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

NCT03568318

STUDY M16-047  |  Version 5.0  |  EudraCT 2017-005126-37
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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
11
3.5
SAFETY ENDPOINTS
14
3.6
PHARMACOKINETIC ENDPOINT
14
3.7
BIOMARKER SAMPLES
14
4
INVESTIGATIONAL PLAN
14
4.1
OVERALL STUDY DESIGN AND PLAN
14
4.2
DISCUSSION OF STUDY DESIGN
16
5
STUDY ACTIVITIES
18
5.1
ELIGIBILITY CRITERIA
18
5.2
CONTRACEPTION RECOMMENDATIONS
22
5.3
PROHIBITED MEDICATIONS AND THERAPY
24
5.4
PRIOR AND CONCOMITANT THERAPY
29
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
32
5.6
FOLLOW-UP FOR SUBJECT WITHDRAWAL FROM STUDY
34
5.7
TREATMENT AFTER END OF STUDY
34
5.8
STUDY DRUG
35
5.9
PROTOCOL DEVIATIONS
38
5.10 OTHER STUDY PROCEDURES
38
6
SAFETY CONSIDERATIONS
58
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6.1
COMPLAINTS AND ADVERSE EVENTS
58
6.2
TOXICITY MANAGEMENT
64
6.3
DATA MONITORING COMMITTEE AND CARDIOVASCULAR ADJUDICATION COMMITTEE
68
6.4
OTHER SAFETY DATA COLLECTION
68
6.5
SUSAR REPORTING
68
7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
69
7.1
STATISTICAL AND ANALYTICAL PLANS
69
7.2
DEFINITION FOR ANALYSIS POPULATIONS
69
7.3
STATISTICAL ANALYSES FOR EFFICACY
71
7.4
STATISTICAL ANALYSES FOR SAFETY
72
7.5
PHARMACOKINETIC AND EXPOSURE-RESPONSE ANALYSES
72
7.6
INTERIM ANALYSIS
73
8
ETHICS
74
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD (IEC/IRB)
74
8.2
ETHICAL CONDUCT OF THE STUDY
74
8.3
SUBJECT CONFIDENTIALITY
74
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
74
10 DATA QUALITY ASSURANCE
75
11 COMPLETION OF THE STUDY
76
12 REFERENCES
76
LIST OF TABLES
TABLE 1.
EXAMPLES OF COMMONLY USED STRONG CYP3A INHIBITORS AND INDUCERS
28
TABLE 2.
POTENCY LEVELS OF RECOMMENDED TOPICAL CORTICOSTEROIDS*
30
TABLE 3.
POTENCY LEVELS OF RECOMMENDED RESCUE TOPICAL CORTICOSTEROIDS*
31
TABLE 4.
DESCRIPTION OF STUDY DRUG AND PLACEBO
35
TABLE 5.
SPECIFIC TOXICITY MANAGEMENT GUIDELINES FOR ABNORMAL LABORATORY VALUES
66
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LIST OF FIGURES
FIGURE 1.
STUDY SCHEMATIC
15
FIGURE 2.
INTERPRETATION AND MANAGEMENT OF HBV SEROLOGIC TEST RESULTS
55
LIST OF APPENDICES
APPENDIX A.
STUDY SPECIFIC ABBREVIATIONS AND TERMS
78
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
82
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
83
APPENDIX D.
ACTIVITY SCHEDULE
84
APPENDIX E.
RELATIVE POTENCIES OF TOPICAL CORTICOSTEROIDS
89
APPENDIX F.
PROTOCOL SUMMARY OF CHANGES
90
APPENDIX G.
OPERATIONS MANUAL
94
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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, psoriatic arthritis, ulcerative colitis, 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 this 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 adverse event (AE), 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 
already available as peer-reviewed manuscripts.2-5  Results from a Phase 2 study in AD showed the 
upadacitinib doses of 15 mg to 30 mg per day had efficacy and safety profiles that can benefit patients 
with moderate to severe AD.
Clinical Hypothesis
Upadacitinib combined with topical corticosteroids (TCS) is expected to provide better efficacy 
compared with placebo combined with TCS and to 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
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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 
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  In addition, nearly 50% 
of dupilumab subjects who were IGA 0 or 1 responders at Week 16 became nonresponders 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 T helper 2 
cell-mediated skin inflammation and itch mediated by JAK1 signaling in AD, 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 results demonstrate 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.
For further details, please see findings from completed studies, including safety data in the 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 combined with TCS 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 a 90% reduction in EASI (EASI 90) at Week 16;
!
Percent change from Baseline of Worst Pruritus NRS at Week 16;
!
Percent change in EASI score from Baseline 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 4;
!
Proportion of subjects achieving EASI 75 at Week 2;
!
Proportion of subjects achieving EASI 90 at Week 4;
!
Proportion of subjects achieving EASI 100 at Week 16 for 30 mg;
!
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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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 4;
!
Proportion of subjects achieving EASI 75 at Week 2;
!
Proportion of subjects achieving EASI 90 at Week 4;
!
Proportion of subjects achieving EASI 100 at Week 16 for 30 mg;
!
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.
3.4 Additional Endpoints
All variables listed as primary or secondary endpoints will be analyzed at all visits other than 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;
!
Proportion of subjects achieving EASI 50 at Week 2;
!
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;
!
Percent change in Scoring Atopic Dermatitis (SCORAD) from Baseline at Week 16;
!
Proportion of subjects achieving EASI 50;
!
Number of TCS free days with EASI 75 response up to Week 16*;
!
Number of medium or higher potency TCS free days with EASI 75 response up to Week 16*;
!
Time to first discontinuation of all TCS with EASI 75 response (discontinuation of all TCS is 
defined as the subject stops the TCS treatment > 7 consecutive days) up to Week 16*;
!
Proportion of subjects achieving Worst Pruritus NRS of 0 or 1 for subjects with Worst Pruritus 
NRS > 1 at Baseline;
!
Change from Baseline in Worst Pruritus NRS;
!
Percent change from Baseline in Scoring AD (SCORAD);
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!
Proportion of subjects achieving 50%/75%/90% reduction in SCORAD (SCORAD 50/75/90) from 
Baseline;
!
Change from Baseline in body surface area (BSA);
!
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);
!
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, by visit after Week 16;
!
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 and percent change from Baseline in Hospital Anxiety and Depression Scale (HADS) 
(total score, HADS-anxiety [HADS-A], HADS-depression [HADS-D]); 
!
Proportion of subjects achieving HADS-A < 8 and HADS-D < 8 for subjects with HADS-A ≥ 8 or 
HADS-D ≥ 8 at Baseline;
!
Proportion of subjects achieving an improvement (reduction) in Atopic Dermatitis Symptom 
Scale (ADerm-SS) 7-item total symptom score (TSS-7) ≥ 28 (minimal clinically important 
difference [MCID]) from Baseline 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-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 to items 1 – 11 of 
the ADerm-SS;
!
Proportion of subjects achieving an improvement (reduction) in ADerm-SS skin pain score ≥4 
(MCID) from Baseline for subjects with ADerm-SS skin pain score ≥ 4 at Baseline;
!
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-SS TSS-7, ADerm-SS TSS-11, and skin pain 
score;
!
Proportion of subjects achieving an improvement (reduction) in Atopic Dermatitis Impact Scale 
(ADerm-IS) sleep domain score ≥ 12 (MCID) from Baseline for subjects with ADerm-IS sleep 
domain score ≥ 12 at Baseline;
!
Proportion of subjects achieving an improvement (reduction) in ADerm-IS emotional state 
domain score ≥ 11 (MCID) from Baseline for subjects with ADerm-IS emotional state domain 
score ≥11 at Baseline;
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!
Proportion of subjects achieving an improvement (reduction) in ADerm-IS daily activities domain 
score ≥ 14 (MCID) from Baseline for subjects with ADerm-IS daily activities domain score ≥14 at 
Baseline;
!
Change and percent change from Baseline in ADerm-IS sleep domain score, emotional state 
domain score, and daily activities domain score;
!
Proportion of subjects achieving an improvement (reduction) of Patient-oriented Eczema 
Measure (POEM) ≥ 4 from Baseline for subjects with POEM ≥ 4 at Baseline;
!
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 POEM;
!
Proportion of subjects age ≥ 16 years old at screening achieving an improvement (reduction) of 
Dermatology Life Quality Index (DLQI) ≥ 4 for subjects with DLQI ≥ 4 at Baseline;
!
Proportion of subjects age ≥ 16 years old at screening achieving DLQI score of 0/1 for subjects 
with DLQI score > 1 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 0/1 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: 
AD (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 Dermatologic Intimacy Scale (DIS) among adults;
!
Change and percent change from Baseline in Patient Global Impression of Severity (PGIS);
!
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 vIGA-AD of 0 with a reduction from Baseline of ≥ 2 points.
*Note:  Days from the start of systemic rescue will not be considered as TCS-free days.
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3.5 Safety Endpoints
The following safety evaluations will be performed during the study:  treatment emergent adverse 
events (TEAEs), SAEs, AEs of special interest (AESIs), AEs leading to discontinuation, vital signs, and 
laboratory tests.
3.6 Pharmacokinetic Endpoint
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, TNF), or other genes believed to be related AD, and other 
inflammatory diseases (filaggrin, Claudin-1, human leukocyte antigen).  For any samples collected in 
Germany, the research will be restricted to upadacitinib and AD.
4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
This is a Phase 3, randomized, double-blind, placebo-controlled multicenter study that will evaluate 
upadacitinib combined with TCS in adolescents (12 to 17 years of age) and adults (18 to 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.
The study is comprised of a 35-day screening period, a 16 week DB Period, a Blinded Extension Period of 
up to Week 136, 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 
concomitant TCS with either daily oral doses of upadacitinib 15 mg (N = 270) or 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] 
versus severe [vIGA-AD 4]), by geographic region (US/Puerto Rico/Canada, Japan, China, and Other), and 
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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] versus severe 
[vIGA-AD 4]) and by geographic region (US/Puerto Rico/Canada and Other).  See Section 5 for 
information regarding eligibility criteria.
At the end of the 16 week DB period, 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 136 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, 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.  An 
additional analysis of the adolescent population will be conducted after all ongoing adolescent subjects 
have provided at least 1 year of upadacitinib exposure.  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.
Figure 1.
Study Schematic
DB = double-blind; QD = once daily; TCS = topical corticosteroids
Notes:
This schematic applies to both the main study and adolescent sub-study.
TCS inhibitors permitted for use in areas where TCS is generally not advisable.
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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, especially for long-term use.  There 
is no anticipated medical risk for subjects randomized to placebo and background concomitant TCS; if 
needed, rescue treatment will be available for these subjects.
Appropriateness of Measurements
Standard statistical, 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.  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.
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.17-21
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 
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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 2b 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 daily 
regimen 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 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).  The literature 
suggests that maturation of the CYP3A activity in children 2 years and above is similar to that of adults.22  
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 AD.
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.
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Placebo Duration Rationale
The 16-week DB treatment period is deemed to be a sufficient duration to be able to test the superiority 
of upadacitinib in combination with TCS versus placebo in combination with TCS 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 age 
≥ 12 to < 18 years old may 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.
2. Adult subjects ≥ 18 years of age at Screening Visit or their legally authorized representative 
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 subject 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, and a 12-lead electrocardiogram (ECG) performed during Screening.
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AD Disease Activity
6. Chronic AD with onset of symptoms at least 3 years prior to Baseline and subject meets 
Hanifin and Rajka criteria.23
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 prior to the Baseline Visit) of inadequate response to 
TCS or topical calcineurin inhibitor (TCI) OR documented systemic treatment for AD within 
6 months prior to the Baseline Visit.
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.
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16. Subjects must not have ≥ 30% of AD lesional surface involvement at Baseline that cannot be 
safely treated with medium or higher potency TCS (e.g., areas of skin atrophy, face, groin, 
intertriginous areas).
17. 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, interferon-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, TCI, or topical PDE4 inhibitors within 
7 days.
18. 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.
19. No systemic use of known strong CYP3A inhibitors or strong CYP3A inducers from Screening 
through the end of the study (refer to Table 1 for examples of commonly used strong CYP3A 
inhibitors and inducers).
20. 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
21. 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;
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!
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 (WBC) count < 2,500/μL;
!
Absolute neutrophil count (ANC) < 1,500/μL;
!
Platelet count < 100,000/μL;
!
Absolute lymphocyte count < 800/μL;
!
Hemoglobin < 10 g/dL.
22. 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;
!
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 positive or detected sensitivity on the HBV 
deoxyribonucleic acid polymerase chain reaction qualitative test for hepatitis B core 
antibody positive subjects (and for hepatitis B surface antibody positive where 
mandated per local requirements);
!
HCV:  HCV ribonucleic acid detectable in any subject with anti-HCV antibody.
!
In Japan, positive result of beta-D-glucan or two consecutive indeterminate results of 
beta-D-glucan (screening for pneumocystis jiroveci infection at central lab).
23. Subjects 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;
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!
Uncontrolled hypertension as defined by a confirmed systolic blood pressure 
> 160 mmHg or diastolic blood pressure > 100 mmHg;
!
Any other unstable clinical condition which, the investigator determines 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 the 
investigator determines, 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
24. 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.
25. No history of clinically significant (per investigator's judgment) drug or alcohol abuse within 
the last 6 months preceding the Baseline Visit.
26. No contraindication to topical corticosteroids or topical calcineurin inhibitors.
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 
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!
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.
!
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.
!
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 
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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.
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.
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.
•
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.
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.
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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, tofacitinib, baricitinib, abrocitinib 
[PF-04965842], and filgotinib) are 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
!
tocilizumab
!
ustekinumab
See also Rescue Therapy in Section 5.4 for further details on systemic rescue.
Other Non-Biologic Systemic Therapy
Non corticosteroid systemic therapy for the treatment of AD is prohibited while on study drug, including 
but not limited to:
!
methotrexate
!
cyclosporine
!
azathioprine
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!
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 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 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 allowed corticosteroid rescue.  
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 psoralen and UVA 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.
Topical Therapy
Aside from the required topical treatments (see Required Concomitant Medications in Section 5.4), no 
other topical treatments for AD should be started through Week 52 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 Inclusion Criterion 8.
Starting at the Week 52 Visit, the use of any concomitant topical medication for AD 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 Medical Director (TA MD).
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Vaccines
Live vaccines are not permitted during study participation and including up to 4 weeks (or longer if 
required locally) after the last dose of study drug.  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; 8 weeks for subjects in Japan), before first dose of study drug with appropriate 
precautions.  Although not mandated by the protocol, vaccines recommended by local guidelines should 
be considered.  Examples of live vaccines include, but are not limited to, the following:
!
Bacille Calmette-Guérin (BCG)
!
herpes zoster
!
measles-mumps-rubella or measles-mumps-rubella-varicella
!
monovalent live attenuated influenza A (intranasal)
!
oral polio vaccine
!
rotavirus
!
seasonal trivalent live attenuated influenza (intranasal)
!
smallpox
!
typhoid
!
varicella (chicken pox)
!
yellow fever
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.
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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.
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.
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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 
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 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 TA MD should be contacted.
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 52.  Starting at the Week 52 Visit, the use 
of emollients can be administered per investigator decision.
Note:  Until Week 52, 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.
Starting at the Baseline Visit and continuing through Week 52, all subjects will initiate treatment with 
TCS and/or TCI with the following step-down regimen:
!
Apply medium potency TCS QD to areas with active lesions for a maximum of 
3 consecutive weeks.  Low potency TCS or TCI should be applied QD on areas of thin skin (face, 
neck, intertriginous and genital areas) or for areas where medium TCS are considered unsafe 
(e.g., areas of skin atrophy).  See Table 2 for types and potency levels of recommended TCS.
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After lesions are under control (clear or almost clear) or after 3 consecutive weeks of medium 
potency TCS QD, switch from medium potency to low potency TCS and treat QD for 7 days, then 
stop.  For sensitive skin locations, low-potency TCS, or TCI are to be tapered and stopped.
!
If lesions return or persist, resume treatment with the step-down approach described above 
until lesion resolution as long as there is no sign of local or systemic TCS toxicity.
!
The subject should be monitored for signs of local or systemic TCS toxicity and step down or 
stopping treatment should be performed as necessary.  Topical therapy may be further limited 
in duration and potency if medically advisable (e.g., in subjects with extensive TCS pretreatment 
and clinical signs of TCS side effects such as striae, skin atrophy, or bruising).
!
At or after Week 4, see also Rescue Therapy below for further details on rescue treatment 
options with higher potency TCS or systemic therapy.
!
At or after Week 52, the use of any concomitant topical medication for AD can be administered 
per investigator discretion and is no longer required.
Table 2.
Potency Levels of Recommended Topical Corticosteroids*
Potency†
Recommended Topical Steroids
Low‡
Hydrocortisone 1% cream
Medium
Triamcinolone acetonide 0.1% cream
Fluocinolone acetonide 0.025% ointment
*
Potency levels are per U.S. guidelines.  
†
If the subject is intolerant to these TCS or they are not available, they may be substituted by a topical steroid with the 
same potency from the list provided in Appendix E.
‡
Low potency steroids are to be applied to sensitive areas (e.g., face, intertriginous areas, groin).
The use of wet wraps for routine application of daily TCS and/or TCIs is not allowed.
After a premature discontinuation of study drug, continuation of the step-down regimen for TCS and/or 
TCIs and twice-daily use of emollients will no longer be mandatory, and use of topical therapy will be per 
the investigator's discretion.
Rescue Therapy
Starting at the Week 4 visit, rescue treatment for AD may be provided, if medically necessary and if 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.
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Investigators should attempt to limit the first step of rescue therapy to high or super-high potency TCS 
(unless higher potency TCS are considered unsafe) or other alternative topical AD medications, and 
escalate to systemic medications only for those subjects who do not respond adequately after at least 
7 days of topical treatment (Table 3).
Starting at the Week 52 visit, the use of any concomitant topical medication for AD 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.
Table 3.
Potency Levels of Recommended Rescue Topical Corticosteroids*
Potency†
Recommended Topical Steroids
High
Mometasone 0.1% ointment
Very high
Augmented betamethasone dipropionate 0.05% ointment
Clobetasol propionate 0.05% cream
*
Potency levels are per U.S. guidelines.  
†
If the subject is intolerant to these TCS or they are not available, they may be substituted by a topical steroid with the 
same potency from the list provided in Appendix E.
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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, 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 corticosteroid or non-corticosteroid systemic rescue 
therapy for AD.
!
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 or the AbbVie TA MD.  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 TA MD.    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 TA MD.    Note:  Intentional/prospective 
deviations from the protocol are not allowed.  See Section 5.9 Protocol Deviations.
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!
Subject is noncompliant 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 noncompliant with study procedures, which would put the subject at risk 
for continued participation in the trial as determined by the investigator or the AbbVie TA MD.    
Note:  Intentional/prospective deviations from the protocol are not allowed.  See Section 5.9
Protocol Deviations.
!
Subject develops a GI perforation.
!
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 
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 subject's final status.  At a minimum, 2 telephone calls must be made and 
1 certified letter must be sent and documented in the subject's source documentation.
Information letters and provision/withdrawal of informed consent in the Netherlands will take into 
account the following:
!
The Medical Research Involving Human Subjects Act requires national approval of separate 
information letters and consent forms for participants and both parents/legal guardians in an 
age appropriate manner
!
The Medical Treatments Agreements Act which states that individuals from 16 Years of age may 
decide independently and have an independent right to information
!
The Code of Conduct of the Dutch Association of Pediatrics regarding the definition of 
(premature) withdrawal of informed consent and/or discontinuation
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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 (withdrawal of informed consent), 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 should come in for 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 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 on study treatment throughout 
the study for a period of up to 136 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 upadacitinib or any other therapy once the subject's participation is 
concluded.
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5.8 Study Drug
The individual study drug information is presented in Table 4.
Table 4.
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 subjects 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.
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.  
For allowed study drug interruption, 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.
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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.
Method of Assigning Subjects to Treatment Groups
Subjects who meet eligibility criteria will be randomized in a 1:1:1 ratio to receive with concomitant TCS, 
either daily oral doses of upadacitinib 15 mg or upadacitinib 30 mg or matching placebo.  Randomization 
for the main study will be stratified by baseline disease severity (moderate [vIGA-AD 3] versus severe 
[vIGA-AD 4]), geographic region (US/Puerto Rico/Canada, Japan, China, and Other), and age group 
(adolescent [ages 12 to 17] versus adult [ages 18 to 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 the end of the 16 week DB Period, subjects in 
the placebo group will be re-randomized in a 1:1 ratio (main study:  stratified by EASI 50 responder 
[Yes/No], geographic region [US/Puerto Rico/Canada, Japan, China, and Other], and age group 
[adolescent/adult subjects]; adolescent sub-study:  stratified by EASI 50 responder [Yes/No] and by 
geographic region [US/Puerto Rico/Canada and Other]) to receive daily oral doses of upadacitinib 15 mg 
or upadacitinib 30 mg.
At the Screening Visit, all subjects will be assigned a unique subject number through the use of the IRT.  
For subjects who do not meet the study selection criteria, the site personnel must contact the IRT 
system and identify the subject as a screen failure.
Subjects who are enrolled will retain their subject number assigned at the Screening Visit throughout 
the study.  Upon receipt of study drug, the site will acknowledge receipt in the IRT system.
Contact information and user guidelines for IRT use will be provided to each site.
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 QD 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.
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 three treatment groups:  
!
Group 1:  Upadacitinib 15 mg with TCS (N = 270)
!
Group 2:  Upadacitinib 30 mg with TCS (N = 270)
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!
Group 3:  Placebo with TCS (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 with TCS
!
Group 2:  Upadacitinib 30 mg with TCS
!
Group 3:  Placebo with TCS
For the main study, randomization will be stratified by baseline disease severity (moderate [vIGA-AD = 3] 
versus 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]).  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 with TCS
!
Group 5:  Upadacitinib 30 mg with TCS
For the main study, the re-randomization will be stratified by EASI 50 responder (Yes/No), 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]).  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 
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 51 subjects (17 subjects per group), with a target enrollment of 
approximately 30 to 51 subjects (10 to 17 subjects per group).
Enrollment in China will be capped at 51 subjects (17 subjects per group), with a target enrollment of 
approximately 30 to 51 subjects (10 to 17 subjects per group).
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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 AESIs 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 MD, we request that the 
AbbVie TA MD 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.
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), 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.
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 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 
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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 as a consequence 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.
Screening and Rescreening 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 Appendix D.  Laboratory values can be retested once during the screening period.  If the retested lab 
value(s) remain(s) exclusionary, the subject will be considered a 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 rescreen once following reconsent.  For 
additional rescreening, AbbVie TA MD/Scientific Director approval is required.  As appropriate, sites are 
encouraged to contact the AbbVie TA MD/Scientific Director to confirm if subjects should or should not 
be rescreened.  All screening procedures with the possible exceptions noted below will be repeated 
during rescreening.  The subject must meet all the eligibility criteria at the time of rescreening in order 
to qualify for the study.  There is no minimum period of time a subject must wait to rescreen 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 rescreening, provided the conditions noted in the 
Section 5.1 (Eligibility Criteria) are met, there are no changes in the subject's medical history that would 
warrant retesting, 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 purified protein derivative (PPD) skin test, if required) 
!
Chest x-ray 
!
ECG
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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.  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 BCG 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.
!
For subjects with HBs Ab positive (+) and/or HBc Ab positive (+) and negative HBV DNA at 
Screening, HBV DNA polymerase chain reaction 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 1 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 international normalized ratio 
(INR) > 1.5 OR
!
ALT or AST > 3 × ULN along with clinical signs of possible hepatitis.
In China, 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 particule 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.
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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
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).  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.
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.
Subjects will complete the following questionnaires (where applicable) below as specified in Appendix D.  
Worst Pruritus NRS, ADerm-SS daily items, ADerm-IS daily items, ADerm-SS weekly items, ADerm-IS 
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weekly items, SCORAD, POEM, PGIS, PGIC, PGIT, CDLQI, DLQI, EQ-5D-5L, HADS, WPAI, and DIS should be 
administered before any study procedures in the order listed.
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.
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 
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 3 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.
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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 Visual Analog Scale (VAS) on 
the electronic 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 electronic tablet at site 
visits throughout the study.  SCORAD components A and B will not be on the electronic tablet and 
performed on paper worksheets and manually 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.
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.  
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 AD 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.  
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 
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AD?"  Responses range from 1 = "Extremely dissatisfied" to 7 = "Extremely satisfied."  The PGIT will be 
administered on the tablet at site visits throughout the study.  
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.  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 minimum clinically important difference (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.
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 to 16 years old.  It consists of 10 questions assessing impact of skin diseases on different 
aspects of subject'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.  Throughout 
this study, the CDLQI will be administered to subjects who are < 16 (12 to 15) years old at the time of 
the Screening Visit, and will continue to be administered to these subjects for the duration of this 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 
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, VAS 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.
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Hospital Anxiety and Depression 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 4 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 10 to 
arrive at a percentage.  The WPAI:AD will be administered on the tablet at site visits throughout the 
study.
Dermatologic Intimacy Scale (DIS)
The DIS includes 18 questions that measure the impact of skin disease on intimacy over the past 
2 weeks.  Responses are quantified using a 5-point Likert scale (0 – not at all, 1 – somewhat, 2 –
moderately, 3 – much and 4 – very much).  Scores can range from 0 to 72; a higher score represents 
greater intimacy impairment, calculated as the sum of all item responses.  The DIS will be administered 
on the tablet at site visits throughout the study.  Throughout this study, the DIS will be administered to 
subjects who are ≥ 18 years old at the time of the Screening Visit.
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).
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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"
(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 5 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 Reported Outcomes.
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 Tdap.
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.
See Section 5.3 (Prohibited Medications and Therapy) for a list of commonly used live vaccines that are 
prohibited during study participation.
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.
Tuberculosis Testing
The TB tests provide 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.  Expert consultation for the evaluation and/or management of 
TB may be considered per investigator discretion.
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At Screening, all subjects will be assessed for evidence of increased risk for TB by a risk assessment form 
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).  The site staff will complete the TB risk assessment form and enter the 
data into the appropriate eCRF.  The TB test and latent 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 
MD.  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.
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.
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.
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!
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 
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.
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.
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Chest X-Ray
CXR (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 chest x-ray 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.
!
Annually after Week 52 for subjects with newly identified TB risk factors as identified by the TB 
risk assessment form, 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).
Subjects can have a repeat CXR 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 CXR.  
The Principal Investigator will indicate the clinical significance of any findings and will sign and date the 
report.  In the assessment of the CXR, 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 CXR 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
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. 
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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
Tanner Staging (also known as the Tanner Scale) is a validated measure used in clinical practice and 
clinical trials to assess physical development.  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 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.
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.
Clinical Laboratory Tests
Blood and urine samples will be collected following a minimum 8-hour fast.  If a subject is not able to 
fast when necessary (except during Screening Visit), the non-fasting status will be recorded in study 
source documentation.
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.  
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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
Serum pregnancy test
HBs Ag
HBs Ab
HBc Ab
HBV DNA PCR reflex only
HCV Ab
HCV RNA reflex only
HIV
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; 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 for female subjects ≤ 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 per local/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 postbaseline 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 must be discontinued;
!
Negative, the subject can continue in the trial;
!
Still borderline ≥ 3 days later, this will be considered documentation of continued lack of a 
positive result and the subject can continue in the study (unless prohibited locally) 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:
!
hepatitis B surface antigen (HBs Ag)
!
hepatitis B core antibodies (HBc Ab)/anti-hepatitis B core antibodies (HBc) 
!
hepatitis B surface antibody (HBs Ab)/anti-hepatitis B surface antibody (HBs) 
A positive result for HBs Ag will be exclusionary.
A negative result for HBs Ag will trigger 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 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, the HBV DNA PCR qualitative testing is not required 
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 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.
!
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; 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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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.
Discontinuation of Study Drug and Subject Withdrawal from 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 or not 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 Appendix D, and adhere to all study 
procedures except for dispensing study drug and PK sample collection.  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.
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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.
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 of 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.
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 
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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 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 
(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.
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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.
AbbVie will be responsible for Suspected Unexpected Serious Adverse Reaction (SUSAR) 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.
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Adverse Events of Special Interest
The following AESIs 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 
!
Adjudicated embolic and thrombotic events (non-cardiac, non-central nervous system)
Adverse Event Severity and Relationship to Study Drug
The investigators will rate the severity of each AE according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events version 5.0.
If no grading criteria are provided for the reported event, then the event should be graded 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)
Severe (Grade 3 to 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:
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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 or a serious opportunistic 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.  If the diagnosis of GI perforation is confirmed, the subject 
must be 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 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.
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 the 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 5 and may require a supplemental eCRF 
to be completed (see Section 6.1 [Complaints and Adverse Events]).  All abnormal laboratory tests that 
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are considered clinically significant by the investigator will be followed to a satisfactory resolution.  If a 
repeat test is required per Table 5, the repeat testing must occur as soon as possible.
Table 5.
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 a 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, 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.
!
Discontinue study drug if confirmed < 500/μL by repeat testing with new 
sample.
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 appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, and/or 
eosinophilia (> 5% increase from baseline). 
!
Interrupt study drug if confirmed ALT or AST > 8 × ULN by repeat 
testing with new sample.
!
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:
!
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.  The investigator should contact the AbbVie TA MD to discuss the 
management of a subject when an alternative etiology has been determined.  
The alternative etiology should be documented appropriately in the eCRF; 
study drug should be discontinued if no alternative etiology can be found.  For 
any confirmed ALT or AST elevations > 3 ULN, complete the appropriate 
supplemental hepatic eCRFs.
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 x baseline value and ≤ ULN.
!
If confirmed serum creatinine ≥ 2 mg/dL, interrupt study drug and re-start 
study drug once serum creatinine returns to normal reference range or its 
baseline value. 
For the above serum creatinine elevation scenarios, complete the appropriate 
supplemental renal eCRFs.
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Laboratory Parameter
Toxicity Management Guideline
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.
Ab = antibody; ALC = absolute lymphocyte counts; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
CPK = creatine phosphokinase; DNA = deoxyribonucleic acid; eCRF = electronic case report form; HB = hepatitis B; 
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 CAC 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 AD should be reported as an AE.
6.5 SUSAR Reporting
AbbVie will be responsible for SUSAR reporting for the 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 reporting period serves as 
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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 assess the efficacy and safety of upadacitinib combined 
with TCS 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.  Upadacitinib group refers to the upadacitinib with TCS, and placebo group refers 
to placebo with TCS.
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.  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.
!
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.
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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:
!
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.
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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 versus 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 the continuous variables.  This handling also will be applied 
to selective additional endpoints (i.e., primary and key secondary variables evaluated at visits from 
Week 16 to Week 52) in the Blinded Extension Period.
Assessments of long-term efficacy (across the DB Period and the Blinded Extension Period) for subjects 
who stay on treatment will also 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.
Primary Analysis of Efficacy
The co-primary endpoints for the Primary Analysis of 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 
versus 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 15 mg with 
concomitant use of TCS, upadacitinib 30 mg with concomitant use of TCS, or placebo with concomitant 
use of TCS in a ratio of 1:1:1 in the main study (270 subjects per treatment group).  The sample size is 
determined by the regulatory requirement to adequately characterize the safety profile.  Assuming an 
EASI 75 response rate of 24%, and vIGA-AD 0 or 1 with at least a 2-point reduction response rate of 13% 
in the topical treatment with placebo arm, this sample size will also provide more than 90% power to 
detect the treatment differences of 38% and 20%, respectively, in the above two endpoints 
simultaneously using two-sided test at a 0.05 significant level.  The assumptions of placebo response 
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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), adding the estimation of 
topical treatment effect which is also based on the difference between the mono- and combo-therapy 
(CHRONOS) studies in dupilumab.  The graphic approach for controlling multiplicity will be outlined in 
the SAP.
Additional adolescent subjects will be enrolled in the adolescent sub-study and randomized to 
upadacitinib 15 mg with concomitant use of TCS, upadacitinib 30 mg with concomitant use of TCS, or 
placebo with concomitant use of TCS 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.
Adverse events 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 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, and 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 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 nonlinear mixed-effects modeling approach with NONMEM software (Version 7, or a higher 
version).  The structure of the starting PK model will be based on the PK analysis 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 
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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 nonlinear 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 nonlinear relationships of primary PK parameters with various covariates will be explored.  
For the same subjects from whom the PK data 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 PK 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 clinical study report.
Additional analyses will be performed if useful and appropriate.
7.6 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.
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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.
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.
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 
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are accurate, complete, and verifiable, and 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).
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 PRO design will be conducted and maintained at AbbVie.
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 
(Individual Treatment Period Visit Activities).  The ePRO data of CDLQI, DLQI, HADS, POEM, PGIS, PGIT, 
PGIC, EQ-5D-5L, WPAI:AD, DIS, 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 (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.
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
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Genovese MC, Smolen JS, Weinblatt ME, et al.  Efficacy and Safety of ABT-494, a Selective JAK-1 
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Response to Methotrexate.  Arthritis Rheumatol.  2016;68(12):2857-66.
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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 
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Genovese MC, Fleischmann R, Combe B, et al.  Safety and efficacy of upadacitinib in patients 
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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 Online.  2018;391(10139):2503-12.
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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.
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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.
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Blauvelt A, de Bruin Weller M, Gooderham M, et al.  Long term management of moderate to 
severe atopic dermatitis with dupilumab and concomitant topical corticosteroid (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 Yaasky 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 [package insert].  Tarrytown, NY; Regeneron Pharmaceuticals, Inc, 2017.
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 Brochure Edition 10.  19 August 2019.
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CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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 AP, 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. Eichenfield LF, Tom WL, Chamlin SL, et al.  Guidelines of care for the management of atopic 
dermatitis:  Section 1.  Diagnosis and assessment of atopic dermatitis.  J Am Acad Dermatol.  
2014;70(2):338-51.
18. 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.
19. 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.
20. Ring J, Alomar A, Bieber T, et al.  Guidelines for treatment of atopic eczema (atopic dermatitis) 
Part II.  J Eur Acad Dermatol Venereol.  2012;26(9):1176-93.
21. 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.
22. Holford N, Heo Y-A, Anderson B.  A pharmacokinetic standard for babies and adults.  J Pharm Sci.  
2013;102(9):2941-52.
23. Hanifin JM, Rajka G.  Diagnostic features of atopic dermatitis.  Acta Derm Venereol Suppl 
(Stockh).  1980;92:44-7.
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APPENDIX A. STUDY SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
Ab
Antibody
AD
Alzheimer disease
ADerm-IS
Atopic Dermatitis Impact Scale
ADerm-SS
Atopic Dermatitis Symptom Scale
AE(s)
adverse event(s)
AESI
adverse events of special interest
ALC
Absolute lymphocyte counts
ALT
alanine aminotransferase
ANC
Absolute neutrophil count
AST
aspartate aminotransferase
BCG
bacilli Calmette-Guérin
BSA
body surface area
CAC
Cardiovascular Adjudication Committee
CD
Crohn's disease
CDLQI
Children's Dermatology Life Quality Index
CL/F
oral clearance
CMH
Cochran-Mantel-Haenszel
CRF
case report form
CXR
chest x-ray
CYPs
cytochrome P450s
DB Period
double-blind treatment period
DIS
Dermatologic Intimacy Scale
DLQI
Dermatology Life Quality Index
DMC
Data Monitoring Committee
EASI
Eczema Area and Severity Index
ECG
electrocardiogram
eCRF
electronic case report form
ePRO
Electronic Patient Reported Outcome
EQ-5D-5L
EuroQol 5 Dimensions 5 Levels
EQ-VAS
EQ visual analogue scale
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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
HBc
hepatitis B core antibodies
HBV
hepatitis B virus
HCV
hepatitis C virus
HCV Ab
hepatitis C virus antibody
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
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed effect model with repeated measures
NMSC
non-melanoma skin cancer
NRI
non-responder imputation
NRS
numerical rating scale
PCR
polymerase chain reaction
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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
PP_M
Per-Protocol Population for the main study
PRO
patient-reported outcome
PT
preferred term
QD
Once daily
QTcF
Fridericia-corrected QT interval
RA
rheumatoid arthritis
RSI
Reference Safety Information
SAE
serious adverse event
SAP
statistical analysis plan
SCORAD
Scoring atopic dermatitis
SOC
system organ class
SUSAR
Suspected Unexpected Serious Adverse Reaction
TA MD
Therapeutic Area Medical Director
TB
tuberculosis
TCI
topical calcineurin inhibitor
TCS
topical corticosteroids
TEAE
treatment-emergent adverse event
TPPA
Treponema pallidum particule agglutination assay
TRUST
Toluidine Red Unheated Serum Test
TSS-7
7-item total symptom score
TSS-11
11-item total symptom score
ULN
upper limit of normal
US
United States
UV
ultraviolet
V/F
apparent volume of distribution
vIGA-AD
validated Investigator Global Assessment for Atopic Dermatitis
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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 M16-047:  A Phase 3 Randomized, Placebo-Controlled, Double-Blind Study to Evaluate 
Upadacitinib in Combination with Topical Corticosteroids in Adolescent and Adult Subjects with 
Moderate to Severe Atopic Dermatitis
Protocol Date:  29 April 2020
Clinical research studies sponsored by AbbVie are subject to the ICH 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 IRB/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 
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.
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APPENDIX E. RELATIVE POTENCIES OF TOPICAL 
CORTICOSTEROIDS
Additionally, use of the following topical corticosteroid will be permitted:
Low potency:  prednisolone 0.5%
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APPENDIX F. PROTOCOL SUMMARY OF CHANGES
Previous Protocol Version
Protocol
Date
Version 1.0
04 May 2018
Version 1.01 VHP
20 August 2018
Version 1.02 Canada
07 August 2018
Version 2.0
18 December 2018
Administrative Change 1
30 January 2019
Version 3.0
23 July 2019
Version 4.0
02 October 2019
The purpose of this Amendment is to incorporate the following changes:
Summary of Protocol Changes:
!
Section 2.2, Benefits and Risks to Subjects:
!
Clarified the statement regarding the risk to the pregnancy of female partners of male 
subjects who are treated with upadacitinib.
Rationale:  Updated for consistency across protocols for the upadacitinib clinical program.
!
Section 3.3, Secondary Endpoints, Key Secondary Endpoints for EU/EMA and US/FDA regulatory 
purposes, the following clarification was made:
!
Added 'Worst' to Pruritus NRS endpoints.
Rationale:  Clarification.
!
Section 3.3, Secondary Endpoints, the following key secondary endpoint for EU/EMA and 
US/FDA regulatory purposes was moved to Section 3.4, Additional Endpoints:
!
Proportion of subjects achieving vIGA-AD of 0 with a reduction from Baseline of ≥2 points.
Rationale:  This endpoint was moved to additional endpoints to minimize redundancy with 
other Key Secondary Endpoints and streamline Type I Error control.
!
Section 3.4, Additional Endpoints, the following clarifications were made:
!
MCID estimates were added for ADerm-SS/IS endpoints.
Rationale:  To pre-specify the thresholds for the minimal clinically important differences for 
these outcome measures.
!
Section 3.4, Additional Endpoints, the following clarifications were made:
!
Added 'for subjects with Worst Pruritus NRS > 1 at Baseline' to the Proportion of subjects 
achieving Worst Pruritus NRS of 0 or 1 endpoint.
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!
Added 'for subjects with EASI ≤ 65.4 at Baseline' to the Proportion of subjects experiencing a 
flare endpoints.
!
Added 'for subjects with ADerm-SS skin pain score > 0 at Baseline' to the Proportion of 
subjects achieving ADerm-SS skin pain score of 0 endpoint.
!
Added 'for subjects with POEM sleep item score > 0 at Baseline' to the Proportion of 
subjects achieving POEM sleep item score of 0 endpoint.
!
Added 'for subjects with DLQI score > 1 at Baseline' to the Proportion of subjects ≥16 years 
old at screening achieving DLQI score of 0/1 endpoint.
!
Added 'for subjects with CDLQI score > 1 at Baseline' to the Proportion of subjects < 16 years 
old at screening achieving Children's Dermatology life Quality Index (CDLQI) score of 0/1 
endpoint.
Rationale:  Clarification.
!
Section 3.4, Additional Endpoints, the following endpoints were added:
!
Proportion of subjects achieving EASI 50 at Week 2;
!
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;
!
Percent change in Scoring Atopic Dermatitis (SCORAD) from Baseline at Week 16;
!
Proportion of subjects achieving EASI 50;
Rationale:  It is necessary for compliance with the Paediatric Investigational Plan.
!
Section 3.4, Additional Endpoints, the following clarification was made to the Note:
"Days from the start of systemic rescue will not be considered as TCS-free days."
Rationale:  Clarification
!
Section 4.1, Overall Study Design and Plan and Section 7.1, Statistical and Analytical Plans the 
following was added:
"In addition, a Week 52 analysis of the main study will be performed after all ongoing subjects
complete the Week 52 visit."
Rationale:  Week 52 interim analysis of the main study added to the protocol to fulfill a 
regulatory requirement.
!
Section 5.1 Eligibility Criterion 10: "(refer to Section 5.10 for details)" was added.
Rationale:  Updated for consistency across protocols for the upadacitinib clinical program.
!
Section 5.1 Eligibility Criterion 23:  clarified the following 'History of gastrointestinal (GI) 
perforation (other than due to appendicitis or mechanical injury), diverticulitis or significantly 
increased risk for GI perforation per investigator judgment;'
Rationale:  Updated for consistency across protocols for the upadacitinib clinical program.
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!
Section 5.3, Prohibited Medications and Therapy, Topical Therapy subjection:
!
Revised the following statement of 'Topical anti-infectives, topical antihistamines, and 
bleach baths may be used in the first 16 weeks of the study if they were used in the 
6 months prior to the Screening visit and are allowed per investigator discretion for the 
remainder of the study.' to '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.'
Rationale:  Updated to clarify this is meant for treatments of AD.
!
Section 5.4, Prior and Concomitant Therapy, Rescue Therapy subsection:
!
Added "compared to the Baseline EASI score" to both parameters.
Rationale:  Clarification.
!
Section 5.5, Withdrawal of Subjects and Discontinuation of Study
!
Updated the study drug discontinuation criteria:
!
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.
Rationale:  Help clarify permanent discontinuation from study drug criteria.
!
Added discontinuation criterion to Section 5.5, Withdrawal of Subjects and Discontinuation of 
Study.
!
"Confirmed diagnosis of deep vein thrombosis, pulmonary embolus, or non-cardiac, 
non-neurological arterial thrombosis."
Rationale:  Added an additional safety precaution for subjects, given the recent concerns raised 
for the JAK inhibitor class regarding the risk of thromboembolic events.
!
Section 6.1, Complaints and Adverse Events, Adverse Events of Special Interest
!
Add "Active" to Tuberculosis
!
Add "Adjudicated" to Gastrointestinal perforations
Rationale:  Active TB is an identified risk for JAK inhibitors including upadacitinib.  Given the 
clinical importance of active TB, it is being monitored and managed more intensively.  
According, latent/active TB as an AESEI is changed to active TB.  GI perforation is a potential risk 
for upadacitinib therapy.  The concern of this risk is the development of spontaneous 
perforation during the therapy.  The sponsor has set up an internal adjudication process and the 
evaluation will be based on the adjudicated events.
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!
Section 6.1, Complaints and Adverse Events
!
Added the Eczema herpeticum eCRF.
Rationale:  To collect additional information in order to better characterize this event that 
occurs more often in the AD population.
!
Updated Section 6.2 Toxicity Management, Management of Thrombosis Events with the 
following:
!
"If the diagnosis of deep vein thrombosis, pulmonary embolus or non-cardiac, 
non-neurological arterial thrombosis is confirmed, the subject must be discontinued from 
study drug."
Rationale:  Added an additional safety precaution for subjects, given the recent concerns raised 
for the JAK inhibitor class regarding the risk of thromboembolic events.
!
Updated Section 6.2 Toxicity Management, Management of Thrombosis Events with the 
following:
!
Removed the Management of Muscle-Related Events statement.
Rationale:  The study is still monitoring CPK and as such this text is not required.
!
Updated Section 6.2 Toxicity Management, Table 5 Specific Toxicity Management Guidelines for 
Abnormal Laboratory Values, AST or ALT parameter column.
!
Clarified toxicity management criteria related to ALT and AST.
!
Added abbreviations to the bottom of the table.
Rationale:  Clarification.
!
Updated Section 7.1, Statistical and Analytical Plans: Add additional analysis at Week 52 for 
main study to support the regulatory submission and add the further clarification when to have 
the primary analysis of adolescent sub study.
Rationale: Clarification.
!
Updated Section 7.3, Statistical Analyses for Efficacy: 1) Clarify the stratification factors in the 
analysis of main study and the analysis of adolescent. 2) Clarify that the primary analysis of 
efficacy will be conducted in the ITT_M Population.
Rationale: Clarification.
In addition to these modifications, this Amendment contains the following minor changes:
!
Minor text edits as needed for consistency and clarity.
!
Added abbreviations under Table 5.
!
Updated list of protocol signatures.
Summary of Operations Manual Changes:
None.
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APPENDIX G. OPERATIONS MANUAL
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-047 Version 5.0
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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
Office:
Mobile:
Email:
Safety Concerns
Immunology Safety Team
Dept. R48S, Bldg. AP31-2
1 North Waukegan Road
North Chicago, IL 60064
Phone:
+1 (847) 938-8737
Email:
GPRD_SafetyManagement_Immunology@abbvie.com
SAE Reporting 
outside of RAVE
Email:
PPDINDPharmacovigilance@abbvie.com
Fax:
+1 (847) 938-0660
Protocol 
Deviations
AbbVie Inc.
1 North Waukegan Road
North Chicago, IL 60064
Office:
Mobile:
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
Email:
sample.receiving@abbvie.com
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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
18
3.1
STUDY SPECIFIC ABBREVIATIONS AND TERMS
18
3.2
PRURITUS (ITCH) NUMERICAL RATING SCALE (NRS) EXAMPLE
19
3.3
ATOPIC DERMATITIS SYMPTOM SCALE (ADERM-SS) QUESTIONNAIRE EXAMPLE
20
3.4
ATOPIC DERMATITIS IMPACT SCALE (ADERM-IS) QUESTIONNAIRE EXAMPLE
22
3.5
SCORING ATOPIC DERMATITIS (SCORAD) EXAMPLE
24
3.6
PATIENT ORIENTED ECZEMA MEASURE (POEM) EXAMPLE
25
3.7
PATIENT GLOBAL IMPRESSION OF SEVERITY (PGIS) QUESTIONNAIRE EXAMPLE
27
3.8
PATIENT GLOBAL IMPRESSION OF CHANGE (PGIC) QUESTIONNAIRE EXAMPLE
28
3.9
PATIENT GLOBAL IMPRESSION OF TREATMENT (PGIT) QUESTIONNAIRE EXAMPLE
29
3.10 DERMATOLOGY LIFE QUALITY (DLQI) EXAMPLE
30
3.11 CHILDREN'S DERMATOLOGY LIFE QUALITY INDEX (CDLQI) EXAMPLE
31
3.12 EUROQOL DIMENSIONS 5 LEVELS (EQ-5D-5L) EXAMPLE
32
3.13 HOSPITAL ANXIETY AND DEPRESSION SCALE (HADS)
33
3.14 WORK PRODUCTIVITY AND ACTIVITY IMPAIRMENT QUESTIONNAIRE:  ATOPIC DERMATITIS (WPAI:AD)
V2.0
35
3.15 DERMATOLOGIC INTIMACY SCALE (DIS) EXAMPLE
37
3.16 VALIDATED INVESTIGATOR'S GLOBAL ASSESSMENT FOR ATOPIC DERMATITIS (VIGA-AD) EXAMPLE
38
3.17 ECZEMA AREA AND SEVERITY INDEX (EASI) SCORING EXAMPLE
39
3.18 TB RISK ASSESSMENT FORM EXAMPLE
41
3.19 TANNER STAGING EXAMPLE
42
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-047 Version 5.0
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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
DIS
Dermatologic Intimacy Scale
DLQI
Dermatology Life Quality Index
DNA
Deoxyribonucleic acid
EASI
Eczema Area and Severity Index
EQ-5D-5L
EuroQol Dimensions 5 Levels
HADS
Hospital Anxiety and Depression Scale
NRS
Numerical Rating Scale
PGIC
Patient Global Impression of Change
PGIS
Patient Global Impression of Severity
PGIT
Patient Global Impression of Treatment
POEM
Patient-oriented Eczema Measure
SCORAD
Scoring atopic dermatitis
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 SCORING ATOPIC DERMATITIS (SCORAD) EXAMPLE
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3.6 PATIENT ORIENTED ECZEMA MEASURE (POEM) EXAMPLE
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3.7 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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3.8 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
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3.9 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
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3.10 DERMATOLOGY LIFE QUALITY (DLQI) EXAMPLE
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3.11 CHILDREN'S DERMATOLOGY LIFE QUALITY INDEX (CDLQI) 
EXAMPLE
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3.12 EUROQOL DIMENSIONS 5 LEVELS (EQ-5D-5L) EXAMPLE
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3.13 HOSPITAL ANXIETY AND DEPRESSION SCALE (HADS)
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3.14 WORK PRODUCTIVITY AND ACTIVITY IMPAIRMENT 
QUESTIONNAIRE:  ATOPIC DERMATITIS (WPAI:AD) V2.0
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?  
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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 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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3.15 DERMATOLOGIC INTIMACY SCALE (DIS) EXAMPLE
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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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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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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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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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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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