A Phase 3 Randomized, Placebo-Controlled, Double-Blind Study to Evaluate Upadacitinib in Adolescent and Adult Subjects With Moderate to Severe Atopic Dermatitis
Phase: PHASE3
Conditions: Atopic Dermatitis
Sponsor: AbbVie

NCT03569293

STUDY M16-045  |  Version 6.0  |  EudraCT 2017-005125-20
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TABLE OF CONTENTS
1
SYNOPSIS
5
2
INTRODUCTION
8
2.1
BACKGROUND AND RATIONALE
8
2.2
BENEFITS AND RISKS TO SUBJECTS
8
3
STUDY OBJECTIVES AND ENDPOINTS
10
3.1
OBJECTIVES
10
3.2
CO-PRIMARY ENDPOINTS
10
3.3
SECONDARY ENDPOINTS
10
3.4
ADDITIONAL ENDPOINTS
12
3.5
SAFETY ENDPOINTS
14
3.6
PHARMACOKINETIC ENDPOINTS
14
3.7
BIOMARKER SAMPLES
14
4
INVESTIGATIONAL PLAN
15
4.1
OVERALL STUDY DESIGN AND PLAN
15
4.2
DISCUSSION OF STUDY DESIGN
16
5
STUDY ACTIVITIES
18
5.1
ELIGIBILITY CRITERIA
18
5.2
CONTRACEPTION RECOMMENDATIONS
23
5.3
PROHIBITED MEDICATIONS AND THERAPY
25
5.4
PRIOR AND CONCOMITANT THERAPY
29
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
31
5.6
FOLLOW-UP FOR SUBJECT WITHDRAWAL FROM STUDY
33
5.7
TREATMENT AFTER END OF STUDY
34
5.8
STUDY DRUG
34
5.9
PROTOCOL DEVIATIONS
37
5.10 OTHER STUDY PROCEDURES
38
6
SAFETY CONSIDERATIONS
60
6.1
COMPLAINTS AND ADVERSE EVENTS
60
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6.2
TOXICITY MANAGEMENT
67
6.3
DATA MONITORING COMMITTEE AND CARDIOVASCULAR ADJUDICATION COMMITTEE
72
6.4
OTHER SAFETY DATA COLLECTION
72
6.5
SUSAR REPORTING
73
7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
73
7.1
STATISTICAL AND ANALYTICAL PLANS
73
7.2
DEFINITION FOR ANALYSIS POPULATIONS
73
7.3
STATISTICAL ANALYSES FOR EFFICACY
75
7.4
STATISTICAL ANALYSES FOR SAFETY
76
7.5
PHARMACOKINETIC AND EXPOSURE-RESPONSE ANALYSES
76
7.6
STATISTICAL ANALYSIS OF IMMUNOPHENOTYPE DATA AND OPTIONAL PROTEOMIC BIOMARKER DATA
77
7.7
INTERIM ANALYSIS
78
8
ETHICS
78
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD (IEC/IRB)
78
8.2
ETHICAL CONDUCT OF THE STUDY
79
8.3
SUBJECT CONFIDENTIALITY
79
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
79
10 DATA QUALITY ASSURANCE
80
11 COMPLETION OF THE STUDY
81
12 REFERENCES
81
LIST OF TABLES
TABLE 1.
EXAMPLES OF COMMONLY USED STRONG CYP3A INHIBITORS AND INDUCERS
29
TABLE 2.
DESCRIPTION OF STUDY DRUG AND PLACEBO
34
TABLE 3.
SPECIFIC TOXICITY MANAGEMENT GUIDELINES FOR ABNORMAL LABORATORY VALUES
70
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LIST OF FIGURES
FIGURE 1.
STUDY SCHEMATIC
16
FIGURE 2.
INTERPRETATION AND MANAGEMENT OF HBV SEROLOGIC TEST RESULTS
56
LIST OF APPENDICES
APPENDIX A.
STUDY SPECIFIC ABBREVIATIONS AND TERMS
83
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
87
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
88
APPENDIX D.
ACTIVITY SCHEDULE
89
APPENDIX E.
PROTOCOL SUMMARY OF CHANGES
96
APPENDIX F.
OPERATIONS MANUAL
99
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2 INTRODUCTION
2.1 Background and Rationale
Why This Study Is Being Conducted
Evidence suggests that inhibition of Janus kinase (JAK)-mediated pathways may be a promising approach 
for the treatment of subjects with moderate to severe atopic dermatitis (AD).  Current treatment 
paradigms for AD suggest that there is a need for additional treatment options for patients.  More 
selective JAK inhibitors may decrease the risk for infection (including viral reactivation) and/or 
malignancy that are observed with pan JAK inhibitors or less selective JAK inhibitors.  AbbVie is 
developing a small molecule inhibitor of JAK, upadacitinib, that may address the current needs for 
subjects with AD.
The second generation of JAK inhibitors, with different selectivity profiles against JAK1, JAK2, JAK3, and 
tyrosine kinase 2, is in development.1  Upadacitinib (ABT-494) is a novel selective JAK1 inhibitor being 
developed for rheumatoid arthritis (RA), psoriatic arthritis (PsA), ulcerative colitis (UC), Crohn's disease 
(CD), and AD.  In an in vitro setting, upadacitinib potently inhibits JAK1 activity, but to a lesser degree, 
inhibits the other isoforms, JAK2 and JAK3.  The enhanced selectivity of upadacitinib against JAK1 may 
offer an improved benefit-risk profile in subjects with AD.  In the upadacitinib Phase 2 AD study, a 
statistically significant difference in the mean percent change from Baseline in EASI score at Week 16 
(primary endpoint) was observed for 7.5 mg (–39.4%; P = 0.032 vs placebo), 15 mg (–61.7%; P < 0.001 vs 
placebo) and 30 mg (–74.4%; P < 0.001 vs placebo) groups compared with placebo (–23.0%).  Through 
Week 16 (Period 1), the percentages of subjects with AEs, SAEs, severe AEs, and AEs leading to 
discontinuation were similar across treatment groups.  There were no deaths reported during Period 1.  
Additionally, upadacitinib was studied in rheumatoid arthritis with the results of two Phase 2 studies 
and two Phase 3 studies available as peer-reviewed manuscripts.2,3,4,5 Results from a Phase 2 study in 
AD showed that upadacitinib doses of 15 mg to 30 mg per day had efficacy and safety profile that can 
benefit patients with moderate to severe AD.
Clinical Hypothesis
Upadacitinib is expected to provide better efficacy compared to placebo and be well tolerated in 
adolescent and adult subjects with moderate to severe AD.
2.2 Benefits and Risks to Subjects
Treatment of AD in adolescent and adult subjects depends on the extent and severity of disease.  
Topical agents alone are commonly used for mild to moderate cases.  The most commonly used topical 
agents are corticosteroids, calcineurin inhibitor agents, and moisturizers.  When topical therapies are 
insufficient for treating the signs and symptoms of AD, systemic therapy or phototherapy are generally 
added to topical agents.6
Treatment guidelines developed by the American Academy of Dermatology recommend the use of 
systemic immunomodulatory agents for subjects in whom optimized topical regimens and/or 
phototherapy do not adequately control the signs and symptoms of disease.  These guidelines recognize 
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that insufficient data exist to firmly recommend optimal dosing, duration of therapy, and precise 
monitoring protocols for any systemic immunomodulating medication.7  Importantly, in addition to the 
lack of well-controlled efficacy data supporting their use in moderate to severe AD, the duration of use 
of many traditional systemic immunomodulatory agents are limited due to cumulative toxicity.
More recently, dupilumab, a monoclonal antibody that inhibits interleukin (IL)-4 and IL-13 signaling, has 
been approved for the treatment of moderate to severe eczema (AD) in adults.  Although dupilumab 
addresses the needs of some patients with moderate to severe AD, a large unmet need still exists in this 
population since, in the dupilumab Phase 3 studies (even when combined with TCS), fewer than 40% of 
patients achieved 0 or 1 on the Investigator's Global Assessment (IGA) scale; therefore, 60% or more of 
patients continued to experience significant symptoms on dupilumab therapy.8,9  Nearly 50% of 
dupilumab subjects who were IGA 0 or 1 responders at Week 16 became non-responders by Week 52.10
At this time very few systemic agents are approved for AD and, of those, cyclosporin A and oral 
prednisone are not suitable for long-term use.  Thus, there is a high unmet need for a significant number 
of patients with an inadequate response to topical agents.
Upadacitinib is a novel selective orally available JAK1 inhibitor with the potential to decrease Th2 
mediated skin inflammation and itch while having minimal inhibitory effects on JAK2 and JAK3.  This 
could potentially minimize some of the reported safety concerns with non-selective JAK inhibition which 
are thought to be mediated by inhibition of JAK2 and JAK3 signaling pathways.11,12  Events of deep vein 
thrombosis and pulmonary embolism have been reported in patients receiving JAK inhibitors including
upadacitinib.
The results of genetic toxicology testing indicate that upadacitinib is not genotoxic; however, 
upadacitinib is teratogenic based on animal studies, which necessitates avoidance of pregnancy in 
females of childbearing potential.  Based on the calculated safety margins for human fetal exposure with 
seminal fluid transfer, there is judged to be no risk to the pregnancy of female partners of male subjects 
who are treated with upadacitinib.
Primary results from the ongoing Phase 2 study demonstrated superior efficacy of upadacitinib with an 
acceptable safety profile at the selected doses for Phase 3 (15 mg and 30 mg once daily [QD]) compared 
to placebo in subjects with moderate to severe AD.  Taken together, the efficacy and safety data from 
the Phase 2 AD study and cumulative safety data from ongoing Phase 2 and 3 programs in other disease 
indications support further development of upadacitinib in subjects with moderate to severe AD.
In view of the Coronavirus Disease – 2019 (COVID-19) pandemic, the benefit:risk profile of various 
immunomodulatory therapies on COVID-19 is being evaluated.  At this time, the effects of upadacitinib 
on the course of COVID-19 are not well defined.
For further details, please see findings from completed studies, including safety data in upadacitinib 
Investigator's Brochure.13
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3 STUDY OBJECTIVES AND ENDPOINTS
3.1 Objectives
To assess the efficacy and safety of upadacitinib for the treatment of adolescent and adult subjects with 
moderate to severe AD who are candidates for systemic therapy.
3.2 Co-Primary Endpoints
The co-primary endpoints to demonstrate superiority of each upadacitinib dose vs. placebo are:
!
Proportion of subjects achieving at least a 75% reduction in Eczema Area and Severity Index 
(EASI 75) from Baseline at Week 16;
!
Proportion of subjects achieving validated Investigator Global Assessment for Atopic Dermatitis 
(vIGA-AD) of 0 or 1 with at least two grades of reduction from Baseline at Week 16.
3.3 Secondary Endpoints
The following key secondary endpoints will be analyzed to demonstrate superiority of each upadacitinib 
dose vs. placebo, unless otherwise specified.
Key Secondary Endpoints for EU/EMA regulatory purposes are:
!
Proportion of subjects achieving an improvement (reduction) in Worst Pruritus Numerical Rating 
Scale (NRS) ≥ 4 from Baseline at Week 16 for subjects with Worst Pruritus NRS ≥ 4 at Baseline;
!
Proportion of subjects achieving EASI 90 at Week 16;
!
Percent change from Baseline of Worst Pruritus NRS at Week 16;
!
Percent change in EASI from Baseline at Week 16;
!
Proportion of subjects achieving EASI 75 at Week 2;
!
Proportion of subjects achieving an improvement (reduction) in Worst Pruritus NRS ≥ 4 from 
Baseline at Week 1 for subjects with Worst Pruritus NRS ≥ 4 at Baseline;
!
Proportion of subjects achieving an improvement (reduction) in Patient Oriented Eczema 
Measure (POEM) ≥ 4 from Baseline at Week 16 for subjects with POEM ≥ 4 at Baseline;
!
Proportion of subjects age ≥ 16 years old at screening achieving an improvement (reduction) in 
Dermatology Life Quality Index (DLQI) ≥ 4 from Baseline at Week 16 for subjects with DLQI ≥ 4 at 
Baseline;
!
Proportion of subjects achieving an improvement (reduction) in Worst Pruritus NRS ≥ 4 from 
Baseline at Day 2 for subjects with Worst Pruritus NRS ≥ 4 at Baseline (upadacitinib 30 mg vs. 
placebo);
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!
Proportion of subjects achieving an improvement (reduction) in Worst Pruritus NRS ≥ 4 from 
Baseline at Day 3 for subjects with Worst Pruritus NRS ≥ 4 at Baseline (upadacitinib 15 mg vs. 
placebo);
!
Proportion of subjects experiencing a flare, characterized as a clinically meaningful worsening in 
EASI, defined as an increase of EASI by ≥ 6.6 from Baseline for subjects with EASI ≤65.4 at 
Baseline, during double-blind treatment period (DB Period);
!
Percent change in Scoring Atopic Dermatitis (SCORAD) from Baseline at Week 16;
!
Proportion of subjects achieving a Hospital Anxiety and Depression Scale-anxiety (HADS-A) < 8 
and Hospital Anxiety and Depression Scale-depression (HADS-D) < 8 at Week 16 among subjects 
with HADS-A ≥ 8 or HADS-D ≥ 8 at Baseline;
!
Proportion of subjects achieving an improvement (reduction) in Atopic Dermatitis Impact Scale 
(ADerm-IS) sleep domain score ≥ 12 (minimal clinically important difference [MCID]) from 
Baseline at Week 16 for subjects with ADerm-IS sleep domain score ≥ 12 at Baseline;
!
Proportion of subjects achieving an improvement (reduction) in Atopic Dermatitis Symptom 
Scale (ADerm-SS) skin pain score ≥ 4 (MCID) from Baseline at Week 16 for subjects with 
ADerm-SS skin pain score ≥ 4 at Baseline;
!
Proportion of subjects achieving an improvement (reduction) in ADerm-SS 7-item total symptom 
score (TSS-7) ≥ 28 (MCID) from Baseline at Week 16 for subjects with ADerm-SS TSS-7 ≥ 28 at 
Baseline; ADerm-SS TSS-7 is defined as the algebraic sum of the responses to items 1 – 7 of the 
ADerm-SS;
!
Proportion of subjects achieving an improvement (reduction) in ADerm-IS emotional state 
domain score ≥ 11 (MCID) from Baseline at Week 16 for subjects with ADerm-IS emotional state 
domain score ≥ 11 at Baseline;
!
Proportion of subjects achieving an improvement (reduction) in ADerm-IS daily activities domain 
score ≥ 14 (MCID) from Baseline at Week 16 for subjects with ADerm-IS daily activities domain 
score ≥ 14 at Baseline;
!
Proportion of subjects achieving EASI 100 at Week 16;
!
Proportion of subjects age ≥ 16 years old at screening achieving DLQI score of 0 or 1 at Week 16
for subjects with DLQI > 1 at Baseline;
Key secondary endpoints for US/FDA regulatory purposes are:
!
Proportion of subjects achieving an improvement (reduction) in Worst Pruritus NRS ≥ 4 from 
Baseline at Week 16 for subjects with Worst Pruritus NRS ≥ 4 at Baseline;
!
Proportion of subjects achieving EASI 90 at Week 16;
!
Proportion of subjects achieving an improvement (reduction) in Worst Pruritus NRS ≥ 4 from 
Baseline at Week 4 for subjects with Worst Pruritus NRS ≥ 4 at Baseline;
!
Proportion of subjects achieving EASI 75 at Week 2;
!
Proportion of subjects achieving an improvement (reduction) in Worst Pruritus NRS ≥ 4 from 
Baseline at Week 1 for subjects with Worst Pruritus NRS ≥ 4 at Baseline;
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!
Proportion of subjects achieving an improvement (reduction) in Worst Pruritus NRS ≥ 4 from 
Baseline at Day 2 for subjects with Worst Pruritus NRS ≥ 4 at Baseline (upadacitinib 30 mg vs. 
placebo);
!
Proportion of subjects achieving an improvement (reduction) in Worst Pruritus NRS ≥ 4 from 
Baseline at Day 3 for subjects with Worst Pruritus NRS ≥ 4 at Baseline (upadacitinib 15 mg vs. 
placebo);
!
Proportion of subjects experiencing a flare, characterized as a clinically meaningful worsening in 
EASI, defined as an increase of EASI by ≥ 6.6 from Baseline for subjects with EASI ≤65.4 at 
Baseline, during DB Period;
!
Proportion of subjects achieving an improvement (reduction) in ADerm-IS sleep domain score 
≥12 (MCID) from Baseline at Week 16 for subjects with ADerm-IS sleep domain score ≥ 12 at 
Baseline;
!
Proportion of subjects achieving an improvement (reduction) in ADerm-SS skin pain score ≥4 
(MCID) from Baseline at Week 16 for subjects with ADerm-SS skin pain score ≥ 4 at Baseline;
!
Proportion of subjects achieving an improvement (reduction) in ADerm-SS TSS-7 ≥ 28 (MCID)
from Baseline at Week 16 for subjects with ADerm-SS TSS-7 ≥ 28 at Baseline;
!
Proportion of subjects achieving an improvement (reduction) in ADerm-IS emotional state 
domain score ≥ 11 (MCID) from Baseline at Week 16 for subjects with ADerm-IS emotional state 
domain score ≥ 11 at Baseline;
!
Proportion of subjects achieving an improvement (reduction) in ADerm-IS daily activities domain 
score ≥ 14 (MCID) from Baseline at Week 16 for subjects with ADerm-IS daily activities domain 
score ≥ 14 at Baseline;
!
Proportion of subjects achieving EASI 100 at Week 16;
3.4 Additional Endpoints
All variables listed as primary or secondary endpoints will be analyzed at all visits other than those listed 
above.  In addition, the following endpoints to demonstrate superiority of each upadacitinib dose vs. 
placebo will be evaluated at all visits:  
!
Change from Baseline in EASI;
!
Change from Baseline in Worst Pruritus NRS;
!
Proportion of subjects achieving EASI 50 at Week 1;
!
Proportion of subjects achieving Worst Pruritus NRS of 0 or 1 for subjects with Worst Pruritus 
NRS > 1 at Baseline;
!
Proportion of subjects achieving at least a 50%/75%/90% reduction in SCORAD (SCORAD 
50/75/90) from Baseline;
!
Proportion of subjects experiencing flare, characterized as a clinically meaningful worsening in 
EASI, defined as an increase of EASI by ≥ 6.6 from Baseline for subjects with EASI ≤65.4 at 
Baseline, by visit after Week 16;
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!
Among responders at Week 16, proportion of subjects experiencing loss of response after 
Week 16 until Week 52, by visit and overall; loss of response is defined as a loss of at least 50% 
of the EASI response at Week 16 and a vIGA-AD score of 2 or higher; for this analysis only, 
responders will be defined as subjects achieving vIGA-AD of 0 or 1 with at least two grades of 
reduction from Baseline and EASI 75 at Week 16;
!
Change from Baseline in body surface area (BSA);
!
Change and percent change from Baseline in HADS-A;
!
Change and percent change from Baseline in HADS-D;
!
Change and percent change from Baseline in HADS total score;
!
Percent Change from Baseline in Hand eczema severity index (HECSI);
!
Proportion of subjects achieving an improvement (reduction) in ADerm-SS 11-item total 
symptom score (TSS-11) ≥ 44 (MCID) from Baseline for subjects with ADerm-SS TSS-11 ≥44 at 
Baseline; ADerm-SS TSS-11 is defined as the algebraic sum of the responses of items 1 – 11 of 
the ADerm-SS;
!
Change and percent change from Baseline in ADerm-SS TSS-7, ADerm-SS TSS-11, and skin pain 
score;
!
Proportion of subjects achieving ADerm-SS skin pain score of 0 for subjects with ADerm-SS skin 
pain score > 0 at Baseline;
!
Change and percent change from Baseline in ADerm-IS sleep domain score, emotional state 
domain score, and daily activities domain score;
!
Change and percent change from Baseline in POEM;
!
Proportion of subjects achieving POEM sleep item score of 0 for subjects with POEM sleep item 
score > 0 at Baseline;
!
Change and percent change from Baseline in DLQI among subjects age ≥ 16 years old at 
screening;
!
Proportion of subjects age < 16 years old at screening achieving Children's Dermatology Life 
Quality Index (CDLQI) score of 0 or 1 for subjects with CDLQI score > 1 at Baseline;
!
Change and percent change from Baseline in CDLQI among subjects age < 16 years old at 
screening;
!
Change and percent change from Baseline in Work Productivity and Activity Impairment Index:  
Atopic Dermatitis (WPAI:AD) domain scores (absenteeism, presenteeism, activity impairment, 
overall work productivity);
!
Change and percent change from Baseline in EuroQoL Dimensions 5 Levels (EQ-5D-5L); 
!
Change and percent change from Baseline in Short Form-36 Health Survey (SF-36) summary 
scores (physical component summary, mental component summary) and scale scores (vitality, 
physical functioning, bodily pain, general health perceptions, physical role functioning, social 
role functioning, mental health);
!
Change and percent change from Baseline in Patient Global Impression of Severity (PGIS);
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!
Proportion of subjects who report symptoms to be "Minimal" or "Absent" on the PGIS for 
subjects who did not report symptoms to be "Minimal" or "Absent" at Baseline;
!
Proportion of subjects who are "Very much improved" or "Much improved" on the Patient 
Global Impression of Change (PGIC);
!
Proportion of subjects who are "Extremely satisfied" or "Very satisfied" on the Patient Global 
Impression of Treatment (PGIT) for subjects who are not "Extremely satisfied" or "Very satisfied"
on the PGIT at Baseline.
!
Proportion of subjects achieving EASI 50;
!
Proportion of subjects achieving a vIGA-AD of 0 with a reduction from Baseline of ≥ 2 points;
3.5 Safety Endpoints
Safety evaluations for the duration of the study include:  treatment emergent adverse events (TEAEs), 
serious adverse events (SAEs), adverse events (AEs) of special interest (AESIs), AEs leading to 
discontinuation, vital signs, and laboratory tests.
3.6 Pharmacokinetic Endpoints
Pharmacokinetic (PK) samples will be collected from subjects at select sites at the visits indicated in 
Appendix D.  Using the data available from these subjects, a nonlinear mixed-effects modeling approach 
will be used to estimate the population central values and the empirical Bayesian estimates of the 
individual values of upadacitinib oral clearance (CL/F) and volume of distribution (V/F).  Additional 
parameters may be estimated if useful in the interpretation of the data.  Data from this study may be 
combined with data from other studies for the population PK analyses.
3.7 Biomarker Samples
The analyses of optional biomarker samples may include but are not limited to genetic markers that will 
help to understand the subject's disease and response to upadacitinib.  Genes of interest may include 
those associated pharmacokinetics (drug metabolizing enzymes, drug transport proteins), genes within 
the target pathway (JAK, Tyrosine kinase 2 [Tyk2], TNF), or other genes believed to be related AD, and 
other inflammatory diseases (FLG, CLDN1, HLA).  Research may also include epigenetic changes in DNA 
that may associate with the subject's response to treatment or disease.  Samples for RNA and 
proteomics will be used to research if any genetic variants result in changes to gene expression or 
protein concentrations.  For any samples collected in Germany, the research will be restricted to 
upadacitinib and AD.
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4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
This is a Phase 3, randomized, double-blind, placebo-controlled multi-center study that will evaluate 
upadacitinib in adolescents (12 – 17 years of age) and adults (18 – 75 years of age) with moderate to 
severe AD who are candidates for systemic therapy.  Eligible subjects must have a documented history 
of inadequate response to treatment with topical AD treatments or documented use of systemic 
treatment for AD or for whom topical treatments are otherwise medically inadvisable.
The study is comprised of a 35-day Screening Period, a 16-week DB Period, a Blinded Extension period of 
up to Week 260, and a 30-day Follow-up Visit.  
Subjects who meet eligibility criteria in the main study will be randomized in a 1:1:1 ratio to receive daily 
oral doses of upadacitinib 15 mg (N = 270) or of upadacitinib 30 mg (N = 270) or matching placebo 
(N = 270).  Upon completion of enrollment of 810 subjects in the main study, a supplemental study will 
continue to enroll adolescent subjects (adolescent sub-study) until a total of 180 adolescent subjects are 
enrolled in the overall study (main study + adolescent sub-study).  Randomization for the main study will 
be stratified by baseline disease severity (moderate [vIGA-AD 3] vs. severe [vIGA-AD 4]), by geographic 
region (US/Puerto Rico/Canada, Japan, China, and Other), and by age (adolescent [ages 12 to 17] versus 
adult [ages 18 to 75]).  The separate randomization for the adolescent sub-study will be stratified by 
baseline disease severity (moderate [vIGA-AD 3] vs. severe [vIGA-AD 4]) and by geographic region 
(US/Puerto Rico/Canada and Other).
At Week 16, subjects in the placebo group will be re-randomized in a 1:1 ratio to receive daily oral doses 
of upadacitinib 15 mg or upadacitinib 30 mg during the Blinded Extension period.  Subjects originally in 
the 15 mg QD and 30 mg QD upadacitinib group will continue their treatment into the Blinded Extension 
period up to the Week 260 visit.  Starting at the Week 4 visit, rescue treatment for AD may be provided 
at the discretion of the investigator if medically necessary (further details are available in Section 5.4).
Information on the Data Monitoring Committee (DMC) and Cardiovascular Adjudication Committee 
(CAC) are described in Section 6.3.
The Primary Analysis for the main study will be conducted after all ongoing subjects have completed 
Week 16.  After the Primary Analysis, an additional analysis for the main study will be conducted when 
the required safety exposure target is reached. In addition, a Week 52 analysis of the main study will be 
performed after all ongoing subjects complete the Week 52 visit. Furthermore, a Primary Analysis for 
the adolescent population (including the adolescent subjects from the main study and the adolescent 
sub-study) will be conducted after all ongoing adolescent subjects have completed Week 16.  An 
additional analysis for the adolescent population will be conducted after all ongoing adolescent subjects 
have provided at least 1 year of upadacitinib exposure.  In addition, interim database locks may be 
performed after all subjects (main study and adolescent sub-study) have completed the study activities 
up to the relevant timepoints after Week 140.  The study sites and subjects will remain blinded to 
treatment assignments for the duration of the study.
The schematic of the overall study is shown in Figure 1.
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Figure 1.
Study Schematic
DB = double-blind; QD = once daily
Note:
This schematic applies to both the main study and adolescent sub-study.
4.2 Discussion of Study Design
Choice of Control Group
Placebo has been selected as the appropriate control group since, as discussed in Section 2.2, there is no 
established standard for systemic therapy in moderate to severe AD.  There is no anticipated medical 
risk for subjects randomized to placebo and if needed, rescue treatment will be available for these 
subjects.
Appropriateness of Measurements
Standard clinical and laboratory procedures will be utilized in this study.  All efficacy measurements in 
this study are standard for assessing disease activity in subjects with AD.  Other than the biomarker 
analyses which are exploratory, all clinical and laboratory procedures in this study are standard and
generally accepted.
Care should be taken to minimize the pain and discomfort of laboratory procedures, especially in 
adolescent subjects.  Use of a butterfly needle for venipuncture and/or a needle gauge appropriate for 
vein size may optimize the comfort for some individuals.  Attempts at venipuncture should be limited to 
the subject's tolerance of the procedure; after 2 unsuccessful attempts for venipuncture, consider 
requesting the subject to return at a later time for the blood sample collection within the timeframe 
allowed by the protocol.
Suitability of Subject Population
The target study population for this study represents an adolescent and adult AD population with 
moderate to severe disease activity appropriate for systemic therapies.
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Subjects who are between ≥ 12 and < 18 years of age at the time of the Screening visit will be 
considered adolescents for the duration of the study.
Inclusion of Adolescent Subjects 12 to 17 Years of Age
The adult phase of AD begins at puberty and frequently continues into adulthood.14  In adolescents and 
adults, the disease presents similarly, typically involving the flexural folds, face, neck, upper arms and 
back, and dorsal surface of the hands and feet with few notable pathogenetic differences between these 
age groups.15,16  While there are no published studies comparing AD disease factors and treatment 
between adolescents 12 to 17 years of age and adults ≥ 18 years of age, published guidelines in both the 
United States and Europe make no distinctions in the diagnosis, assessment, and treatment of AD in 
adolescents and adults.6,7,16
The rationale for selection of doses for adolescents is detailed below.  To confirm dose assumptions, PK 
evaluation will be performed for adolescents and adults in the study.
Selection of Doses in the Study
This study will evaluate two doses of Upadacitinib (15 mg and 30 mg QD).  The selection of these doses 
was informed by the analyses of the 16-week safety, efficacy, and exposure-response data from Period 1 
of the Phase 2 AD Study M16-048, which evaluated 3 doses of upadacitinib (7.5 mg, 15 mg or 30 mg QD) 
versus placebo.  In addition, available PK, pharmacodynamic, and safety data from upadacitinib studies 
in other disease indications were used to support the selection of these doses.
The Phase 2 study results demonstrated superior efficacy of upadacitinib with an acceptable safety 
profile at the selected doses (15 mg and 30 mg QD) compared to placebo in subjects with moderate to 
severe AD.  A statistically significant difference in the mean percent change from Baseline in EASI score 
at Week 16 (primary endpoint) was observed for 7.5 mg (–39.4%; P = 0.032 vs placebo), 15 mg (–61.7%; 
P < 0.001 vs placebo) and 30 mg (–74.4%; P < 0.001 vs placebo) groups compared with placebo (–23.0%).  
Through Week 16 (Period 1), the percentages of subjects with AEs, SAEs, severe AEs, and AEs leading to 
discontinuation were similar across treatment groups.  There were no deaths reported during Period 1.  
Preliminary exposure-response analyses for Period 1 of the Phase 2 study show that the percentage of 
subjects achieving EASI 75, EASI 90, or IGA 0/1 increased with increasing upadacitinib plasma exposures.  
Simulations using preliminary exposure-response models indicate that doses lower than 15 mg QD 
(e.g., 7.5 mg QD) are not predicted to provide adequate efficacy in subjects with moderate-to-severe 
AD.
Bodyweight was not found to be correlated with upadacitinib apparent clearance within the evaluated 
range of 39 kg to 152 kg in the preliminary population-pharmacokinetic analysis across healthy 
volunteers and in subjects with RA, CD, and AD.  Consistent with this finding, upadacitinib estimated 
apparent clearance was found to be similar between adult subjects with low body weight (< 50 kg) and 
rest of the subjects across Phase 1 and 2 studies (bodyweight greater than or equal to 50 kg).  Adult 
subjects with CD have been evaluated with chronic dosing of upadacitinib up to 24 mg twice a day using 
the immediate release formulation (exposures equivalent to that of 60 mg QD regimen using the 
extended release tablet formulation) with acceptable safety profile.  Therefore, there is no anticipated 
risk resulting from higher exposures for adult subjects weighing less than 40 kg receiving the 30 mg QD 
dose in the AD clinical trials.  As for adolescents, given that no adolescents have been exposed to 
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upadacitinib before, the 40 kg cutoff is implemented as an additional safety precaution for this 
population only.
Among the cytochrome P450s (CYPs), upadacitinib is mainly eliminated via CYP3A mediated metabolism 
(approximately 24% and 38% of upadacitinib immediate-release dose is excreted as unchanged 
upadacitinib in urine and feces, respectively and 34% is excreted as metabolites).  Literature suggests 
that maturation of the CYP3A activity in children 2 years and above is similar to that of adults.17
Therefore, upadacitinib clearance is not expected to be different between adolescents and adults 
because of age.
Given the evidence in literature with regards to comparable maturation of the CYP3A activity in 
adolescents relative to adults and that upadacitinib clearance (the key pharmacokinetic parameter that 
drives the steady state exposures [area under the plasma drug concentration-time curve]) was shown 
not to be correlated with the bodyweight (within the range of 39 kg to 152 kg), it is estimated that 
upadacitinib exposures will be comparable within this body weight range in adolescents and adult 
subjects with atopic dermatitis.
In summary, exposures associated with upadacitinib 15 mg QD and 30 mg QD using the once-daily 
formulation are predicted to be effective and have an acceptable safety profile across the proposed age 
range for the treatment of subjects with moderate to severe AD.
Placebo Duration Rationale
The 16-week DB Period is deemed to be a sufficient duration to be able to test the superiority of 
upadacitinib versus placebo for achieving the co primary endpoints (EASI 75 and vIGA-AD) at Week 16 
and several secondary endpoints, while minimizing undue burden for subjects.  The placebo-controlled 
period will allow for a 16-week assessment of efficacy and safety versus a control group. To ensure 
appropriate medical care for subjects, starting from Week 4, all subjects with an inadequate response 
may be rescued with escalating therapies ranging from higher potency topical agents to systemic agents 
of the investigator's choice (see Rescue Therapy in Section 5.4 for further details).
5 STUDY ACTIVITIES
5.1 Eligibility Criteria
Subjects must meet all of the following criteria in order to be included in the study.  Anything other than 
a positive response to the questions below will result in exclusion from study participation.
Consent and Demographics
1. Subject must be ≥ 12 years old and ≤ 75 years old at Screening Visit.  Adolescent subjects 
below the age of 18 years old will be enrolled if approved by the country or regulatory/health 
authority.  If these approvals have not been granted, only subjects ≥ 18 years old at the 
Screening Visit will be enrolled.
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2. Adult subjects ≥ 18 years of age at Screening Visit must voluntarily sign and date an informed 
consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), 
prior to the initiation of any screening or study-specific procedures and comply with the 
requirements of this study protocol.
In Japan, if a subject is under 20 years of age, then the subject and their parent or legal guardian 
must voluntarily sign and date an informed consent.  
3. For subjects ≥ 12 years old and < 18 years old at Screening Visit:  Parent or legal guardian, as 
required, has voluntarily signed and dated an informed consent form, approved by an IEC, after 
the nature of the study has been explained and the subject's parent or legal guardian has had 
the opportunity to ask questions.  Subjects will be included in all discussions in order to obtain 
verbal/and or written assent.  Parent/legal guardian and subject must comply with the 
requirements of this study protocol.  If a subject becomes of legal age during the course of the 
study, that subjects will need to be consented using the approved informed consent form.  
4. Body weight ≥ 40 kg at the Baseline Visit for subjects between ≥ 12 and < 18 years of age.
5. Subject is judged to be in general good health (other than AD) as determined by the Principal 
Investigator, based upon the results of medical history, laboratory profile, physical examination, 
chest x-ray (CXR), and a 12-lead electrocardiogram (ECG) performed during Screening.
AD Disease Activity
6. Chronic AD with onset of symptoms at least 3 years prior to baseline and subject meets 
Hanifin and Rajka criteria.18
7. Subject meets all of the following disease activity criteria:
!
EASI score ≥ 16 at the Screening and Baseline Visits;
!
vIGA-AD score ≥ 3 at the Screening and Baseline Visits;
!
≥ 10% BSA of AD involvement at the Screening and Baseline Visits;
!
Baseline weekly average of daily Worst Pruritus NRS ≥ 4.  Note:  The baseline weekly 
average of daily Worst Pruritus NRS will be calculated from the 7 consecutive days 
immediately preceding the Baseline Visit.  A minimum of 4 daily scores out of the 7 days is 
needed.
8. Subject has applied a topical emollient (moisturizer) twice daily for at least 7 days before the 
Baseline Visit.  Note:  Subject may use prescription moisturizers or moisturizers containing 
ceramide, urea, filaggrin degradation products or hyaluronic acid if such moisturizers were 
initiated before the screening visit.
9. Documented history (within 6 months of the Baseline Visit) of inadequate response to TCS or 
TCI OR documented systemic treatment for atopic dermatitis within 6 months prior to the 
Baseline Visit, OR for whom topical treatments are otherwise medically inadvisable 
(e.g., because of important side effects or safety risks).
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Contraception
10. Females of childbearing potential must not have a positive serum pregnancy test at the 
Screening Visit and must have a negative urine pregnancy test at the Baseline Visit prior to study 
drug dosing.  Note:  subjects with borderline pregnancy test at Screening must have a serum 
pregnancy test ≥ 3 days later to determine eligibility (refer to Section 5.10 for details).
11. If female, subject must be postmenopausal OR permanently surgically sterile OR for females 
of childbearing potential practicing at least one protocol specified method of birth control (refer 
to Section 5.2), that is effective from the Baseline Visit through at least 30 days after the last 
dose of study drug.
12. Female subject must not be pregnant, breastfeeding or considering becoming pregnant 
during the study or for approximately 30 days after the last dose of the study drug.
13. Additional local requirements may apply.
Prior/Concomitant Therapy
14. No prior exposure to any JAK inhibitor (including but not limited to ruxolitinib, tofacitinib, 
baricitinib, upadacitinib, abrocitinib [PF-04965842], and filgotinib).
15. No prior exposure to dupilumab.
16. Subjects must not have used the following AD treatments within the specified timeframe 
prior to Baseline Visit:
!
Systemic therapy for AD, including but not limited to corticosteroids, methotrexate, 
cyclosporine, azathioprine, phosphodiesterase type 4 (PDE4)-inhibitors, IFN-γ and 
mycophenolate mofetil within 4 weeks;
!
Targeted biologic treatments (refer to within 5 half-lives [if known]) or within 12 weeks, 
whichever is longer;
!
Phototherapy treatment, laser therapy, tanning booth, or extended sun exposure that could 
affect disease severity or interfere with disease assessments within 4 weeks;
!
Oral or parenteral traditional Chinese medicine within 4 weeks;
!
Marijuana use within 2 weeks;
!
Topical treatments (with the exception of topical emollient treatments, described in 
Eligibility Criterion 8), including but not limited to TCS, TCIs, or topical PDE-4 inhibitors 
within 7 days.
17. Subjects must not have received any live vaccine within 4 weeks (or longer if required 
locally) prior to the first dose of study drug, or expected need of live vaccination during study 
participation including at least 4 weeks (or longer if required locally) after the last dose of study 
drug.
In Japan, subject must not have received any live vaccine within 8 weeks prior to the first dose 
of study drug, or expected need of live vaccination during study participation including at least 
8 weeks after the last dose of study drug.
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18. No systemic use of known strong CYP3A inhibitors or strong CYP3A inducers from Screening 
through the end of the study (refer to Table 1 in Section 5.3 for examples of commonly used 
strong CYP3A inhibitors and inducers).
19. No treatment with any investigational drug of chemical or biologic nature within 4 weeks or 
five half-lives of the drug (whichever is longer) prior to Baseline Visit or is currently enrolled in 
another clinical study.
In China, subject must have no current or past history of infection including active syphilis 
infection or confirmed syphilis antibody positive (+).
Medical History
20. Subjects must not have laboratory values meeting the following criteria within the Screening 
period prior to the first dose of study drug:
!
Serum aspartate transaminase (AST) > 2 × upper limit of normal (ULN);
!
Serum alanine transaminase (ALT) > 2 × ULN;
!
Estimated glomerular filtration rate (GFR) of < 40 mL/min/1.73 m2 by simplified 4-variable 
Modification of Diet in Renal Disease (MDRD) formula for adult subjects or by Schwartz 
equation for adolescent subjects;
!
Total white blood cell count (WBC) < 2,500/μL;
!
Absolute neutrophil count (ANC) < 1,500/μL;
!
Platelet count < 100,000/μL;
!
Absolute lymphocyte count < 800/μL;
!
Hemoglobin < 10 g/dL.
21. No current or past history of the following:
!
Other active skin diseases or skin infections (bacterial, fungal, or viral) requiring systemic 
treatment within 4 weeks of the Baseline Visit or would interfere with the appropriate 
assessment of AD lesions;
!
History of recurrent herpes zoster, or one or more episodes of disseminated herpes zoster;
!
History of one or more episodes of disseminated herpes simplex (including eczema 
herpeticum);
!
History of known invasive infection (e.g., listeriosis and histoplasmosis);
!
Active human immunodeficiency virus (HIV) or immunodeficiency syndrome.  Active HIV is 
defined as confirmed positive anti-HIV antibody test;
!
Subject has active Tuberculosis (TB) or meets TB exclusionary parameters (refer to 
Section 5.10 for specific requirements for TB testing);
!
Non-skin related active infection(s) requiring treatment with parenteral anti-infectives 
within 30 days, or oral anti-infectives within 14 days prior to the Baseline Visit;
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!
Chronic recurring infection and/or active viral infection that, based on the investigator's 
clinical assessment, makes the subject an unsuitable candidate for the study;
!
Active hepatitis B virus (HBV) or hepatitis C virus (HCV):
!
HBV:  hepatitis B surface antigen (HBs Ag) positive (+) or detected sensitivity on the HBV 
deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) qualitative test for 
hepatitis B core antibody (HBc Ab) positive (+) subjects (and for hepatitis B surface 
antibody positive [+] where mandated per local requirements);
!
HCV:  HCV ribonucleic acid (RNA) detectable in any subject with anti-HCV antibody (HCV 
Ab). 
!
In Japan, positive result of beta D glucan or 2 consecutive indeterminate results of 
beta-D-glucan (screening for pneumocystis jiroveci infection at central lab).
22. Subject must not have any of the following medical conditions:
!
Any of the following cardiovascular conditions:
!
Recent (within past 6 months) cerebrovascular accident, myocardial infarction, coronary 
stenting;
!
Uncontrolled hypertension as defined by a confirmed systolic blood pressure 
> 160 mmHg or diastolic blood pressure > 100 mmHg;
!
Any other unstable clinical condition which, in the opinion of the investigator, would put 
the subject at risk by participating in the protocol.
!
Subject has been a previous recipient of an organ transplant which requires continued 
immunosuppression;
!
History of gastrointestinal (GI) perforation (other than due to appendicitis or mechanical
injury), diverticulitis or significantly increased risk for GI perforation per investigator 
judgment;
!
Conditions that could interfere with drug absorption including but not limited to short 
bowel syndrome; 
!
History of any malignancy except for successfully treated non-melanoma skin cancer (NMSC) 
or localized carcinoma in situ of the cervix;
!
History of clinically significant medical conditions or any other reason, which in the opinion 
of the investigator, would interfere with the subject's participation in this study or would 
make the subject an unsuitable candidate to receive study drug or would put the subject at 
risk by participating in the study.
Miscellaneous
23. No history of an allergic reaction or significant sensitivity to constituents of the study drugs 
(or its excipients) and/or other products in the same class.
24. No history of clinically significant (per investigator's judgment) drug or alcohol abuse within 
the last 6 months preceding the Baseline Visit.
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5.2 Contraception Recommendations
Contraception Requirements for Females
A female who is permanently surgically sterile or postmenopausal is not considered to be a female of 
childbearing potential and is not required to follow contraception recommendations.
Surgically sterile is defined as: 
!
bilateral oophorectomy (surgical removal of both ovaries); or
!
bilateral salpingectomy (surgical removal of both fallopian tubes); or
!
hysterectomy (surgical removal of uterus) 
Postmenopausal is defined as:
!
Age > 55 years with no menses for 12 or more months without an alternative medical cause; or 
!
Age ≤55 years with no menses for 12 or more months without an alternative medical cause 
AND a follicle-stimulating hormone (FSH) level > 40 IU/L.
If the female subject is ≤ 55 years of age, postmenarchal, and has had no menses for ≥ 12 months AND 
has no history of permanent surgical sterilization (defined above), FSH should be tested at Screening.
!
If FSH is not tested, it is assumed that the subject is of childbearing potential and protocol-
specified contraception is required.
!
If the FSH is tested and the result is consistent with postmenopausal status, contraception is not 
required.
!
If the FSH is tested and the result is consistent with premenopausal status, contraception is 
required, and pregnancy testing requirements for women of childbearing potential must be 
followed (see below).
A female who does not meet the definition of postmenopausal or permanently surgically sterile, and 
who is postmenarchal or pubertal and has not yet had menses (premenarchal, Tanner stage 3 or higher), 
is considered of childbearing potential and is required to practice at least one of the following highly 
effective methods of birth control that is effective from Baseline Visit (or earlier) through at least 
30 days after the last dose of study drug.
!
Combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, 
transdermal, injectable) associated with the inhibition of ovulation, initiated at least 30 days 
prior to Baseline Visit.
!
Progestogen-only hormonal contraception (oral, injectable, implantable) associated with 
inhibition of ovulation, initiated at least 30 days prior to Baseline Visit.
!
Bilateral tubal occlusion/ligation. 
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!
Vasectomized partner(s) provided the vasectomized partner has received medical confirmation 
of the surgical success and is the sole sexual partner of the women of childbearing potential trial 
participant.
!
Intrauterine device.
!
Intrauterine hormone-releasing system (IUS).
!
True abstinence (if acceptable per local requirements):  Refraining from heterosexual 
intercourse when this is in line with the preferred and usual lifestyle of the subject.  Periodic 
abstinence (e.g., using calendar, ovulation, symptothermal, postovulation methods) and 
withdrawal are not acceptable.
If required per local guidelines, male or female condom with or without spermicide OR cap, diaphragm 
or sponge with spermicide should be used in addition to one of the birth control methods listed above 
(excluding true abstinence).
For female adolescents not considered as having childbearing potential at baseline, if during the course 
of the study a female adolescent becomes of childbearing potential, she is required to take the 
recommended contraception measures (including true abstinence if acceptable per local requirements) 
listed above.
If during the course of the study a female becomes surgically sterile or postmenopausal (defined above) 
and complete documentation is available, contraceptive measures as defined above are no longer 
required.  It is important to note that contraception requirements described above are specifically 
intended to prevent pregnancy during exposure to the investigational therapy upadacitinib.
Contraception recommendations related to use of concomitant therapies prescribed per standard of 
care should be based on the local label.
Additional local requirements may apply.  In Japan, a Japanese female who does not meet the definition 
of postmenopausal or permanently surgically sterile is considered of childbearing potential and is 
required to practice at least one of the following highly effective methods of birth control that is 
effective from Baseline Visit (or earlier) through at least 30 days after the last dose of study drug.
!
Combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, 
transdermal) associated with the inhibition of ovulation, initiated at least 30 days prior to 
Baseline Visit.
!
Progestogen-only hormonal contraception (oral, injectable, implantable) associated with 
inhibition of ovulation, initiated at least 30 days prior to Baseline Visit.
!
Bilateral tubal ligation 
!
Vasectomized partner(s) provided the vasectomized partner has received medical confirmation 
of the surgical success and is the sole sexual partner of the females of childbearing potential trial 
participant.
!
Intrauterine device.
!
Intrauterine hormone-releasing system.
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!
True abstinence (if acceptable per local requirements):  Refraining from heterosexual
intercourse when this is in line with the preferred and usual lifestyle of the subject.  Periodic 
abstinence (e.g., using calendar, ovulation, symptothermal, postovulation methods) and 
withdrawal are not acceptable.
At each visit, the study staff should review the pregnancy avoidance recommendations with each female 
of childbearing potential and document this discussion in the subject's source records.
5.3 Prohibited Medications and Therapy
Medications to treat chronic or acute conditions are permitted (with the exception of the treatments 
listed below).  Prohibited medications and therapy are allowed after permanent discontinuation of study 
drug or after completion of study drug treatment.
JAK Inhibitors
Prior and concomitant oral and topical exposure to any other JAK inhibitors including the investigational 
drug, upadacitinib (including but not limited to ruxolitinib [Jakafi®], tofacitinib [Xeljanz®], baricitinib, 
abrocitinib [PF-04965842], and filgotinib) is not allowed.
Targeted Biologic Therapies
Current and concomitant biologic therapies and biosimilar versions of biologic drugs are prohibited 
during the study.  Examples of biologic therapies include but are not limited to the following:
!
abatacept 
!
adalimumab
!
anakinra
!
belimumab
!
certolizumab pegol
!
dupilumab
!
efalizumab
!
etanercept
!
golimumab
!
guselkumab
!
infliximab
!
ixekizumab
!
natalizumab
!
omalizumab
!
rituximab
!
secukinumab
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!
tocilizumab
!
ustekinumab
See also Rescue Therapy in Section 5.4 for further details on systemic rescue.
Other Non-Biologic Systemic Therapy
Non-corticosteroid systemic therapies for the treatment of AD are prohibited concomitant with study 
drug, including but not limited to: 
!
methotrexate
!
cyclosporine
!
azathioprine
!
PDE4-Inhibitors (e.g., apremilast)
!
mycophenolate mofetil
See also Rescue Therapy in Section 5.4 for further details on systemic rescue.
Corticosteroids
Inhaled, ophthalmic drops and nasal corticosteroid formulations are allowed throughout the study.  
Subjects may be treated with systemic corticosteroids for non-AD reasons if medically necessary after 
Week 16.  Any subject who receives systemic corticosteroid for more than 2 consecutive weeks 
regardless of the dosage of corticosteroid should permanently discontinue study drug.  Subjects who 
permanently discontinue study drug are encouraged to continue to participate in the study (no study 
drug given) and will complete the schedule of study visits and assessments.
Intravenous, intramuscular, intralesional corticosteroids are prohibited throughout the study for 
treatment of AD.  The use of oral corticosteroids for routine treatment for AD during the study is 
prohibited.  See Rescue Therapy in Section 5.4 for further details on corticosteroid rescue allowances.
Investigational Drugs
Subjects who have been treated with any investigational drug within 4 weeks or five half-lives of the 
drug (whichever is longer) prior to the first dose of study drug are excluded from participation in this 
study.  Investigational drugs are also prohibited during the study.
Phototherapy, Tanning Booth, and Extended Sun Exposure
Ultra-violet (UV) B or UVA phototherapy including PUVA or laser therapy for at least 4 weeks prior to the 
Baseline visit and during the study are not allowed.  Also not allowed is tanning booth use or extended 
sun exposure that could affect disease severity or interfere with disease assessments for at least 
4 weeks prior to the Baseline visit and during the study.
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Topical Therapy
No topical treatments for AD should be started through Week 16 except for rescue treatment (see 
Rescue Therapy in Section 5.4).  This includes but is not limited to calcineurin inhibitors, corticosteroids, 
prescription moisturizers or moisturizers containing additives such as ceramide, hyaluronic acid, urea, or 
filaggrin.  Topical emollient treatments are allowed per Eligibility Criterion 8.
Starting at the Week 16 Visit, the use of any concomitant topical medication for atopic dermatitis can be 
administered per investigator discretion.
Topical anti-infectives, topical antihistamines, and bleach baths are not prohibited during the study if 
they are used for reasons other than AD.  Topical anti-infectives, topical antihistamines, and bleach 
baths may be used in the first 16 weeks of the study for AD if they were used in the 6 months prior to 
the Screening visit.
If there is any question regarding whether a concomitant medication may be used during the study, the 
study site should contact the AbbVie Therapeutic Area Scientific Director (TA SD).
Vaccines
If the subject and investigator choose to administer live vaccines, these vaccinations must be completed 
(per local label) at least 4 weeks (or longer if required locally) before first dose of study drug with 
appropriate precautions.  Although not mandated by the protocol, vaccines recommended by local 
guidelines should be considered.  Live vaccines are not permitted during study participation before week 
52 and including up to 4 weeks (or longer if required locally) after the last dose of study drug for those 
who discontinued study drug at or before Week 52.  Examples of live vaccines include, but are not 
limited to, the following:
!
Bacille Calmette-Guérin
!
herpes zoster (Zostavax)
!
measles-mumps-rubella or measles-mumps-rubella-varicella
!
monovalent live attenuated influenza A (H1N1) (intranasal)
!
oral polio vaccine
!
rotavirus
!
seasonal trivalent live attenuated influenza (intranasal)
!
smallpox
!
typhoid
!
varicella (chicken pox)
!
yellow fever
After week 52, if a live vaccine must be administered during study participation, study drug must be held 
for at least 30 days prior to the vaccination and at least 30 days after the vaccination (or longer if 
required locally).
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Administration of inactivated (non-live) vaccines is permitted prior to or during the study according to 
local practice guidelines.
In Japan, live vaccines are not permitted during study participation and including up to 8 weeks after the 
last dose of study drug.  If the subject and investigator choose to administer live vaccines, these 
vaccinations must be completed at least 8 weeks, whichever is longer, before first dose of study drug 
with appropriate precautions.
Cannabis
Use of medicinal and recreational marijuana is prohibited during the study and subjects must have 
discontinued use at least 2 weeks prior to Baseline until study drug discontinuation.
Traditional Chinese Medicine
Traditional oral or parenteral Chinese medicine is not permitted during the study as these may interfere 
with upadacitinib metabolism and exposure and may impact efficacy and safety of upadacitinib 
treatment.  Subjects must have discontinued oral or parenteral traditional Chinese medicine at least 
4 weeks prior to the first dose of study drug. 
Strong CYP3A Inhibitors or Inducers
Systemic use of known strong CYP3A inhibitors or strong CYP3A inducers is excluded from the Screening 
Visit through the end of the study.  The most common strong CYP3A inhibitors and inducers are listed in 
Table 1.
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Table 1.
Examples of Commonly Used Strong CYP3A Inhibitors and Inducers
Strong CYP3A Inhibitors 
Strong CYP3A Inducers
Boceprevir
Avasimibe
Clarithromycin
Carbamazepine
Cobicistat
Phenytoin
Conivaptan
Rifampin (Rifampicin)
Grapefruit (fruit or juice)
Rifapentine
Indinavir
St. John's Wort
Itraconazole
Ketoconazole
Lopinavir/Ritonavir
Mibefradil
Nefazodone
Nelfinavir
Posaconazole
Ritonavir
Saquinavir
Telaprevir
Telithromycin
Troleandomycin
Voriconazole
Elective and Emergency Surgeries
Elective surgery will not be allowed during the study until the primary endpoint has been assessed.  If 
the subject undergoes elective surgery, see Section 5.8 for allowed study drug interruption parameters. 
If the subject must undergo emergency surgery, the study drug should be interrupted at the time of the 
surgery.  See Section 5.8 for allowed study drug interruption parameters. 
5.4 Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins and/or herbal 
supplements including folic acid) that the subject is receiving within 28 days prior to screening, or 
receives during the study, must be recorded.
Vaccines recommended by local guidelines should be considered.  If the investigator chooses to 
administer a vaccine, this should be completed before the first dose of study drug with appropriate 
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precautions and time interval.  It is recommended that subjects be up to date for recommended 
vaccines that are inactivated, toxoid or biosynthetic vaccines, such as injectable flu vaccine, 
pneumococcal, and tetanus-diphtheria-acellular pertussis (Tdap).  It is recommended that the live 
herpes zoster vaccine be considered for administration at least 4 weeks before the first dose of study 
drug in subjects greater than 50 years of age (per label).  If the herpes zoster vaccine is to be 
administered, pre-existing immunity should be confirmed through antibody testing at or prior to 
screening and prior to administration of the herpes zoster vaccine.  If screening varicella antibody 
testing is negative the herpes zoster vaccine should not be administered.  See Section 5.3 for a list of 
commonly used live vaccines.
If there are any questions regarding concomitant or prior therapies the AbbVie Therapeutic Area 
Scientific Director should be contacted who will then discuss with the AbbVie Medical Director and 
provide a recommendation.
In Japan, it is recommended that the live herpes zoster vaccine be considered for administration at least 
8 weeks before the first dose of study drug in subjects greater than 50 years of age (per label).
Prior Therapy
Any systemic treatments for AD since initial diagnosis (as determined through medical history records or 
through subject or parent or legal representative interview) and any prescribed treatments for AD prior 
to study entry will be recorded on the electronic case report form (eCRF).
Required Concomitant Medications
Beginning at the screening visit, twice daily use of an additive-free, bland emollient is required for at 
least 7 days prior to Baseline and during the study until Week 16.  Starting at the Week 16 Visit or after 
premature discontinuation of study drug, the use of emollients can be administered per investigator 
discretion.
Note:  Until Week 16, the subject may use prescription moisturizers or moisturizers containing 
ceramide, urea, filaggrin degradation products or hyaluronic acid if such moisturizers were initiated 
before the screening visit.
Rescue Therapy
Starting at the Week 4 visit, rescue treatment for AD may be provided, if medically necessary and the 
following parameters are met:
!
At Week 4 through Week 24:  subjects with < 50% reduction in EASI (EASI 50) response at any 
two consecutive scheduled visits (e.g., at Week 2 and Week 4 with rescue at Week 4; or at 
Week 20 and Week 24 with rescue at Week 24), compared to the Baseline EASI score.
!
After Week 24:  subjects with < EASI 50 response at any scheduled or unscheduled visit, 
compared to the Baseline EASI score.
Investigators should attempt to limit the first step of rescue therapy to topical medications, and escalate 
to systemic medications only for those subjects who do not respond adequately after at least 7 days of 
topical treatment.
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Starting at the Week 16 Visit, the use of any concomitant topical medication for atopic dermatitis can be 
administered per investigator discretion and will no longer be considered as rescue therapy.  Only 
systemic treatments for AD will be considered as rescue therapy for the purposes of statistical analyses 
of efficacy.
Subjects who receive topical rescue treatment or oral corticosteroids during the study treatment period 
can continue study drug.  Oral corticosteroids are not allowed for routine treatment of AD (see 
Prohibited Medications and Therapy in Section 5.3).  If oral corticosteroids must be used, rescue 
treatment will be limited to prednisone or prednisolone for up to 1 mg/kg for no more than 
2 consecutive weeks.  Any subject who receives oral corticosteroid for more than 2 consecutive weeks 
regardless of the dosage of corticosteroid should permanently discontinue study drug.
If a subject needs rescue treatment with a non-corticosteroid systemic agent (including but not limited 
to cyclosporine, methotrexate, mycophenolate mofetil, azathioprine, dupilumab) or with an injectable 
or parenteral corticosteroid, study drug should be permanently discontinued prior to the initiation of 
rescue systemic agent.
If rescue treatment is medically necessary outside of the parameters described above (i.e., to control 
intolerable AD symptoms), study drug should be permanently discontinued.
Subjects who permanently discontinue study drug are encouraged to continue to participate in the 
study (no study drug given) and complete the schedule of study visits and assessments.
Investigators should conduct efficacy and safety assessments (e.g., disease severity scores, safety labs) 
before administering any rescue treatment.  An unscheduled visit may be used for this purpose if 
necessary.
5.5 Withdrawal of Subjects and Discontinuation of Study
Subjects may withdraw from the study completely (withdrawal of informed consent) for any reason at 
any time.  Subjects who discontinue the study prematurely after randomization will not be replaced.  
Subjects may discontinue study drug treatment but may choose to continue to participate in the study.
Subjects can request to be discontinued from participating in the study at any time for any reason 
including, but not limited to, disease progression or lack of response to treatment.  The investigator may 
discontinue any subject's participation at any time for any reason, including but not limited, to disease 
progression, lack of response to treatment, an AE, safety concerns, or failure to comply with the 
protocol.  Refer to Section 6.2 for additional discontinuation criteria relating to Toxicity Management of 
serious infections, GI perforation, cardiovascular and thromboembolic events, malignancy, ECG 
abnormality and select laboratory abnormalities.
Subjects will have study drug discontinued immediately if any of the following occur:
!
Rescue treatment is administered outside of the parameters described in Section 5.4 (Rescue 
Therapy).
!
Oral corticosteroid for more than 2 consecutive weeks.
!
Initiation of injectable or parenteral non-corticosteroid systemic rescue therapy for AD.
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!
Permanent discontinuation from study drug will be mandatory after Week 4 for any subject with 
an EASI score worsening of 25% or more compared with their Baseline EASI score at any 
2 consecutive scheduled study visits after Week 4 (after a trial of rescue treatment, if 
appropriate; see Rescue Therapy in Section 5.4).  For example, permanent study drug 
discontinuation would apply at Week 8 if EASI score worsening criteria are met at Week 4 and 
Week 8 without rescue therapy given at Week 4. Permanent study drug discontinuation would 
apply at Week 12 if EASI score worsening criteria are met at Week 8 and Week 12 with rescue 
therapy given at Week 4. This rule applies similarly to later timepoints.
!
Clinically significant abnormal laboratory results or AEs, which rule out continuation of the study 
drug, as determined by the investigator and the AbbVie Therapeutic Area Medical/Scientific 
Director.  Note:  Intentional/prospective deviations from the protocol are not allowed.  See 
Section 5.9 Protocol Deviations.
!
The investigator believes it is in the best interest of the subject.
!
The subject requests withdrawal from the study.
!
Eligibility criteria violation was noted after the subject started study drug, when continuation of 
the study drug would place the subject at risk as determined by the AbbVie Therapeutic Area 
Medical/Scientific Director.  Note:  Intentional/prospective deviations from the protocol are not 
allowed.  See Section 5.9 Protocol Deviations.
!
Introduction of prohibited medications or dosages when continuation of the study drug would 
place the subject at risk, as determined by the AbbVie Therapeutic Area Medical/Scientific 
Director.  Note:  Intentional/prospective deviations from the protocol are not allowed.  See 
Section 5.9 Protocol Deviations.
!
Subject is non-compliant with TB prophylaxis (if applicable) or develops active TB at any time 
during the study.
!
The subject becomes pregnant or plans to become pregnant while on study drug.
!
Malignancy, except for localized NMSC or carcinoma in-situ of the cervix. 
!
Subject is significantly non-compliant with study procedures which would put the subject at risk 
for continued participation in the trial in consultation with the AbbVie Therapeutic Area 
Medical/Scientific Director.  Note:  Intentional/prospective deviations from the protocol are not 
allowed.  See Section 5.9 Protocol Deviations.
!
Subject develops a GI perforation (defined as acute, spontaneous perforation of the GI tract that 
requires inpatient medical care or urgent surgical intervention other than appendicitis or 
mechanical injury). See also Section 6.2 Toxicity Management.
!
An ECG change considered clinically significant and with reasonable possibility of relationship to 
study drug, OR a confirmed absolute Fridericia's correction formula (QTcF) value > 500 msec in 
adults or > 450 msec in adolescents OR a change of QTc interval > 60 msec from baseline.
!
Confirmed diagnosis of deep vein thrombosis, pulmonary embolus, or non-cardiac, 
non-neurologic arterial thrombosis.
The study will be discontinued or terminated in case of an unacceptable risk, any relevant toxicity, or a 
negative change in the risk/benefit assessment.  This might include the occurrence of AEs with a 
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character, severity or frequency that is new in comparison to the existing risk profile.  In addition, any 
data deriving from other clinical trials or toxicological studies that negatively influence the risk/benefit 
assessment may cause discontinuation or termination of the study.
AbbVie may terminate this study prematurely, either in its entirety or at any site.  The investigator may 
also stop the study at his/her site if he/she has safety concerns.  If AbbVie terminates the study for 
safety reasons, AbbVie will promptly notify the investigator.
For subjects to be considered lost to follow-up, reasonable attempts must be made to obtain 
information on the final status of the subject.  At a minimum, 2 telephone calls must be made and 
1 certified letter must be sent and documented in the subject's source documentation.
State of Emergency or Pandemic Related Acceptable Protocol Modifications
During the COVID-19 pandemic, it has been necessary to employ mitigation strategies to enable the 
investigator to ensure subject safety and continuity of care.  Acceptable mitigation strategies are 
identified and included in the Operations Manual in Appendix F.  These mitigation strategies are only to 
be implemented locally during the COVID-19 pandemic.
The investigator should contact the AbbVie medical contact before discontinuing a subject from the 
study for a reason other than "planned per protocol," to ensure that all acceptable mitigation steps have 
been explored.
Refer to the Operations Manual in Appendix F for details on how to handle study activities/procedures.
Interruption/Discontinuation of Study Drug Due to COVID-19 Infection
Delays in study drug dosing due to COVID-19 must be discussed with the AbbVie medical contact, along 
with the possibility of premature discontinuation from the study drug dosing period.  Follow subsequent 
protocol Section 5.6 for subjects who discontinue study drug.
5.6 Follow-Up for Subject Withdrawal from Study
To minimize missing data for efficacy and safety assessments, subjects who prematurely discontinue 
study drug treatment should continue to be followed for all regularly scheduled visits, unless subjects 
have decided to discontinue the study participation entirely (withdrawal of informed consent).  Subjects 
should be advised on the continued scientific importance of their data even if they prematurely 
discontinue treatment with study drug.
If a subject prematurely discontinues study participation, the procedures outlined for the Premature 
Discontinuation visit (PD visit) should be completed as soon as possible, preferably within 2 weeks of 
study drug discontinuation.  In addition, a 30-day follow-up visit should occur to determine the status of 
any ongoing AEs/SAEs or the occurrence of any new AEs/SAEs.
Subjects who prematurely discontinue study drug, but continue study participation should complete a 
PD visit as soon as possible, preferably within 2 weeks.  Afterwards, subjects should follow the regular 
visit schedule as outlined in Appendix D, and adhere to all study procedures except for dispensing study 
drug and PK sample collection.  Once the subject has discontinued study drug, all rescue and efficacy 
driven discontinuation criteria no longer apply.  If at any point a subject no longer wants to provide 
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assessments (withdrawal of informed consent) following discontinuation of study drug, a second PD visit 
is not required.  The 30-Day Follow-Up visit is not applicable for subjects who discontinued study drug 
and continued study participation and completed at least one study visit at least 30 days after last dose 
of study drug.
All attempts must be made to determine the date of the last study drug dose and the primary reason for 
discontinuation of study drug or study participation.  The information will be recorded on the 
appropriate eCRF page.  However, these procedures should not interfere with the initiation of any new 
treatments or therapeutic modalities that the investigator feels are necessary to treat the subject's 
condition.  Following discontinuation of study drug, the subject will be treated in accordance with the 
investigator's best clinical judgment, irrespective of whether or not the subject decides to continue 
participation in the study.
In the event a subject withdraws consent from the clinical study, biomarker research will continue 
unless the subject explicitly requests analysis to be stopped.  When AbbVie is informed that samples are 
withdrawn from research, samples will not be analyzed, no new biomarker analysis data will be 
collected, and the samples will be destroyed.  Data generated for biomarker research before subject 
withdrawal of consent will remain part of the study results.
5.7 Treatment After End of Study
For active subjects randomized to upadacitinib, subjects will continue study treatment throughout the 
study for a period of up to 260 weeks or until premature discontinuation of study drug.  At the subject's 
last study visit, the investigator will discuss the appropriate subsequent treatment with the subject.  
AbbVie will not provide drug or any other therapy once the subject's participation is concluded.
5.8 Study Drug
The individual study drug information is presented in Table 2.
Table 2.
Description of Study Drug and Placebo
Investigational Product
Mode of 
Administration
Formulation
Strength
Manufacturer
Upadacitinib (ABT-494)
oral
Film-Coated Tablet
15 mg 
30 mg
AbbVie
Placebo for upadacitinib (ABT-494)
oral
Film-Coated Tablet
NA
AbbVie
NA = not applicable
Upadacitinib and matching placebo will be taken QD beginning on Day 1 (Baseline) and should be taken 
at approximately the same time each day.  The study drug can be taken with or without food.  The study 
drug should be taken whole and should not be split, crushed, dissolved, etc.  If a subject should forget to 
take upadacitinib or matching placebo dose at their regularly scheduled dosing time, they should take 
the forgotten dose as soon as they remember as long as it is at least 10 hours before their next 
scheduled dose.  Otherwise they should take the next dose at the next scheduled dosing time.
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The subject will be instructed to return all drug containers (even if empty) to the study site personnel at 
each study visit.  The study site personnel will document compliance.
AbbVie will not supply drug other than upadacitinib or matching placebo.  If a subject is unable to come
to the study site to pick up their study drug due to a state of emergency or pandemic (e.g., COVID-19 
pandemic), a direct-to-patient (DTP) study drug shipment can be made from the study site to the subject 
if allowed by local regulations. AbbVie will submit any required notifications to the regulatory authority 
as applicable. Refer to Section 5.10 for details on DTP shipment of study drug.
There are no time limits for study drug interruption if no permanent study discontinuation criteria have
been met.
For allowed study drug interruption due to elective and emergency surgeries, the following rules apply:
1.
If the subject must undergo emergency surgery, the study drug should be interrupted at the 
time of the surgery.  After emergency surgery, allow reintroduction of study drug once the 
physician has examined the surgical site and determined that it has healed and there is no sign 
of infection.
2.
Elective surgery, and interruption of study drug for such a surgery, will not be allowed during 
the study until the primary endpoint has been assessed (Week 16).  If the subject undergoes 
elective surgery, the study drug should be interrupted at least 1 week prior to the planned 
surgery.  Allow reintroduction of study drug once the physician has examined the surgical site 
and determined that it has healed and there is no sign of infection.
Packaging and Labeling
Upadacitinib and matching placebo will be packaged in bottles with quantities sufficient to 
accommodate study design.  Each bottle (kit) label will contain a unique kit number.  This kit number is 
assigned to a subject via IRT and encodes the appropriate study drug to be dispensed at the subject's 
corresponding study visit.  Each kit will be labeled as required per country requirements.  Labels must 
remain affixed to the bottles (kits).  All blank spaces on the label will be completed by the site staff prior 
to dispensing to the subjects.
Storage and Disposition of Study Drug
Upadacitinib and matching placebo must be stored at controlled room temperature (15° to 25°C/59° to 
77°F).  The investigational products are for investigational use only and are to be used only within the 
context of this study.  The study drug supplied for this study must be maintained under adequate 
security and stored under the conditions specified on the label until dispensed for subject use or 
destroyed as appropriate.
Selection and Timing of Dose for Each Subject
The study drug (upadacitinib or placebo) will be dispensed in the form of bottles with 15 mg, 30 mg, or 
matching placebo tablets at the visits listed in Appendix D.  Subjects will be instructed to take study drug 
orally as 1 tablet once daily at approximately the same time each day with or without food.  The study 
drug should be taken whole and should not be split, crushed, dissolved, etc.
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Randomization/Drug Assignment
All subjects will be assigned a unique identification number by the IRT at the screening visit.  For 
subjects who rescreen, the screening number assigned by the IRT at the initial screening visit should be 
used.  The IRT will assign a randomization number that will encode the subject's treatment group 
assignment according to the randomization schedule generated by the statistics department at AbbVie. 
Subjects in the main study will be randomized in a 1:1:1 ratio to one of the three treatment groups:
!
Group 1:  Upadacitinib 15 mg (N = 270)
!
Group 2:  Upadacitinib 30 mg (N = 270)
!
Group 3:  Placebo (N = 270)
Upon completion of enrollment of 810 subjects in the main study, the adolescent sub-study will 
continue to enroll adolescent subjects until a total of 180 adolescent subjects are enrolled in the overall 
study (main study + adolescent sub-study).  Subjects in the adolescent sub-study will be randomized in a 
1:1:1 ratio to one of the three treatment groups:
!
Group 1:  Upadacitinib 15 mg
!
Group 2:  Upadacitinib 30 mg
!
Group 3:  Placebo
For the main study, randomization will be stratified by baseline disease severity (moderate 
[Investigator's Global Assessment (vIGA-AD) = 3] versus severe [vIGA-AD = 4] AD), by geographic region 
(US/Puerto Rico/Canada, Other, China, and Japan), and age (adolescent [ages 12 - 17] versus adult [ages 
18 - 75]).  For the adolescent sub-study, randomization will be stratified by baseline disease severity 
(moderate [vIGA-AD = 3] versus severe [vIGA-AD = 4]) and by geographic region (US/Puerto Rico/Canada 
and Other).
At Week 16 of the main study and of the adolescent sub-study, the subjects remaining in Group 3 will be 
re-randomized in a 1:1 ratio to one of two treatment groups:
!
Group 4:  Upadacitinib 15 mg 
!
Group 5:  Upadacitinib 30 mg 
For the main study, the re-randomization will be stratified by EASI 50 responder (Yes/No), by geographic 
region (US/Puerto Rico/Canada, China, Japan, and Other), and by age (adolescent [ages 12 to 17] versus 
adult [ages 18 to 75]).  For the adolescent sub-study, the re-randomization will be stratified by EASI 50 
responder (Yes/No) and by geographic region (US/Puerto Rico/Canada and Other).
IRT will provide the appropriate study drug kit number(s) to dispense to each subject.  Returned study 
drug must not be re-dispensed to any subject.
All AbbVie personnel with direct oversight of the conduct and management of the trial (with the 
exception of AbbVie Drug Supply Management Team), the investigator, study site personnel, and the 
subject will remain blinded to each subject's treatment throughout the study.  To maintain the blind, the 
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upadacitinib tablets and placebo tablets provided for the study will be identical in appearance.  The IRT 
will provide access to unblinded subject treatment information in the case of a medical emergency.
Enrollment in Japan will be capped at 45 subjects (15 subjects per group), with a target enrollment 
number of approximately 30 to 45 subjects (10 to 15 subjects per group).
Enrollment in China will be capped at 45 subjects (15 subjects per group), with a target enrollment 
number of approximately 30 to 45 subjects (10 to 15 subjects per group).
Blinding
Study sites and subjects will remain blinded for the duration of the study.  To maintain integrity of the 
trial and avoid introduction of bias, the study team will only have access to unblinded subject level data 
for AEs of special interests and SAEs for regulatory submissions.  In order to maintain the blind, the 
upadacitinib tablets and placebo tablets provided for the study will be identical in appearance.  The IRT 
will provide access to unblinded subject treatment information in the case of medical emergency.
Unblinding is available in the IRT system via the Unblind Subject transaction, which is available only to 
the investigator.  If the IRT system is unavailable, unblinding may occur by contacting EndPoint technical 
support via either phone (preferred) or email (support@endpointclinical.com).  For country-specific 
phone numbers, please see the following website:  http://www.endpointclinical.com/helpdesk/.  
In the event that the blind is broken before notification to the AbbVie TA SD, we request that the AbbVie 
TA SD be notified within 24 hours of the blind being broken.  The date and reason that the blind was 
broken must be conveyed to AbbVie and recorded on the appropriate eCRF.
Treatment Compliance
The investigator or his/her designated and qualified representatives will administer/dispense study drug 
only to subjects enrolled in the study in accordance with the protocol.  The study drug must not be used 
for reasons other than that described in the protocol.
Subject dosing will be recorded on a subject dosing diary.  Subjects will be instructed to return all drug 
containers (even if empty) to the study site personnel at each clinic visit.  The study site personnel will 
document compliance in the study source documents.
5.9 Protocol Deviations
The investigator is responsible for complying with all protocol requirements, written instructions and 
applicable laws regarding protocol deviations.  Protocol deviations are prohibited except when 
necessary to eliminate an immediate hazard to study subjects.  If a protocol deviation occurs (or is 
identified, including those that may be due to a state of emergency or pandemic (e.g., COVID-19 
pandemic), the investigator is responsible for notifying IEC/IRB, regulatory authorities (as applicable) 
and AbbVie.
In Japan, the investigator will record all protocol deviations in the appropriate medical records at site.
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5.10 Other Study Procedures
Subject Information and Informed Consent
The investigator or his/her representative will explain the nature of the study to the subject, the 
benefits and risks anticipated from participation in the study, and answer all questions regarding this 
study.  Prior to any study-related screening procedures being performed on the subject or any 
medications being discontinued by the subject in order to participate in this study, the informed consent 
statement will be reviewed, signed, and dated by the subject or their legally authorized representative, 
parent or legal guardian (for subject ≥ 12 years old and < 18 years old) the person who administered the 
informed consent, and any other signatories according to local requirements.  A copy of the signed 
informed consent will be given to the subject and the original will be placed in the subject's medical 
record.  An entry must also be made in the subject's dated source documents to confirm that informed 
consent was obtained prior to any study-related procedures and that the subject received a signed copy.  
An assent form may need to be signed and dated for adolescent subjects, according to the country 
requirements.  If a subject becomes of legal age during the course of the study, that subject will need to 
be consented using the approved informed consent form.
Information regarding benefits for subjects and information regarding provisions for treating and/or 
compensating subjects who are harmed because of participation in the study can be found in the 
informed consent form.
Optional biomarker samples will only be collected if the subject has voluntarily provided consent, 
approved by an IRB/IEC, after the nature of the testing has been explained and the subject has had an 
opportunity to ask questions.  If the subject does not consent to optional biomarker samples, it will not 
impact the subject's participation in the study.  In the event a subject withdraws consent to participate 
from the study, optional biomarker samples will continue to be stored and used for research.  In the 
event that a subject would like to withdraw consent for research using these samples, the subject may 
request that their samples be withdrawn.  Once AbbVie receives the request, remaining biomarker 
samples will be destroyed.  If the subject changes his/her consent, and the samples have already been 
tested, those results will still remain as part of the overall research data.
Optional photography will be performed at selected sites and only if the subject has voluntarily provided 
consent, approved by an IRB/IEC, after the nature of the photography sub-study has been explained and 
the subject has had an opportunity to ask questions.  If the subject does not consent to the optional 
photography sub-study, it will not impact the subject's participation in the study.
Due to a state of emergency or pandemic (e.g., COVID-19), it is possible that additional protocol 
modifications not outlined in this protocol may become necessary. If this situation arises, in addition to 
the study informed consent, additional verbal consent may be obtained prior to these adaptations or 
substantial changes in study conduct in accordance with local regulations.
Screening and Re-Screening Procedures
Within 35 days prior to the Baseline Visit, subjects will receive a full explanation of the study design and 
study procedures, provide a written informed consent, and undergo the screening procedures outlined 
in Operations Manual Section 2.1 (Appendix F).  Laboratory values can be re-tested once during the 
screening period.  If the re-tested lab value(s) remain(s) exclusionary, the subject will be considered a 
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screen failure.  Redrawing samples if previous samples were unable to be analyzed would not count as a 
retest since previous result was never obtained.
Subjects who initially screen-fail for the study are permitted to re-screen once following re-consent.  For 
additional re-screening, AbbVie TA SD approval is required.  As appropriate, sites are encouraged to 
contact the AbbVie TA SD to confirm if subjects should or should not be re-screened.  All screening 
procedures with the possible exceptions noted below will be repeated during rescreening.  The subject 
must meet all eligibility criteria at the time of re-screening in order to qualify for the study.  There is no 
minimum period of time a subject must wait to re-screen for the study.
If the subject had a complete initial screening evaluation including the following assessments, these 
tests will not be required to be repeated for re-screening, provided the conditions noted in Section 5.1, 
there are no changes in the subject's medical history that would warrant re-testing, and no more than 
90 days have passed: 
!
HBV, HCV and HIV serology 
!
Interferon-gamma release assay (IGRA; QuantiFERON TB Gold test [or IGRA equivalent such as T 
SPOT test] and/or local PPD skin test, if required) 
!
Chest x-ray 
!
ECG
Subjects who are between ≥ 12 and < 18 years of age at the time of the Screening visit will be 
considered adolescents for the duration of the study.  The age at the time of Re-Screening Visit will be 
used for subjects who Re-Screen.
Medical History
A complete non-AD medical history, including demographics, history of tobacco, alcohol, and nicotine 
use, will be taken at Screening.  Additionally, a list of each subject's specific AD related medical history 
should be recorded at Screening.  History of clinical herpes zoster, herpes zoster vaccination, and 
hepatitis B vaccination status will be recorded as part of the medical history.
The subject's medical history will be updated prior to study drug administration at the Study Day 1 visit.  
This updated medical history will serve as the baseline for clinical assessment and to ensure the subject 
is still eligible for enrollment.
A detailed medical history with respect to TB risk factors will be documented in the study source 
documentation.  This information will include Bacillus Calmette–Guérin vaccination, cohabitation with 
individuals who have had TB, and travel to, residence in, or work in TB endemic locations.
In Japan, the hepatitis screen requirements are as follows:
!
A positive test result for HBc Ab or HBs Ab requires HBV DNA PCR testing (automatic reflex 
testing).
!
A positive result for HBV DNA or a result that exceeds detection sensitivity will be exclusionary.
!
A subject with a negative result for HBV DNA may be enrolled.
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!
For subjects with HBs Ab positive (+) and/or HBc Ab positive (+) and negative HBV DNA at 
Screening, HBV DNA PCR test should be performed approximately every 12 weeks (in correlation 
with a scheduled visit).  HBV-DNA PCR testing approximately every 12 weeks is not necessary in 
case of subjects with history of HBV vaccine and HBs Ab positive (+) and HBc Ab negative (–).  
!
Subjects with HBc Ab+ (irrespective of HBs Ab status) and negative HBV DNA at Screening who 
develop a positive result for HBV DNA PCR testing during the study accompanied by the 
following should be referred to a hepatologist within one week for consultation and 
recommendation regarding subsequent treatment, and study drug interruption should be 
considered per local guidelines:
!
an ALT or AST > 5 × ULN OR
!
ALT or AST > 3 × ULN and either a total bilirubin > 2 × ULN or INR > 1.5 OR
!
ALT or AST > 3 × ULN along with clinical signs of possible hepatitis.
In China, a syphilis Ab test will be performed at Screening utilizing the Toluidine Red Unheated Serum 
Test (TRUST) to test anticardiolipin antibody in serum.  Subjects with a positive TRUST result will have a 
Treponema pallidum particle agglutination assay (TPPA) to confirm a syphilis infection.  A positive test 
result for both the TRUST and TPPA tests will be exclusionary.  The syphilis tests will be performed by a 
certified laboratory.
Drug and Alcohol History
Subjects should have no history of clinically significant (per investigator's judgment) drug or alcohol 
abuse within the last 6 months preceding the Baseline Visit.  Results are reported from the subject 
interview.
Urine specimens will be tested at the screening visit for the presence of drugs of abuse.  The panel for 
drugs of abuse will minimally include the drugs listed below.  Any positive result must be assessed for 
clinical significance.  These analyses will be performed by the certified central laboratory chosen for the 
study.
!
Opiates
!
Barbiturates
!
Amphetamines
!
Cocaine
!
Benzodiazepines
!
Alcohol
!
Phencyclidine
!
Propoxyphene
!
Methadone
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Adverse Event Assessment
The subjects will undergo physical examination for any active AEs and AEs that have occurred and 
resolved since the last visit as well as be interviewed for AEs that are not apparent in a physical 
examination.  SAEs and protocol related nonserious AEs that occur after a subject signs the informed 
consent will be collected, prior to the first dose of study drug.  Please refer to Section 6.1.
Patient-Reported Outcomes
Subjects will complete the self-administered patient-reported outcome (PRO) instrument (when allowed 
per local regulatory guidelines) at study visits specified in Appendix D.  Subjects should be instructed to 
follow the instructions provided with the instrument and to provide the best possible response to each 
item.  Site personnel shall not provide interpretation or assistance to subjects other than 
encouragement to complete the tasks.  Subjects who are functionally unable to read any of the 
instruments may have site personnel read the questionnaire to them.  Site personnel will encourage 
completion of the instrument at all specified visits and will ensure that a response is entered for all 
items.
Subjects will complete the following questionnaires below as specified in Operations Manual Section 2.1
(Appendix F).  Worst Pruritus NRS, ADerm-SS daily items, ADerm-IS daily items, ADerm-SS weekly items, 
ADerm-IS weekly items, SCORAD, POEM, PGIS, PGIC, PGIT, DLQI, CDLQI, EQ-5D-5L, SF-36, HADS, and 
WPAI should be administered before any study procedures in the order listed. 
A validated translation will be provided in their local language, as applicable.  All PROs are collected 
electronically.  The subject should complete the questionnaires before site personnel perform any 
clinical assessments and preferable before any interaction with site personnel has occurred to avoid 
biasing the subject's response.
The PRO instrument should be completed prior to drug administration on Day 1 and prior to any 
discussion of AEs or any review of laboratory findings.
State of Emergency or Pandemic-Related Acceptable Protocol Modifications
Due to a state of emergency or pandemic (e.g., COVID-19 pandemic), subject visits may be conducted 
via phone or video conference.  The primary site monitor will inform the site which PROs are eligible for 
completion by interview.  In this situation, sites will read the PRO questions and response options to the 
subject and record the subject's responses.  The subject's ability to view the PRO to understand the 
questions and response options should be preserved.  Sites may share the questionnaire by 
videoconference or send the questionnaires (email or hard copy) to the subjects to allow them to 
read/understand the questions and responses when the subject is providing responses over the phone.  
The date and time of PRO data collection should be recorded along with who collected the information.
Worst Pruritus Numerical Rating Scale (NRS)
The Worst Pruritus NRS is an assessment tool that subjects used to report the intensity of their pruritus 
during a daily recall period.  Subjects are asked the question:  "On a scale of 0 to 10, with 0 being 'no 
itch' and 10 being the 'worst imaginable itch,' how would you rate your itch at its worst during the past 
24 hours?"  The Worst Pruritus NRS will be administered on electronic hand-held devices from Screening 
through Week 16; devices will be given to subjects to take home at Screening.  Hand-held device usage 
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ends at the Week 16 visit.  Starting at the Week 20 visit, the frequency of administration will be reduced 
from daily assessments to assessments only at scheduled site visits using a tablet at the site.
Atopic Dermatitis Symptom Scale (ADerm-SS)
The ADerm-SS is an 11-item PRO questionnaire designed to assess signs and symptoms that subjects 
may experience due to AD using a 24-hour recall period.  The ADerm-SS includes three items that 
subjects complete daily and 8 items that subjects completed each week.  The daily items include:  worst 
itch during sleep hours, worst itch during awake hours, and worst skin pain.  The 8 weekly items are also 
assessed using a 24-hour recall period.  These items include worst skin cracking, worst pain caused by 
skin cracking, worst dry skin, worst skin flaking, worst rash (i.e., redness, blisters, bumpy skin), worst skin 
thickening, worst bleeding, and worst skin oozing.  All items of the ADerm-SS are scored on an 11-point 
NRS ranging from 0 (no [sign/symptom concept]) to 10 (worst possible [sign/symptom concept]). 
The ADerm-SS will be administered on electronic hand-held devices from Screening through Week 16; 
devices will be given to subjects to take home at Screening.  Hand-held device usage ends at the 
Week 16 visit.  Starting at the Week 20 visit, the frequency of administration will be reduced from 
daily/weekly assessments to assessments only at scheduled site visits using a tablet at the site.
Atopic Dermatitis Impact Scale (ADerm-IS)
The ADerm-IS is a 10-item PRO questionnaire designed to assess a variety of impacts that subjects 
experience from their AD across both a 24-hour recall period (the daily items 1 to 3) and 7-day recall 
period (the weekly items 4 to 10).  Daily items are related to sleep, and include difficulty falling asleep, 
impact on sleep, and waking at night.  Weekly items include household activities (e.g., washing dishes, 
sweeping, doing laundry), physical activities (e.g., walking, exercising), social activities, concentration, 
self-consciousness, embarrassment, and sadness.  All items of the ADerm-IS are scored on an 11-point 
NRS from 0 (no impact) to 10 (extreme impact).  
The ADerm-IS will be administered on electronic hand-held devices from Screening through Week 16; 
devices will be given to subjects to take home at Screening.  Hand-held device usage ends at the 
Week 16 visit.  Starting at the Week 20 visit, the frequency of administration will be reduced from 
daily/weekly assessments to assessments only at scheduled site visits using a tablet at the site.
Dermatology Life Quality Index (DLQI)
The DLQI is a 10-item, validated questionnaire used in clinical practice and clinical trials to assess the 
impact of AD disease symptoms and treatment on quality of life (QoL).  It consists of 10 questions 
assessing impact of skin diseases on different aspects of subject's QoL over the prior week.  The DLQI 
items include symptoms and feelings, daily activities, leisure, work or school, personal relationships and 
the side effects of treatment.  Each item is scored on a 4-point scale:  0 = not at all/not relevant; 1 = a 
little; 2 = a lot; and 3 = very much.  Item scores (0 to 3) are added to provide a total score range of 0 to 
30; higher scores indicate greater impairment of QoL.  For general inflammatory skin conditions, a 
change in DLQI score of at least 4 points is considered the MCID.  The DLQI will be administered on the 
tablet at site visits throughout the study.  Throughout this study, the DLQI will be administered to 
subjects who are ≥ 16 (16 to 75) years old at the time of the Screening visit.
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Children's Dermatology Life Quality Index (CDLQI)
The CDLQI is a 10-item, validated questionnaire used in clinical practice and clinical trials to assess the 
impact of AD disease symptoms and treatment on QoL.  The CDLQI has been validated for use in 
subjects 4 - 16 years old.  It consists of 10 questions assessing impact of skin diseases on different 
aspects of patient's QoL over the prior week.  The CDLQI items include symptoms and feelings, daily
activities, leisure, school, relationships, sleep, and treatment.  Each item is scored on a 4-point scale:  
0 = not at all; 1 = only a little; 2 = quite a lot; and 3 = very much.  Item scores (0 to 3) are added to 
provide a total score range of 0 to 30; higher scores indicate greater impairment of QoL.  In this study, 
the CDLQI will be administered to subjects who are < 16 years old at the time of the Screening visit, and 
will continue to be administered to these subjects for the duration of this study.
Patient-Oriented Eczema Measure (POEM)
The POEM is a 7-item, validated questionnaire used in clinical practice and clinical trials to assess disease 
symptoms in both children and adults.  Subjects respond to 7 items, including dryness, itching, flaking, 
cracking, sleep loss, bleeding, and weeping, each scored on a 5-point scale based on frequency:  0 = no 
days, 1 = 1 to 2 days, 2 = 3 to 4 days, 3 = 5 to 6 days, and 4 = all days.  Item scores (0 to 4) are added to 
provide a total score range of 0 to 28; the total score reflects disease-related morbidity.  A change in 
POEM score of 3.4 points is considered the MCID.  The POEM will be administered on the tablet at site 
visits throughout the study.
Hospital Anxiety and Depress Scale (HADS)
The HADS is a 14-item questionnaire, with seven items related to anxiety (HADS-A) and seven items 
related to depression (HADS-D).  Each item is scored from 0 to 3; scores for each subscale range from 
0 to 21 and scores for the entire scale (emotional distress) range from 0 to 42, with higher scores 
indicating more distress.  For each domain, scores 7 or lower are considered normal, 8 to 10 are 
borderline, and 11 or higher indicate clinical anxiety or depression.  HADS will be administered on the 
tablet at site visits throughout the study.
Work Productivity and Activity Impairment Index:  Atopic Dermatitis (WPAI:AD)
The WPAI:AD is a validated instrument used to measure loss of productivity at work and impairment in 
daily activities over the past 7 days.  The questionnaire includes four items:  absenteeism, presenteeism, 
overall work impairment, and activity impairment, that range from 0% to 100%, with higher values 
indicating greater impairment.  While absenteeism represents the percentage of work time missed due 
to AD, presenteeism represents the percentage of impairment while at work due to AD.  Overall work 
impairment represents the total percentage of work time missed due to either absenteeism or 
presenteeism (since those are mutually exclusive).  Activity impairment represents the percentage of 
impairment during daily activities other than work.  The 4 items are all evaluated using an 11-point 
Likert-type scale from 0 (no effect) to 10 (completely prevented), and the scores are multiplied by ten to 
arrive at a percentage.
The WPAI:AD will be administered on the tablet at site visits throughout the study.
EuroQoL Dimensions 5 Levels (EQ-5D-5L)
The EQ-5D-5L is a standardized measure of health status developed by the EuroQol Group in order to 
provide a simple, generic measure of health for clinical and economic appraisal.  The EQ-5D-5L consists 
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of 2 parts:  the descriptive system and the EQ visual analogue scale (EQ-VAS).  The EQ-5D-5L descriptive 
system comprises the following 5 dimensions:  mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression.  Each dimension has 3 levels of perceived problems:  "no problem" (level 1), "some 
problems" (level 2), "extreme problems" (level 3).  The respondent is asked to indicate his/her health 
state by ticking (or placing a cross) in the box against the most appropriate statement (i.e., no problems, 
some problems, or severe problems) in each of the 5 dimensions; this results in a 1-digit number 
expressing the level for that dimension.  The digits for 5 dimensions can be combined in a 5-digit 
number describing the respondent's health state. 
The EQ-VAS records the respondent's self-rated health on a vertical, visual analogue scale where the 
endpoints are labeled "best imaginable health state (100)" and "worst imaginable health state (0)."  This 
information can be used as a quantitative measure of health outcome as judged by the individual 
respondents.
The EQ-5D-5L will be administered on the tablet at site visits throughout the study.
Patient Global Impression of Severity (PGIS)
The PGIS asks subjects to describe the severity of their AD symptoms right now.  Subjects rate their AD 
symptoms on a 7-point scale ranging from 0 = Absent (no symptoms) to 6 = Very Severe (cannot be 
ignored and markedly limits my daily activities).
The PGIS will be administered on the tablet at site visits throughout the study.
Patient Global Impression of Change (PGIC)
The PGIC asks subjects to rate the overall change in their AD symptoms by comparing the severity of 
their AD symptoms right now with the severity of their AD symptoms before they began study 
treatment.  Subjects are asked:  "Compared to before your study treatment began, how would you rate 
the overall change in your atopic dermatitis symptoms?" Responses range from 1 = "Very much 
improved" to 7 = "Very much worse."
The PGIC will be administered on the tablet at site visits throughout the study.  The PGIC will not be 
collected at Baseline.
Patient Global Impression of Treatment (PGIT)
The PGIT asks subjects to rate their level of satisfaction/dissatisfaction with their current treatment for 
AD.  Subjects are asked:  "Overall, how satisfied or dissatisfied are you with your current treatment for 
atopic dermatitis?"  Responses range from 1 = "Extremely dissatisfied" to 7 = "Extremely satisfied."
The PGIT will be administered on the tablet at site visits throughout the study.
Short Form-36 Health Survey (SF-36)
The SF-36 Health Survey is a generic assessment that measures general health status.  The SF-36 
includes eight domains rated over the prior four weeks:  physical function, role limitations – physical, 
bodily pain, general health perceptions, vitality, social function, and role limitations with regard to 
emotional and mental health.  Two component scores, the Physical Component Summary and the 
Mental Component Summary (MCS) are calculated.  The SF-36 domain and summary scores are 
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transformed to a normative scale with a mean of 50 and standard deviation of 10, with higher scores 
indicating better physical function or well-being.
The SF-36 will be administered on the tablet at site visits throughout the study.
SCORing Atopic Dermatitis (SCORAD)
The SCORAD is a validated tool used in clinical research and clinical practice that was developed to 
standardize the evaluation of the extent and severity of AD.  There are 3 components to the assessment:  
A = extent or affected body surface area, B = severity, and C = subjective symptoms.  The extent of AD is 
assessed as a percentage of each defined body area and reported as the sum of all areas, with a 
maximum score of 100% (assigned as "A" in the overall SCORAD calculation).  The severity of 6 specific 
symptoms of AD (redness, swelling, oozing/crusting, excoriation, skin thickening/lichenification, dryness) 
is assessed using the following scale:  none (0), mild (1), moderate (2), or severe (3) (for a maximum of 
18 total points, assigned as "B" in the overall SCORAD calculation).  Subjective assessment of itch and 
sleeplessness is recorded for each symptom by the subject or relative on a VAS on the tablet, where 0 is 
no itch (or sleeplessness) and 10 is the worst imaginable itch (or sleeplessness), with a maximum 
possible score of 20.  This parameter is assigned as "C" in the overall SCORAD calculation.  The SCORAD 
is calculated as:  A/5 + 7B/2 + C where the maximum is 103.
The SCORAD subjective symptoms (component C) will be administered on the tablet at site visits 
throughout the study.  SCORAD components A and B will not be on the tablet and performed on paper 
worksheets and entered into the electronic case report form (eCRF).  The rule of 9's method should be 
used to assess the percentage of each defined body area on the paper worksheets for component A.
Investigator Assessment
The investigator assessments will be recorded on paper worksheets and entered into the eCRF and 
conducted at the study visits specified in Appendix D.  If possible, the investigator assessments should 
be performed by an independent and blinded assessor who should not perform any other study related 
procedures.  In order to minimize variability, the same independent assessor should evaluate the subject 
at each visit for the duration of the study.  A back-up independent assessor should be identified.  The 
independent assessor must be a qualified medical professional (e.g., nurse, physician's assistant, or 
physician).  Any assessor must be trained and competent in performing such assessments.  It is the 
responsibility of the investigator to ensure that all assessors are qualified and trained to perform 
assessments and that all training is documented.  If the independent assessor is not available, the 
pre-identified back-up assessor should perform such assessments.
Validated Investigator's Global Assessment for Atopic Dermatitis (vIGA-AD)
The vIGA-AD is a validated assessment instrument used in clinical studies to rate the severity of AD 
globally, based on a 5-point scale ranging from 0 (clear) to 4 (severe).
Eczema Area and Severity Index (EASI)
The EASI is a validated measure used in clinical practice and clinical trials to assess the severity and 
extent of AD.  The EASI is a composite index with scores ranging from 0 to 72.  Four AD disease 
characteristics (erythema, thickness [induration, papulation, edema], scratching [excoriation], and 
lichenification) will each be assessed for severity by the investigator or designee on a scale of "0" 
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(absent) through "3" (severe).  In addition, the area of AD involvement will be assessed as a percentage 
by body area of head, trunk (including the genital area), upper extremities, and lower extremities 
(including the buttocks), and converted to a score of 0 to 6.  In each body region, the area is expressed 
as 0, 1 (1% to 9%), 2 (10% to 29%), 3 (30% to 49%), 4 (50% to 69%), 5 (70% to 89%), or 6 (90% to 100%).
Body Surface Area Involvement of Atopic Dermatitis (BSA, %)
A qualified investigator or designee should select the subject's right or left hand as the measuring 
device.  For purposes of clinical estimation, the total surface of the palm plus five digits will be assumed 
to be approximately equivalent to 1%.  Measurement of the total area of involvement by the 
investigator is aided by imagining if scattered plaques were moved so that they were next to each other 
and then estimating the total area involved.  The site should make every attempt to have the same 
qualified investigator or designee perform all BSA assessments on a given subject throughout the study.
SCORing Atopic Dermatitis (SCORAD)
See description above in Patient-Report Outcomes.
Hand eczema severity index (HECSI)
Each hand is divided into five areas [fingertips, fingers (except the tips), palms, back of hands and 
wrists].  For each of these areas the intensity of the six following clinical signs:  erythema, 
induration/papulation, vesicles, fissuring, scaling and edema is graded on the following scale:  0, no skin 
changes; 1, mild disease; 2, moderate and 3, severe.  For each location (total of both hands) the affected 
area is given a score from 0 to 4 (0, 0%; 1, 1 – 25%; 2, 26 – 50%; 3, 51 – 75% and 4, 76 – 100%) for the 
extent of clinical symptoms.  Finally, the score given for the extent at each location is multiplied by the 
total sum of the intensity of each clinical feature, and the total sum called the HECSI score is calculated, 
varying from 0 to a maximum severity score of 360 points.
None of the investigator assessments described above (vIGA-AD, EASI, BSA, SCORAD and HECSI) can be
performed remotely, as they require in-person evaluation of the skin.
Vaccines
Vaccines recommended by local guidelines should be considered.  If the investigator chooses to 
administer a vaccine, this should be completed before first dose of study drug with appropriate 
precautions and time interval.  It is recommended that subjects be up to date for recommended 
inactivated, toxoid, or biosynthetic vaccines, such as injectable flu vaccine, pneumococcal, and pertussis 
(tetanus-diphtheria-acellular pertussis).
If the live herpes zoster vaccine is to be administered, and there is no known history of primary varicella 
(chicken pox), preexisting immunity to varicella should be confirmed with antibody testing at or prior to 
screening and prior to administration of the herpes zoster vaccine.  If screening varicella antibody 
testing is negative the live herpes zoster vaccine should not be administered.
In Japan, it is recommended that the live herpes zoster vaccine should be considered for administration 
at least 8 weeks before first dose of study drug or administered at least 30 days after last dose of study 
drug. 
See Section 5.3 for a list of commonly used live vaccines that are prohibited during study participation.
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Tuberculosis Testing
The TB screening tests are diagnostic test results to be interpreted in the context of the subject's 
epidemiology, history, exam findings, etc., and it is the responsibility of the investigator to determine if a 
subject has previous, active, or latent TB.
At Screening, all subjects will be assessed for evidence of increased risk for TB by a risk assessment form 
(Operations Manual Section 3.18 [Appendix F]) and tested for TB infection (QuantiFERON TB Gold test 
[or IGRA equivalent such as T-SPOT test] and/or local PPD skin test, if required) as described below.  The 
site staff will complete the TB risk assessment form and enter the data into an appropriate eCRF.  The TB 
risk factor questionnaire will be done at Week 52 and annually after Week 52, regardless of TB test 
results.
If a subject had a negative PPD test within 90 days prior to Screening and a QuantiFERON-TB Gold test 
(or IGRA equivalent such as T-SPOT test) cannot be performed at Screening and source documentation is 
available, TB testing by PPD skin test does not need to be repeated, provided nothing has changed in the 
subject's medical history to warrant a repeat test.  These cases may be discussed with the AbbVie TA SD.  
The results of the TB test(s) will be retained at the site as the original source documentation. 
Subjects with a negative TB test and chest x-ray not suggestive of active TB or prior TB exposure may be 
enrolled.
Subjects with a positive TB test must be assessed for evidence of active TB versus latent TB, including 
signs and symptoms and chest x-ray.  Subjects with no signs or symptoms and a chest x-ray not 
suggestive of active TB may be enrolled after initiation of TB prophylaxis (see below).  
Subjects with evidence of active TB must not be enrolled.
For subjects with a negative TB test result at Screening or the most recent evaluation, an annual TB 
follow-up test will be performed.  In cases where the annual QuantiFERON-TB Gold test by the central 
laboratory is positive and the investigator considers the subject at low risk for TB (i.e., no risk factors 
identified using the TB risk assessment form) and has no clinical suspicion of TB, the investigator may 
perform a QuantiFERON TB gold test at a local lab (or through the central laboratory if not locally 
available) to confirm the positive test result:  if repeat testing result is negative, then the investigator 
may consider the subject to be negative based on his/her clinical judgment; if repeat testing result is 
positive, then the subject is considered to be positive.
The annual TB test can be completed at the earliest feasible opportunity if not able to be completed per 
protocol schedule due to a state of emergency or pandemic restrictions.  If an annual TB test is newly 
positive (seroconversion), a chest x-ray needs to be performed as soon as possible to aid in 
distinguishing active versus latent TB, and subsequent annual TB follow-up tests are not required.  Any 
positive TB test after the subject has started the study, should be reported as an AE of latent TB or 
active TB (as applicable). 
If the subject is experiencing signs or symptoms suspicious for TB or something has changed in the 
subject's medical history to warrant a repeat test before the next scheduled annual TB re-test, the case 
(including the TB test results) must be discussed with the AbbVie TA MD.
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TB test
!
Subjects with documentation of prior positive result of QuantiFERON-TB Gold test (or IGRA 
equivalent such as T-SPOT TB test) and/or PPD are not required to repeat either test at 
Screening or during the study and should be considered positive. 
!
For regions that require both PPD and QuantiFERON-TB Gold testing (or IGRA equivalent, such 
as T-SPOT TB test), both will be performed.  If either PPD or QuantiFERON-TB Gold (or IGRA 
equivalent, such as T-SPOT TB test) is positive, the TB test is considered positive.
!
The PPD Skin Test (also known as a TB Skin Test or Mantoux Test) should be utilized only when a 
QuantiFERON-TB Gold test (or IGRA equivalent, such as T-SPOT TB test) is not possible for any 
reason (unless both tests are required per local guidelines).  
!
If only a PPD is placed at Screening, then the TB test to be used for the remainder of the study 
for that subject is the PPD.  Similarly, if a subject enters the study with a QuantiFERON-TB Gold 
Test (or IGRA equivalent, such as T-SPOT TB test) alone, then the subject should have their 
annual TB test performed with a QuantiFERON-TB Gold Test (or IGRA equivalent, such as T-SPOT 
TB test).
!
If the QuantiFERON-TB Gold test (or IGRA equivalent, such as T-SPOT TB test) is NOT possible (or 
if both the QuantiFERON-TB Gold test (or IGRA equivalent, such as T-SPOT TB test) and the PPD 
are required per local guidelines) the PPD will be performed.  The PPD should be read by a 
licensed healthcare professional between 48 and 72 hours after administration.  A subject who 
does not return within 72 hours will need to be rescheduled for another skin test.  The reaction 
will be measured in millimeters (mm) of induration and induration ≥ 5 mm is considered a 
positive reaction.  The absence of induration will be recorded as "0 mm" not "negative."  
Subjects who have an ulcerating reaction to the PPD in the past should not be re-exposed and 
the PPD should be considered positive.
!
If the QuantiFERON-TB Gold test is indeterminate, then the investigator should perform a 
QuantiFERON TB gold test at a local lab (or through the central laboratory if not locally available) 
to rule out a positive test result.  If testing remains indeterminate or is positive, then the subject 
is considered to be positive for the purpose of this study.  If the testing result is negative, then 
the subject is considered to be negative.
TB prophylaxis
At Screening, if the subject has evidence of latent TB infection, prophylactic treatment must be initiated 
at least 2 weeks prior to administration of study drug (or per local guidelines, whichever is longer); at 
least 6 months of prophylaxis need to be completed, however, the full course of prophylaxis does not 
need to be completed prior to the first dose of study drug.  
Of note:  Rifampicin or rifapentine is not allowed for TB prophylaxis.
Subjects with a prior history of latent TB that have documented completion of a full course of anti-TB 
therapy will be allowed to enter the study provided nothing has changed in the subject's medical history 
to warrant repeat treatment.  For subjects with completion of a full course of anti-TB therapy, but 
insufficient documentation, the investigator should consult with the AbbVie TA MD. 
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During the study, subjects with new evidence of latent TB must initiate prophylactic treatment 
immediately per local guidelines and complete at least 6 months of prophylaxis.  Study drug(s) should 
not be withheld.  Two to 4 weeks later, the subject should be re-evaluated (unscheduled visit) for signs 
and symptoms as well as laboratory assessment of toxicity to TB prophylaxis.
Newly initiated prophylactic treatment and prior therapy should be captured in the eCRF.
Chest X-Ray
A chest x-ray (posterior-anterior and lateral views) is required:
!
For all subjects at Screening to rule out the presence of TB or other clinically relevant findings.  
The screening CXR will not be required if the subject had a previous normal CXR 
(posterior-anterior and lateral views) within 90 days of Screening, provided all source 
documentation is available at the site, as outlined below and provided nothing has changed in 
the subject's medical history to warrant a repeat test.
!
At Week 52, and annually thereafter, for subjects with newly identified TB risk factors as 
identified by the TB risk assessment form (Operations Manual Section 3.18 [Appendix F]), or for 
subjects living in areas endemic for TB or for subjects with newly positive PPD and/or 
QuantiFERON-TB Gold test (or IGRA equivalent, such as T-SPOT TB test).  The chest x-ray can be 
completed at the earliest feasible opportunity if not able to be completed per protocol schedule 
due to state of emergency or pandemic (e.g., COVID-19 pandemic) restrictions.  
Subjects can have a repeat chest x-ray at any time during the study as warranted based on the opinion 
of the investigator.  A radiologist or pulmonologist must perform and document an assessment of the 
chest x-ray.  The Principal Investigator will indicate the clinical significance of any findings and will sign 
and date the report.  In the assessment of the chest x-ray, the Principal Investigator or their delegate 
must indicate the presence or absence of (1) calcified granulomas, (2) pleural scarring/thickening, and 
(3) signs of active TB.  If the chest x-ray demonstrates changes suggestive of previous TB (e.g., calcified 
nodule, fibrotic scar, apical or basilar pleural thickening) or other findings that are clinically significant, 
the Principal Investigator should contact the AbbVie TA MD before enrolling the subject.
12-Lead Electrocardiogram
A 12-lead ECG will be performed at the designated study visits as specified in Appendix D.  The ECG 
should be performed prior to blood collection.
The ECGs will be evaluated by an appropriately trained physician at the site ("local reader").  The local 
reader from the site will sign and date all ECG tracings and will provide his/her global interpretation as a 
written comment on the tracing using the following categories:
!
Normal ECG
!
Abnormal ECG – not clinically significant
!
Abnormal ECG – clinically significant
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Only the local reader's evaluation of the ECG will be collected and documented in the subject's source 
folder.  The automatic machine reading (i.e., machine-generated measurements and interpretation that 
are automatically printed on the ECG tracing) will not be collected.
Height and Body Weight
Height and body weight will be measured without shoes at visits specified in Appendix D.  Weight will be 
performed throughout the study for all subjects (both adults and adolescents).  For adults, collection of 
height will be at the Baseline Visit only.  For adolescent subjects (subjects who were 12 to 17 years of 
age at Screening Visit), collection of height will be at the Screening and Baseline Visits and designated 
visits thereafter.  All measurements will be recorded in imperial or metric units where applicable.
State of Emergency or Pandemic-Related Acceptable Protocol Modifications
In the event this may not be performed due to study modifications related to a state of emergency or
pandemic (e.g., COVID-19 pandemic), perform the 12-lead ECG at the next earliest feasible visit.
Vital Signs
Vital sign determinations of systolic and diastolic blood pressure, pulse rate, respiratory rate, and body 
temperature will be obtained at visits as specified in Appendix D.  Blood pressure and pulse rate should 
be measured after the subject has been sitting for at least 3 minutes.
Physical Examination
A complete physical examination will be performed at the designated study visits as specified in 
Appendix D.  The physical examination at the Baseline Visit will serve as the baseline physical 
examination for the entire study.  Physical examination abnormalities noted by the investigator at 
baseline prior to the first dose of study drug will be recorded in the subject's medical history; 
abnormalities noted after the first dose of study drug will be evaluated and documented by the 
investigator as to whether or not the abnormality is an AE.  All findings, whether related to an AE or part 
of each subject's medical history, will be captured on the appropriate eCRF page.
At any time, a symptom-directed physical examination can be performed as deemed necessary by the 
investigator.
Tanner Staging
The Tanner Scale (also known as the Tanner Stages) is a validated measure used in clinical practice and 
clinical trials to assess physical development (Operations Manual Section 3.19 [Appendix F]).  The Scale 
defines physical measurements of development based on external primary and secondary sex 
characteristics, such as the size of the breasts, genitals, testicular volume and development of pubic 
hair.
Throughout this study, Tanner Staging will be assessed at Baseline for subjects who are < 18 (12 to 17) 
years old at the time of the Screening Visit, and will continue to be assessed for these subjects for the 
duration of this study.  Once a subject reaches stage 5 in both categories, Tanner Staging will no longer 
need to be assessed for that subject.
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Dispense Study Drug
Study drug will be dispensed to subjects beginning at Baseline (Day 1) and as specified in Appendix D.  
The first dose of study drug will be administered after all other screening procedures are completed.  
Each site will be responsible for maintaining drug accountability records including product description, 
manufacturer, and lot numbers for all non-investigational products dispensed by the site.
Subjects will be instructed to take study drug orally as 1 tablet once daily at approximately the same 
time each day with or without food.
State of Emergency or Pandemic-Related Acceptable Protocol Modifications
Study drug may be shipped from the study site directly to the study subject's home if all the following
criteria are met:
!
DTP shipment of study drug is allowed by local regulations and the relevant ethics committee 
!
Study drug can be administered by the subject (or subject's caregiver) at home
!
Subject agrees to have the study drug shipped directly to their home
!
At the Week 16 and 20 visits, or at any visit wherein the subject has previous lab abnormalities 
that required follow-up, study drug cannot be dispensed without labs being obtained. At all 
other visits, study drug can be dispensed if labs have been obtained within the prior 3 months 
until Week 124 and within the prior 6 months between Week 124 and Week 260 and as long as 
the investigator has determined that it would be safe for the subject to continue to receive 
study treatment.
!
Shipments may also include other study supplies (e.g., drug dosing diaries, paper copies of 
PROs). Instructions will be provided by AbbVie as to how a study site can initiate a DTP 
shipment using Marken, a global vendor selected by AbbVie to provide this service when 
necessary. Shipments of study drugs from the study site to a subject's home will be 
appropriately temperature controlled (qualified shipper or temperature monitoring) within 
the labeled storage conditions. Signature is required upon delivery; due to COVID-19 
related social distancing, this may be provided by the courier after delivery. Documentation 
of the shipment is to be retained by the clinical site.
!
AbbVie will not receive subject identifying information related to these shipments, as the 
site will work directly with the courier.
The study site is responsible for meeting IRB/IEC reporting requirements related to DTP shipments of
study drug, and for obtaining consent to provide delivery information to the courier and documenting
this consent in source documents.
Clinical Laboratory Tests
Blood and urine samples will be collected at the designated study visits as specified in Appendix D and 
following a minimum 8-hour fast.  If a subject is not able to fast when necessary (except during 
Screening visit), due to unforeseen circumstances, the non-fasting status will be recorded in study 
source documentation.
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A certified laboratory will be utilized to process and provide results for the clinical laboratory tests.  
Laboratory reference ranges will be obtained prior to the initiation of the study.  
Instructions regarding the collection, processing, and shipping of these samples will be provided by the 
central laboratory.
A urine dipstick macroscopic urinalysis will be completed by the central laboratory at all required visits.  
A microscopic analysis will be performed in the event the dipstick results show leukocytes, nitrite, 
protein, ketones, or blood greater than negative or glucose greater than normal.
If a laboratory test value is outside the reference range and the investigator considers the laboratory 
result to be clinically significant, the investigator will:
!
repeat the test to verify the out-of-range value;
!
follow the out-of-range value to a satisfactory clinical resolution.  
A laboratory test value that requires a subject to be discontinued from the study drug or requires a 
subject to receive treatment will be recorded as an AE.  The central laboratory chosen for this study will 
provide instructions regarding the collection, processing and shipping of these samples.  The baseline 
laboratory test results for clinical assessment for a particular test will be defined as the last 
measurement prior to the initial dose of study drug.
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Clinical Laboratory Tests
Hematology
Clinical Chemistry
Other Tests
Hematocrit
Hemoglobin
RBC count
WBC count
Neutrophils
Bands 
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count
BUN
Creatinine
Total bilirubin
INR (reflex only)a
Albumin
ALT 
AST
Alkaline phosphatase
CPK
Sodium
Potassium 
Bicarbonate/CO2
Chloride
Calcium
Inorganic phosphorus
Uric acid
Total protein
Glucose
Cholesterol
LDL-C
HDL-C
Triglycerides
Central Lab Tests:
Serum pregnancy (bHCG) test
HBs Ag
HBs Ab
HBc Ab
HBV DNA PCR reflex only
HCV Ab
HCV RNA reflex only
HIV Ab
QuantiFERON-TB Gold test  
hs-CRP
FSHb
Total IgE
Urine drug screen
Local Lab Tests:
Urine pregnancy test
IGRA equivalent such as T-SPOT 
test if central QuantiFERON-
TB Gold test not done
Urinalysis
Specific gravity
Ketones
pH
Protein
Blood
Glucose
Urobilinogen
Bilirubin
Leukocytes
Nitrites
Microscopic examination, 
if needed
Ab = antibody; ALT = alanine aminotransferase; AST = aspartate aminotransferase; bHCG = beta human chorionic gonadotropin; 
BUN = blood urea nitrogen; CO2 = carbon dioxide; CPK = creatine phosphokinase; DNA = deoxyribonucleic acid; 
FSH = Follicle-Stimulating Hormone; HBc Ab = hepatitis B core antibody; HBs Ab = hepatitis B surface antibody; HBs 
Ag = hepatitis B surface antigen; HBV = hepatitis B virus; HCV Ab = hepatitis C virus antibody; HDL-C = high-density lipoprotein 
cholesterol; HIV = human immunodeficiency virus; hsCRP = high sensitivity C-reactive protein; IGRA = interferon-gamma release 
assay; INR = international normalized ratio; LDL-C = low-density lipoprotein cholesterol; PCR = polymerase chain reaction; RBC = 
red blood cell; RNA = ribonucleic acid; TB = tuberculosis; WBC = white blood cell
a.
INR will only be measured if ALT and/or AST > 3 × upper limit of normal (ULN).
b.
At screening only for female ≤55 years old.
Serum Pregnancy Test
A serum pregnancy test will be performed for females of childbearing potential at the Screening Visit.  
The serum pregnancy test will be sent to and performed by the central laboratory.  If the serum 
pregnancy test is positive the subject is considered a screen failure.  If the serum pregnancy test is 
borderline, it should be repeated ≥ 3 days later to determine eligibility.  If the repeat serum pregnancy 
test is:
!
Positive, the subject is considered a screen failure or should be discontinued from study;
!
Negative, the subject can be enrolled into the trial or continue in the study;
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!
Still borderline ≥ 3 days later, this will be considered documentation of continued lack of a 
positive result and the subject can be enrolled into the study or continue in the study (unless 
prohibited locally/country requirements) in the absence of clinical suspicion of pregnancy and 
other pathological causes of borderline results.
Urine Pregnancy Test
A urine pregnancy test will be performed locally for all females of childbearing potential at the Baseline 
Visit prior to the first dose of study drug and at minimum at monthly intervals (either at study visits or at 
home between scheduled study visits).  The results of the monthly at home tests must be 
communicated to the site.  More frequent pregnancy tests will be performed throughout the study if 
required per local/country requirements.
!
If the Baseline urine pregnancy test performed at the site is negative, then dosing with study 
drug may begin.  
!
If the Baseline or post-baseline urine pregnancy test performed at the site is positive, dosing 
with study drug must be withheld and a serum pregnancy test is required.  The serum pregnancy 
test will be performed by the central laboratory.  If the serum pregnancy test is negative, study 
drug may be started or resumed.  If the serum pregnancy test is positive, study drug must be 
permanently discontinued.  In the event a pregnancy test comes back borderline, a repeat test is 
required (≥ 3 days later).  If the repeat serum pregnancy test is:
!
Positive, the subject is considered a screen failure or should be discontinued from study
drug;
!
Negative, the subject can be enrolled into the trial or continue on study drug;
!
Still borderline ≥ 3 days later, this will be considered documentation of continued lack of a 
positive result and the subject can be enrolled into the study or continue in the study 
(unless prohibited locally/country requirements) in the absence of clinical suspicion of 
pregnancy and other pathological causes of borderline results.
If time between visits is longer than 1 month, then collect the results of the monthly at home urine 
pregnancy test between scheduled visits.
If during the course of the study a female becomes surgically sterile or postmenopausal and complete 
documentation as described in Section 5.2 (Contraception Requirements for Females) is available, 
pregnancy testing is no longer required.
A pregnant or breastfeeding female will not be eligible to enter the study or be allowed to continue 
study drug.
High-sensitivity C Reactive Protein (hsCRP)
The hsCRP results will remain blinded to the Sponsor, investigator, study site personnel, and subject for 
all visits except Screening.  Investigators should refrain from locally and periodically testing hsCRP and 
serum amyloid A.  Investigators should also refrain from locally testing procalcitonin except for safety 
evaluations of signs and symptoms of infection or AEs.
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Clinical Chemistry
A minimum 8-hour fast will be necessary for blood samples to be drawn for chemistry.  If a subject is not 
able to fast when necessary due to unforeseen circumstances, the nonfasting status will be recorded in 
study source documentation.
Urinalysis
Dipstick urinalysis will be completed by the central laboratory at all required visits.  Specified abnormal 
macroscopic urinalyses defined as leukocytes, nitrite, protein, ketones, or blood greater than negative, 
or glucose greater than normal will be followed up with a microscopic analysis at the central laboratory.
Hepatitis Screen
All subjects will be tested for the presence of HBV and HCV at screening.
Hepatitis B Virus
Subjects will be tested for the presence of HBV at screening using the following tests:
!
HBs Ag
!
HBc Ab/HBc 
!
HBs Ab/HBs
A positive result for HBs Ag will be exclusionary.
A negative result for HBs Ag will be tested (automatic reflex testing) for core antibodies (HBc Ab) and 
surface antibodies (HBs Ab).
!
A negative test result for HBc Ab does not require HBV DNA polymerase chain reaction (PCR) 
qualitative testing and the subject may be enrolled (Figure 2, Scenarios A and B).  
!
For a subject who has had an HBV vaccination (should document in the medical history), a 
positive test result for HBs Ab is expected and the subject may be enrolled (Figure 2, 
Scenario B).*
!
A positive test result for HBc Ab requires HBV DNA PCR testing (automatic reflex testing) 
(Figure 2, Scenarios C and D).
!
A positive result for HBV DNA or a result that exceeds detection sensitivity will be 
exclusionary.
!
A subject with a negative result for HBV DNA testing may be enrolled.
!
Where mandated by local requirements:  A positive result for HBs Ab requires HBV DNA PCR 
testing.
!
A result that exceeds detection sensitivity by central laboratory will be considered a positive 
result for HBV DNA and will be exclusionary.
!
A subject with a negative result for HBV DNA may be enrolled.
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!
For subjects with HBs Ab+ and/or HBc Ab+ and negative HBV DNA at screening, HBV DNA 
PCR test should be performed approximately every 12 weeks (in correlation with a 
scheduled visit).  HBV DNA PCR testing approximately every 12 weeks is not necessary when 
the subject has a history of HBV vaccine and HBs Ab+, HBc Ab–.
!
Subjects with HBc Ab+ (irrespective of HBs Ab status) and negative HBV DNA at screening 
who develop a positive result for HBV DNA PCR testing during the study accompanied by the 
following should be referred to a hepatologist within one week for consultation and 
recommendation regarding subsequent treatment, and immediate study drug interruption 
will be required (or per local guidelines): 
!
an ALT > 5 × ULN OR  
!
ALT or AST > 3 × ULN and either a total bilirubin > 2 × ULN or INR > 1.5 OR 
!
ALT or AST > 3 × ULN along with clinical signs of possible hepatitis.
Figure 2.
Interpretation and Management of HBV Serologic Test Results
DNA = deoxyribonucleic acid; HBc Ab = hepatitis B core antibodies; HBs Ab = hepatitis B surface antibody; HBs Ag = hepatitis B 
surface antigen; HBV = hepatitis B virus; PCR = polymerase chain reaction
*
A positive test result for HBs Ab is expected for subjects who have had an HBV vaccination.  For subjects without a history 
of HBV vaccination (and for subjects in Japan and China or where mandated by local requirements) a positive result for 
HBs Ab/anti-HBs requires HBV DNA PCR testing. 
**
Where mandated by local requirements; subjects with HBs Ab+ and/or HBc Ab+ and negative HBV DNA at Screening 
should have HBV DNA PCR testing performed approximately every 12 weeks (in correlation with a scheduled visit).  HBV 
DNA PCR testing approximately every 12 weeks is not necessary when the subject has a history of HBV vaccine and HBs 
Ab+ and HBc Ab–.
Hepatitis C Virus (HCV)
Blood samples for HCV serology will be obtained at the Screening Visit.  A positive HCV Ab (antibody) will 
trigger an HCV RNA test.  A subject will not be eligible for study participation if test results indicate 
active Hepatitis C (HCV RNA detectable in any subject with anti HCV Ab).
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Human Immunodeficiency Virus (HIV)
Subjects with HIV infection (positive HIV test) are excluded from study participation.  HIV testing will be 
performed at Screening, unless prohibited by local regulations.  The investigator must discuss any local 
reporting requirements to local health agencies with the subject.  The site will report confirmed positive 
results to their health agency per local regulations, if necessary.  If a subject has a confirmed positive 
result, the investigator must discuss with the subject the potential implications to the subject's health 
and subject should receive or be referred for clinical care promptly.  This testing is to be done at the 
central lab.  AbbVie will not receive results from the testing and will not be made aware of any positive 
result.
TBNK Assessment By Immunophenotyping
Blood samples will be utilized to assess effects of Janus kinase inhibition on certain leukocyte subsets, 
including T (CD4+ and CD8+) cells, B (CD19+) cells, natural killer (NK) cells, and natural killer-T (NKT) cells.  
Instructions for the preparation and shipment of the samples will be provided in the laboratory manual.
State of Emergency or Pandemic-Related Acceptable Protocol Modifications
If travel restrictions or other changes in local regulations in light of a state of emergency or pandemic
(e.g., COVID-19 pandemic) prevent the subject from having blood drawn for laboratory testing at the 
study site, if possible, arrange for subjects to have laboratory work done at a local lab, hospital, or other 
facility. Local lab results should be obtained along with reference ranges and kept within the subjects' 
source documentation. Local lab results should be reviewed by the investigator as soon as possible.
If laboratory samples cannot be obtained, study drug administration may be continued provided the
investigator has reviewed all prior laboratory results and confirms and discusses with the subject that
there is no safety concern for the subject to continue use of the study drug in the absence of current
labs (also refer to section "Dispense Study Drug"). The subject should be scheduled for laboratory draws 
as soon as feasible within the protocol defined visit window from the scheduled visit, as described in 
Section 2.1 of the Operations Manual (Appendix F).
Discontinuation of Study Drug and Subject Withdrawal from the Study
All attempts must be made to determine the date of the last study drug dose and the primary reason for 
discontinuation of study drug or study participation.  The information will be recorded on the 
appropriate eCRF page.  However, these procedures should not interfere with the initiation of any new 
treatments or therapeutic modalities that the investigator feels are necessary to treat the subject's 
condition.  Following discontinuation of study drug, the subject will be treated in accordance with the 
investigator's best clinical judgment, irrespective of whether the subject decides to continue 
participation in the study.
Discontinuation of Study Drug and Continuation of Study Participation
During the study, subjects may discontinue study drug treatment but may choose to continue to 
participate in the study.  Subjects who prematurely discontinue study drug should complete a 
Premature Discontinuation visit (PD visit) as soon as possible, preferably within 2 weeks.  Afterwards, 
subjects should follow the regular visit schedule as outlined in Operations Manual Section 2.1 (Appendix 
F) and Protocol Appendix D, and adhere to all study procedures except for dispensing study drug and PK 
sample collection, and blood sample collection for optional exploratory research and validation studies.  
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As the subject has discontinued study drug, all rescue and efficacy driven discontinuation criteria may no 
longer apply.  If at any point a subject no longer wants to provide assessments (withdrawal of informed 
consent) following discontinuation of study drug, a second PD visit is not required.
Premature Discontinuation of Study (Withdrawal of Informed Consent)
Subjects may withdraw from the study completely (withdrawal of informed consent) for any reason at 
any time.  If a subject prematurely discontinues study drug treatment AND study participation 
(withdrawal of informed consent), the procedures outlined for the PD visit should be completed as soon 
as possible, preferably within 2 weeks of study drug discontinuation.  In addition, if the subject is willing, 
a 30-day follow-up visit may occur to determine the status of any ongoing AEs/SAEs or the occurrence of 
any new AEs/SAEs. 
All attempts must be made to determine the date of the last study drug dose and the primary reason for 
discontinuation of study drug or study participation.  The information will be recorded on the 
appropriate eCRF page.  However, these procedures should not interfere with the initiation of any new 
treatments or therapeutic modalities that the investigator feels are necessary to treat the subject's 
condition.
Following discontinuation of study drug, the subject will be treated in accordance with the investigator's 
best clinical judgment, irrespective of whether or not the subject decides to continue participation in the 
study.
Follow-Up Visit
A Follow-Up Visit will occur approximately 30 days after the last dose of study drug to obtain 
information on any new or ongoing AE/SAEs and concomitant medications.  Subjects will complete the 
Follow-Up Visit when they have either.
!
Completed the last study visit while are still on treatment; OR
!
Prematurely discontinued study drug and/or study participation and have completed a PD visit.  
The Follow-Up visit is not applicable for subjects who discontinued study drug and continued study 
participation and completed at least one study visit at least 30 days after last dose of study drug.
State of Emergency or Pandemic-Related Acceptable Protocol Modifications 
Subjects may be offered the option of home healthcare visits provided by a study nurse or third-party 
vendor.  Study procedures conducted in the home setting may include those detailed in Section 2.1 of 
the Operations Manual (Appendix F) and the collection of blood samples for central or local lab testing.  
This option can only be offered in countries and sites that comply with local regulatory and IRB/IEC 
requirements for homecare.  Any pre-requisite submissions or notifications to the site IRB/IEC and local 
competent health authority should be made, and approvals must be obtained prior to implementation.  
The investigator should be available via phone call if a consultation is necessary.
It is recommended that medical personnel entering a subject's home adhere to local health regulations 
during a pandemic (e.g., COVID-19 pandemic), such as the use of Personal Protective Equipment (PPE), 
as required.
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Protocol deviations must be recorded per AbbVie's standard process.
Sites may collect blood samples for central or local lab testing after the following requirements are met:
1.
Submission and approval of home healthcare collections of blood samples from local competent 
health authority and IRB/IEC, as applicable
2.
Confirmation that the subject's written consent to home healthcare has been obtained
If the home visits will not be performed by site personnel, the site may be responsible for selecting a 
vendor, contracting with a vendor, and for ensuring continued compliance with the terms of the Clinical 
Study Agreement.
Individuals performing home visits need to be added to the delegation log.  The Principal Investigator 
must ensure that any staff collecting blood samples are qualified and trained to do so per local 
regulations.
Pharmacokinetic Sampling
Collection of Samples for Analysis
Blood samples for the analysis of upadacitinib plasma concentrations will be collected from subjects at 
select sites throughout the treatment period on the study days and time points specified in Appendix D.
At Week 2 and Week 8 visits, PK samples should be collected prior to dosing and the subjects should 
take the study drug dose at the clinic after collecting the PK blood sample.  However, if the subject 
normally takes the study drug dose at a time that is after the time of the scheduled study visit, the 
subject should follow the regular dosing schedule and the PK sample will be collected at any time during 
the visit.
For all PK samples, the date and accurate time of the PK sample collection will be recorded on the lab 
requisition form.  The date and accurate time the last two study drug doses will be recorded on the eCRF 
to the nearest minute.
Refer to the study specific laboratory manual for detailed instructions on sample collection, processing, 
and shipment.
Measurement Method
Plasma concentrations of upadacitinib will be determined by the Bioanalysis Department at AbbVie 
using a validated liquid chromatography/mass spectrometry method.
Photography Sub-Study
The photography sub-study will be done only at selected sites.  During the screening visit, subjects will 
be asked to consent to participate in the photography sub-study.  The subjects that provide a signed and 
dated written informed consent will be asked to have photographs taken of their disease response 
during the study.  Photographs will be taken during the Baseline, Week 2, Week 4 and Week 16 visits.
Sites will submit the digital images to the centralized photography service.  The cameras for the 
photographs will be standardized and supplied to the sites by a central photography service.  The 
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photography data on the server will be considered source; and maintained and managed by the vendor.  
Training and detailed instructions will be provided by the central photography service.
Biomarker Samples
Optional biomarker samples (whole blood) will be collected at visits detailed in Appendix D.  All 
biomarker samples should be labeled and shipped as outlined in the study-specific laboratory manual.  
AbbVie (or people or companies working with AbbVie) will store the samples and data in a secure 
storage space with adequate measures to protect confidentiality.  Samples will be retained while 
research on upadacitinib (or drugs of this class) or AD and related conditions continues, but for no 
longer than 20 years after study completion, or per local requirement.  Based on the value of different 
technologies, samples may also be used to assess other biomarker signatures, including but not limited 
to epigenetic, metabolomics, lipidomics, and other applications.
The results from these analyses are exploratory in nature and may not be included with the clinical 
study report.
6 SAFETY CONSIDERATIONS
6.1 Complaints and Adverse Events
Complaints
A complaint is any written, electronic, or oral communication that alleges deficiencies related to the 
physical characteristics, identity, quality, purity, potency, durability, reliability, safety, effectiveness, or 
performance of a product/device.  Complaints associated with any component of this investigational 
product must be reported to AbbVie.
Product Complaint
A product complaint is any complaint related to the biologic or drug component of the product or to the 
medical device component(s).
For a product this may include, but is not limited to, damaged/broken product or packaging, product 
appearance whose color/markings do not match the labeling, labeling discrepancies/inadequacies in the 
labeling/instructions (e.g., printing illegible), missing components/product, device damage or not 
working properly, or packaging issues.
Product complaints concerning the investigational product and/or device must be reported to AbbVie 
within 1 business day of the study site's knowledge of the event.  Product complaints occurring during 
the study will be followed up to a satisfactory conclusion.
Medical Complaints/Adverse Events and Serious Adverse Events
An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
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(investigational) product, whether or not the event is considered causally related to the use of the 
product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as well as from 
accidental or intentional overdose, drug abuse, or drug withdrawal.  Any worsening of a pre-existing 
condition or illness is considered an AE.  Worsening in severity of a reported AE should be reported as a 
new AE.  Laboratory abnormalities and changes in vital signs are considered to be AEs only if they result 
in discontinuation from the study drug, necessitate therapeutic medical intervention, meets protocol 
specific criteria (see Section 6.2 regarding toxicity management) and/or if the investigator considers 
them to be AEs.
The investigators will monitor each subject for clinical and laboratory evidence of AEs on a routine basis 
throughout the study.  All AEs will be followed to a satisfactory conclusion.
An elective surgery/procedure scheduled to occur during a study will not be considered an AE if the 
surgery/procedure is being performed for a pre-existing condition and the surgery/procedure has been 
pre-planned prior to study entry.  Elective surgery will not be allowed during the study until the primary 
endpoint has been assessed.  However, if the pre-existing condition deteriorates unexpectedly during 
the study (e.g., surgery performed earlier than planned), then the deterioration of the condition for 
which the elective surgery/procedure is being done will be considered an AE.
If any of the following events are reported, then the following supplemental form must be completed.
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If a subject has a confirmed or suspected COVID-19 infection and study drug was interrupted, the 
investigator should contact the sponsor emergency medical contact listed above before reintroducing 
study drug.
If an AE meets any of the following criteria, it is to be reported to AbbVie or CRO (as appropriate) as an 
SAE within 24 hours of the site being made aware of the SAE:
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not been 
taken.  This does not include an event that would have been fatal if it 
had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any length 
of time or prolongs the subject's hospital stay.  This does not include 
an emergency room visit or admission to an outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that results in 
fetal loss.
Persistent or Significant 
Disability/Incapacity
An event that results in a condition that substantially interferes with 
the activities of daily living of a study subject.  Disability is not 
intended to include experiences of relatively minor medical 
significance such as headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle).
Important Medical Event 
Requiring Medical or Surgical 
Intervention to Prevent 
Serious Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but based on 
medical judgment may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the outcomes 
listed above (i.e., death of subject, life threatening, hospitalization, 
prolongation of hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity).  Additionally, any elective or 
spontaneous abortion or stillbirth is considered an important 
medical event.  Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or 
drug abuse.
All AEs reported from the time of study drug administration until 30 days after discontinuation of study 
drug administration will be collected, whether solicited or spontaneously reported by the subject.  In 
addition, SAEs and protocol-specified nonserious AEs will be collected from the time the subject signs 
the study-specific informed consent.
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AbbVie will be responsible for Suspected Unexpected Serious Adverse Reactions reporting for the 
Investigational Medicinal Product in accordance with global and local requirements.
Adverse events will be monitored throughout the study to identify any of special interest that may 
indicate a trend or risk to subjects.
Adverse Events of Special Interest
The following AEs of special interest will be monitored during the study:
!
Serious infections
!
Opportunistic infections
!
Herpes zoster
!
Active Tuberculosis
!
Malignancy (all types)
!
Adjudicated GI perforations
!
Adjudicated cardiovascular events (e.g., major adverse cardiovascular event [MACE])
!
Anemia
!
Neutropenia
!
Lymphopenia 
!
Increased serum creatinine and renal dysfunction 
!
Hepatic events and increased hepatic transaminases 
!
Elevated creatine phosphokinase (CPK) 
!
Adjudicated embolic and thrombotic events (non-cardiac, non-CNS)
Adverse Event Severity and Relationship to Study Drug
The investigators will rate the severity of each AE according to the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
If no grading criteria are provided for the reported event, then the event should be graded as follows:
Mild (Grade 1)
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated
Moderate (Grade 2)
Minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL)
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Severe (Grade 3 - 5)
Grade 3
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self care ADL (Self care ADL refer to bathing, dressing and 
undressing, feeding self, using the toilet, taking medications, and not 
bedridden)
Grade 4
Life-threatening consequences; urgent intervention indicated
Grade 5
Death related to AE
The investigator will use the following definitions to assess the relationship of the AE to the use of study 
drug:
Reasonable Possibility – After consideration of factors including timing of the event, biologic plausibility, 
clinical judgment, and potential alternative causes, there is sufficient evidence (information) to suggest 
a causal relationship.
No Reasonable Possibility – After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is insufficient evidence 
(information) to suggest a causal relationship.
For causality assessments, events assessed as having a reasonable possibility of being related to the 
study drug will be considered "associated."  Events assessed as having no reasonable possibility of being 
related to study drug will be considered "not associated."  In addition, when the investigator has not 
reported a causality or deemed it not assessable, AbbVie will consider the event associated.
If an investigator's opinion of no reasonable possibility of being related to study drug is given, an Other 
cause of event must be provided by the investigator for the SAE.
Pregnancy
Pregnancy in a study subject must be reported to AbbVie within 1 working day of the site becoming 
aware of the pregnancy.  Subjects who become pregnant during the study must be discontinued 
(Section 5.5).
Information regarding a pregnancy occurrence in a study subject and the outcome of the pregnancy will 
be collected.
Pregnancy in a study subject is not considered an AE. The medical outcome for either mother or infant, 
meeting any serious criteria including an elective or spontaneous abortion, is considered a serious 
adverse event and must be reported to AbbVie within 24 hours of the site becoming aware of the event.
Methods and Timing of Safety Assessment
All SAEs as well as protocol-related nonserious AEs will be collected from the time the subject signed the 
study-specific informed consent until study drug administration.  From the time of study drug 
administration until 30 days after discontinuation of study treatment, all nonserious AEs and SAEs will 
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Product complaints concerning the investigational product and/or device must be reported to AbbVie 
within 1 business day of the study site's knowledge of the event.  Product complaints occurring during 
the study will be followed up to a satisfactory conclusion.
All follow-up information is to be reported to the Sponsor (or an authorized representative) and 
documented in source as required by the Sponsor.  Product complaints associated with AEs will be 
reported in the study summary.  All other complaints will be monitored on an ongoing basis.
For subjects who discontinued study drug but continued study participation and are on standard of care 
therapies, these toxicity management requirements do not apply (including alerts from the central lab) 
and any intolerability to standard of care therapies should be managed by the prescribing physician.
Management of Serious Infections
Subjects should be closely monitored for the development of signs and symptoms of infection during 
and after treatment with study drug.  Study drug should be interrupted if a subject develops a serious 
infection.  A subject who develops a new infection during treatment with study drug should undergo 
prompt diagnostic testing appropriate for an immunocompromised subject.  As appropriate, 
antimicrobial therapy should be initiated, and the subject should be closely monitored.  Study drug may 
be restarted once the infection has been successfully treated.  Subjects who develop active TB must be 
permanently discontinued from study drug.
Management of Herpes Zoster
If a subject develops herpes zoster, consider temporarily interrupting study drug until the episode 
resolves.
Management of Serious Gastrointestinal Events
Subjects presenting with the onset of signs or symptoms of a GI perforation should be evaluated 
promptly for early diagnosis and treatment.  Subjects with acute, spontaneous perforation of the 
gastrointestinal tract that requires inpatient medical care or urgent surgical intervention (except for 
appendicitis or mechanical injury) must be permanently discontinued from study drug.  
Management of Thrombosis Events
Subjects who develop symptoms of thrombosis should be promptly evaluated and treated 
appropriately. If the diagnosis of deep vein thrombosis, pulmonary embolus or non-cardiac, 
non-neurologic arterial thrombosis is confirmed, the subject must be discontinued from study drug.
Management of Malignancy
Subjects who develop malignancy other than NMSC or carcinoma in-situ of the cervix must be 
discontinued from the study drug.  Information including histopathological results should be queried for 
the confirmation of the diagnosis.
Periodic skin examination is recommended for patients who are at increased risk for skin cancer.
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Management of COVID-19
Interrupt study drug in subjects with a confirmed diagnosis of COVID-19. Consider interrupting study 
drug in subjects with signs and/or symptoms and suspicion of COVID-19.  The COVID-19 eCRF must be 
completed.
Management of ECG Abnormality
Subjects must be discontinued from study drug for an ECG change considered clinically significant and 
with reasonable possibility of relationship to study drug, OR a confirmed absolute QTcF value 
> 500 msec or > 450 msec in adolescents, OR a change of QTc interval > 60 msec from baseline.
Management of Select Laboratory Abnormalities
For any given laboratory abnormality, the investigator should assess the subject, apply the standard of 
care for medical evaluation and treatment following any local guidelines.  Specific toxicity management 
guidelines for abnormal laboratory values are described in Table 3, and may require a supplemental 
eCRF to be completed (see Section 6.1 [Complaints and Adverse Events]).  All abnormal laboratory tests 
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that are considered clinically significant by the investigator will be followed to a satisfactory resolution.  
If a repeat test is required per Table 3, the repeat testing must occur as soon as possible.
Table 3.
Specific Toxicity Management Guidelines for Abnormal Laboratory Values
Laboratory Parameter
Toxicity Management Guideline
Hemoglobin
!
If hemoglobin < 8 g/dL interrupt study drug dosing and confirm by 
repeat testing with new sample
!
If hemoglobin decreases ≥ 3.0 g/dL from baseline, without an alternative 
etiology, interrupt study drug dosing and confirm by repeat testing with 
new sample.
!
If hemoglobin decreases ≥ 3.0 g/dL from baseline and an alternative 
etiology is known, or the hemoglobin value remains in the normal 
reference range, the subject may remain on study drug at the 
investigator's discretion.
!
If confirmed, continue to withhold study drug until hemoglobin value 
returns to normal reference range or its baseline value.
Absolute neutrophil count 
(ANC)
!
If confirmed < 1000/μL by repeat testing with new sample, interrupt 
study drug dosing until ANC value returns to normal reference range or 
its baseline value.
!
Interrupt study drug if confirmed < 500/μL by repeat testing with new 
sample.  If value returns to normal reference range or its Baseline value, 
restarting study drug is allowed if there is an alternative etiology 
identified; documentation should include reason that rechallenge is 
expected to be safe for the subject.
!
Study drug should be discontinued if no alternative etiology can be 
found.
Absolute lymphocyte counts 
(ALC)
!
If confirmed < 500/μL by repeat testing with new sample, interrupt 
study drug dosing until ALC returns to normal reference range or its 
baseline value.
Total white blood cell count 
!
If confirmed < 2000/μL by repeat testing with new sample, interrupt 
study drug dosing until white blood cell count returns to normal 
reference range or its baseline value.
Platelet count 
!
If confirmed < 50,000/μL by repeat testing with new sample, interrupt 
study drug dosing until platelet count returns to normal reference range 
or its baseline value.
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Laboratory Parameter
Toxicity Management Guideline
AST or ALT
!
Interrupt study drug immediately if confirmed ALT or AST > 3 × ULN 
by repeat testing with new sample and either a total bilirubin > 2 × 
ULN or an international normalized ratio > 1.5. 
!
A separate blood sample for INR testing will be needed to 
measure INR at the time of repeat testing for ALT or AST.  A 
repeat test of INR is not needed for determination if above 
toxicity management criteria are met.
!
Interrupt study drug if confirmed ALT or AST > 3 × ULN by repeat 
testing with new sample along with new appearance of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, 
rash, and/or eosinophilia (> 5% increase from baseline). 
!
If ALT or AST > 8 × ULN, interrupt study drug immediately, confirm 
by repeat testing with a new sample, and contact the TA MD.
!
Interrupt study drug if confirmed ALT or AST > 5 × ULN by repeat 
testing with new sample for more than 2 weeks.
For subjects with HBc Ab+ (irrespective of HBs Ab status) and negative 
HBV DNA at screening who develop the following should have HBV DNA 
by PCR testing performed within 1 week (based on initial elevated 
value):
!
ALT > 5 × ULN OR;
!
ALT or AST > 3 × ULN if an alternate cause is not readily 
identified
!
A separate blood sample for HBV DNA PCR testing will be 
needed at the time of repeat testing for ALT or AST.  As with 
INR, a separate tube is needed.
A positive result for HBV DNA PCR testing will require immediate 
interruption of study drug (unless not acceptable by local practices) and a 
hepatologist consultation should occur within 1 week for recommendation 
regarding subsequent treatment.
Subjects who meet any of the above criteria should be evaluated for an 
alternative etiology of the ALT or AST elevation and managed as medically 
appropriate. If applicable, the alternative etiology should be documented in 
the eCRF.  If ALT or AST values return to the normal reference range or its 
Baseline value, study drug may be restarted.  If restarting study drug, 
documentation should include reason that rechallenge is expected to be 
safe.  If after clinically appropriate evaluation, no alternative etiology for ALT 
or AST elevation is found or the ALT or AST elevation has not resolved or is 
not trending down toward normal, the subject should be discontinued from 
study drug.
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Laboratory Parameter
Toxicity Management Guideline
Serum Creatinine
If serum creatinine is > 1.5 × the baseline value and > ULN, repeat the 
test for serum creatinine (with subject in an euvolemic state) to confirm 
the results.  If the results of the repeat testing still meet this criterion 
then interrupt study drug and re-start study drug once serum creatinine 
returns to ≤ 1.5 × baseline value and ≤ULN.
For this serum creatinine elevation scenario, complete the appropriate 
supplemental renal eCRF(s).
Creatine Phosphokinase
!
If confirmed CPK value ≥ 4 × ULN and there are no symptoms suggestive 
of myositis or rhabdomyolysis, the subjects may continue study drug at 
the investigator's discretion.
!
If CPK ≥ 4 × ULN accompanied by symptoms suggestive of myositis or 
rhabdomyolysis, interrupt study drug and contact AbbVie TA MD.
For the above CPK elevation scenarios, complete supplemental increased 
CPK eCRF.
ALC = absolute lymphocyte counts; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine 
phosphokinase; DNA = deoxyribonucleic acid; eCRF = electronic case report form; HBc Ab+ = Hepatitis B core antibody 
positive; HBs Ab = Hepatitis B surface antibody; HBV = hepatitis B virus; INR = international normalized ratio; PCR = polymerase 
chain reaction; TA MD = Therapeutic Area Medical Director; ULN = upper limit of normal
6.3 Data Monitoring Committee and Cardiovascular Adjudication 
Committee
An external DMC comprised of persons independent of AbbVie and with relevant expertise in their field 
will review unblinded safety and if necessary, efficacy data from the ongoing study.  The DMC members 
consist of two clinicians and one biostatistician with one clinician being an expert in the management of 
subjects with AD.  The primary responsibility of the DMC will be to protect the safety of the subjects 
participating in this study. 
A separate DMC charter will be prepared outside of the protocol and will describe the roles and 
responsibilities of the DMC members, frequency of data reviews, and relevant safety data to be 
assessed.  
Communications from the DMC to the Study Teams will not contain information that could potentially 
unblind the team to subject treatment assignments.
An independent committee of physician experts in cardiovascular adjudication will be utilized to assess 
potential cardiovascular and thromboembolic AEs in a blinded manner as defined by the Cardiovascular 
Adjudication Committee charter.
6.4 Other Safety Data Collection
Specific manifestations of AD (i.e., itching, excoriations, oozing, crusting, erythema, etc.) should not be 
reported as individual AEs if they are considered to be a worsening of the underlying disease; instead, 
worsening of atopic dermatitis should be reported as the AE.
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6.5 SUSAR Reporting
AbbVie will be responsible for Suspected Unexpected Adverse Reactions (SUSAR) reporting for the 
Investigational Medicinal Product (IMP) in accordance with global and local guidelines and Appendix A of 
the Investigator Brochure will serve as the Reference Safety Information (RSI).  The RSI in effect at the 
start of a Development Safety Update Report (DSUR) reporting period serves as the RSI during the 
reporting period.  For follow-up reports, the RSI in place at the time of occurrence of the 'suspected' 
Serious Adverse Reaction will be used to assess expectedness.
7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
7.1 Statistical and Analytical Plans
The objective of the statistical analyses is to evaluate the efficacy and safety of upadacitinib for the 
treatment of adolescent and adult subjects with moderate to severe AD who are candidates for systemic 
therapy.
For ease of description, the DB Period refers to Week 0 to 16, and the Blinded Extension Period refers to 
the rest of the study.
The Primary Analysis of the main study for all efficacy endpoints pertaining to the DB Period (including 
the primary efficacy endpoints) will be conducted after all continuing subjects in the main study have 
completed the study activities up to Week 16 and all data pertaining to the DB Period are cleaned.  This 
is the one and final efficacy analysis for the DB Period of the main study.  After the Primary Analysis of 
the main study, an additional analysis of the main study will be conducted when the required safety 
exposure target is reached. In addition, a Week 52 analysis of the main study will be performed after all 
ongoing subjects complete the Week 52 visit. Furthermore, the Primary Analysis for the adolescent 
population (including the adolescent subjects from the main study and the adolescent sub-study) will be 
conducted after all ongoing adolescent subjects have completed Week 16, and all data pertaining to the 
DB Period are cleaned.  An additional analysis of the adolescent population will be conducted after all 
ongoing adolescent subjects have provided at least 1 year of upadacitinib exposure.  Interim database 
locks may be performed after all subjects (main study and adolescent sub-study) have completed the 
study activities up to the relevant timepoints after Week 140.  The Type-I error control will be applied to 
the Primary Analysis of the main study.  Study sites and subjects will remain blinded for the duration of 
the entire study.  
The statistical analysis will be described and fully documented in the Statistical Analysis Plan (SAP).  The 
SAP will be finalized prior to the blind break and database lock for the Primary Analysis.  The statistical 
analyses will be performed using SAS (SAS Institute Inc., Cary, North Carolina, USA).
7.2 Definition for Analysis Populations
Intent-to-Treat (ITT) Populations:
!
The ITT Population (ITT) consists of all subjects who are randomized in the overall study.
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!
The ITT Population for the main study (ITT_M) consists of all subjects who are randomized in the 
main study.
!
The ITT Population for adolescents (ITT_A) consists of all adolescent subjects who are 
randomized in the main study or the adolescent sub-study.
Subjects who are randomized to placebo in the DB Period and do not continue into the Blinded 
Extension Period will be excluded from the analysis in the Blinded Extension Period.
The ITT populations will be used for efficacy analyses.  Subjects will be analyzed according to treatment 
as randomized.
Per Protocol Population:
A Per-Protocol Population for the main study (PP_M) will be defined to exclude subjects with major 
protocol violations.  The criteria to define the Per-protocol Population will be detailed in the SAP.  
Subjects to be excluded from the Per-Protocol Population will be finalized before database lock and 
blind break.  The PP_M Population will be used to analyze the primary efficacy endpoint.
Safety Populations:
!
The Safety Population in the DB Period (Safety_DB) consists of all randomized subjects who 
received at least 1 dose of study drug in the overall study during the DB Period.
!
The Safety Population in the Blinded Extension Period (Safety_BE) consists of all randomized 
subjects who received at least 1 dose of study drug in the overall study during the Blinded 
Extension Period.
!
The Safety Population for the main study in the DB Period (Safety_DB_M) consists of all
randomized subjects who received at least 1 dose of study drug in the main study during the DB 
Period.
!
The Safety Population for the main study in the Blinded Extension Period (Safety_BE_M) consists 
of all randomized subjects who received at least 1 dose of study drug in the main study during 
the Blinded Extension Period.
!
The Safety Population for adolescents in the DB Period (Safety_DB_A) consists of all randomized 
adolescent subjects who received at least 1 dose of study drug in the main study or the 
adolescent sub-study during the DB Period.
!
The Safety Population for adolescents in the Blinded Extension Period (Safety_BE_A) consists of 
all randomized adolescent subjects who received at least 1 dose of study drug in the main study 
or the adolescent sub-study during the Blinded Extension Period.
In all safety analyses, subjects will be analyzed according to treatment received regardless of 
randomization.
Cross-period summaries will be provided for subjects initially randomized to the two upadacitinib 
groups.
In addition, the following populations will provide comprehensive summaries:
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!
The All Upadacitinib Treated Population (ALL_UPA) consists of all subjects who received at least 
1 dose of upadacitinib in the overall study.
!
The All Upadacitinib Treated Population for the main study (ALL_UPA_M) consists of all subjects 
who received at least 1 dose of upadacitinib in the main study.
!
The All Upadacitinib Treated Population for adolescents (ALL_UPA_A) consists of all adolescent 
subjects who received at least 1 dose of upadacitinib in the main study or the adolescent 
sub-study.
7.3 Statistical Analyses for Efficacy
The efficacy analysis of the main study will be conducted in the ITT_M Population.  The efficacy analysis 
for adolescents will be conducted in the ITT_A Population.  In addition, the primary efficacy endpoints 
will be analyzed in the PP_M Population.  Subjects will be included in the treatment group to which they 
are randomized.  
In the DB Period, categorical variables will be analyzed using Cochran-Mantel-Haenszel (CMH) test, 
stratified by vIGA-AD categories and age (adolescent vs. adult) in the ITT_M Population, and stratified by 
vIGA-AD categories and study portion (main study vs. adolescent sub-study) in ITT_A Population.  
Continuous variables will be analyzed using mixed-effect model with repeated measures (MMRM).
In the DB Period, missing values and visits after the rescue will be handled by non-responder imputation 
(NRI) for categorical variables or MMRM for continuous variables.  
Assessments of long-term efficacy (across the DB and Blinded Extension Periods) for subjects who stay 
on treatment will be summarized by Observed Case approach at each visit.  No missing data imputation 
will be applied, and all assessments prior to premature discontinuation from study drug will be used.  
For selected efficacy endpoints (e.g., EASI 75), long-term efficacy analysis will be performed using 
multiple imputation (MI).
Primary Analysis of Efficacy
The co-primary endpoints for the efficacy are:
!
Proportion of subjects achieving at least an EASI 75 from Baseline at Week 16; 
!
Proportion of subjects achieving vIGA-AD of 0 or 1 with at least two grades of reduction from 
Baseline at Week 16.
Comparison of the primary endpoints will be made between each upadacitinib group and the placebo 
group in ITT_M Population using the CMH test, adjusting for vIGA-AD categories and age (adolescent vs. 
adult).  NRI will be the primary approach, with MI and tipping point analysis as the sensitivity approach 
to handle missing values.  The primary endpoints will also be evaluated in the PP_M Population.
Sample Size Estimation
Approximately 810 adolescent and adult subjects will be randomized to upadacitinib 30 mg, upadacitinib 
15 mg, or placebo in a ratio of 1:1:1 in the main study (270 subjects per treatment group).  The sample 
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size is determined by the regulatory requirement to adequately characterize the safety profile.  
Assuming an EASI 75 response rate of 15%, and vIGA-AD 0 or 1 with at least a 2-point reduction 
response rate of 10% in the placebo arm, this sample size will also provide more than 90% power to 
detect the treatment differences of 32% and 21%, respectively, for the above two endpoints 
simultaneously using two-sided test at a 0.05 significant level.  The assumptions of placebo response 
rates for EASI 75 and IGA-AD 0/1 were based on the maximum placebo rate in upadacitinib AD Phase 2b 
study and dupilumab Phase 3 monotherapy studies (SOLO 1 and SOLO 2).  The graphic approach for 
controlling multiplicity will be outlined in the Statistical Analysis Plan.
Additional adolescent subjects will be enrolled in the adolescent sub-study and randomized to 
upadacitinib 15 mg, upadacitinib 30 mg, or placebo in a ratio of 1:1:1 for a total of 180 adolescent 
subjects in the overall study (main study + adolescent sub-study).  This sample size was determined to 
ensure a total of 225 subjects per dose across 3 pivotal studies will provide 1 year of data.
7.4 Statistical Analyses for Safety
The safety analyses will be carried out using the safety populations in the DB Period, the Blinded 
Extension Period, and across both periods, and will be based on treatments the subjects actually 
received.  Safety will be assessed by AEs, physical examination, laboratory assessments, and vital signs.  
Note that missing safety data will not be imputed.  Analysis details will be specified in the SAP.
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA).  TEAEs are defined as 
those that began or worsened in severity after the first dose of study drug but within 30 days after the 
last dose of study drug.  The number and percentage of subjects experiencing TEAEs will be tabulated 
using the MedDRA system organ class (SOC) and preferred term (PT), by severity, and by relationship to 
the study drug as assessed by the investigator.  Summaries (including percentages and events per 
100 patient-years) of SAEs, deaths, AEs leading to discontinuation and AESIs will be provided as well.  
Pre-treatment AEs will be summarized separately.
For laboratory and vital signs, mean change from Baseline and percentage of subjects with evaluations 
meeting criteria for pre-defined Potentially Clinically Significant values will be summarized.
7.5 Pharmacokinetic and Exposure-Response Analyses
Individual upadacitinib plasma concentrations at each study visit will be tabulated and summarized with 
appropriate statistical methods.
Data from this study may be combined with data from other studies for the population PK and 
exposure-response analyses.  Population PK and exposure-response analyses of only data from this 
study may not be conducted.  The following general methodology will be used for the population PK and 
exposure-response analyses.
Population PK analyses (using the available PK data from the subjects from whom the PK samples will be 
collected) will be performed using the actual sampling time relative to dosing.  PK models will be built 
using a non-linear mixed-effects modeling approach with non-linear mixed effects modeling software 
(Version 7, or a higher version).  The structure of the starting PK model will be based on the PK analysis 
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of data from previous studies.  The CL/F and V/F of upadacitinib will be the PK parameters of major 
interest in the analyses.  If necessary, other parameters, including the parameters describing absorption 
characteristics, may be fixed if useful in the analysis.
The evaluation criteria described below will be used to examine the performance of different models.
1.
The objective function of the best model is significantly smaller than the alternative model(s).
2.
The observed and predicted concentrations from the preferred model are more randomly 
distributed across the line of unity (a straight line with zero intercept and a slope of one) than 
the alternative model(s).
3.
Visual inspection of model fits, standard errors of model parameters and change in inter-subject 
and intra-subject error.
Once an appropriate base PK model (including inter- and intra-subject error structure) is developed, 
empirical Bayesian estimates of individual model parameters will be calculated by the posterior 
conditional estimation technique using non-linear mixed effects modeling.  The relationship between 
these conditional estimates CL/F and V/F values with only potentially physiologically relevant or clinically 
meaningful covariates (such as subject age, sex, body weight, concomitant medications, laboratory 
markers of hepatic or renal function, etc.) will be explored using stepwise forward selection method, or 
another suitable regression/smoothing method at a significance level of 0.05.  After identification of all 
relevant covariates, a stepwise backward elimination of covariates from the full model will be employed 
to evaluate the significance (at P < 0.005, corresponding to a decrease in objective function > 7.88 for 
one degree of freedom) of each covariate in the full model.
Linear or non-linear relationships of primary PK parameters with various covariates will be explored.  
For the same subjects from whom the PK samples will be collected, relationships between upadacitinib 
exposure and clinical observations (primary efficacy variable) will be explored.  Exposure-response 
relationships for secondary efficacy variables and/or some safety measures of interest may also be 
explored.  The relationship between exposure (e.g., population PK model predicted average 
concentrations, area under the curve, trough concentrations, the individual model-predicted PK profiles, 
or some other appropriate measure of exposure) and drug effect will be explored.  Several classes of 
models (e.g., linear, log-linear, exponential, Emax, sigmoid Emax, etc.) will be evaluated to characterize the 
exposure-response relationship based on observed data.  Results of the pharmacokinetic and 
exposure-response analyses may be summarized in a separate report prior to regulatory filing of 
upadacitinib for the treatment of AD, rather than in the CSR.
Additional analyses will be performed if useful and appropriate.
7.6 Statistical Analysis of Immunophenotype Data and Optional 
Proteomic Biomarker Data
For biomarkers in T-lymphocyte, B-lymphocyte, and natural killer cells (TBNK) immunophenotype data 
(natural killer cells, natural killer T cells [NKT], B cells, and T cells) or optional whole blood proteomic and 
targeted serum protein investigations, summary statistics at Baseline and post treatment time points, in 
addition to change from Baseline at each time point will be provided; this will include mean, standard 
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deviation, median, quartiles, and range for each treatment group.  The PD effect of each biomarker 
between the placebo and upadacitinib treatment groups will be evaluated via a mixed-effects modeling 
approach with change from Baseline of the biomarker score (after log transformation if appropriate) as 
response variable, Treatment, Time, and Treatment × Time interaction as fixed-effects, the 
corresponding Baseline biomarker score as a covariate, and "subjects nested within the treatment 
group" as a random-effect.  Other Baseline covariates such as age, weight, etc., may be considered in 
the model if appropriate.
Additional analysis may be conducted on TBNK immunophenotype and/or optional proteomic 
biomarker data for the purpose of identification of prognostic, predictive, surrogate and PD biomarkers 
associated with efficacy or safety.  The association of biomarkers to the efficacy or safety endpoints may 
be explored for each biomarker one at a time, and also for combinations of biomarkers via some 
multivariate predictive modeling approaches.
7.7 Interim Analysis
There will be no efficacy or futility interim analyses.  Safety data will be reviewed by an external DMC as 
described in Section 6.3.
8 ETHICS
8.1 Independent Ethics Committee/Institutional Review Board 
(IEC/IRB)
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the IEC/IRB for review and approval.  Approval of both the protocol and the informed 
consent form(s) must be obtained before any subject is enrolled.  Any amendment to the protocol will 
require review and approval by the IEC/IRB before the changes are implemented to the study.  In 
addition, all changes to the consent form(s) will be IEC/IRB approved.
In Japan, the investigator will prepare the consent form and explanatory material required to obtain 
subject's consent to participate in the study with the cooperation of the sponsor and will revise these 
documents as required.  The prepared or revised consent forms and explanatory material will be 
submitted to the sponsor.  Approval of the IRB will be obtained prior to use in the study.
In Japan, when important new information related to the subject's consent becomes available, the 
investigator will revise the consent form and explanatory material based on the information without 
delay and will obtain the approval of the IRB prior to use in the study.  The investigator will provide the 
information, without delay, to each subject already participating in the study, and will confirm the 
intention of each subject to continue the study or not.  The investigator shall also provide a further 
explanation using the revised form and explanatory material and shall obtain written consent from each 
subject of their own free will to continue participating in the study.
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8.2 Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, Operations Manual, International Council 
for Harmonisation (ICH) guidelines, applicable regulations and guidelines governing clinical study 
conduct and the ethical principles that have their origin in the Declaration of Helsinki.  Responsibilities of 
the investigator are specified in Appendix B.
In the event of a state of emergency or pandemic (e.g., COVID-19) leading to difficulties in performing
protocol-specified procedures, AbbVie will engage with study site personnel in efforts to ensure the
safety of subjects, maintain protocol compliance, and minimize risks to the integrity of the study while
trying to best manage subject continuity of care. This may include alternative methods for assessments
(e.g., phone contacts or virtual site visits), alternative locations for data collection (e.g., use of a local lab
instead of a central lab), and shipping investigational product and/or supplies direct to subjects to
ensure continuity of treatment where allowed. Refer to the Operations Manual in Appendix F for
additional details. In all cases, these alternative measures must be allowed by local regulations and
permitted by IRB/IEC. Investigators should notify AbbVie if any urgent safety measures are taken to
protect the subjects against any immediate hazard.
8.3 Subject Confidentiality
To protect subjects' confidentiality, all subjects and their associated samples will be assigned numerical 
study identifiers or "codes."  No identifiable information will be provided to AbbVie.
9 SOURCE DOCUMENTS AND CASE REPORT FORM 
COMPLETION
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported.  All source documents should be attributable, legible, contemporaneous, original, 
accurate, and complete to ensure accurate interpretation of data.  Clinical site monitoring is conducted 
to ensure that the rights and well-being of human subjects are protected, that the reported trial data 
are accurate, complete, and verifiable.  That the conduct of the trial is in compliance with the currently 
approved protocol, ICH Good Clinical Practice (GCP), and applicable local regulatory requirement(s).
During a state of emergency or pandemic (e.g., COVID-19), remote monitoring of data may be employed 
if allowed by the local regulatory authority, IRB/IEC, and the study site.
Electronic Patient Reported Data
Patient reported data must be completed for each subject screened/enrolled in this study.  Some of 
these data are being collected with an Electronic Patient Reported Outcome (ePRO) system called 
Trialmax, provided by the technology vendor CRF Health of Plymouth Meeting, PA, USA.  The ePRO 
system is in compliance with Title 21 CFR Part 11.  The documentation related to the system validation 
of the ePRO system is available through the vendor, CRF Health; while the user acceptance testing of the 
study-specific patient reported outcome design will be conducted and maintained at AbbVie.
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The subject will be entering the data on an electronic device; these data will be uploaded to a server.  
The data on the server will be considered source, and maintained and managed by CRF Health.  Daily 
Worst Pruritus NRS, daily and weekly ADerm-SS, and daily and weekly ADerm-IS ePROs will be collected 
from subjects electronically every evening via a handheld device provided to the subject at Screening.  
Handheld device usage stops at the Week 16 visit.  The handheld electronic device will be programmed 
to allow data entry once per day.  Starting at the Week 16 visit, Daily Worst Pruritus NRS, ADerm-SS, and 
ADerm-IS ePROs will be collected electronically via an onsite tablet device into which the subject will 
directly enter the required pieces of information at visits specified in the Operations Manual Section 2.1
(Appendix F) (Individual Treatment Period Visit Activities).  The ePRO data of CDLQI, DLQI, HADS, POEM, 
PGIS, PGIT, PGIC, EQ-5D-5L, WPAI:AD, SF-36, and patient-reported items from SCORAD will be collected 
electronically via an onsite tablet device into which the subject will directly enter the required pieces of 
information at visits specified in the Operations Manual Section 2.1 (Appendix F) (Individual Treatment 
Period Visit Activities).  The electronic tablet device will be programmed to allow data entry for only the 
visits specified in the protocol and will not allow for subjects to complete more than one of the same 
assessments at any one visit.  All data entered on the devices will be immediately stored to the devices 
itself and automatically uploaded to a central server administrated by CRF Health.  The investigator and 
delegated staff will be able to access all uploaded subject entered data via a password protected 
website, up until the generation, receipt and confirmation of the study archive.
Internet access to the ePRO data will be provided by CRF Health for the duration of the study.  This 
access will be available for the duration of the study to the site investigator, as well as delegated 
personnel.  Such access will be removed from investigator sites following the receipt of the study 
archive.  Data from the ePRO system will be archived on appropriate data media (CD-ROM, etc.) and 
provided to the investigator at that time as a durable record of the site's ePRO data.  It will be possible 
for the investigator to make paper print-outs from that media.
Photography
Photography data will be collected from subjects at select sites who consent to participate in the 
Photography sub-study and are considered eligible to be enrolled in this study.  Subjects that consent to 
participate will be asked to have photographs taken of their disease response during the study.  The 
photographs will be taken as outlined in Appendix D, Activity Schedule and in the Operations Manual 
Section 2.1 (Appendix F).
The cameras for the photographs will be standardized and supplied to the sites by a central photography 
service.  The photography data on the server will be considered source; and maintained and managed 
by the vendor.  Training and detailed instructions will be provided by the central photography service. 
10
DATA QUALITY ASSURANCE
AbbVie will ensure that the clinical trial is conducted with a quality management system that will define 
quality tolerance limits in order to ensure human subject protection and reliability of study results.  Data 
will be generated, documented, and reported in compliance with the protocol, ICH GCP, and applicable 
regulatory requirements.
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11
COMPLETION OF THE STUDY
The end-of-study is defined as the date of the last subject's last visit.
12
REFERENCES
1.
Hsu L, Armstrong AW. JAK inhibitors: treatment efficacy and safety profile in patients with psoriasis. 
J Immunol Res. 2014;2014:283617.
2.
Genovese MC, Smolen JS, Weinblatt ME, et al. Efficacy and safety of ABT-494, a selective JAK-1 
Inhibitor, in a Phase IIb study in patients with rheumatoid arthritis and an inadequate response to 
methotrexate. Arthritis & Rheumatology (Hoboken, NJ). 2016;68(12):2857-66.
3.
Kremer JM, Emery P, Camp HS, et al. A Phase IIb study of ABT-494, a selective JAK-1 inhibitor, in 
patients with rheumatoid arthritis and an inadequate response to anti-tumor necrosis factor 
therapy. Arthritis & rheumatology (Hoboken, NJ). 2016;68(12):2867-77.
4.
Genovese MC, Fleischmann R, Combe B, et al. Safety and efficacy of upadacitinib in patients with 
active rheumatoid arthritis refractory to biologic disease-modifying anti-rheumatic drugs (SELECT-
BEYOND): a double-blind, randomised controlled phase 3 trial. Lancet. 2018;391(10139):2513-24.
5.
Burmester GR, Kremer JM, Van den Bosch F, et al. Safety and efficacy of upadacitinib in patients 
with rheumatoid arthritis and inadequate response to conventional synthetic disease-modifying 
anti-rheumatic drugs (SELECT-NEXT): a randomised, double-blind, placebo-controlled phase 3 trial. 
Lancet. 2018;391(10139):2503-12.
6.
Eichenfield LF, Tom WL, Berger TG, et al. Guidelines of care for the management of atopic 
dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies. J Am 
Acad Dermatol. 2014;71(1):116-32.
7.
Sidbury R, Davis DM, Cohen DE, et al. Guidelines of care for the management of atopic dermatitis: 
section 3. Management and treatment with phototherapy and systemic agents. J Am Acad 
Dermatol. 2014;71(2):327-49.
8.
Blauvelt A, de Bruin-Weller M, Gooderham M, et al. Long-term management of moderate-to-severe 
atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 
1-year, randomised, double-blinded, placebo-controlled, phase 3 trial. Lancet. 
2017;389(10086):2287-303.
9.
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(24):2335-48.
10. Dupixent (dupilumab) injection, for subcutaneous use [prescribing information]. Bridgewater, NJ; 
Sanofi-Aventis, 2017.
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11. Banerjee S, Biehl A, Gadina M, et al. JAK-STAT signaling as a target for inflammatory and 
autoimmune diseases: current and future prospects. Drugs. 2017;77(5):521-46.
12. Norman P. Selective JAK1 inhibitor and selective Tyk2 inhibitor patents. Expert Opin Ther Pat. 
2012;22(10):1233-49.
13. AbbVie. Upadacitinib Investigator's Brochure Edition 10. 19 August 2019.
14. Akdis CA, Akdis M, Bieber T, et al. Diagnosis and treatment of atopic dermatitis in children and 
adults: European Academy of Allergology and Clinical Immunology/American Academy of Allergy, 
Asthma and Immunology/PRACTALL Consensus Report. Allergy. 2006;61(8):969-87.
15. Kunz B, Oranje A, Labrèze L, et al. Clinical Validation and Guidelines for the SCORAD Index:  
Consensus Report of the European Task Force on Atopic Dermatitis. Dermatology. 1997;195(1):10-9.
16. Ring J, Alomar A, Bieber T, et al. Guidelines for treatment of atopic eczema (atopic dermatitis) Part I. 
J Eur Acad Dermatol Venereol. 2012;26(8):1045-60.
17. Holford N, Heo YA, Anderson B. A pharmacokinetic standard for babies and adults. J Pharm Sci. 
2013;102(9):2941-52.
18. Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol. 1980;92 
(suppl):44-7.
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APPENDIX A. STUDY SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
AD
Atopic dermatitis
ADerm-IS
Atopic dermatitis impact scale
ADerm-SS
Atopic dermatitis symptom scale
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase
BSA
Body surface area
CAC
Cardiovascular Adjudication Committee
CD
Crohn's disease
CDLQI
Children's Dermatology Life Quality Index
CL/F
Oral clearance
CNS
Central nervous system
COVID-19
Coronavirus Disease – 2019 
CPK
Creatine phosphokinase
CRF
Case report form
CRO
Contract research organization
CSR
Clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
CXR
Chest x-ray
CYP3A
Cytochrome P450 3A
DB Period
double-blind treatment period
DLQI
Dermatology Life Quality Index
DMC
Data Monitoring Committee
DSUR
Development Safety Update Report
DTP
Direct-to-patient
EASI
Eczema Area and Severity Index
EASI 50/75/90
50%/75%/90% reduction in Eczema Area and Severity Index
EC
Ethics Committee
ECG
Electrocardiogram
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eCRF
Electronic case report form
ePRO
Electronic Patient Reported Outcome
EQ-5D-5L
EuroQol 5 Dimensions 5 Levels
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
GFR
Glomerular filtration rate
GI
Gastrointestinal
HADS
Hospital Anxiety and Depression Scale
HADS-A
Hospital Anxiety and Depression Scale-anxiety
HADS-D
Hospital Anxiety and Depression Scale-depression
HB
hepatitis B
HBV
hepatitis B virus
HCV
hepatitis C virus
HCV Ab
hepatitis C virus antibody
HECSI
Hand eczema severity index
HIV
Human immunodeficiency virus
hsCRP
High-sensitivity C Reactive Protein
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IGA
Investigator's Global Assessment
IL
Interleukin
IMP
Investigational Medicinal Product
INR
international normalized ratio
IRB
Institutional review board
ITT
Intent-to-Treat
ITT_A
Intent-to-Treat Population for adolescents
ITT_M
Intent-to-Treat Population for the main study
JAK
Janus kinase
MACE
Major adverse cardiac event
MCID
Minimal clinically important difference
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multiple imputation
NKT
Natural killer T
NMSC
Non-melanoma skin cancer
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NRI
Non-responder imputation
NRS
numerical rating scale
PD
Premature discontinuation
PDE4
Phosphodiesterase type 4
PGIC
Patient Global Impression of Change
PGIS
Patient Global Impression of Severity
PGIT
Patient Global Impression of Treatment
PK
Pharmacokinetic
POEM
Patient oriented Eczema Measure
PPD
purified protein derivative
PPE
Personal Protective Equipment
PP_M
Per-Protocol Population for the main study
PRO
patient-reported outcome
PsA
Psoriatic arthritis
PT
Preferred term
QD
Once daily
QoL
Quality of Life
QTcF
Fridericia-corrected QT interval
RA
Rheumatoid arthritis
RSI
Reference Safety Information
SAE
Serious adverse event
SAP
Statistical analysis plan
SCORAD
Scoring atopic dermatitis
SCORAD 50/75/90
50%/75%/90% reduction in scoring atopic dermatitis
SF-36
Short Form Health Survey
SOC
System organ class
SUSAR
Suspected Unexpected Serious Adverse Reaction
TA SD
Therapeutic Area Scientific Director
TB
Tuberculosis
TCI
Topical calcineurin inhibitor
TCS
Topical corticosteroids
Tdap
Tetanus-diphtheria-acellular pertussis
TEAE
Treatment-emergent adverse event
TNF
tumor necrosis factor
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TPPA
Treponema pallidum particle agglutination assay
TRUST
Toluidine Red Unheated Serum Test
TSS-7
7-item total symptom score
TSS-11
11-item total symptom score
Tyk2
Tyrosine kinase 2
UC
Ulcerative colitis
ULN
Upper limit of normal
UV
Ultraviolet
VHP
Voluntary Harmonisation Procedure
vIGA-AD
validated Investigator Global Assessment for Atopic Dermatitis
V/F
Volume of distribution
WBC
White blood cell
WPAI:AD
Work Productivity and Activity Impairment Index:  Atopic Dermatitis
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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M16-045:  A Phase 3 Randomized, Placebo-Controlled, Double-Blind Study to Evaluate 
Upadacitinib in Adolescent and Adult Subjects with Moderate to Severe Atopic Dermatitis
Protocol Date:  28 January 2021
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation 
(ICH) Good Clinical Practices (GCP) and local regulations and guidelines governing the study at the site 
location.  In signing the Investigator Agreement, the investigator is agreeing to the following:
1.
Conducting the study in accordance with ICH GCP, the applicable regulatory requirements, 
current protocol and operations manual, and making changes to a protocol only after notifying 
AbbVie and the appropriate Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC), except when necessary to protect the subject from immediate harm.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed consent and 
ethics committees (e.g., IEC or IRB) review and approval of the protocol and its amendments.
4.
Reporting complaints that occur in the course of the investigation(s) to AbbVie.
5.
Reading the information in the Investigator's Brochure/safety material provided, including the 
instructions for use and the potential risks and side effects of the investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the study about 
their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making those records 
available for inspection by representatives of AbbVie and/or the appropriate regulatory agency, 
and retaining all study-related documents until notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and approved the initial 
clinical protocol and all of its amendments.
9.
Reporting promptly, all changes in the research activity and all unanticipated problems involving 
risks to human subjects or others, to the appropriate individuals (e.g., coordinating investigator, 
institution director) and/or directly to the ethics committees and AbbVie.
10. Providing direct access to source data documents for study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s).
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
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APPENDIX C. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
Clinical Pharmacology and Pharmacometrics
Clinical Program Development
Data and Statistical Sciences 
Data and Statistical Sciences
Immunology Clinical Development
Immunology Clinical Development
Medical Writing
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APPENDIX D. ACTIVITY SCHEDULE
The following table shows the required activities across Screening and subsequent study visits.  The 
individual activities are described in detail throughout the protocol and in the Operations Manual 
Section 2.1 (Appendix F).  Allowed modifications due State of Emergency of Pandemic-Related 
Acceptable Protocol Modifications are detailed within Operations Manual.
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APPENDIX E. PROTOCOL SUMMARY OF CHANGES
Previous Protocol Versions
Protocol
Date
Version 1.0
04 May 2018
Version 1.01 VHP
20 August 2018
Version 1.02 Canada
08 August 2018
Version 2.0
18 December 2018
Administrative Change 1
30 January 2019
Version 3.0
24 July 2019
Version 4.0
02 October 2019
Version 5.0
29 April 2020
Version 5.1 VHP
31 July 2020
The purpose of this Amendment is to incorporate the following changes:
Summary of Protocol Changes:
The primary purposes of this Amendment are to extend the blinded extension period from Week 136 to 
Week 260 and to incorporate necessary protocol modifications due to the COVID-19 pandemic.  These 
changes and other clarifications are listed below.
The rationale for the following changes was to incorporate modifications due to the COVID-19 
pandemic:
!
Section 2.2 – Included information on the re-evaluation of the benefit and risk to subjects 
participating in the study.  The benefit-risk profile of various immunomodulatory therapies is 
being evaluated.
!
Section 5.5 – Added instructions referring to the Operations Manual for necessary changes to 
activities or procedures in the event of temporary study [drug] interruption/halt.
!
Section 5.8 – Included information on DTP study drug shipment and details on time limits for 
study drug interruption.
!
Section 5.9 – Clarified that protocol deviations may include modifications due to COVID-19.
!
Section 5.10 – Updated to include details on how to perform specific activities/procedures that 
may be impacted by changes in global/local regulations due to the pandemic.
!
Section 6.1 – Included information on how to handle COVID-19 related missed/virtual visits, 
study drug interruptions or discontinuations, or adverse events.
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!
Section 6.2 – Added instruction to interrupt study drug in subjects with confirmed diagnosis of 
COVID-19.
!
Section 8.2 – Noted that AbbVie will modify the study protocol as necessary due to the 
pandemic, referring to the Operations Manual in Appendix F for additional details. Investigators 
must also notify AbbVie if any urgent safety measures are taken.
!
Section 9 – Noted that remote monitoring may be employed as needed.
!
Appendix D – Added reference to Operations Manual for allowed COVID-19 modifications.
!
Appendix F – Operations Manual updated to include details on how to perform specific 
activities/procedures that may be impacted by changes in global/local regulations due to the 
pandemic.
Other protocol changes:
!
Title page – Updated the Sponsor/Emergency Medical Contact for the study from 
 
to 
!
Section 1, Section 4.1, Section 5.7, Appendix D – Change the last date of the Blinded Extension 
Period from Week 136 to Week 260.
Rationale: 
 
!
Section 4.1, Section 7.1 – Added that an interim analysis after Week 140 may be performed 
after all subjects (main study and adolescent sub-study) have completed the study activities.
Rationale:  To provide longer term safety and efficacy data for the use of upadacitinib 15 mg or 
30 mg in patients with moderate-to-severe atopic dermatitis.
!
Section 5.3 – Provided guidance regarding the use of live vaccines.
Rationale:  Due to the study extension of 2 years, the longer period of the study increases the 
likelihood that a subject may require a live vaccine (e.g., adolescents who may need measles-
mumps-rubella vaccine or varicella vaccine).
!
Section 5.5, Section 6.2 – Provided definition of GI perforation.
Rationale:  To provide further clarity on the characterization of GI perforations for investigators.
!
Section 6.2 – Updated Specific Toxicity Management Guidelines for Abnormal Laboratory Values 
for hemoglobin, absolute neutrophil count, ALT, and AST in Table 3.
Rationale:  Provided clarity regarding the management of abnormal hemoglobin, absolute 
neutrophil count, ALT/AST, and creatinine.
!
Section 7.3 – Added for selected efficacy endpoints, long-term efficacy analysis will be 
performed using MI.
Rationale: 
 
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!
Appendix D – Changed from Week 64 to Week 136 (every 12 weeks) to Week 64 to Week 124 
(every 12 weeks) and Week 140.
Rationale:  To align the study visit and interval to accommodate the extension to Week 260.
!
Appendix D – Added prior/concomitant therapy, review and document pregnancy avoidance 
recommendations, AE assessment at Week 152 to Week 260.  Added latent TB risk factor 
questionnaire, body weight, height (adolescent subjects), vital signs, physical exam, Tanner 
staging, 12-lead ECG, chest x-ray, urine pregnancy test, dispense urine pregnancy test, clinical 
chemistry, hematology, urinalysis, TB test, and dispense study drug at Week 164 to Week 260.
Rationale:  Safety assessments will continue at all phone call and site visits to allow the 
monitoring of participant safety while receiving upadacitinib.
!
Appendix D – Added Worst Pruritus NRS, EASI, BSA, and vIGA-AD at Week 164 to 260.
Rationale:  After Week 124, long-term efficacy measures conducted at the site will be simplified 
to measures of AD disease activity that study drug directly impacts.
!
Appendix D, Appendix F – Specified that after Week 52, latent TB risk factor questionnaire,
12-lead ECG, and chest x-ray will be taken at Weeks 100, 164, 212, and 260.
!
Appendix D – Clarified that blood samples for PK assay should not be taken at the PD Visit if the 
PD Visit occurs after Week 16.
!
Appendix F – Updated the Operations Manual to reflect the extension of the Blinded Extension 
Period from Week 136 to Week 260.
!
Appendix F – Updated the Sponsor/Emergency Medical Contact for the study from 
 
 to 
In addition to these modifications, this Amendment contains the following minor changes:
!
Minor text edits as needed for consistency and clarity.
!
Section 6.1, Appendix F – Updated contact number and email address for safety concerns.
!
Appendix C – Updated list of protocol signatures.
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STUDY M16-045  |  Version 6.0  |  EudraCT 2017-005125-20
CONFIDENTIAL INFORMATION
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APPENDIX F. OPERATIONS MANUAL
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1 CONTACTS
Sponsor/
Emergency 
Medical Contact
AbbVie Inc.
1 North Waukegan Road
North Chicago, IL 60064
EMERGENCY 24 hour Number:  
+1 (973) 784-6402
Mobile:
Email:
Safety Concerns
Therapeutic Area Safety Team
1 North Waukegan Road
North Chicago, IL 60064
Toll Free: +1 (833) 942-2226
Email:
SafetyManagement_TA@abbvie.com
SAE Reporting 
outside of EDC
Email:
PPDINDPharmacovigilance@abbvie.com
Fax:
1 (847) 938-0660
Protocol 
Deviations
AbbVie Inc.
41-45 Marinou Antypa Street
141 21 N. Irakleio
Athens, Greece
Office:
Fax:
Email:
Certified Clinical 
Lab
Covance Central Laboratory Services SA
8211 Scicor Drive
Indianapolis, IN 46214
Phone:
+1 (866) 762-6209 (Toll free)
+1 (317) 271-1200 (Local calls) 
Fax:
+1 (317) 616-2362
For country specific toll free numbers please refer to 
Covance Lab Manual.  
Pharmacokinetic 
Lab
AbbVie Inc.
Sample Receiving
Dept. R46W, Bldg. AP13A, Rm. 2310
1 North Waukegan Rd.
North Chicago, IL 60064
Phone:
+1 (847) 937-0889
Fax:
+1 (847) 938-9898
Exploratory 
Sample Lab
BioStorage Technologies Inc
2910 Fortune Circle West, Suite E
Indianapolis, IN 46241
Phone:
+1 (317) 268-5749
Fax:
+1 (317) 390-1868
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TABLE OF CONTENTS
1
CONTACTS
2
2
PROTOCOL ACTIVITIES BY VISIT
4
2.1
INDIVIDUAL TREATMENT PERIOD VISIT ACTIVITIES
4
3
APPENDICES
23
3.1
STUDY SPECIFIC ABBREVIATIONS AND TERMS
23
3.2
PRURITUS (ITCH) NUMERICAL RATING SCALE (NRS) EXAMPLE
24
3.3
ATOPIC DERMATITIS SYMPTOM SCALE (ADERM-SS) QUESTIONNAIRE EXAMPLE
25
3.4
ATOPIC DERMATITIS IMPACT SCALE (ADERM-IS) QUESTIONNAIRE EXAMPLE
28
3.5
DERMATOLOGY LIFE QUALITY (DLQI) EXAMPLE
30
3.6
CHILDREN'S DERMATOLOGY LIFE QUALITY (CDLQI) EXAMPLE
31
3.7
PATIENT ORIENTED ECZEMA MEASURE (POEM) EXAMPLE
32
3.8
HOSPITAL ANXIETY AND DEPRESS SCALE (HADS)
34
3.9
WORK PRODUCTIVITY AND ACTIVITY IMPAIRMENT QUESTIONNAIRE:  ATOPIC DERMATITIS V2.0
(WPAI:AD)
36
3.10 EUROQOL DIMENSIONS 5 LEVELS (EQ-5D-5L) QUESTIONNAIRE
38
3.11 PATIENT GLOBAL IMPRESSION OF SEVERITY (PGIS) QUESTIONNAIRE EXAMPLE
40
3.12 PATIENT GLOBAL IMPRESSION OF CHANGE (PGIC) QUESTIONNAIRE EXAMPLE
41
3.13 PATIENT GLOBAL IMPRESSION OF TREATMENT (PGIT) QUESTIONNAIRE EXAMPLE
42
3.14 SHORT FORM-36 (SF-36) HEALTH SURVEY
43
3.15 SCORING ATOPIC DERMATITIS (SCORAD) EXAMPLE
53
3.16 VALIDATED INVESTIGATOR'S GLOBAL ASSESSMENT FOR ATOPIC DERMATITIS (VIGA-AD) EXAMPLE
54
3.17 ECZEMA AREA AND SEVERITY INDEX (EASI) SCORING EXAMPLE
55
3.18 TB RISK ASSESSMENT FORM EXAMPLE
57
3.19 TANNER STAGING EXAMPLE
58
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2 PROTOCOL ACTIVITIES BY VISIT
Study visits may be impacted due to a state of emergency or pandemic (e.g., Coronavirus Disease – 2019 
[COVID-19] pandemic). This may include changes such as phone or virtual visits, visits at alternative 
locations, or changes in the visit frequency and timing of study procedures, among others. Additional 
details are provided in the subsequent section. Every effort should be made to ensure the safety of 
subjects and site staff, while maintaining the integrity of the study. If visits cannot be conducted onsite 
due to travel restrictions or other pandemic-related reasons, follow the updates below on how to 
proceed.
2.1 Individual Treatment Period Visit Activities
This section presents a list of activities performed during each visit, organized by visit.  The dot pattern 
on the upper right indicates the place of the visit in the overall Treatment Period Activity Schedule.
Visit window is ± 3 days until the Week 24 visit and beyond is a ± 7 day visit window.  Any of the 
procedures may be performed at an unscheduled visit at the discretion of the Investigator.
Activities are grouped by category (Interview, Exam, etc.).  Further information about each activity is 
provided in Protocol Section 5.
State of Emergency or Pandemic-Related Acceptable Protocol Modifications
During a state of emergency or pandemic (e.g., COVID-19), if it is not possible for all study procedures to 
be performed as specified due to travel restrictions or other reasons, the following modifications are 
allowed:
!
If permitted by local regulations, the IRB/IEC and the subject, all visits with the exception of 
Week 16 may be conducted remotely or in the subject's home residence.
!
Some study visits and/or activities may be performed by phone/virtually. These are indicated by 
a hashtag (#) in the appropriate visit tables below.
!
During a virtual visit, the Investigator assessments related to EASI, BSA, vIGA-AD, SCORAD, 
and HECSI will not be performed, as they need to be performed during an in-person 
assessment.
!
Some study visits and/or activities may be performed by a local clinic/hospital/laboratory. These 
are indicated by a plus sign (+) in the appropriate visit tables below. All procedures performed at 
local facilities must be performed by appropriately qualified personnel.
!
Study Visits and/or activities should be performed as scheduled whenever possible.
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3 APPENDICES
3.1 STUDY SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
AD
Atopic dermatitis
ADerm-IS
Atopic dermatitis impact scale
ADerm-SS
Atopic dermatitis symptom scale
AE
Adverse event
CDLQI
Children's Dermatology Life Quality Index
COVID-19
Coronavirus Disease – 2019 
DLQI
Dermatology life quality index
EASI
Eczema Area and Severity Index
EQ-5D-5L
Euroqol Dimensions 5 Levels
HADS
Hospital Anxiety and Depression Scale
IGA
Investigator global assessment
NRS
Numerical rating scale
PD
Premature discontinuation
PGIC
Patient Global Impression of Change
PGIS
Patient Global Impression of Severity
PGIT
Patient Global Impression of Treatment
PK
Pharmacokinetic
POEM
Patient-oriented Eczema Measure
SAE(s)
Serious adverse event(s)
SCORAD
Scoring atopic dermatitis
SF-36
Short Form-36 Health Survey
TB
Tuberculosis
vIGA-AD
Validated Investigator Global Assessment for atopic dermatitis
WPAI:AD
Work Productivity and Activity Impairment Index: Atopic Dermatitis
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3.2 PRURITUS (ITCH) NUMERICAL RATING SCALE (NRS) EXAMPLE
On a scale 0 to 10, with 0 being "no itch" and 10 being "worst imaginable itch," how would you rate your 
itch at its worst during the past 24 hours?
0
1
2
3
4
5
6
7
8
9
10
         No Itch
  Worst Imaginable Itch
Worst Pruritus NRS  V1    © AbbVie 12-7-2017
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3.5 DERMATOLOGY LIFE QUALITY (DLQI) EXAMPLE
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3.6 CHILDREN'S DERMATOLOGY LIFE QUALITY (CDLQI) EXAMPLE
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3.7 PATIENT ORIENTED ECZEMA MEASURE (POEM) EXAMPLE
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3.8 HOSPITAL ANXIETY AND DEPRESS SCALE (HADS)
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3.9 WORK PRODUCTIVITY AND ACTIVITY IMPAIRMENT 
QUESTIONNAIRE:  ATOPIC DERMATITIS V2.0 (WPAI:AD)
The following questions ask about the effect of your AD on your ability to work and perform regular 
activities.  Please fill in the blanks or circle a number, as indicated.
1.
Are you currently employed (working for pay)?
____NO
___YES
If NO, check "NO" and skip to question 6
The next questions are about the past seven days, not including today.
2.
During the past seven days, how many hours did you miss from work because of problems 
associated with your AD? Include hours you missed on sick days, times you went in late, left 
early, etc. because of AD.  Do not include time you missed to participate in this study.
______HOURS
3.
During the past seven days, how many hours did you miss from work because of any other 
reason, such as vacation, holidays, time off to participate in this study?
______HOURS
4.
During the past seven days, how many hours did you actually work? 
______HOURS (If "0," skip to question 6)
5.
During the past seven days, how much did AD affect your productivity while you were working?  
Think about days you were limited in the amount or kind of work you could do, days you 
accomplished less than you would like, or days you could not do your work as carefully as usual.  If 
AD affected your work only a little, choose a low number.  Choose a high number if AD affected your 
work a great deal.
Consider only how much AD affected 
productivity while you were working.
Atopic dermatitis 
had no
Atopic dermatitis 
completely
effect on my work
0
1
2
3
4
5
6
7
8
9
10
prevented me from
working
CIRCLE A NUMBER
6.
During the past seven days, how much did AD affect your ability to do your regular daily 
activities, other than work at a job?  
By regular activities, we mean the usual activities you do, such as work around the house, shopping, 
child care, exercising, studying, etc.  Think about times you were limited in the amount or kind of 
activities you could do and times you accomplished less than you would like.  If AD affected your 
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activities only a little, choose a low number.  Choose a high number if AD affected your activities a 
great deal.
Consider only how much AD affected your ability 
to do your regular daily activities, other than work at a job.
Atopic dermatitis 
had no
Atopic dermatitis 
completely
effect on my daily 
activities
0
1
2
3
4
5
6
7
8
9
10
prevented me from 
doing my daily 
activities
CIRCLE A NUMBER
WPAI:AD v2.0 (US English)
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3.10 EUROQOL DIMENSIONS 5 LEVELS (EQ-5D-5L) QUESTIONNAIRE
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3.11 PATIENT GLOBAL IMPRESSION OF SEVERITY (PGIS) 
QUESTIONNAIRE EXAMPLE
Seven point response scale
Please mark an "X" in the box (
) that best describes the severity of your AD symptoms right now.
1.
Right now, my AD symptoms are:
0
Absent: No symptoms
1
Minimal: Can be easily ignored without effort
2
Mild: Can be ignored with effort
3
Moderate: Cannot be ignored but does not influence my daily activities
4
Moderately severe: Cannot be ignored and occasionally limits my daily activities
5
Severe: Cannot be ignored and often limits my concentration on daily activities
  6
Very severe: Cannot be ignored and markedly limits my daily activities.
© AbbVie Inc., 19October2016 V1
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3.12 PATIENT GLOBAL IMPRESSION OF CHANGE (PGIC) 
QUESTIONNAIRE EXAMPLE
Seven-point response scale
Please mark an "X" in the box (☒) that best describes the severity of your AD symptoms right now.
1.
Compared to before your study treatment began, how would you rate the overall change in your AD 
symptoms?:
☐1
Very much improved
☐2
Much improved
☐3
Minimally improved
☐4
No change
☐5
Minimally worse
☐6
Much worse
☐7
Very much worse
© AbbVie Inc., 19October2017 V1
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3.13 PATIENT GLOBAL IMPRESSION OF TREATMENT (PGIT) 
QUESTIONNAIRE EXAMPLE
Seven-point response scale
Please mark an "X" in the box (☒) that best describes how satisfied or dissatisfied you are overall with 
your current treatment for AD.
1.
Overall, how satisfied or dissatisfied are you with your current treatment for AD?:
☐1
Extremely dissatisfied
☐2
Very dissatisfied
☐3
Somewhat dissatisfied
☐4
Neither dissatisfied nor satisfied
☐5
Somewhat satisfied
☐6
Very satisfied
☐7
Extremely satisfied
© AbbVie Inc., 19October2017 V1
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3.14 SHORT FORM-36 (SF-36) HEALTH SURVEY
SF-36v2® Health Survey © 1992, 1996, 2000, 2010
Medical Outcomes Trust and 
QualityMetric Incorporated.
All Rights Reserved.
SF-36® is a registered trademark of 
Medical Outcomes Trust.
(SF-36v2® Health Survey Standard, 
United States (English))
Your Health and Well-Being
This survey asks for your views about your health.  This information will help keep track of 
how you feel and how well you are able to do your usual activities.  Thank you for completing 
this survey!
For each of the following questions, please select the one response that best describes your 
answer.
In general, would you say your health is:
Excellent
Very good
Good
Fair
Poor
Compared to one year ago, how would you rate your health in general now?
Much better now than one year ago
Somewhat better now than one year ago
About the same as one year ago
Somewhat worse now than one year ago
Much worse now than one year ago
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The following question is about activities you might do during a typical day.
Does your health now limit you in vigorous activities, such as running, lifting heavy objects, 
participating in strenuous sports?  If so, how much?
Yes, limited a lot
Yes, limited a little
No, not limited at all
The following question is about activities you might do during a typical day.
Does your health now limit you in moderate activities, such as moving a table, pushing a 
vacuum cleaner, bowling, or playing golf?  If so, how much?
Yes, limited a lot
Yes, limited a little
No, not limited at all
The following question is about activities you might do during a typical day.
Does your health now limit you in lifting or carrying groceries?  If so, how much?
Yes, limited a lot
Yes, limited a little
No, not limited at all
The following question is about activities you might do during a typical day.
Does your health now limit you in climbing several flights of stairs?  If so, how much?
Yes, limited a lot
Yes, limited a little
No, not limited at all
The following question is about activities you might do during a typical day.
Does your health now limit you in climbing one flight of stairs?  If so, how much?
Yes, limited a lot
Yes, limited a little
No, not limited at all
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The following question is about activities you might do during a typical day.
Does your health now limit you in bending, kneeling, or stooping? If so, how much?
Yes, limited a lot
Yes, limited a little
No, not limited at all
The following question is about activities you might do during a typical day.
Does your health now limit you in walking more than a mile?  If so, how much?
Yes, limited a lot
Yes, limited a little
No, not limited at all
The following question is about activities you might do during a typical day.
Does your health now limit you in walking several hundred yards?  If so, how much?
Yes, limited a lot
Yes, limited a little
No, not limited at all
The following question is about activities you might do during a typical day.
Does your health now limit you in walking one hundred yards?  If so, how much?
Yes, limited a lot
Yes, limited a little
No, not limited at all
The following question is about activities you might do during a typical day.
Does your health now limit you in bathing or dressing yourself?  If so, how much?
Yes, limited a lot
Yes, limited a little
No, not limited at all
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During the past 4 weeks, how much of the time have you had any of the following problems 
with your work or other regular daily activities?
Cut down on the amount of time you spent on work or other activities as a result of your 
physical health
All of the time
Most of the time
Some of the time
A little of the time
None of the time
During the past 4 weeks, how much of the time have you had any of the following problems 
with your work or other regular daily activities?
Accomplished less than you would like as a result of your physical health
All of the time
Most of the time
Some of the time
A little of the time
None of the time
During the past 4 weeks, how much of the time have you had any of the following problems 
with your work or other regular daily activities?
Were limited in the kind of work or other activities as a result of your physical health
All of the time
Most of the time
Some of the time
A little of the time
None of the time
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During the past 4 weeks, how much of the time have you had any of the following problems 
with your work or other regular daily activities?
Had difficulty performing the work or other activities as a result of your physical health (for 
example, it took extra effort)
All of the time
Most of the time
Some of the time
A little of the time
None of the time
During the past 4 weeks, how much of the time have you had any of the following problems 
with your work or other regular daily activities?
Cut down on the amount of time you spent on work or other activities as a result of any 
emotional problems (such as feeling depressed or anxious)
All of the time
Most of the time
Some of the time
A little of the time
None of the time
During the past 4 weeks, how much of the time have you had any of the following problems 
with your work or other regular daily activities?
Accomplished less than you would like as a result of any emotional problems (such as feeling 
depressed or anxious)
All of the time
Most of the time
Some of the time
A little of the time
None of the time
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During the past 4 weeks, how much of the time have you had any of the following problems 
with your work or other regular daily activities?
Did work or other activities less carefully than usual as a result of any emotional problems
(such as feeling depressed or anxious)
All of the time
Most of the time
Some of the time
A little of the time
None of the time
During the past 4 weeks, to what extent has your physical health or emotional problems 
interfered with your normal social activities with family, friends, neighbors, or groups?
Not at all
Slightly
Moderately
Quite a bit
Extremely
How much bodily pain have you had during the past 4 weeks?
None
Very mild
Mild
Moderate
Severe
Very Severe
During the past 4 weeks, how much did pain interfere with your normal work (including both 
work outside the home and housework)?
Not at all
A little bit
Moderately
Quite a bit
Extremely
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This question is about how you feel and how things have been with you during the past 
4 weeks.  Please give the one answer that comes closest to the way you have been feeling.  
How much of the time during the past 4 weeks did you feel full of life?
All of the time
Most of the time
Some of the time
A little of the time
None of the time
This question is about how you feel and how things have been with you during the past 
4 weeks. Please give the one answer that comes closest to the way you have been feeling.  
How much of the time during the past 4 weeks have you been very nervous?
All of the time
Most of the time
Some of the time
A little of the time
None of the time
This question is about how you feel and how things have been with you during the past 4 
weeks.  Please give the one answer that comes closest to the way you have been feeling.  
How much of the time during the past 4 weeks have you felt so down in the dumps that 
nothing could cheer you up?
All of the time
Most of the time
Some of the time
A little of the time
None of the time
This question is about how you feel and how things have been with you during the past 
4 weeks.  Please give the one answer that comes closest to the way you have been feeling.  
How much of the time during the past 4 weeks have you felt calm and peaceful?
All of the time
Most of the time
Some of the time
A little of the time
None of the time
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This question is about how you feel and how things have been with you during the past 
4 weeks.  Please give the one answer that comes closest to the way you have been feeling.  
How much of the time during the past 4 weeks did you have a lot of energy?
All of the time
Most of the time
Some of the time
A little of the time
None of the time
This question is about how you feel and how things have been with you during the past 
4 weeks.  Please give the one answer that comes closest to the way you have been feeling.  
How much of the time during the past 4 weeks have you felt downhearted and depressed?
All of the time
Most of the time
Some of the time
A little of the time
None of the time
This question is about how you feel and how things have been with you during the past 
4 weeks.  Please give the one answer that comes closest to the way you have been feeling.  
How much of the time during the past 4 weeks did you feel worn out?
All of the time
Most of the time
Some of the time
A little of the time
None of the time
This question is about how you feel and how things have been with you during the past 
4 weeks.  Please give the one answer that comes closest to the way you have been feeling.  
How much of the time during the past 4 weeks have you been happy?
All of the time
Most of the time
Some of the time
A little of the time
None of the time
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This question is about how you feel and how things have been with you during the past 
4 weeks.  Please give the one answer that comes closest to the way you have been feeling.  
How much of the time during the past 4 weeks did you feel tired?
All of the time
Most of the time
Some of the time
A little of the time
None of the time
During the past 4 weeks, how much of the time has your physical health or emotional 
problems interfered with your social activities (like visiting with friends, relatives, etc.)?
All of the time
Most of the time
Some of the time
A little of the time
None of the time
How TRUE or FALSE is the following statement for you?
I seem to get sick a little easier than other people.
Definitely true
Mostly true
Don't know
Mostly false
Definitely false
How TRUE or FALSE is the following statement for you?  
I am as healthy as anybody I know.
Definitely true
Mostly true
Don't know
Mostly false
Definitely false
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-045 Version 6.0
CONFIDENTIAL INFORMATION
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How TRUE or FALSE is the following statement for you?  
I expect my health to get worse.
Definitely true
Mostly true
Don't know
Mostly false
Definitely false
How TRUE or FALSE is the following statement for you?  
My health is excellent.
Definitely true
Mostly true
Don't know
Mostly false
Definitely false
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-045 Version 6.0
CONFIDENTIAL INFORMATION
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3.15 SCORING ATOPIC DERMATITIS (SCORAD) EXAMPLE
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-045 Version 6.0
CONFIDENTIAL INFORMATION
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3.17 ECZEMA AREA AND SEVERITY INDEX (EASI) SCORING EXAMPLE
An EASI score is a tool used to measure the extent (area) and severity of atopic eczema (Eczema Area 
and Severity Index).  EASI score does not include a grade for dryness or scaling.
Assignments for the following body regions are as follows:
!
Head and Neck
!
Trunk:  (including the genital area)
!
Upper extremities
!
Lower extremities (including the buttocks)
Area Score
Area score is recorded for each of the four regions of the body.  The area score is the percentage of skin 
affected by eczema.
Area score Percentage of skin affected by eczema in each region:
!
0 = no eczema in this region
!
1 = 1% – 9%
!
2 = 10% – 29% 
!
3 = 30% – 49% 
!
4 = 50% – 69% 
!
5 = 70% – 89% 
!
6 = 90% – 100%:  the entire region is affected by eczema
Severity Score
Severity score is recorded for each of the four regions of the body.  The severity score is the sum of the 
intensity scores for four signs.
The four signs are: 
1.
Redness (erythema, inflammation)
2.
Thickness (induration, papulation, swelling – acute eczema)
3.
Scratching (excoriation)
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-045 Version 6.0
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4.
Lichenification (lined skin, prurigo nodules – chronic eczema)
The average intensity of each sign in each body region is assessed as:  none (0), mild (1), moderate (2) 
and severe (3).
Score Intensity of redness, thickness/swelling, scratching, lichenification:
0 = None, absent 
1 = Mild 
2 = Moderate 
3 = Severe
For each region, record the intensity for each of four signs and calculate the severity score.
Severity score = redness intensity + thickness intensity + scratching intensity + lichenification intensity
For each region, multiply the severity score by the area score and by a multiplier.
!
Head and neck:  severity score × area score × 0.1
!
Trunk:  severity score × area score × 0.3
!
Upper limbs:  severity score × area score × 0.2
!
Lower limbs:  severity score × area score × 0.4
Add up the total scores for each region to determine the final EASI score.  The minimum EASI score is 0 
and the maximum EASI score is 72.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-045 Version 6.0
CONFIDENTIAL INFORMATION
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3.18 TB RISK ASSESSMENT FORM EXAMPLE
1.
Have you or an immediate family member or other close contact ever been diagnosed or 
treated for tuberculosis?
2.
Have you lived in or had prolonged travels to countries in the following regions:
!
Africa
!
Eastern Europe
!
Asia
!
Latin America
!
Caribbean Islands
!
Russia
3.
Have you lived or worked in a prison, homeless shelter/refugee camp, immigration center, 
health care worker in a hospital or nursing home?
4.
Have you, or an immediate family member, had any of the following problems for the past 
3 weeks or longer:
!
Chronic Cough
!
Chest pain, or pain with breathing or coughing
!
Blood-Streaked Sputum (coughing up blood)
!
Unexplained Weight Loss
!
Fever
!
Fatigue/Tiredness
!
Night Sweats
!
Shortness of Breath
From:
http://www.mayoclinic.org/diseases-conditions/tuberculosis/symptoms-causes/dxc-20188557
http://www.in.gov/fssa/files/Tuberculosis_Questionnaire.pdf
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-045 Version 6.0
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3.19 TANNER STAGING EXAMPLE
BOYS
Stage 
Pubic Hair
□ 1
None
□ 2
Scanty, long, slightly pigmented
□ 3
Darker, starts to curl, small amount
□ 4
Resembles adult type, less in quantity; coarse, curly
□ 5
Adult distribution, spread to medial surface of thighs
Stage 
Genitals
Penis
Testes
□ 1
Preadolescent
Preadolescent
□ 2
Slight enlargement
Enlarged scrotum, pink 
texture altered
□ 3
Longer
Larger
□ 4
Larger, glans and breadth 
increase in size
Larger, scrotum dark
□ 5
Adult
Adult
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-045 Version 6.0
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GIRLS
Stage 
Breasts
□ 1
Preadolescent
□ 2
Breast and papilla elevated 
as small mound, aureolar 
diameter increased
□ 3
Breast and areola enlarged.  
No contour separation
□ 4
Areola and papilla form 
secondary mound
□ 5
Mature, nipple projects, 
areola part of general breast 
contour
Stage
Pubic Hair
□ 1
None
□ 2
Sparse, lightly pigmented, 
straight, medial border of 
labia
□ 3
Darker, beginning to curl, 
increased amount
□ 4
Coarse, curly, abundant but 
amount less than in adult
□ 5
Adult feminine triangle, 
spread to medial surface of 
thighs
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