each treatment arm at 
each Week.
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•
The LSM difference along with the corresponding p-value and 95% confidence 
interval will be presented for each PF-04965842 dose group versus placebo arm at 
each Week.
6.2.3. Secondary Efficacy Endpoints
6.2.3.1. Binary Endpoints
•
Endpoints:
•
PP-NRS4 Response each day from Days 2-15 and Week 8;
•
Weeks 2, 4 and 8 EASI-75, IGA Response;
•
Weeks 2, 4, 8 and 12 EASI-50, EASI-90, EASI-100 Response;
•
Weeks 2, 4, 8 and 12 SCORAD50, SCORAD75;
•
Weeks 2, 4, 8 and 12 BSA <5% Response.
•
Estimand strategy: Composite, Estimand 1(Section 2.1.1).
•
Analysis set: FAS (Section 4). Participants must have baseline PP-NRS ≥4 to be 
included in the analysis of PP-NRS4.
•
Analysis methodology: CMH and normal approximation in Section 5.2.1.
•
Intercurrent events and missing data: The intercurrent event is captured through the 
variable definition; for participants who drop out for any reason, the response will be 
defined as “non-responsive” after that point.
•
The number of participants, number and percent of response at each specified 
timepoints along with the 95% confidence interval by normal approximation will be 
presented for each treatment arm.
•
The CMH test p-value, the estimate of the difference in proportions of response at 
each specified timepoints along with the corresponding 95% confidence interval by 
CMH normal approximation will be presented for each PF-04965842 dose group 
versus placebo.
6.2.3.2. Time to Achieve at Least 4 Points Improvement in the Peak Pruritus NRS from 
Baseline 
•
Analysis set: FAS (Section 4). Participants must have baseline PP-NRS ≥4 to be 
included in the analysis.
•
Analysis methodology: Analyses for Time to Event Data in Section 5.2.5.
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•
Intercurrent events and missing data: For all participants who have not experienced 
the event, their time to event will be right censored at the last available measurement 
time.
•
The number of participants, number and percent of participants censored and 
participants with Peak Pruritus NRS4 Response will be provided for each treatment 
arm.
•
Estimated survival curves using the Kaplan-Meier method and number of patients at 
risk will be displayed graphically for each treatment arm. The 25%, 50% and 75% 
quartiles with their 95% confidence intervals will also be presented for each treatment 
arm.
•
The log-rank test (stratified using baseline disease severity) p-value will be presented 
for each PF-04965842 dose group versus placebo.
6.2.3.3. Continuous Endpoints
•
Endpoints:
•
Weeks 2, 4, 8 and 12 Change from Baseline and Percent Change from Baseline in 
%BSA;
•
Weeks 2, 4, 8 and 12 Percent Change from Baseline in EASI;
•
Weeks 2, 4, 8 and 12 Change from Baseline and Percent Change from Baseline in 
Total SCORAD score, SCORAD subjective assessments of sleep loss (VAS);
•
Percent Change from Baseline in PP-NRS from Days 2-15, Weeks 4, 8 and 12.
•
Estimand strategy: Hypothetical, Estimand 2 (Section 2.1.2).
•
Analysis set: FAS (Section 4). Participants must have observed baseline measure to 
be included in the corresponding analysis.
•
Analysis methodology: MMRM in Section 5.2.3.
•
Intercurrent events and missing data: All data collected will be utilized.
•
Number of participants included in the analysis will be presented for each treatment 
arm.
•
The least square mean (LSM) of change from baseline or percentage change from 
baseline along with the corresponding 95% confidence interval will be presented for 
each treatment arm at each specified time points.
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•
The LSM difference along with the corresponding p-value and 95% confidence 
interval will be presented for each PF-04965842 dose group versus placebo arm at 
each specified time points.
6.2.3.4. Week 12 Corticosteroid-free Days
•
Definition: Number of days when neither topical nor systemic corticosteroids was 
taken (from Day 1 up to Week 12/Day 88 during the study treatment exposure 
period).
•
Analysis set: FAS (Section 4). 
•
Analysis methodology: ANCOVA in Section 5.2.2.
•
Intercurrent events and missing data: All data collected will be utilized.
•
Number of participants, least square mean (LSM) along with the corresponding 
95% confidence interval will be presented for each treatment arm.
•
The LSM difference along with the corresponding p-value and 95% confidence 
interval will be presented for each PF-04965842 dose group versus placebo arm.
6.2.4. Patient Reported Outcomes 
6.2.4.1. Continuous Endpoints
•
Endpoints:
•
Weeks 2, 4, 8 and 12 Change from Baseline in in CDLQI, Anxiety and 
Depression Scales of HADS, POEM, DFI, PtGA and EQ-5D-Y (VAS score and 
index value).
•
Estimand strategy: Hypothetical, Estimand 2 (Section 2.1.2).
•
Analysis set: FAS (Section 4). Participants must have observed baseline measure to 
be included in the corresponding analysis.
•
Analysis methodology: MMRM in Section 5.2.3. 
•
Intercurrent events and missing data: All data collected will be utilized. 
•
Number of participants included in the analysis will be presented for each treatment 
arm.
•
The least square mean (LSM) of change from baseline along with the corresponding 
95% confidence interval will be presented for each treatment arm at each specified 
time points.
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•
The LSM difference along with the corresponding p-value and 95% confidence 
interval will be presented for each PF-04965842 dose group versus placebo arm at 
each specified time points.
6.2.4.2. Change from Baseline at Week 12 in Peds FACIT-F
•
Analysis set: FAS (Section 4). Participants must have observed baseline measure to 
be included in the analysis.
•
Analysis methodology: ANCOVA in Section 5.2.2.
•
Intercurrent events and missing data: All data collected will be utilized.
•
Number of participants, least square mean (LSM) along with the corresponding 
95% confidence interval will be presented for each treatment arm.
•
The LSM difference along with the corresponding p-value and 95% confidence 
interval will be presented for each PF-04965842 dose group versus placebo arm.
6.2.4.3. Binary Endpoints
•
Endpoints:
•
Weeks 2, 4, 8 and 12 Response based on Achieving ≥2.5-point Improvement from 
Baseline in the CDLQI Score;
•
Weeks 2, 4, 8 and 12 Response based on the PtGA of clear (0) or almost clear (1) 
(on a 5 point scale) and a reduction from baseline of ≥2 points at all scheduled 
time points.
•
Estimand strategy: Composite, Estimand 1(Section 2.1.1).
•
Analysis set: FAS (Section 4). Participants must have baseline CDLQI ≥2.5 to be 
included in the analysis of CDLQI. Participants must have baseline PtGA ≥2 to be 
included in the analysis of PtGA.
•
Analysis methodology: CMH and normal approximation in Section 5.2.1.
•
Intercurrent events and missing data: The intercurrent event is captured through the 
variable definition; for participants who drop out for any reason, the response will be 
defined as “non-responsive” after that point.
•
The number of participants, number and percent of response at each specified 
timepoints along with the 95% confidence interval by normal approximation will be 
presented for each treatment arm.
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Protocol B7451036 (PF-04965842) Statistical Analysis Plan
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•
Baseline disease severity (moderate, severe);
•
Baseline EASI group (16-25, >25);
•
Baseline % BSA group (10-30, >30-50, >50);
•
Previous use of systemic immunosuppressant for AD (Yes, No).
Estimates of the difference between the active dose groups and placebo, along with the 
95% confidence interval (no p-value) will be presented for each defined category of each 
subgroup. 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 participants.
Graphical display (eg, forest plots) of the differences between treatment groups will be 
presented, along with the Total difference. There is no intention to have any specific 
inference within subgroups.
6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline Summaries
Demographics and medical history including variables defined in Section 3.4 will be 
summarized by treatment group according to Pfizer standards.
6.5.2. Study Conduct and Participant Disposition
Participants evaluation, disposition, discontinuation will be summarized according to Pfizer 
standards.
6.5.3. Study Treatment Exposure
•
Duration of Treatment is defined as the total number of dosing days on which study 
drug was actually administered; if N total doses missed on unknown dates, it reduces 
the Duration of Treatment by N/2 (when N is an event 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%
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Protocol B7451036 (PF-04965842) Statistical Analysis Plan
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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%.
6.5.4. Concomitant Medications and Nondrug Treatments
Prior drug and non-drug treatment, concomitant drug and non-drug treatment will be 
summarized according to CaPS.
6.5.4.1. 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 6.5.2). “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);
•
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% and ≥80%.
6.6. 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 participants.
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 participant
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 
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6.6.3. Vital Signs, including Height and Weight
Vital signs will be summarized at Baseline and at Weeks 2, 4, 8 and 12.  Height will be 
reported at the Screening Visit and Week 12.  Weight will be summarized at baseline and 
Week 12.
6.6.4. Electrocardiograms
ECG parameters, if applicable, will be summarized at by visits.
6.6.5. Physical Examination
Physical examinations will be summarized at baseline and all-available post-baseline visits.
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 participants 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.
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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 IS, Zhang X.  Text-based exact confidence intervals for the difference of two 
binomial proportions.  Biometrics 1999; 55(4):1202-9.
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9. APPENDICES
Appendix 1. Summary of 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
Weeks 2, 4, and 12
NRS4 for severity 
Response
FAS
CMH
NR
Weeks 1-12 CFBL 
in PSAAD
FAS
MMRM
OD
Days 2-15 and
Week 8 NRS4 for 
Severity Response
FAS
CMH
NR
Time to NRS4 for 
severity
FAS
Time to Event
Weeks 2, 4 and 8
IGA, EASI-75
Response
FAS
CMH
NR
Weeks 2, 4, 8 and
12 EASI-50, 
EASI-90, 
EASI-100 
Response
FAS
CMH
NR
Weeks 2, 4, 8 and
12 Percent CFBL 
in Total EASI 
Score
FAS
MMRM
OD
Days 2-15, Weeks 
4, 8 and 12 Percent 
CFBL in NRS for 
severity
FAS
MMRM
OD
Weeks 2, 4, 8 and
12 CFBL and
Percent CFBL in 
%BSA
FAS
MMRM
OD
Weeks 2, 4, 8 and
12 SCORAD50, 
SCORAD75 
Response
FAS
CMH
NR
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Weeks 2, 4, 8 and
12 CFBL and 
Percent CFBL in
SCORAD Total
Score, 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 Visit Windows in Reporting
Visit windows will be used for efficacy variables, and for any safety data that display or 
summarize by study visit.  For other endpoints (eg, ECG, vital signs), visit windows will be 
applied for summary statistics by study visits if required.
Visit Label
Target Day
Definition [Day window]
Baseline
Day 1 (Day of first 
dose)
Last observation prior to and 
including day of first dose
Week 2
15
Days 2 to 22
Week 4
29
Days 23 to 43
Week 8
57
Days 44 to 71
Week 12
85
Days 72 to 99
Follow Up/End of Study
Week 16
113
Days 100 to -
For the lab values, if the calculated study day for the labelled baseline visit is not study Day 1 
but falls within 28 days before the start of the study dosing, then that data should be used for 
the baseline instead of leaving baseline missing.
For the other values, if the calculated study day for the labelled baseline visit is not study 
Day 1, but falls before the start of the study dosing, then that data should be used for the 
baseline instead of leaving baseline missing.
If two or more visits fall into the same window, keep the one closest to the Target Day.  If 
two visits are equaled distant from the Target Day in absolute value, the later visit should be 
used.
Observations on the actual day will be used to analyze Days 2-15 Pruritus NRS. Weeks 2, 4, 
8 and 12 Pruritus NRS will be based on the windowing method.
Safety analysis will 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, 4ሻ. 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
ସ
௝ୀଵ
ஶ
ିஶ
ே
௜ୀଵ
݀ݑ௜
There is no closed analytical form for this likelihood.
For the present study, the primary endpoint is evaluated at Visit 8 / Week 12 ሺ݆ൌ4ሻ. There 
are three treatment groups, so the model term ߚᇱݔ௜௝when written out looks like,
ߚ଴൅෍ߚଵ௞
ଷ
௞ୀଵ
ൈ1ሺ்೔ୀ௞ሻ൅ߚଶ௝൅෍ߚଷ௝௞
ଷ
௞ୀ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 (this can be changed using 
programming syntax) in standard statistical software is to assume ߚଵଷൌ0, ߚଶସൌ0, thereby 
interpreting ߚଵଵ, ߚଵଶas the difference in treatment effect relative to ܶൌ3 and ߚଶଵ, ߚଶଶ, ߚଶଷas 
the difference in visit effect relative to ܸൌ4. Consequently, ߚଷ௝௞ൌ0 when ݆ൌ4 or ݇ൌ3. 
So, for example, for a subject taking PF-04965842 100 mg QD at Week 12, the expression 
would be ߚ଴൅ߚଵଵ. For a subject taking PF-04965842 200 mg QD at Week 12, the 
expression would be ߚ଴൅ߚଵଶ. For a subject on placebo at Week 12, the expression would 
be ߚ଴.
Tipping Point Analysis
A method to analyze the longitudinal data of a binary endpoint measured during the 
placebo-controlled period (eg, IGA and EASI-75 response rates at Weeks 2, 4, 8 and 12) 
under the MNAR assumption is called the tipping point analysis.  This tipping point analysis 
includes 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 
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Protocol B7451036 (PF-04965842) Statistical Analysis Plan
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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, 10000ሻ  and assign a 
weakly informative prior for ߪଶas an Inverse-Gamma distribution with shape=1 and scale=1.  
With this prior distribution, the 90th percentile for ߪଶis approximately 9. 
Let ߚ௕, ݑ௜
௕, ܾൌ1, 2, … , ܤbe a sample from the posterior distribution.  A single imputation 
ܻప,ఫ௕
෪of missing ܻ௜௝is based on the posterior predictive distribution of the response 
probabilities estimated from the GLMM.  For example, if subject ݅is randomized to 
PF-04965842 100 mg QD ሺܶ௜ൌ1ሻ, then at Week 12 ሺܸൌ4ሻ,
݈݋݃݅ݐሺߨ௜,ଵ,ସ
௕
ሻൌ݈݋݃݅ݐቀܲሺܻప,ସ
௕
෪ൌ1|ܶ௜ൌ1, ܸൌ4ሻቁൌߚ଴
௕൅ߚଵଵ
௕൅ݑ௜
௕.
If subject ݅is randomized to PF-04965842 200 mg QD ሺܶ௜ൌ2ሻ, then at Week 12 ሺܸൌ4ሻ,
݈݋݃݅ݐሺߨ௜,ଶ,ସ
௕
ሻൌ݈݋݃݅ݐቀܲሺܻప,ସ
௕
෪ൌ1|ܶ௜ൌ2, ܸൌ4ሻቁൌߚ଴
௕൅ߚଵଶ
௕൅ݑ௜
௕.
If subject ݅is randomized to placebo ሺܶ௜ൌ3ሻ, then at Week 12 ሺܸൌ4ሻ,
݈݋݃݅ݐሺߨ௜,ଷ,ସ
௕
ሻൌ݈݋݃݅ݐቀܲሺܻప,ସ
௕
෪ൌ1|ܶ௜ൌ3, ܸൌ4ሻቁൌߚ଴
௕൅ݑ௜
௕.
In the tipping analysis, we apply a series of fixed quantities ߜൌሺߜଵ, ߜଶሻ′ to account for 
MNAR. We define,
ߨ௜,ଷ,ସ
∗௕
ൌߨ௜,ଷ,ସ
௕
,
ߨ௜,ଵ,ସ
∗௕
ൌߜଵߨ௜,ଷ,ସ
௕
൅ሺ1 െߜଵሻߨ௜,ଵ,ସ
௕
,
ߨ௜,ଶ,ସ
∗௕
ൌߜଶߨ௜,ଷ,ସ
௕
൅ሺ1 െߜଶሻߨ௜,ଶ,ସ
௕
We then sample the single imputed value ܻప,ఫ௕
෪from a Bernoulli distribution with probability 
of success ߨ௜,்೔,ସ
∗௕
. For the present analysis, the responses from the placebo arm are not 
shifted.
Analysis of an imputed data set will produce an estimate as well as standard error of the 
treatment difference using CMH and normal approximation in Section 5.2.1.  For a given 
value of MNAR parameter ߜ, this is repeated for B (typically, B=500) times to generate B
complete imputed data sets and these B sets of estimates are combined using the Rubin’s 
Method (Rubin, 1987).4  This can then be repeated for different values of MNAR 
parameter ߜto evaluate the impact of missing data. Note that ߜൌሺ0, 0ሻ′ corresponds to an 
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MAR analysis and ߜൌሺ1, 1ሻ′corresponds to an analysis commonly known as 
Jump-To-Reference (JTR).  As a special case, we will consider ߜଵൌߜଶfor our analyses.
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Appendix 4. Investigators Global Assessment
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
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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.
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).
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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)
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. Peak Pruritus Numerical Rating Scale (NRS)
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Appendix 8. Scoring Atopic Dermatitis (SCORAD)
SCORAD is a validated scoring index for atopic dermatitis, which combines extent (0-100), 
severity (0-18), and subjective symptoms (0-20) based on pruritus and sleep loss, each scored 
(0-10).
Extent (A, maximum of 100%): To determine extent of AD, rule of 9 is used to calculate 
body surface area affected by AD as a percentage of the whole body surface area.  Body 
surface area as percentage of total body surface area for each body region is as follows:
•
Head and neck 9%;
•
Upper limbs 9% each;
•
Lower limbs 18% each;
•
Anterior trunk 18%;
•
Back 18%;
•
1% for genitals.
The score for each body region is added up to determine the BSA affected by AD (A), which 
has a possible maximum of 100%.
Severity (B, maximum of 18): A representative area of AD is selected.  In this area, the 
severity of each of the following signs is assessed as none (0), mild (1), moderate (2) or 
severe (3).
•
Erythema (reddening);
•
Edema (swelling);
•
Oozing/crusting;
•
Excoriation (scratch marks);
•
Skin thickening (lichenification);
•
Xerosis (dryness) (this is assessed in an area where there is no inflammation).
The severity scores are added together to give 'B' (maximum of 18).
Subjective Symptoms (C, maximum of 20): Subjective symptom (ie, itch and 
sleeplessness) are each scored by the subject or caregiver using a numerical rating scale 
(NRS) where the score ranges from 0 to 10.  These scores are added to give 'C' (maximum 
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). 7B/2 + C (can range from 0 to 103).
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Abbreviation
Term
IGA Response
Response based on the Investigator's Global Assessment 
(IGA) score of clear (0) or almost clear (1) and a reduction 
from baseline of ≥2 points
JTR
Jump To Reference
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
Peak Pruritus NRS4
improvement in the Peak Pruritus NRS from baseline by at 
least 4 points
Peds-FACIT-F
Pediatric Functional Assessment of Chronic Illness Therapy 
Fatigue Scale
PK
Pharmacokinetic(s)
POEM
Patient-Oriented Eczema Measure
PPAS
per-protocol analysis set
PP-NRS
Peak Pruritus numerical rating scale
PP-NRS4
improvement in the severity of Pruritus NRS from baseline by 
at least 4 points
PRO
patient reported outcome
Pruritus NRS4
improvement in the severity of Pruritus NRS from baseline by 
at least 4 points
PSAAD
Pruritus and Symptoms Assessment for Atopic Dermatitis
PtGA
Patient Global Assessment
QD
once daily
QoL
quality of life
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Abbreviation
Term
RBC
red blood cell
REML
restricted maximum likelihood 
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
Tdap
tetanus, diphtheria and acellular pertussis combination 
vaccine
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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