Conditions: Atopic Dermatitis
Keywords: Atopic Dermatitis (AD) Upadacitinib RINVOQ
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 461
Healthy volunteers: no

Brief summary:
Atopic dermatitis (AD) is a skin condition that may cause a rash and itching due to inflammation of the skin. Therapies spread over the skin may not be enough to control the AD in trial participants who require systemic anti-inflammatory treatment. This study evaluates the dosing flexibility of upadacitinib in adult participants with moderate to severe AD. Adverse events and change in the disease activity will be assessed.

Upadacitinib is an approved drug for the treatment of moderate to severe/active immune-mediated inflammatory diseases such as rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis (UC), Crohn's Disease (CD), and AD. The study is comprised of a 35-day Screening Period, a 12-week double-blind period and a 12-week single-blind period. During the double-blind period, participants are placed in 1 of 2 groups, called treatment arms and will be randomized in a 1:1 ratio to receive upadacitinib. At 12 weeks during the single blind period, participants will be blinded to the upadacitinib dose based on their EASI response and reassigned to in 1 of 4 arms. After the last study visit, there is a 30-day follow-up visit. Approximately 454 adult participants ages 18 to 64 with moderate to severe AD who are candidates for systemic therapy will be enrolled at up to 160 sites worldwide.

The study is comprised of a 12-week double-blind period, followed by a 12-week single-blind period. Participants will receive upadacitinib oral tablets once daily for up to 24 weeks.

There may be higher treatment burden for participants in this trial compared to their standard of care (due to study procedures). Participants will attend regular visits during the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests, checking for side effects and completing questionnaires.

Detailed description:

Arms:
arm 1: Participants received 15 mg upadacitinib orally once daily (QD) for 12 weeks during the Double-Blind Treatment Period. arm 2: Participants received 30 mg upadacitinib orally once daily (QD) for 12 weeks during the Double-Blind Treatment Period. arm 3: At Week 12 in the Double-Blind Treatment Period, participants receiving 15 mg upadacitinib orally once daily (QD) achieving a ≥ 90% reduction in the Eczema Area and Severity Index (EASI) (≥ EASI 90) were allocated to receive 15 mg upadacitinib orally once daily (QD) for 12 weeks during the Single-Blind Treatment Period. arm 4: At Week 12 in the Double-Blind Treatment Period, participants receiving 15 mg upadacitinib orally once daily (QD) achieving a \< 90% reduction in the Eczema Area and Severity Index (EASI) (\< EASI 90) were allocated to receive 30 mg upadacitinib orally once daily (QD) for 12 weeks during the Single-Blind Treatment Period. arm 5: At Week 12 in the Double-Blind Treatment Period, participants receiving 30 mg upadacitinib orally once daily (QD) achieving a ≥ 90% reduction in the Eczema Area and Severity Index (EASI) (≥ EASI 90) were allocated to receive 15 mg upadacitinib orally once daily (QD) for 12 weeks during the Single-Blind Treatment Period. arm 6: At Week 12 in the Double-Blind Treatment Period, participants receiving 30 mg upadacitinib orally once daily (QD) achieving a \< 90% reduction in the Eczema Area and Severity Index (EASI) (\< EASI 90) were allocated to receive 30 mg upadacitinib orally once daily (QD) for 12 weeks during the Single-Blind Treatment Period.

Interventions: intervention 1: Upadacitinib
Intervention descriptions: intervention 1: Oral tablet

Protocol document:
Prot_000.pdf: 


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TABLE OF CONTENTS
1
SYNOPSIS
5
2
INTRODUCTION
9
2.1
BACKGROUND AND RATIONALE
9
2.2
BENEFITS AND RISKS TO SUBJECTS
10
3
OBJECTIVES AND ENDPOINTS
11
3.1
OBJECTIVES, HYPOTHESES, AND ESTIMANDS
11
3.2
PRIMARY ENDPOINT(S)
12
3.3
SECONDARY ENDPOINT(S)
12
3.4
ADDITIONAL EFFICACY ENDPOINTS
13
3.5
SAFETY ENDPOINTS
15
3.6
BIOMARKER RESEARCH ENDPOINTS
15
4
INVESTIGATIONAL PLAN
15
4.1
OVERALL STUDY DESIGN AND PLAN
15
4.2
DISCUSSION OF STUDY DESIGN
17
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
27
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
29
5.6
FOLLOW-UP AFTER SUBJECT DISCONTINUATION OF STUDY DRUG OR FROM STUDY
31
5.7
STUDY DRUG
32
5.8
RANDOMIZATION/DRUG ASSIGNMENT
33
5.9
PROTOCOL DEVIATIONS
34
5.10 DATA MONITORING COMMITTEE
34
5.11 PUBLICATION POLICY
34
5.12 PAPER DIARY CARDS FOR SITES IN CHINA ONLY
35
6
SAFETY CONSIDERATIONS
35
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6.1
COMPLAINTS AND ADVERSE EVENTS
35
6.2
TOXICITY MANAGEMENT
41
6.3
OTHER SAFETY DATA COLLECTION
44
7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
44
7.1
STATISTICAL AND ANALYTICAL PLANS
44
7.2
DEFINITION FOR ANALYSIS POPULATIONS
45
7.3
HANDLING POTENTIAL INTERCURRENT EVENTS FOR THE PRIMARY AND SECONDARY ENDPOINTS
45
7.4
STATISTICAL ANALYSES FOR EFFICACY
45
7.5
STATISTICAL ANALYSES FOR SAFETY
46
7.6
SAMPLE SIZE DETERMINATION
47
8
ETHICS
47
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD (IEC/IRB)
47
8.2
ETHICAL CONDUCT OF THE STUDY
47
8.3
SUBJECT CONFIDENTIALITY
48
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
48
10 DATA QUALITY ASSURANCE
48
11 START AND COMPLETION OF THE STUDY
49
12 REFERENCES
49
LIST OF TABLES
TABLE 1.
EXAMPLES OF COMMONLY USED STRONG CYP3A INHIBITORS AND INDUCERS
26
TABLE 2.
DESCRIPTION OF STUDY DRUG
32
TABLE 3.
SPECIFIC TOXICITY MANAGEMENT GUIDELINES FOR ABNORMAL LABORATORY VALUES
42
LIST OF FIGURES
FIGURE 1.
STUDY SCHEMATIC
17
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LIST OF APPENDICES
APPENDIX A.
STUDY-SPECIFIC ABBREVIATIONS AND TERMS
51
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
55
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
56
APPENDIX D.
ACTIVITY SCHEDULE
57
APPENDIX E.
PROTOCOL SUMMARY OF CHANGES
61
APPENDIX F.
OPERATIONS MANUAL
64
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2 INTRODUCTION
2.1 Background and Rationale
Why Is This Study Being Conducted?
The Janus kinase (JAK) or JAKs are a family of intracellular tyrosine kinases that function as dimers in the 
signaling process of many cytokine receptors.1  The JAKs play a critical role in both innate and adaptive 
immunity, making them attractive targets for the treatment of inflammatory diseases.2-6  Targeting the 
JAK signaling pathway for autoimmune diseases is supported by the involvement of various 
proinflammatory cytokines that signal via JAK pathways in the pathogenesis of these immune-related 
disorders.  The activation of JAK signaling initiates expression of survival factors, cytokines, chemokines, 
and other molecules that facilitate leukocyte cellular trafficking and cell proliferation, which contribute 
to inflammatory and autoimmune disorders.
Upadacitinib is an oral, once-daily, selective, and reversible small-molecule JAK inhibitor, engineered to 
have greater inhibitory potency for JAK1 versus JAK2, JAK3, and tyrosine kinase 2 (TYK2).  Janus kinase 1 
inhibition blocks the signaling of many important pro-inflammatory cytokines, including interleukin
(IL)-2, IL-6, IL-7, and IL-15, IFN-γ, which are known contributors to inflammatory disorders.  It also blocks 
the signaling of IL-4, IL-13, IL-31, IL-22, IFN-γ, TSLP cytokines that play an important role in the 
pathogenesis of atopic dermatitis (AD).
Upadacitinib has been approved for the treatment of moderate to severe/active immune-mediated 
inflammatory diseases such as rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, non-
radiographic axial spondyloarthritis, ulcerative colitis (UC), Crohn's disease (CD), and AD. 
In AD, the efficacy and safety of upadacitinib 15 mg and 30 mg once daily (QD) was assessed in three 
Phase 3 randomized, double-blind, multicentre studies (MEASURE UP 1, MEASURE UP 2 and AD UP),7,8
and the two doses (upadacitinib 15 mg and 30 mg QD) studied in the pivotal trials for AD were approved 
for the treatment of moderate to severe AD in several jurisdictions, including but not limited to the 
European Union, Japan, Canada, and the United States.9  However, the Phase 3 studies for AD were 
designed with a stable regimen of upadacitinib 15 mg or 30 mg QD for 5 years and no dose escalation or 
dose reduction were assessed. 
Regarding treatment targets in AD, an extensive group of experienced dermatologists have been 
working to develop optimized and practical criteria for identifying patients who should receive systemic 
therapy, including definitions of treatment goals, treatment failure, and disease severity following a 
modified eDelphi methodology and expert recommendation.  As a result of this work, a new minimal 
disease activity (MDA) concept and criteria and consensus-based recommendations for optimizing the 
management of AD has been recently published and communicated to the scientific community.10  
Following this new concept, different treatment targets based on the achievement of different 
outcomes measures are categorized as "moderate" and "optimal" targets and the achievement of 
"optimal" targets is defined as MDA.  Physicians and patients/caregivers should aim for optimal 
treatment targets to optimize disease control and patient outcomes when possible.  In terms of Eczema 
Area and Severity Index (EASI) score, EASI 90 (or absolute EASI ≤ 3) is the optimal target to achieve.
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This study aims to provide descriptive data on the efficacy and safety of dose escalation to upadacitinib 
30 mg QD and dose reduction to upadacitinib 15 mg QD based on a clinical response target (EASI 90)
after 12 weeks of treatment.  This data will inform the clinical management for subjects with moderate 
to severe AD treated with both approved doses of upadacitinib.
2.2 Benefits and Risks to Subjects
In the EU SmPC, upadacitinib has been approved for the treatment of moderate to severe AD in adults 
and adolescents 12 years and older who are candidates for systemic therapy.9
In adults, the recommended dose of upadacitinib is 15 mg or 30 mg QD based on individual patient 
presentation.  A dose of 15 mg is recommended for patients at higher risk of venous thromboembolism, 
major adverse cardiovascular events (MACE), and malignancy.  A dose of 30 mg may be appropriate for 
patients with high disease burden who are not at higher risk of venous thromboembolism, MACE, and 
malignancy or patients with an inadequate response to 15 mg.  The lowest effective dose to maintain 
response should be used.9
For patients ≥ 65 years of age the recommended dose is upadacitinib 15 mg QD.9  The above indication 
and posology correspond to the European Union and may vary within different jurisdictions.
The efficacy and safety of upadacitinib 15 mg and 30 mg QD was assessed in 3 Phase 3 randomized, 
double-blind, multicentre studies (MEASURE UP 1, MEASURE UP 2 and AD UP)7,8 in a total of 
2584 subjects (12 years of age and older).  A significantly greater proportion of subjects treated with 
upadacitinib 15 mg or 30 mg QD achieved validated Investigator´s Global Assessment for AD (vIGA-AD) 0 
or 1, EASI 75, EASI 90, EASI 100, Dermatology Life Quality Index (DLQI) 0 or 1, or a ≥4-point 
improvement on the Worst Pruritus Numerical Rating Scale (NRS) compared to placebo at Week 16.  
Rapid improvements in skin clearance and itch were also achieved.  Results at Week 16 were maintained 
through Week 52 in subjects treated with upadacitinib 15 mg or 30 mg QD.
Adverse events (AEs) such as infections including herpes zoster, major adverse cardiovascular events 
(MACE defined as cardiovascular death, non-fatal myocardial infarctions and non-fatal strokes), 
thrombosis, malignancies, hypersensitivity (serious anaphylactic reaction and angioedema), 
gastrointestinal perforation, bone fractures, and some laboratory abnormalities have been observed in 
patients receiving JAK inhibitors including upadacitinib.
An increased risk of infection including opportunistic infections (e.g., mucosal candida infections) and 
herpes zoster, non-melanoma skin cancer (NMSC), and abnormal laboratory changes have been 
observed (e.g., elevations of serum transaminases, lipids, creatine phosphokinase [CPK], and reductions 
in hemoglobin and neutrophils with upadacitinib therapy. 
In ORAL Surveillance, a post-approval safety study in RA patients 50 years of age and older with at least 
1 cardiovascular risk factor, higher rates of malignancies (excluding NMSC), MACE (cardiovascular death, 
myocardial infarction, and stroke), thrombosis (overall thrombosis, deep vein thrombosis [DVT], and 
pulmonary embolism), and all-cause mortality were seen with a different JAK inhibitor, tofacitinib, 
versus TNF blockers.11  These higher rates were primarily observed in patients 65 years of age and older, 
patients with a history of atherosclerotic cardiovascular disease, and patients with other cardiovascular 
risk factors (such as current or past long-time smokers).  Although upadacitinib clinical trial data to date 
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have not indicated a higher risk for MACE, venous thromboembolism, malignancies excluding NMSC, or 
deaths in RA patients treated with upadacitinib versus adalimumab, the findings of the ORAL 
Surveillance study may potentially also apply to other JAK inhibitors and an increased risk for these 
events compared to TNF blockers cannot be completely excluded.  Therefore, the investigator should 
consider the benefits and risks of upadacitinib treatment and suitable treatment alternatives in 
determining study participation and the continued use of upadacitinib in patients 65 years of age and 
older, patients with a history of atherosclerotic cardiovascular disease or other cardiovascular risk 
factors, patients who are current or past long-time smokers, and/or patients with other malignancy risk 
factors (e.g., current malignancy or history of malignancy).
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.
A detailed discussion of the pre-clinical and clinical toxicology, metabolism, pharmacology, and safety 
experience with upadacitinib can be found in the current Investigator's Brochure.
Taken together, the safety and efficacy data from upadacitinib studies to date show a favorable 
benefit:risk profile for upadacitinib and support the continued investigation of upadacitinib in patients 
with various immune-mediated inflammatory conditions.
The benefit:risk profile of various immunomodulatory therapies on COVID-19 is being evaluated. At this
time, the effects of upadacitinib on the course of COVID-19 are not well defined.  For further details, 
please see findings from completed studies, including safety data in the current upadacitinib 
Investigator's Brochure.
3 OBJECTIVES AND ENDPOINTS
3.1 Objectives, Hypotheses, and Estimands
Primary Objective
The primary study objectives are: 
1.
Sub-Study 1 (SS1):  The primary study objective for SS1 is to evaluate the efficacy and safety of 
dose escalation to upadacitinib 30 mg QD in subjects who do not achieve EASI 90 on 
upadacitinib 15 mg QD after 12 weeks.
2.
Sub-Study 2 (SS2):  The primary study objective for SS2 is to evaluate the efficacy and safety of 
dose reduction to upadacitinib 15 mg QD in subjects who achieve EASI 90 on upadacitinib 30 mg 
QD after 12 weeks.
No hypothesis testing will be performed in this study.
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The estimand corresponding to the primary endpoint is defined as:

The proportion of subjects who achieve EASI 90 at Week 24, regardless of treatment 
discontinuation, with upadacitinib treatments (upadacitinib 15 mg or 30 mg QD) in adult 
subjects with moderate to severe AD.
Additional Objective

To generate evidence on patient impact (patient reported outcomes [PROs]) with upadacitinib 
treatment based on a clinical response target (EASI 90) (Treat-to-Target).
This study will generate descriptive data that will provide information regarding:

Efficacy and safety of dose escalation to upadacitinib 30 mg QD in subjects that did not achieve 
EASI 90 on upadacitinib 15 mg QD after 12 weeks.

Efficacy and safety of dose reduction to upadacitinib 15 mg QD in subjects that achieve EASI 90 
on upadacitinib 30 mg QD after 12 weeks.

The effect of a treat-to-target approach based on EASI 90 response for subjects' reported itch, 
sleep, emotional health, and quality of life [QoL].
3.2 Primary Endpoint(s)
The primary endpoint is:

Achievement of EASI 90 at Week 24.
3.3 Secondary Endpoint(s)
The secondary endpoints are:

Achievement of EASI 75 / 100 at Week 24.

Achievement of EASI 75 / 90 / 100 at Week 12.

Achievement of EASI 90 and a Worst Pruritus NRS of 0 or 1 for subjects with Worst Pruritus NRS 
> 1 at Baseline at Week 12 and Week 24.

Achievement of a vIGA-AD of 0 or 1 at Week 12.

Achievement of vIGA-AD of 0 or 1 at Week 24.

Achievement of an improvement (reduction) in Worst Pruritus NRS ≥ 4 for subjects with Worst 
Pruritus NRS ≥ 4 at Baseline at Week 12. 

Achievement of an improvement (reduction) in Worst Pruritus NRS ≥ 4 for subjects with Worst 
Pruritus NRS ≥ 4 at Baseline at Week 24.
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
Achievement of Worst Pruritus NRS of 0 or 1 for subjects with Worst Pruritus NRS > 1 at Baseline 
at Week 12.

Achievement of Worst Pruritus NRS of 0 or 1 for subjects with Worst Pruritus NRS > 1 at Baseline 
at Week 24.

Achievement of an improvement (reduction) from Baseline in DLQI ≥ 4 for subjects with DLQI ≥ 4 
at Baseline at Week 12. 

Achievement of an improvement (reduction) from Baseline in DLQI ≥ 4 for subjects with DLQI ≥ 4 
at Baseline at Week 24.

Achievement of DLQI 0/1 for subjects with DLQI > 1 at Baseline at Week 12.

Achievement of DLQI 0/1 for subjects with DLQI > 1 at Baseline at Week 24.
3.4 Additional Efficacy Endpoints
All variables listed as primary or secondary endpoints will be analyzed at all applicable visits other than 
those listed above.  In addition, the following endpoints will be evaluated at all applicable visits unless 
otherwise specified.
Additional Efficacy Endpoints are:

Experience of a loss of response after Week 12 until Week 24 (defined as a loss of at least 50% 
of the EASI improvement gained from Baseline to Week 12) among subjects who had an EASI 90 
response at Week 12.

Achievement of EASI score < 7 / < 3 / < 1.

Achievement of Worst Pruritus NRS of 0 for subjects with Worst Pruritus NRS >0 at Baseline.

Achievement of an improvement (reduction) in Patient Oriented Eczema Measure (POEM) ≥ 4 
from Baseline for subjects with POEM ≥ 4 at Baseline.

Achievement of POEM ≤ 2 / = 0 for subjects with POEM > 2 / > 0 at Baseline, respectively.

Achievement of POEM Itch item score of 0 for subjects with POEM Itch item score >0 at 
Baseline.

Achievement of POEM Sleep item score of 0 for subjects with POEM Sleep item score > 0 at 
Baseline.

Change and percent change from Baseline in Patient Global Impression of Severity (PGIS).

Achievement of "Minimal" or "Absent" on the PGIS for subjects who are "Mild" or worse on the 
PGIS at Baseline.

Achievement of "Absent" on the PGIS for subjects who are "Minimal" or worse on the PGIS at 
Baseline.

Change and percent change from Baseline in Patient Global Impression of Treatment (PGIT).

Achievement of "Extremely satisfied" or "Very satisfied" on the PGIT for subjects who are 
"Somewhat satisfied" or worse on the PGIT at Baseline.
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
Achievement of "Extremely Satisfied" on the PGIT for subjects who are "Very satisfied" or worse 
on the PGIT at Baseline.

Achievement of an improvement (reduction) in Atopic Dermatitis Impact Scale (ADerm-IS) Sleep 
≥ 12 from Baseline for subjects with ADerm-IS Sleep ≥12 at Baseline.

Achievement of an improvement (reduction) in ADerm-IS Emotional State ≥ 11 from Baseline for 
subjects with ADerm-IS Emotional State ≥ 11 at Baseline.

Achievement of an improvement (reduction) in ADerm-IS Daily Activities ≥ 14 from Baseline for 
subjects with ADerm-IS Daily Activities ≥ 14 at Baseline.

Achievement of ADerm-IS Sleep ≤3 / = 0 for subjects with ADerm-IS Sleep > 3/> 0 at Baseline, 
respectively.

Achievement of ADerm-IS Daily Activities ≤2 /= 0 for subjects with ADerm-IS Daily Activities 
> 2/> 0 at Baseline, respectively.

Achievement of ADerm-IS Emotional State ≤2 / = 0 for subjects with ADerm-IS Emotional State 
> 2/> 0 at Baseline, respectively.

Achievement of an improvement (reduction) in Atopic Dermatitis Symptom Scale (ADerm-SS) 
Skin Pain ≥ 4 from Baseline for subjects with ADerm-SS Skin Pain ≥ 4 at Baseline.

Achievement of ADerm-SS Skin Pain ≤1 / = 0 for subjects with ADerm-SS Skin Pain > 1/> 0 at 
Baseline, respectively.

Achievement of an improvement (reduction) in ADerm-SS 7-item total symptom 
score (TSS-7) ≥28 from Baseline for subjects with ADerm-SS TSS-7 ≥ 28 at Baseline.

Achievement of ADerm-SS TSS-7 ≤11 / ≤1 for subjects with ADerm-SS TSS-7 > 11 / > 1 at 
Baseline, respectively.

Achievement of EASI 75 / 90, for subjects who experienced an inadequate response to previous 
treatment with dupilumab for AD as reported by the investigator

Achievement of EASI 90 and a Worst Pruritus NRS of 0 or 1, for subjects with Worst Pruritus NRS 
> 1 at Baseline and experienced an inadequate response to previous treatment with dupilumab 
for AD as reported by the investigator.

Achievement of EASI 75 / 90, for subjects who were previously treated with dupilumab for AD.

Achievement of EASI 90 and a Worst Pruritus NRS of 0 or 1, for subjects with Worst Pruritus NRS 
> 1 at Baseline and were previously treated with dupilumab for AD.

For subjects participating in the Wearable Tool Substudy:

Change from Baseline in average nightly nocturnal scratch: total scratch time and number of 
scratch events.

Change from Baseline in the following sleep parameters: total sleep time, wake after sleep 
onset, sleep efficiency, and sleep onset latency.
For PROs that are assessed daily (Worst Pruritus NRS, ADerm-SS, ADerm-IS), the associated endpoints 
will also be analyzed daily for the initial 28 days of the double-blind treatment period and the initial 
28 days of the single-blind treatment period.
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3.5 Safety Endpoints
Safety will be assessed by AE monitoring, physical examination, vital signs, and clinical laboratory testing 
during the study.  Laboratory assessments will include hematologic parameters, chemistry, liver function 
tests, and lipid parameters.
3.6 Biomarker Research Endpoints
Optional biospecimens (blood, plasma, serum, and PBMC) will be collected at specified time points 
(Appendix D) throughout the study to evaluate known and/or novel disease-related or drug-related 
biomarkers in circulation.  Types of biomarkers may include nucleic acids, proteins, lipids, and/or 
metabolites, either free or in association with particular cell types.  In addition, pharmacogenetic DNA 
samples may be collected for exploratory analysis of genetic factors contributing to disease pathology 
and subject's response to study treatment.  The biomarker research results may not be included with 
the clinical study report.  Further details regarding the biomarker research rationale and collection time 
points are located in the Operations Manual, Appendix F, Section 3.8.
No biomarker samples will be collected in China.
4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
This is a Phase 3b/4, randomized, blinded, treat-to-target, dose-flexibility, multi-center study that will 
evaluate upadacitinib, as monotherapy, in approximately 454 adult subjects (≥ 18 and < 65 years of age) 
with moderate to severe AD who are candidates for systemic therapy.
The study is comprised of a 35-day Screening Period, a 12-week double- blind period and a 12-week 
single-blind period.  During the single-blind period, subjects will be blinded to the upadacitinib dose and 
EASI score evaluations.
The study treatment duration will be 24 weeks.
After the last study visit, a 30-day follow-up visit (or phone call if a visit is not possible) will be completed 
to determine the status of any new or ongoing AEs/SAEs and concomitant medications.
Subjects who meet the eligibility criteria will be randomized in a 1:1 ratio to enter SS1 to receive oral 
doses of upadacitinib 15 mg QD at Baseline or SS2 to receive oral doses of upadacitinib 30 mg QD at 
Baseline.

SS1:

Subjects randomized to enter the SS1 at Baseline will receive oral doses of upadacitinib 
15 mg QD during the 12-week double-blind period.
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
At Week 12, subjects from SS1 receiving upadacitinib 15 mg QD will be reassigned based on 
their EASI response, which is calculated based on the observed EASI values regardless of the 
use of rescue medications:

Subjects achieving a < 90% reduction in EASI (< EASI 90) will be allocated to receive oral 
doses of upadacitinib 30 mg QD.  This constitutes the Study Cohort 1 (SC1).

Subjects achieving a ≥ 90% reduction in EASI (≥ EASI 90) will continue to receive oral 
doses of upadacitinib 15 mg QD.  This constitutes the Study Cohort 2 (SC2).

SS2:

Subjects randomized to enter SS2 at Baseline will receive oral doses of upadacitinib 30 mg 
QD during the 12-week double-blind period.

At Week 12, subjects from SS2 receiving upadacitinib 30 mg QD will be reassigned based on 
their EASI response, which is calculated based on the observed EASI values regardless of the 
use of rescue medications:

Subjects achieving < EASI 90 will continue to receive oral doses of upadacitinib 30 mg 
QD.  This constitutes the Study Cohort 3 (SC3).

Subjects achieving ≥ EASI 90 will be allocated to receive oral doses of upadacitinib 15 mg 
QD.  This constitutes the Study Cohort 4 (SC4).
The final and only database lock will occur at the end of the study.
The schematic of the study is shown in Figure 1.  Further details regarding study procedures are in the 
Operations Manual.
See Section 5 for information regarding eligibility criteria.  See also Section 5.4, Rescue Therapy for 
further details on allowed rescue.
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Figure 1.
Study Schematic
EASI = Eczema Area and Severity Index; QD = once daily; SS1 = Sub-Study 1; SS2 = Sub-Study 2; SC1 = Study Cohort 1; 
SC2 = Study Cohort 2; SC3 = Study Cohort 3; SC4 = Study Cohort 4
Note:
The study will be stratified by Baseline vIGA-AD categories (3; 4) and prior use of dupilumab (yes; no).
Wearable Tool Substudy
Subjects in select countries and sites where the digital health technology device is deployed and 
available will participate in a Wearable Tool Substudy, using ADAM (ADvanced Acousto-Mechanic) 
sensor made by Sibel Health.  Subjects participating in this substudy will wear a digital tool on the back 
of their dominant hand while sleeping for 7 nights prior to the Baseline visit, then for specified weeks 
during the study.  The tool will collect data reflecting the subject's nocturnal scratch and sleep 
parameters by Bluetooth signal to a provided tablet, which transfers the data by cellular network to a 
secure cloud-based server.  Enrollment will be capped at 90 subjects.
The ADAM Sensor, manufactured by Sibel, collects actigraphy data through raw acoustic signals and 
mechanical movement to quantify nocturnal scratch duration and intensity.  The sensor offers streaming 
ability through the mobile ADAM application and is integrated with the vendor's cloud and web 
application.  Data, which may be in raw/preliminary format, collected by the vendor, will be accessible 
to the clinical investigator.  The digital tool is for Research Use Only and will not be used for diagnosis or 
treatment.  All source data will be retained by AbbVie and the investigators per 21 CFR 312.62(b), 
812.140(a)(3), and ICH-GCP 8.1.
4.2 Discussion of Study Design
Choice of Control Group
A dose comparison concurrent control was selected for this study.
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Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  All efficacy and 
safety related measurements in this study are standard for assessing disease activity in subjects with 
moderate to severe 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.  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 more than 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 adult AD population with moderate to severe 
disease activity appropriate for systemic therapies.  Adult subjects ≥ 18 and < 65 years of age will be 
eligible for the study.
Selection of Doses in the Study
This study will evaluate two doses of upadacitinib (15 mg and 30 mg QD).
The dose selection was informed by the 2 doses (upadacitinib 15 mg and 30 mg QD) studied in the 
pivotal trials for AD and approved for the treatment of moderate to severe AD in several jurisdictions, 
including but not limited to the European Union, Japan, Canada, and United States.  Both doses showed 
a positive benefit-risk profile, and the objective of this study is to generate data that will help inform the 
more appropriate use of both approved doses.
All currently available Pharmacokinetic(s), Pharmacodynamic, Safety and Efficacy Data from upadacitinib 
studies were used to support the selection of these doses.
5 STUDY ACTIVITIES
5.1 Eligibility Criteria
Subjects must meet all of the following criteria in order to be included in the study, in consideration of 
the benefits and risks of treatment with upadacitinib (Section 2.2).  Anything other than a positive 
response to the questions below will result in exclusion from study participation.
Consent
1. Adult subjects ≥ 18 and < 65 years of age at the Screening Visit.  Subjects must be able to 
understand and willing to adhere to all protocol requirements and 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.  If the subject is 
64 years old at the Screening Visit, the subject must also not turn 65 years old at or after 
Baseline or before completing study participation.
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Atopic Dermatitis Disease History
2. Chronic AD with onset of symptoms at least 3 years prior to Baseline and subject meets 
Hanifin and Rajka criteria.
3. EASI score ≥ 16, vIGA-AD score ≥ 3 and ≥ 10% BSA of AD involvement at the Baseline Visit.
4. 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.
5. Candidate for systemic treatment defined as prior use of systemic treatment for AD, OR 
previous inadequate response to TCS, TCI or PDE-4 inhibitors, OR for whom topical treatments 
are otherwise medically inadvisable.

Subjects with a prior history of biologic use for AD (dupilumab, tralokinumab, lebrikizumab 
or nemolizumab) will be capped at 50%.
6. Wearable Tool Substudy only: Subjects must not have active AD on the back of their dominant 
hand where the tool will be worn at screening.  Subjects with this finding may participate in the 
study as a whole if all other eligibility criteria are met.
Laboratory Assessments
7. Laboratory values meeting the following criteria within the screening period prior to the 
first dose of study drug:  

Serum aspartate transaminase (AST) ≤ 2× upper limit of normal (ULN);

Serum alanine transaminase (ALT) ≤ 2 × ULN;

Estimated glomerular filtration rate (GFR) by simplified 4-variable Modification of Diet in 
Renal Disease (MDRD) formula ≥40 mL/min/1.73 m2;

Total white blood cell (WBC) count ≥2,500/µL;

Absolute neutrophil count (ANC) ≥1,200/µL;

Platelet count ≥100,000/µL;

Absolute lymphocyte count (ALC) ≥750/µL;

Hemoglobin ≥9 g/dL.
Subject History
8. Subject is judged to be in good health as determined by the Principal Investigator, based upon 
the results of medical history, laboratory profile, physical examination, and a 12-lead 
electrocardiogram (ECG) performed during Screening.  In addition, a chest x-ray (CXR) (or 
computed tomography equivalent if performed outside study setting) is required if requested 
per local guidelines and for subjects with a positive purified protein derivative (PPD) and/or 
QuantiFERON-TB Gold Plus test and/or one or more "yes" response on Part I of the Tuberculosis 
(TB) Risk Assessment Questionnaire.
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9. Subject must have no current or past history of infection including:

Two or more episodes of herpes zoster, or one or more episodes of disseminated herpes 
zoster;

One or more episodes of disseminated herpes simplex (including eczema herpeticum);

Human immunodeficiency virus (HIV) infection defined as confirmed positive anti-HIV 
antibody (HIV Ab) test;

Active TB or meet TB exclusionary parameters (specific requirements for TB testing are 
provided in the operations manual [Appendix F]);

Japan only:  Positive result of beta-D-glucan (screening for Pneumocystis jirovecii infection) 
or two consecutive indeterminate results of beta-D-glucan during the Screening Period;

Active infection(s) requiring treatment with intravenous anti-infectives within 30 days, or 
oral/intramuscular 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;

COVID-19 infection:  In subjects who tested positive for COVID, at least 5 days must have 
passed since a COVID-19 positive test result for study entry of asymptomatic subjects.  
Subjects with mild/moderate COVID-19 infection can be enrolled if fever is resolved without 
use of antipyretics for 24 hours and other symptoms improved, or if 5 days have passed 
since the COVID-19 positive test result (whichever comes last).  Subjects may be rescreened 
if judged to be in good general health, as determined by the investigator based upon the 
medical history and physical examination.
10. Subjects must not have evidence of:

Hepatitis B virus (HBV): hepatitis B surface antigen (HBs Ag) positive (+) test or detectable 
HBV deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) qualitative test for 
subjects who are hepatitis B core antibody (HBc Ab) positive (+) (and for Hepatitis B surface 
antibody positive [+] subjects where mandated by local requirements); 

Hepatitis C virus (HCV): detectable HCV ribonucleic acid (RNA) in any subject with anti-HCV 
antibody (HCV Ab).
11. Subject must not have any of the following medical diseases or disorders:

Recent (within past 6 months) cerebrovascular accident, myocardial infarction, coronary 
stenting, and aorto-coronary bypass surgery;

History of an organ transplant which requires continued immunosuppression;

Subject must not have a history of an allergic reaction or significant sensitivity to 
constituents of the study drug (and its excipients) and/or other products in the same class;

History of gastrointestinal (GI) perforation (other than due to appendicitis or mechanical 
injury), diverticulitis, or significantly increased risk for GI perforation per investigator 
judgment;
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
Conditions that could interfere with drug absorption including but not limited to short 
bowel syndrome or gastric bypass surgery; subjects with a history of gastric 
banding/segmentation are not excluded;

History of malignancy except for successfully treated non-melanoma skin cancer (NMSC) or 
localized carcinoma in situ of the cervix.
12. Subject must not have a history of clinically significant (per investigator judgment) drug or 
alcohol abuse within the last 6 months.
13. There must be no reason the investigator believes that the subject is an unsuitable 
candidate to participate in the study, receive study drug, or would be placed at risk by 
participating in the study.
14. France only:  Subjects must be registered with a social security scheme.  Subjects may not 
fall within the scope of Article L1121-6 of the French Public Health Code (persons deprived of 
their freedom further to a judicial or administrative decision, persons receiving psychiatric care, 
and persons admitted to a health and social facility for reasons unrelated to the study) or 
Article L1121-8 (adults under a legal protection order or unable to express their consent).
15. Wearable Tool Substudy only: Subjects must not have a history of pre-existing sleep 
disorders, including insomnia, obstructive sleep apnea, restless leg syndrome or currently on 
prescription sleep medications to participate in the sleep assessment portion of the study.  
Subjects with these histories may participate in the study as a whole if all other eligibility criteria 
are met.
Contraception
16. For all females of child-bearing potential (as defined in Section 5.2): must not have a positive 
serum pregnancy test at the Screening Visit and must have a negative urine pregnancy test at 
Baseline prior to the first dose of study drug (local practices may require serum pregnancy 
testing at Baseline).  Subjects with a borderline serum pregnancy test at Screening must have 
absence of clinical suspicion of pregnancy or other pathological causes of borderline results and 
a serum pregnancy test ≥3 days later to document continued lack of a positive result (unless 
prohibited by local requirements).
17. Female subjects of childbearing potential must practice at least 1 protocol-specified method 
of birth control that is effective from Study Day 1 (or earlier as defined in Section 5.2) through at 
least 30 days after the last dose of study drug (local practices may require 2 methods of birth 
control) (refer to Section 5.2 for more detail on contraception).  Female subjects of non-
childbearing potential do not need to use birth control.
18. Females must not be pregnant, breastfeeding, or considering becoming pregnant during 
the study and for approximately 30 days after the last dose of study drug.
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Prior and Concomitant Medications
19. No prior exposure to any oral or topical JAK inhibitor (including but not limited to 
upadacitinib [Rinvoq®], tofacitinib [Xeljanz®], ruxolitinib [Jakafi® or Opzelura®], baricitinib 
[Olumiant®], peficitinib [Smyraf®], abrocitinib [Cibinqo®], filgotinib [Jyseleca®], or 
deucravacitinib [Sotyktu®]).
20. Subjects must not have used the following AD treatments within the specified timeframe 
prior to Baseline Visit:

Systemic therapy for AD, including but not limited to corticosteroids, methotrexate, 
cyclosporine, azathioprine, phosphodiesterase type 4 (PDE4)- inhibitors, IFN-γ, 
mycophenolate mofetil within 3 weeks;

Topical treatments including but not limited to TCS, TCIs, or topical PDE-4 inhibitors within 
7 days;

Targeted biologic treatments within 6 weeks; or

Phototherapy treatment, laser therapy, tanning booth, or extended sun exposure that could 
affect disease severity or interfere with disease assessments within 3 weeks.
21. Subject must not have been treated with any investigational drug of chemical or biologic 
nature within a minimum of 30 days or 5 half-lives (whichever is longer) prior to the first dose of 
study drug or is currently enrolled in another interventional clinical study.
22. Subject must have no systemic use of known strong cytochrome P450 3A (CYP3A) inhibitors 
from Screening through the end of study drug administration or strong CYP3A inducers 30 days 
prior to Baseline through the end of study drug administration (refer to Table 1 in Section 5.3 for 
examples of commonly used strong CYP3A inhibitors and inducers).  Subjects may not use herbal 
therapies or other traditional medicines with unknown effects on CYP3A from Baseline through 
the end of study drug administration.
23. Subject must not have received any live vaccine with replicating potential within 28 days (or 
longer if required locally) prior to the first dose of study drug or have expected need of live 
vaccine with replicating potential during study participation including at least 30 days (or longer 
if required locally) after the last dose of study drug.  Live vaccines that are incapable of 
replicating are permitted.
5.2 Contraception Recommendations
Contraception Requirements for Females
Subjects must follow the following contraceptive guidelines as specified:
Females, Non-Childbearing Potential

Females do not need to use birth control during or following study drug treatment if considered 
of non-childbearing potential due to meeting any of the following criteria:
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1.
Premenopausal female with permanent sterility or permanent infertility due to one of the 
following:

Permanent sterility due to a hysterectomy, bilateral salpingectomy, bilateral oophorectomy.

Non-surgical permanent infertility due to Mullerian agenesis, androgen insensitivity, or 
gonadal dysgenesis; investigator discretion should be applied to determining study entry for 
these individuals.
2.
Postmenopausal female:

Age > 55 years with no menses for 12 or more months without an alternative medical cause.

Age ≤ 55 years with no menses for 12 or more months without an alternative medical cause 
AND a follicle-stimulating hormone (FSH) level > 30 IU/L.
Females, of Childbearing Potential
A female who does not meet the criteria above for females of non-childbearing potential is 
considered to be a female of childbearing potential.

Females of childbearing potential must avoid pregnancy while taking study drug and for at least 
30 days after the last dose of study drug.  Contraception methods must be continued while 
taking study drug and for at least 30 days after the last dose of study drug.  Females must 
commit to using a contraceptive method listed below that is highly effective (with a failure rate 
of < 1% per year, when used consistently and correctly):

Combined (estrogen- and progestogen-containing) hormonal birth control (oral, 
intravaginal, transdermal, injectable) associated with inhibition of ovulation initiated at least 
30 days prior to study Baseline.

Progestogen-only hormonal birth control (oral, injectable, implantable) associated with 
inhibition of ovulation initiated at least 30 days prior to study Baseline.

Bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a hysterosalpingogram 
confirms success of the procedure) (For Japan:  only bilateral tubal ligation).

Intrauterine device (IUD).

Intrauterine hormone-releasing system (IUS).

Vasectomized sexual partner (the partner has received medical confirmation of the surgical 
success of the vasectomy and is the sole sexual partner of the trial subject).

Practice true abstinence (unless not acceptable per local practices), defined as:  refraining 
from heterosexual intercourse when this is in line with the preferred and usual lifestyle of 
the subject (periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation 
methods] and withdrawal are not acceptable).
If required per local regulations, a barrier method (preferably a male condom with or without 
spermicide; other barrier methods include female condom OR cap, diaphragm or sponge with 
spermicide) should be used in addition to one of the birth control methods listed above 
(excluding true abstinence).
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Contraception recommendations related to the use of concomitant therapies prescribed per 
standard of care should be based on the local label.
Contraceptive Counseling

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.

Females for whom the childbearing potential changes during the study due to meeting any of 
the criteria for non-childbearing potential above do not need to continue using birth control 
during or following study drug treatment.
5.3 Prohibited Medications and Therapy
Biologic Therapies
Subjects must have discontinued biologic therapies with immunosuppressive potential at least 6 weeks 
prior to the first dose of study drug.
Biologic therapies with immunosuppressive potential are prohibited through the end of study drug 
administration, and include, but are not limited to, the following:

Abatacept

Adalimumab

Anakinra

Anifrolumab

Belimumab

Certolizumab

Dupilumab

Etanercept

Golimumab

Infliximab

Ixekizumab

Lebrikizumab

Natalizumab

Nemolizumab

Risankizumab

Rituximab

Secukinumab
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
Tocilizumab

Tralokinumab

Ustekinumab

Vedolizumab
Other Non-Biologic Systemic Therapy
Concomitant treatment with systemic non-steroidal immunosuppressive drugs is prohibited during 
treatment with study drug, including but not limited to:

Methotrexate

Cyclosporine

Azathioprine

PDE4-Inhibitors (e.g., apremilast)

Mycophenolate mofetil
Oral antihistamines are allowed per investigator discretion for the duration of the study.
See also Section 5.4, Rescue Therapy for further details on allowed rescue.
Corticosteroids
Concomitant treatment with systemic corticosteroids (oral, intravenous, intramuscular) and intralesional 
corticosteroids for the treatment of AD is prohibited during treatment with study drug.
Inhaled, ophthalmic drops, and nasal corticosteroid formulations are allowed throughout the study.
Strong CYP3A Inhibitors or Inducers (includes over-the-counter or prescription medicines, 
vitamins and/or herbal supplements)
Systemic use of known strong cytochrome P450 3A (CYP3A) inhibitors is not permitted from Screening 
through the end of study drug administration.  Use of strong CYP3A inducers is not permitted from 
30 days prior to study drug administration through the end of study drug administration.  Table 1
includes examples of commonly used strong CYP3A inhibitors and inducers.  In addition, herbal 
therapies and other traditional medicines with unknown effects on CYP3A are not permitted from 
Screening through the end of study drug administration. 
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Table 1.
Examples of Commonly Used Strong CYP3A Inhibitors and Inducers
Strong CYP3A Inhibitors
Strong CYP3A Inducers
Boceprevir
Ceritinib
Cobicistat
Clarithromycin
Conivaptan
Grapefruit (fruit or juice)
Idelalisib
Itraconazole
Ketoconazole
Mibefradi
Nefazodone
Nelfinavir
Posaconazole
Ritonavir (alone or in combination with danoprevir, 
elvitegravir, indinavir, lopinavir, nirmatrelvir, 
paritaprevir, saquinavir, telaprevir, tipranavir, 
ombitasvir and/or dasabuvir)
Telithromycin
Troleandomycin
Voriconazole
Apalutamide 
Carbamazepine
Enzalutamide 
Ivosidenib
Lumacaftor
Mitotane,
Phenytoin
Rifampin (Rifampicin)
Rifapentine
St. John's Wort
CYP3A = cytochrome P450 3A
Investigational Drugs
Subjects who have been treated with any investigational drug within 30 days or 5 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 treatment with study drug.
Phototherapy, Tanning Booth, and Extended Sun Exposure
Ultra-violet (UV) B or UVA phototherapy including psoralen and ultraviolet A (PUVA) or laser therapy are 
not allowed during the study.  Tanning booth use or extended sun exposure that could affect disease 
severity or interfere with disease assessments are not allowed during treatment with study drug.
Topical Therapy
No topical treatments for AD should be started for the duration of the treatment with study drug except 
for rescue treatment (see Section 5.4, Rescue Therapy).  This includes but is not limited to calcineurin 
inhibitors, corticosteroids, phosphodiesterase-4 inhibitors and prescription moisturizers.  Topical 
emollient treatments are allowed.
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Topical anti-infectives, topical antihistamines, and bleach baths are allowed per investigator discretion 
for the duration of the study.
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) or Therapeutic Area 
Scientific Director (TA SD).
Other Medications Prohibited during the Study

Oral and topical JAK inhibitors, including but not limited to commercial upadacitinib (Rinvoq®), 
tofacitinib (Xeljanz®), ruxolitinib (Jakafi® or Opzelura®), baricitinib (Olumiant®), peficitinib 
(Smyraf®), abrocitinib (Cibinqo®), filgotinib (Jyseleca®), and deucravacitinib [Sotyktu®]).

Treatment with a live (attenuated) vaccine with replicating potential.
5.4 Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins and/or herbal 
supplements) that the subject is receiving at the time of screening, and/or receives during the study, 
must be recorded along with the reason for use, date(s) of administration including start and end dates, 
and dosage information including dose, route and frequency on the appropriate electronic case report 
form (eCRF).  Also, medications taken for moderate to severe AD since date of diagnosis (based on 
subject recollection and available medical records) should be entered into the appropriate eCRF 
inclusive of the dates of first and last dose, maximum dosage taken, route of administration.
For sites in China only, subjects must record concomitant medication daily on the subject paper diary 
cards (see Section 5.12).
Rescue Therapy
Starting at Week 4 rescue treatment for AD may be provided, if medically necessary and the following 
parameter is met:

Subjects achieving a < 50% reduction in EASI (< EASI 50) response at any visit compared to the 
Baseline EASI score.
Investigators should attempt to limit the first step of rescue therapy to topical medications and escalate 
to systemic medications only for those subjects who do not respond adequately after at least 7 days of 
topical treatment.  Subjects who receive topical rescue treatment during the study treatment period can 
continue study drug.
If a subject needs rescue treatment with a systemic agent (including but not limited to corticosteroids, 
cyclosporine, methotrexate, mycophenolate mofetil, azathioprine, biologics) or phototherapy, study 
drug should be permanently discontinued prior to the initiation of rescue systemic agent or 
phototherapy and the subject should be discontinued from the study.  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.
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Vaccines
If the subject and investigator choose to receive/administer live vaccines with replicating potential, 
these vaccinations must be completed (per local label) at least 30 days (or longer if required locally) 
before first dose of study drug.  Live vaccines with replicating potential are prohibited during study 
participation including at least 30 days (or longer if required locally) after the last dose of study drug.  
Examples of live vaccines with replicating potential include, but are not limited to, the following:

Monovalent live influenza A (H1N1) (intranasal);

Seasonal trivalent live influenza (intranasal);

Herpes zoster (Zostavax®, live attenuated);

Rotavirus;

Varicella (chicken pox);

Measles-mumps-rubella or measles-mumps-rubella-varicella;

Oral polio vaccine;

Smallpox/monkeypox vaccine capable of replicating (ACAM2000®);

Yellow fever;

Bacille Calmette-Guérin (BCG);

Typhoid (oral).
If the live herpes zoster vaccine is to be administered (should be administered at least 30 days [or longer 
if required locally] before first dose of study drug) and there is no known history of primary varicella 
(chicken pox), preexisting immunity to varicella should be confirmed with antibody testing at or prior to 
Screening and prior to administration of the herpes zoster vaccine.  If screening varicella antibody 
testing is negative, the live herpes zoster vaccine should not be administered.
In Japan, it is recommended that the live herpes zoster vaccine be considered for administration at least 
8 weeks before the first dose of study drug in subjects greater than 50 years of age.
Administration of inactivated (non-live) vaccines is permitted prior to or during the study according to 
local practice guidelines.  Examples of common vaccines that are inactivated, toxoid or biosynthetic 
include, but are not limited to, injectable influenza vaccine, pneumococcal, Shingrix (zoster vaccine, 
recombinant, adjuvanted), pertussis (Tdap) vaccines and SARS-CoV-2 (inactivated, mRNA, RNA). 
Whenever possible, subjects should not have received a COVID-19 vaccination in the 7 days prior to 
randomization or plan to receive a COVID-19 vaccination within the first 7 days after initiation of study 
drug.  Viral vector vaccines that are not of replicating potential (such as Convidecia® and Convidecia Air 
to treat COVID-19) are allowed.
COVID-19 Pandemic-Related Vaccination Guidance
Given the ongoing COVID-19 pandemic, selected non-live vaccines (e.g., mRNA, non-replicating viral 
vector, protein subunit, etc.) to prevent SARS-CoV-2 infection may be administered during screening, 
the treatment period, or follow up, as long as components of the vaccine are not contraindicated.
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The decision to receive a locally available vaccine should be based on local guidance and an individual 
discussion between the treating physician and the subject.
The potential impact of upadacitinib on SARS-CoV-2 vaccination is unknown.  Therefore, study drug 
should be administered as follows:

The first dose of upadacitinib, when possible, is preferred to be given at least ± 7 days from the 
SARS-CoV-2 vaccine administration.
Note:  The above guidance applies to all SARS-CoV-2 vaccine doses given as part of the complete 
vaccination course.
These recommendations may be subject to change based on the evolving knowledge around the use of 
SARS-CoV-2 vaccines in patients with AD and as more data are collected in real-world scenarios and 
clinical trials.
Any SARS-CoV-2 vaccine information must be documented on the COVID-19 vaccine eCRF.  Refer to the 
Operations Manual for instructions on reporting any AEs associated with the COVID-19 vaccine.
5.5 Withdrawal of Subjects and Discontinuation of Study
AbbVie may terminate this study prematurely, either in its entirety or at any site.  The study may 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, data deriving from other 
clinical trials or toxicological studies which negatively influence the risk/benefit assessment might cause 
discontinuation or termination of the study.  The investigator may also stop the study at their site if they 
have safety concerns.  If AbbVie terminates the study for safety reasons, AbbVie will promptly notify the 
investigator.  Advance notice is not required by either party if the study is stopped due to safety 
concerns.
Subjects can request to be discontinued from participating in the study at any time for any reason.  The 
investigator may discontinue any subject's participation at any time for any reason.
Subjects must have study drug discontinued immediately if any of the following occur:

The subject requests withdrawal from study drug or the study.

The investigator believes it is in the best interest of the subject.

Abnormal laboratory results or AEs that either meet the criteria for discontinuation of study 
drug as stated in Section 6.2, or rule out safe continuation of the study drug.  

Serious infections (e.g., sepsis) which cannot be adequately controlled by anti-infective 
treatment or would put the subject at risk with continuation of the study drug.

Confirmed diagnosis of deep vein thrombosis (DVT), pulmonary embolus (PE) or non-cardiac, 
non-neurologic arterial thrombosis.
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
Subject is non-compliant with TB prophylaxis (if applicable) or develops active TB at any time 
during the study.

Malignancy, except for localized NMSC or carcinoma in-situ of the cervix if this can be 
successfully treated at its localization

Subject develops a gastrointestinal perforation (other than due to appendicitis or mechanical 
injury).

The subject experiences a serious hypersensitivity reaction without an alternative etiology.

The subject becomes pregnant while on study drug.

Eligibility criteria violation was noted after the subject started study drug, when continuation of 
the study drug would place the subject at risk.

Introduction of prohibited medications or dosages when continuation of the study drug would 
place the subject at risk.

The investigator determines the subject is significantly non-compliant with the study.

Initiation of any prohibited systemic therapy for AD. 

Initiation of phototherapy.

Treatment with a live (attenuated) vaccine with replicating potential.
Additional requirements related to abnormal laboratory values and selected AE of special interest 
(AESIs) are in Protocol Section 6.2 (Toxicity Management).
COVID-19 Pandemic-Related Acceptable Protocol Modifications
During the COVID-19 pandemic, it has been necessary to employ mitigation strategies to enable the 
investigator to ensure subject safety and continuity of care.  Acceptable mitigation strategies are 
identified and included in the Operations Manual in Appendix F.
The investigator should contact the sponsor medical contact before discontinuing a subject from the 
study for a reason other than described in the protocol to ensure all acceptable mitigation steps have 
been explored.
Interruption/Discontinuation of Study Drug Due to COVID-19 Infection
During the study drug dosing period, for a subject with confirmed (viral test positive) or suspected 
COVID-19 infection, the timing of next administration of study drug or possibility of premature 
discontinuation would be at the discretion of the investigator.  Follow Section 5.6 for subjects who 
discontinued study drug.
Delays in study drug dosing due to the above COVID-19 testing guidance for subjects must be discussed 
with the AbbVie medical contact, along with the possibility of premature discontinuation from the study 
drug dosing period.  Follow subsequent protocol Section 5.6 for subjects who discontinued study drug.
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5.6 Follow-Up After Subject Discontinuation of Study Drug or From
Study
Discontinuation of Study Drug
Following discontinuation of study drug, the subject should be treated in accordance with the 
investigator's best clinical judgment based on the available approved treatment options within their 
country or region.
Subjects who prematurely discontinue study drug treatment will be discontinued from study 
participation entirely.
If a subject prematurely discontinues study drug, the procedures outlined for the Premature 
Discontinuation visit (PD Visit) should be completed as soon as possible, preferably within 2 weeks, and 
preferably prior to initiation of another therapy.  In addition, a 30-Day Follow-up Visit after the last dose 
of study drug is required to ensure all treatment-emergent AEs/SAEs have been resolved.  For subjects 
who prematurely discontinued study participation, this visit may be a telephone call if a site visit is not 
possible.  A follow-up phone call following the last dose of upadacitinib during the study will not occur 
for subjects who begin commercially available upadacitinib.
Premature Discontinuation of Study (Withdrawal of Informed Consent)
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 and preferably prior to initiation of another therapy.  In addition, if 
the subject is willing, a 30-day follow-up phone call after the last dose of study drug may be completed 
to ensure all treatment-emergent AEs/SAEs have been resolved.  The follow-up phone call following the 
last dose of upadacitinib during the study will not occur for subjects who begin commercially available 
upadacitinib.
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.
If a subject withdraws from study follow up or withdraws permission for the collection of their personal 
data, the study staff may still use available public records to obtain information about survival status 
only, as appropriate per local regulations.
If 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 for the 
withdrawn subject or added to the existing data or database(s), and the samples will be destroyed.  A 
subject may withdraw consent for optional biomarker research at any time and remain in the clinical 
study.  Data generated from clinical study and/or optional biomarker research, before subject 
withdrawal of consent, will remain part of the study results.
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5.7 Study Drug
The individual study drug information is presented in Table 2.
Table 2.
Description of Study Drug
Investigational Product
Investigational Product
Investigational product name
upadacitinib
upadacitinib
Mode/Route of Administration 
(ROA) 
Oral
Oral
Formulation
15 mg
30 mg
Dosage Form
Extended-release tablets
Extended-release tablets
Masking
Blinded
Blinded
Frequency of administration
QD
QD
Manufacturer
AbbVie
AbbVie
QD = once daily
Upadacitinib will be taken orally once daily, beginning on Day 1 (Baseline) and can be taken with or 
without food.  Upadacitinib should be taken whole and should not be split, crushed, dissolved, etc.  If 
subjects should forget to take upadacitinib 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 provide upadacitinib.  AbbVie-provided study drug should not be substituted or alternately 
sourced unless otherwise directed by AbbVie.
AbbVie will not supply drug other than upadacitinib.  Subjects will continue their AD disease-related 
concomitant medications therapy as allowed per protocol.  AbbVie will not supply any AD disease-
related concomitant medication therapy taken during the study.
Study drug will be packaged in quantities sufficient to accommodate study design.  Each kit will be 
labeled per local requirements, and this label must remain affixed to the kit.  Upon receipt, study drug 
should be stored as specified on the label and kept in a secure location.  Each kit will contain a unique kit 
number.  This kit number is assigned to a subject via Interactive response technology (IRT) and encodes 
the appropriate study drug to be dispensed at the subject's corresponding study visit.  All blank spaces 
on the label will be completed by the site staff prior to dispensing to subjects.  Study drug will only be 
used for the conduct of the study.
During the COVID-19 pandemic, study drug shipment can be made from the study site to the subject if 
allowed by local regulations.  Refer to the Operations Manual for details on direct-to patient shipment 
of study drug (Appendix F).
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Upon completion of or discontinuation from study treatment, all original study drug units (containing 
unused study drugs) will be returned to the sponsor (or designee) or destroyed on site.  All return or 
destruction procedures will be according to instructions from the Sponsor according to local regulations 
following completion of drug accountability procedures.
5.8 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 study will be randomized in a 1:1 ratio to one of the 2 treatment groups:

Upadacitinib 15 mg QD

Upadacitinib 30 mg QD
The study will be stratified by Baseline vIGA-AD categories (3; 4) and prior use of dupilumab (yes; no).
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 (apart from the 
AbbVie Drug Supply Management Team), the investigator, study site personnel, and the subject will 
remain blinded to each subject's treatment through Week 12.  After Week 12, the subject will be 
blinded to the upadacitinib dose they will receive.
Blinding of Investigational Product
During the 12-week double-blind period, study sites and subjects will remain blinded.  During the single 
blind period, only the subjects will be blinded to the upadacitinib dose and the EASI score evaluations.  
In order to maintain the blind, the upadacitinib 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.
In the event of a medical emergency that requires unblinding of the study drug assignment, the 
investigator is requested to contact the AbbVie TA MD prior to breaking the blind.  However, if an 
urgent therapeutic intervention is necessary which warrants breaking the blind prior to contacting the 
AbbVie TA MD, the investigator can directly access the IRT system to break the blind without AbbVie 
notification or agreement.  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 technical support via either phone (preferred) or email.
In the event that the blind is broken before notification to the AbbVie Therapeutic Area Medical Director 
(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.
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5.9 Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol except when necessary to 
eliminate an immediate hazard to study subjects.  The investigator is responsible for complying with all 
protocol requirements, written instructions, and applicable laws regarding protocol deviations.  If a 
protocol deviation occurs (or is identified, including those that may be due to the COVID-19 pandemic), 
the investigator is responsible for notifying the independent ethics committee (IEC)/independent review 
board (IRB), regulatory authorities (as applicable by local requirements), and AbbVie.
In Japan, the investigator will record all protocol deviations in the appropriate medical records at site.
5.10 Data Monitoring Committee
Given no subjects participating in the study will receive placebo or other active comparators, the 
causality of any AEs reported in the participants can be adequately assessed in the context of 
upadacitinib treatment.  The study team will monitor and evaluate any AEs to identify findings that 
could put the study participants at risk and then make clinical decisions regarding the study conduct, 
which could include modification or termination of the study.  This can adequately safeguard the 
participants.  Given the above, it is not necessary to implement an independent Data Monitoring 
Committee for the conduct of this study.
5.11 Publication Policy
AbbVie as the sponsor has proprietary interest in this study. Authorship and manuscript composition will 
reflect joint cooperation between multiple investigators and sites and sponsor personnel. Authorship 
will be established prior to the writing of the manuscript. As this study involves multiple centers, no 
individual publications will be allowed prior to completion of the final clinical study report of the 
multicenter study except as agreed with the sponsor.
The sponsor will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the sponsor will generally support publication of multicenter 
studies only in their entirety and not as individual site data.
Investigators are NOT employed by the organization sponsoring the study. There is an agreement 
between investigators and the sponsor (or its agents) that restricts the investigator's rights to discuss or 
publish study results after the study is completed.
AbbVie requests that any investigator or institution that plans on presenting/publishing results, provide 
written notification of their request 60 days prior to their presentation/publication. AbbVie requests 
that no presentation/publication will be instituted until 12 months after a study is completed or after 
the first presentation/publication, whichever occurs first. A delay may be proposed for a 
presentation/publication if AbbVie needs to secure patent or proprietary protection.
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5.12 Paper Diary Cards for Sites in China Only
For sites in China only, a paper diary card will be provided to subjects.  Subjects will be trained on how 
to complete the diary cards by site staff.  If subjects require re-training during the study, the site staff 
will accommodate this requirement.
All subjects should complete their paper diary cards until completion of the study.  Subjects will be 
instructed to bring their paper diary cards back to the site to be reviewed and collected at each visit, 
including at any visit at which a dose level change may be required.  If COVID-19 circumstances warrant 
a virtual visit, diary cards should be reviewed virtually with the subject and the site should collect the 
paper diary card at the next onsite visit.  Subjects will be instructed to record the date and time each 
dose of study drug is taken, indicating if any doses of study drugs are missed.
Subjects will also be instructed to record AE symptoms and concomitant medications in the paper diary 
cards.  At each visit, the paper diary cards are to be reviewed by the investigator, assessed for any 
updates needed, and collected from the subject by study staff.  Relevant information will be recorded in 
existing AE, drug administration, and concomitant medication forms in the eCRF as applicable.  At each
visit after the paper diary card is initially dispensed, including the final/PD Visit, the paper diary cards are 
to be returned to the site and appropriately filed with the subject's source documents for this study.  At 
each visit after the paper diary card is initially dispensed (except the final/PD Visit), the subject will be 
provided with a new diary card.
In case of missing diary card information, or when discrepancies are discovered, site personnel should 
discuss with the subject and document changes to data in site records forms and eCRFs, if applicable.  
The need for completion of the paper diary card will be reinforced with the subject during study visits, 
as necessary, by the site personnel.
6 SAFETY CONSIDERATIONS
6.1 Complaints and Adverse Events
Complaints
A complaint is any written, electronic, or oral communication that alleges deficiencies related to the 
physical characteristics, identity, quality, purity, potency, durability, reliability, safety, effectiveness, or 
performance of a product/device.  Complaints associated with any component of this investigational 
product must be reported to AbbVie.
Product Complaint
A product complaint is any complaint related to the biologic or drug component of the product or to the 
medical device component(s).
For a product this may include, but is not limited to, damaged/broken product or packaging, product 
appearance whose color/markings do not match the labeling, labeling discrepancies/inadequacies in the 
labeling/instructions (e.g., printing illegible), missing components/product, device damage or not 
working properly, or packaging issues.
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Product complaints concerning the investigational product and/or device must be reported to AbbVie 
within 24 hours of the study site's knowledge of the event.
Reporting will be done via electronic data capture (EDC).  The date the product complaint details are 
entered into EDC and the form is saved represents the date reported to AbbVie.  A back-up paper form 
will be provided for reporting complaints related to unassigned product or in the event of an EDC system 
issue.  If a back-up paper form is used, the date the form is emailed to RD_PQC_QA@abbvie.com 
represents the date reported to AbbVie.
All follow-up information is to be reported to the sponsor (or an authorized representative) and 
documented in source as required by the sponsor.  Product complaints associated with AEs will be 
reported in the study summary.  All other complaints will be monitored on an ongoing basis.  Product 
complaints occurring during the study will be followed up to a satisfactory conclusion.
Medical Complaints/Adverse Events and Serious Adverse Events:  Upadacitinib
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 
"special situations" such as accidental or intentional overdose, medication error, occupational or 
accidental exposure, off-label use, drug abuse, drug misuse, or drug withdrawal, all which must be 
reported whether associated with an AE or not.  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, necessitate therapeutic medical intervention, meet protocol-specific criteria (see 
Section 6.2 regarding toxicity management), and/or if the investigator considers them to be AEs.
The investigators will monitor each subject for clinical and laboratory evidence of AEs on a routine basis 
throughout the study.  All AEs will be followed to a satisfactory conclusion.
An elective surgery/procedure scheduled to occur during a study will not be considered an AE if the 
surgery/procedure is being performed for a pre-existing condition and/or the surgery/procedure has 
been pre-planned prior to study entry.  However, if the pre-existing condition deteriorates unexpectedly 
during the study (e.g., surgery performed earlier than planned), then the deterioration of the condition 
for which the elective surgery/procedure is being done will be considered an AE.
If any of the following events are reported, then the following supplemental report must be completed.
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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 adverse events 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.  After 30 days following the last dose of study drug, only spontaneously 
reported SAEs will be collected (nonserious AEs will not be collected).  In addition, study 
procedure-related serious and nonserious adverse events will be collected from the time the subject 
signs the study-specific informed consent.
If a subject prematurely discontinues study participation and begins commercially available upadacitinib 
(Rinvoq), all AEs reported by healthcare professionals or the patient will be captured as post-marketing 
reports.  The 30-day follow-up phone call following the last dose of upadacitinib study drug during the 
study will not occur for subjects who begin commercially available upadacitinib.
The following definitions will be used for Serious Adverse Reactions (SAR) and Suspected Unexpected 
Serious Adverse Reaction (SUSAR):
SAR
Defined as all noxious and unintended responses to an IMP related to any dose 
administered that result in an SAE as defined above.
SUSAR
Refers to individual SAE case reports from clinical trials where a causal 
relationship between the SAE and the IMP was suspected by either the sponsor 
or the investigator, is unexpected (not listed in the applicable Reference Safety 
Information), and meets one of the above serious criteria.
AbbVie will be responsible for SUSAR reporting for the IMP in accordance with global and local 
requirements, including reporting to Eudravigilance database in accordance with EU Clinical Trial 
Regulation 536/2014.
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Adverse events will be monitored throughout the study to identify any of special interest that may 
indicate a trend or risk to subjects.
Adverse Events of Special Interest
The following adverse events of special interest (AESIs) will be monitored during the study:

Serious infections;

Opportunistic infections;

Herpes zoster;

Active tuberculosis;

Malignancy (all types);

Anemia;

Neutropenia;

Lymphopenia;

Renal dysfunction;

Hepatic disorder;

Adjudicated GI perforations;

Adjudicated cardiovascular events (e.g., major adverse cardiovascular event [MACE]); and

Adjudicated embolic and thrombotic events (non-cardiac, non-CNS).

Fractures

Retinal detachment
Cardiovascular Adjudication Committee
An independent external committee of physician experts in cardiovascular adjudication will be utilized 
to assess potential cardiovascular and thromboembolic AEs in a blinded manner as defined by the 
Cardiovascular Adjudication Committee charter.
Gastrointestinal Perforation Adjudication Committee
An internal GI perforation committee will identify and adjudicate AEs of spontaneous GI perforation.  
The internal committee will be comprised of at least 2 gastroenterologists or physicians with 
appropriate expertise who are independent of the clinical study team and blinded to subject treatment 
assignments.  The committee's primary responsibility is to review potential events of GI perforation and 
adjudicate against a pre-specified case definition.  A separate GI perforation charter will be prepared 
outside of the protocol and will describe the case definition, procedures, roles, and responsibilities.
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Adverse Event Severity and Relationship to Study Drug
Investigators will rate the severity of each AE according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE Version 5.0), which can be accessed at: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
If no specific grading criteria are provided for the reported event, then the event should be as follows:

Mild (Grade 1):  asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated;

Moderate (Grade 2):  minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living (ADL) (instrumental ADL refer to preparing 
meals, shopping for groceries or clothes, using the telephone, managing money, etc.);

Severe (Grade 3 - 5):

Grade 3: severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADL (self-care ADL 
refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications,
and not bedridden);

Grade 4: Life-threatening consequences; urgent intervention indicated;

Grade 5: Death related to AE.
The investigator will use the following definitions to assess the relationship of the AE to the use of study 
drug:
Reasonable 
Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is 
sufficient evidence (information) to suggest a causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is 
insufficient evidence (information) to suggest a causal relationship.
Pregnancy
While not an AE, pregnancy in a study subject must be reported to AbbVie within 24 hours after the site 
becomes aware of the pregnancy.  If a pregnancy occurs in a study subject information regarding the 
pregnancy and the outcome will be collected.
Female subjects should avoid pregnancy throughout the course of the study, starting with the Screening 
Visit through 30 days after the last study drug administration.  Results of a positive pregnancy test or 
confirmation of a pregnancy will be assessed starting with the Screening Visit through the final study 
visit.
Subjects who become pregnant during the study must be discontinued from study drug treatment and 
study (Section 5.5 Withdrawal of Subjects and Discontinuation of Study).
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The pregnancy outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a SAE and must be reported to AbbVie within 24 hours after the site becomes aware of the 
event.
Recording of Adverse Event Symptoms on the Subject Paper Diary Cards
For sites in China only, subjects will be instructed to record AE symptoms on the subject paper diary 
cards (see Section 5.12, Paper Diary Cards for Sites in China Only, for description of paper diary cards).
6.2 Toxicity Management
The toxicity management of the AEs including AESIs consists of safety monitoring (review of AEs on an 
ongoing basis) and, if applicable, interruption of study drug dosing with appropriate clinical 
management and/or discontinuation of the subjects from study drug.  The management of specific AEs 
and laboratory parameters is described below.
Serious Infections:  Study drug should be interrupted if a subject develops a serious infection. A subject 
who develops a new infection during treatment with study drug should undergo prompt diagnostic 
testing appropriate for an immunocompromised subject. Study drug may be restarted once the 
infection has been successfully treated.  Subjects who develop active TB must be permanently 
discontinued from study drug. 
Herpes zoster:  If a subject develops herpes zoster, consider temporarily interrupting study drug until 
the episode resolves.
Gastrointestinal Perforation:  If a diagnosis of gastrointestinal perforation is confirmed (other than due 
to appendicitis or mechanical injury), the subject must be permanently discontinued from study drug.
Major cardiovascular event:  For subjects who develop a major cardiovascular event (MACE: acute 
myocardial infarction, stroke) while on study drug, the investigator should evaluate the benefit/risk of, 
and discuss with the TA MD, whether it is appropriate to continue study drug.
Malignancy:  Subjects who develop malignancy other than localized NMSC or carcinoma in situ of the 
cervix must be permanently discontinued from study drug.  Information including histopathological 
results should be queried for confirmation of the diagnosis.  Periodic skin examination is recommended 
for subjects who are at increased risk for skin cancer.  Subjects who develop malignancies should be 
referred to appropriate specialists and managed as per standard of care.
Muscle-related symptoms:  If a subject experiences symptoms suggestive of myositis or 
rhabdomyolysis, consider checking CPK and aldolase with clinical management and/or study drug 
interruption as deemed appropriate by the investigator.
Thrombosis Events:  Subjects who develop symptoms of thrombosis should be promptly evaluated and 
treated appropriately.  If the diagnosis of deep vein thrombosis (DVT), pulmonary embolus or non-
cardiac, non-neurologic arterial thrombosis is confirmed, the subject must be discontinued from study 
drug.
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COVID-19:  Interrupt study drug in subjects with a confirmed diagnosis of COVID-19.  Consider 
interrupting study drug in subjects with signs and/or symptoms and suspicion of COVID-19.  Study drug 
may be restarted if fever is resolved without use of antipyretics for 24 hours and other symptoms 
improved, or if 5 days have passed since the COVID-19 positive test result (whichever comes last). The 
COVID-19 eCRF must be completed.
Management of Select Laboratory Abnormalities:  For any given laboratory abnormality, the 
investigator should assess the subject, apply the standard of care for medical evaluation and treatment 
following any local guidelines.  Specific toxicity management guidelines for abnormal laboratory values 
are described in Table 3, and may require a supplemental eCRF to be completed.  For subjects with 
ongoing laboratory abnormalities which require data entry into an eCRF, an additional eCRF related to 
subsequent laboratory abnormalities is only required if the subject has relevant changes in history (e.g., 
new onset signs or symptoms) or laboratory values which have returned to normal reference range or 
its Baseline value followed by subsequent laboratory abnormalities meeting toxicity guidelines 
(considered a new event).  All abnormal laboratory tests that are considered clinically significant by the 
investigator will be followed to a satisfactory resolution.  If a repeat test is required per Table 3, the 
repeat testing is to occur as soon as possible.
Table 3.
Specific Toxicity Management Guidelines for Abnormal Laboratory Values
Laboratory Parameter
Toxicity Management Guideline
Hemoglobin

If hemoglobin < 8 g/dL interrupt study drug dosing and confirm by 
repeat testing with a new sample.  If confirmed, continue to withhold 
study drug until hemoglobin value returns to ≥ 8 g/dL.
OR

If hemoglobin decreases ≥ 3.0 g/dL from Baseline without an 
alternative etiology, interrupt study drug dosing and confirm by 
repeat testing with new sample.

If hemoglobin decreases ≥ 3.0 g/dL from Baseline and an 
alternative etiology is known or the hemoglobin value remains in 
the normal reference range, the subject may remain on study 
drug at the investigator's discretion.

If confirmed, continue to withhold study drug until hemoglobin 
value returns to within 3.0 g/dL from Baseline.
Absolute neutrophil count 
(ANC)

If confirmed < 1000/μL by repeat testing with new sample, interrupt 
study drug dosing until ANC value returns to ≥ 1000/μL.

For confirmed < 500/μL, if value returns to ≥ 1000/μL, restarting study 
drug is allowed if there is an alternative etiology identified; 
documentation should include reason that rechallenge is expected to 
be safe for the subject.  Study drug should be discontinued if no 
alternative etiology can be found.
Absolute lymphocyte counts 
(ALC)

If confirmed < 500/μL by repeat testing with new sample, interrupt 
study drug dosing until ALC returns to ≥ 500/μL.  
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 ≥2000/μL.
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Laboratory Parameter
Toxicity Management Guideline
AST or ALT
Interrupt study drug if any of the following scenarios are confirmed by repeat 
testing of AST/ALT:

ALT or AST > 3 × ULN and either a total bilirubin > 2 × ULN or an 
international normalized ratio (INR) > 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.

If a creatine phosphokinase (CPK) value is not available, a CPK 
should be drawn to exclude AST/ALT elevations related to muscle 
injury.

ALT or AST > 3 × ULN along with new appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, and/or 
new-onset eosinophilia.

ALT or AST > 5 × ULN for more than 2 weeks.
If ALT or AST > 8 × ULN, interrupt study drug immediately, repeat testing with a 
new sample, and if repeat test confirms result, contact the TA MD.
Subjects with HBc Ab+ (irrespective of HBs Ab status) and negative HBV DNA 
PCR testing at Screening who develop the following laboratory findings should 
have HBV DNA PCR testing performed within 1 week (based on initial elevated 
value):

ALT> 5 × ULN OR 

ALT or AST > 3 × ULN if an alternative 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. 
A positive result for HBV DNA PCR testing will require immediate interruption 
of study drug (unless not acceptable by local practices).  Within one week of 
the first episode of a positive HBV DNA PCR test, a hepatologist consultation 
should occur for recommendation regarding subsequent treatment. 
Subjects who meet any of the above criteria should be evaluated for an 
alternative etiology of the ALT or AST elevation and managed as medically 
appropriate.  If applicable, the alternative etiology should be documented in 
the eCRF.  If ALT or AST values return to the normal reference range or its 
Baseline value, study drug may be restarted.  If restarting study drug, 
documentation should include reason that rechallenge is expected to be safe.  
If after clinically appropriate evaluation, no alternative etiology for ALT or AST 
elevation is found or the ALT or AST elevation has not resolved or is not 
trending down toward normal, the subject should be discontinued from study 
drug. 
For any confirmed ALT or AST elevations > 3 ULN, complete the appropriate 
supplemental hepatic eCRF(s). 
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Laboratory Parameter
Toxicity Management Guideline
Serum Creatinine
If serum creatinine is > 1.5 × the Baseline value and > ULN, repeat the test for 
serum creatinine (with subject in an euvolemic state) to confirm the results.  If 
the results of the repeat testing still meet this criterion, interrupt study drug 
and re-start study drug once serum creatinine returns to ≤ 1.5 x Baseline value.
For the above serum creatinine elevation scenario, complete the appropriate 
supplemental renal eCRF(s).
ALC = Absolute lymphocyte count; ALT = alanine transaminase; ANC = Absolute neutrophil count; AST = aspartate transaminase; 
DNA = deoxyribonucleic acid; eCRF = electronic case report form; HBc Ab+ = Hepatitis B core antibody positive; HBs 
Ab = Hepatitis B surface antibody; HBV = Hepatitis B virus; INR = international normalized ratio; OR = odds ratio; 
PCR = Polymerase chain reaction; TA MD = Therapeutic Area Medical Director; ULN = upper limit of normal
Elective and Emergency Surgeries
For elective and emergency surgeries the following rules will apply:

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.

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 24).  If elective surgery is 
considered prior to the primary endpoint visit (Week 24), it must be discussed with the TA MD 
and performed with TA MD approval. 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.
6.3 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.
7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
7.1 Statistical and Analytical Plans
The statistical methods provided in this protocol will be focused on primary and secondary analyses.  
Complete and specific details of the statistical analysis will be described in the Statistical Analysis Plan 
(SAP).
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7.2 Definition for Analysis Populations
The Intent to Treat (ITT) Populations for the efficacy analyses are defined as:

ITT Population of SS1 in the double-blind period (ITT_1_SS1 Population) includes all subjects 
who are randomized into SS1.

ITT Population of SS1 in the single-blind period (ITT_2_SS1 Population) includes all subjects who 
are randomized into SS1 at Baseline and continued into the single-blind period.

ITT Population of SS2 in the double-blind period (ITT_1_SS2 Population) includes all subjects 
who are randomized into SS2.

ITT Population of SS2 in the single-blind period (ITT_2_SS2 Population) includes all subjects who 
are randomized into SS2 at Baseline and continued into the single-blind period.
The Safety Populations for the safety analyses are defined as:

Safety Population of SS1 in the double-blind period (Safety_1_SS1 Population) consists of all 
subjects who are randomized into SS1 and received at least 1 dose of study drug in the 
doubleblind period.

Safety Population of SS1 in the single-blind period (Safety_2_SS1 Population) consists of all 
subjects who received at least 1 dose of study drug in the single-blind period of SS1.

Safety Population of SS2 in the double-blind period (Safety_1_SS2 Population) consists of all 
subjects who are randomized into SS2 and received at least 1 dose of study drug in the 
doubleblind period.

Safety Population of SS2 in the single-blind period (Safety_2_SS2 Population) consists of all 
subjects who received at least 1 dose of study drug in the single-blind period of SS2.

Safety Population for all upadacitinib treatment (ALL_UPA Population) consists of all subjects 
who received at least 1 dose of upadacitinib in the study.
These populations will be used to provide a comprehensive summary of safety based on treatment 
received regardless of randomization. 
7.3 Handling Potential Intercurrent Events for the Primary and 
Secondary Endpoints
For all endpoints, no intercurrent event will be considered in the primary approach (treatment strategy 
policy), i.e., all observed data will be included in the primary analysis.
7.4 Statistical Analyses for Efficacy
The efficacy analyses will be summarized in the ITT Populations descriptively and no statistical testing 
will be performed in this study.
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Categorical endpoints will be summarized by counts and percentages, as well as 95% confidence interval 
(CI) of the percentage.  Continuous variables will be summarized by the number of observations, mean, 
standard deviation, median, minimum, maximum, and well as 95% confidence intervals (CIs) of the 
mean values.
The primary approach for efficacy summary is As Observed (AO). 
Summary and Analysis of the Primary Endpoint
The primary endpoint will be summarized in the ITT_2_SS1 and ITT_2_SS2 Populations by counts and 
percentages, as well as the 95% CIs of the percentage.  The AO approach will be used as the primary 
approach.
Sensitivity analyses of the primary endpoint will be conducted.  The primary endpoint will be 
summarized using the Multiple Imputation (MI) to handle missing data.  The details will be specified in 
the SAP.
Summary and Analysis of Secondary Endpoints
Summary of the secondary efficacy endpoints will be conducted using the ITT Populations with the 
treatment as randomized.  Categorical variables will be summarized by counts and percentages, as well 
as 95% CIs of the percentage.  The AO approach will be used.
Summary and Analysis of Additional Efficacy Endpoints
Additional endpoints, as described in the Section 3.4, will also be summarized using the AO approach.  
The analysis details will be provided in the SAP.
Subgroup Analysis for Efficacy
The primary endpoints, as described in Section 3.1, will be also summarized by the following subgroups 
using the AO approach:

Baseline vIGA-AD (3; 4),

Baseline EASI score (<21; ≥21), and

Baseline EASI score (<median; ≥median).
7.5 Statistical Analyses for Safety
The safety analyses will be summarized in the double-blind period, single-blind period, and across study 
periods by the upadacitinib doses, based on the Safety_1_SS1 and Safety_1_SS2 Populations, 
Safety_2_SS1 and Safety_2_SS2 Populations, and ALL_UPA Population, respectively.
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 the Medical Dictionary for Regulatory Activities (MedDRA).  Treatment-emergent AEs in 
each period are defined as those that began or worsened in severity after the first dose of study drug in 
each period and up to the minimum of the end date of each period and 30 days after the last dose of the 
study drug in each period.  The number and percentage of subjects experiencing TEAEs in each period 
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and across study periods by the upadacitinib doses will be tabulated using the MedDRA SOC and PT, by 
severity, and by relationship to the study drug as assessed by the investigator.  Summaries (including 
number of subjects, percentages and events per 100 patient-years) of SAEs, deaths, AEs leading to 
discontinuation, and AESI will be provided in each period and across study periods by the upadacitinib 
doses as well.
For laboratory and vital signs, mean change from Baseline will be summarized in each period and 
percentage of subject with evaluations meeting criteria for pre-defined Potentially Clinically Significant 
values will be summarized in each period and across study periods by the upadacitinib doses.  For 
selected laboratory parameters, a shift table analysis will be provided in each period and across study 
periods by the upadacitinib doses.
7.6 Sample Size Determination
Assuming:

In SS1, 54% of subjects would be EASI 90 non-responders at Week 12.

In SS2, 65% of the subjects would be EASI 90 responders at Week 12.

There would be no more than 8% dropouts every 12 weeks.
A total sample size of 454 subjects will result in at least 96 subjects in SC1 and SC4, to ensure the half 
width of 95% CI will be within 10% for EASI 90 response estimation at Week 24.
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.
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.
For subjects in Japan only:  This study will be conducted in Good Clinical Practice (GCP) compliance with 
Good Post-marketing Study Practice (GPSP).
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8.3 Subject Confidentiality
For personal data that AbbVie controls and maintains, AbbVie has developed a robust security program 
to protect subject personal data focused on due diligence in design, managed change, and information 
security governance Information security policies govern the information security functions including 
identity and access management, operations, infrastructure, application, and third-party security 
requirements.  The risk-based AbbVie Data Classification Tool dictates the level of scrutiny and control 
required for the relevant activities per AbbVie's information security policies taking into account the 
sensitivity of the data.
Before data is shared with AbbVie, the study doctor and staff will replace any information that could 
directly identify a subject (such as name, address, and contact information) with a generic code which 
AbbVie cannot link to that subject's identity in order to protect the confidentiality of the data.
AbbVie has a Data Protection Impact Assessment program to ensure and document the appropriate 
controls and safeguards stated above are in place for clinical trial data that it controls and maintains, 
and these processing activities respect privacy of clinical trial subjects.  AbbVie also maintains robust 
security incident response policies and procedures, including requirements for the containment of any 
data-related incidents, the mitigation measures where needed, and notification to authorities or 
affected individuals where required.
AbbVie as the sponsor shall document any personal data breaches for which it is a controller and notify 
where required the competent national supervisory authority and/or affected participants and/or 
principal investigator and/or site personnel without undue delay and at the latest within 48 hours after 
becoming aware of such an incident. The sponsor shall create and maintain appropriate records of such 
an incident.
9 SOURCE DOCUMENTS AND CASE REPORT FORM 
COMPLETION
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported.  All source documents should be attributable, legible, contemporaneous, original, 
accurate, and complete to ensure accurate interpretation of data.  Clinical site monitoring is conducted 
to ensure that the rights and well-being of human subjects are protected, that the reported trial data 
are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the 
currently approved protocol, ICH GCP, and applicable local regulatory requirement(s), including EU 
Clinical Trial Regulation 536/2014.  During the COVID-19 pandemic, remote data review/verification may 
be employed if allowed by the local regulatory authority, IRB/IEC, and the study site.
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, including EU Clinical Trial Regulation 536/2014.
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11
START AND COMPLETION OF THE STUDY
The start-of-study is defined as the date of the first activated site.
The end-of-study is defined as the date of end of study participation by the last subject in the last 
country where the study was conducted.  
12
REFERENCES
1.
Murray PJ. The JAK-STAT signaling pathway: input and output integration. J Immunol. 
2007;178(5):2623-9.
2.
Vaddi K, Luchi M. JAK inhibition for the treatment of rheumatoid arthritis: a new era in oral DMARD 
therapy. Expert Opin Investig Drugs. 2012;21(7):961-73.
3.
Cheung TT, McInnes IB. Future therapeutic targets in rheumatoid arthritis? Semin Immunopathol. 
2017;39(4):487-500.
4.
Iwata S, Tanaka Y. Progress in understanding the safety and efficacy of Janus kinase inhibitors for 
treatment of rheumatoid arthritis. Expert Rev Clin Immunol. 2016;12(10):1047-57.
5.
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.
6.
McInnes IB, Szekanecz Z, McGonagle D, et al. A review of JAK-STAT signalling in the pathogenesis of 
spondyloarthritis and the role of JAK inhibition. Rheumatology (Oxford). 2021.
7.
Guttman-Yassky E, Teixeira HD, Simpson EL, et al. Once-daily upadacitinib versus placebo in 
adolescents and adults with moderate-to-severe atopic dermatitis (Measure Up 1 and Measure Up 
2): results from two replicate double-blind, randomised controlled phase 3 trials. Lancet. 
2021;397(10290):2151-68.
8.
Reich K, Teixeira HD, de Bruin-Weller M, et al. Safety and efficacy of upadacitinib in combination 
with topical corticosteroids in adolescents and adults with moderate-to-severe atopic dermatitis (AD 
Up): results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 
2021;397(10290):2169-81.
9.
RINVOQ [SmPC]. Ludwigshafen, Germany; AbbVie Deutschland GmbH & Co. KG. Available from: 
https://www.ema.europa.eu/en/documents/product-information/rinvoq-epar-product-
information_en.pdf, 2021.
10. Silverberg JI, Gooderham M, Katoh N, et al. Optimizing the management of atopic dermatitis with a 
new minimal disease activity concept and criteria and consensus-based recommendations for 
systemic therapy.  Poster presented at the Revolutionizing Atopic Dermatitis (RAD) Virtual 
Conference, December 11, 2022.
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11. Ytterberg SR, Bhatt DL, Mikuls TR, et al. Cardiovascular and cancer risk with tofacitinib in rheumatoid 
arthritis. N Engl J Med. 2022;386(4):316-26.
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APPENDIX A. STUDY-SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
Ab
antibody
AD
atopic dermatitis
ADerm-IS
Atopic Dermatitis Impact Scale 
ADerm-SS
Atopic Dermatitis Symptom Scale 
ADL
activities of daily living
AE
Adverse event
AESIs
AE of special interest
Ag
antigen
ALC
Absolute lymphocyte count
ALT
alanine transaminase
ANC
Absolute neutrophil count
AO
As Observed
AST
aspartate transaminase
axSpA
axial spondyloarthritis
BCG
bacilli Calmette-Guérin
BSA
body surface area
CD
Crohn's disease
CI
confidence interval
COVID-19
Coronavirus Disease – 2019
CPK
creatine phosphokinase
CRP
C-reactive protein
CS
Clinically significant
CTCAE
Common Terminology Criteria for Adverse Events
CTEP
Cancer Treatment Evaluation Program
CXR
chest x-ray
CYP3A
cytochrome P450 3A
DLQI
Dermatology Life Quality Index
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DTP
direct-to-patient
DVT
deep vein thrombosis
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EASI
Eczema Area and Severity Index
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
electronic case report form
EDC
Electronic data capture
FAS
Full analysis set
FSH
follicle-stimulating hormone
GCA
giant cell arteritis
GCP
Good clinical practice
GFR
glomerular filtration rate
GI
gastrointestinal
GPSP
Good Post-marketing Study Practice
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HCV Ab
HCV antibody
HIV
Human immunodeficiency virus
HIV Ab
HIV antibody
hsCRP
High-sensitivity C Reactive Protein
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use
IEC
Independent ethics committee
IEC/IRB
Independent Ethics Committee/Institutional Review Board
IFN
interferon
IGRA
Interferon-Gamma Release Assay
IL
interleukin
IMP
Investigational Medicinal Product
INR
International normalized ratio
IRB
Institutional review board
IRT
Interactive response technology
ITT
Intent to Treat
IU
International Unit
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
JAK
Janus kinase
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JAK1
Janus kinase 1
JAK2
Janus kinase 2
MACE
major adverse cardiovascular event
MCID
minimum clinically important difference
MDA
minimal disease activity
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
mRNA
messenger ribonucleic acid
N/A
not applicable
NCI
National Cancer Institute
NCS
Not clinically significant
NMSC
non-melanoma skin cancer
NRS
Numerical Rating Scale
OR
odds ratio
PCR
Polymerase chain reaction
PD
Premature discontinuation
PD Visit
Premature Discontinuation visit
PDE4
phosphodiesterase type 4
PGI
Patient Global Impression
PGIS
Patient Global Impression of Severity
PGIT
Patient Global Impression of Treatment
PK
Pharmacokinetic(s)
POEM
Patient Oriented Eczema Measure
PPD
purified protein derivative
PPE
Personal Protective Equipment
PRO
patient reported outcomes
PsA
psoriatic arthritis
PT
preferred term
PUVA
psoralen and ultraviolet A
QD
once daily
QoL
quality of life
QTcF
QT interval corrected for heart rate using Fridericia's formula
RA
rheumatoid arthritis
RNA
ribonucleic acid
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ROA
Route of Administration
RSI
Reference Safety Information
SAE
Serious adverse event
SAP
Statistical analysis plan
SAR
serious adverse reaction
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SC1
Study Cohort 1
SC2
Study Cohort 2
SC3
Study Cohort 3
SC4
Study Cohort 4
SmPC
Summary of Product Characteristics
SOC
System Organ Class
SS1
Sub-Study 1
SS2
Sub-Study 2
SUSAR
Suspected unexpected serious adverse reactions
TA MD
Therapeutic Area Medical Director
TA SD
Therapeutic Area Scientific Director
TB
tuberculosis
TEAEs
treatment emergent adverse events
TNF
tumor necrosis factor
TYK2
tyrosine kinase 2
ULN
upper limit of normal
UV
Ultra-violet
vIGA-AD
validated Investigator´s Global Assessment for AD
WBC
white blood cell
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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M22-000:  A Phase 3b/4 Randomized, Blinded, Treat-to-Target and Dose-Flexibility Study of Upadacitinib 
in Adult Subjects with Moderate to Severe Atopic Dermatitis (Flex-Up)
Protocol Date: 21 December 2023
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practices (GCP) and local laws and 
regulations and guidelines governing the study at the site location.  In signing the Investigator Agreement, the 
investigator is agreeing to the following:
1.
Conducting the study in accordance with ICH GCP, the applicable regulatory requirements, current 
protocol and operations manual, and making changes to a protocol only after notifying AbbVie and the 
appropriate Institutional Review Board (IRB)/Independent Ethics Committee (IEC), except when necessary 
to protect the subject from immediate harm.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for investigational 
purposes and complying with the requirements relating to informed consent and ethics committees (e.g., 
IEC or IRB) review and approval of the protocol and its amendments.
4.
Reporting complaints that occur in the course of the investigation(s) to AbbVie.
5.
Reading the information in the Investigator's Brochure/safety material provided, including the 
instructions for use and the potential risks and side effects of the investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the study about their 
obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making those records available 
for inspection by representatives of AbbVie and/or the appropriate regulatory agency, and retaining all 
study-related documents until notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and approved the initial clinical 
protocol and all of its amendments.
9.
Reporting promptly (within 1 calendar day) to AbbVie, the ethics committees/institutional review boards 
(as required) and other appropriate individuals (e.g., coordinating investigator, institution director):

All changes in the research activity and all unanticipated problems involving risks to human subjects 
or others.

Any departure from relevant clinical trial law or regulation, GCP, or trial protocol that has the 
potential to affect the following:

Rights, safety, physical or mental integrity of the subjects in the trial.

Scientific value of the clinical trial, reliability, or robustness of data generated.
10. 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.
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
Page 55 of 108
 


STUDY M22-000  |  Version 3.0  |  EU CT 2023-504869-23-00  
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX C. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
Global Medical Affairs, Dermatology
Global Medical Affairs
Statistics
Page 56 of 108
 


STUDY M22-000  |  Version 3.0  |  EU CT 2023-504869-23-00  
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX D. ACTIVITY SCHEDULE
The following table shows the required activities across the Screening and subsequent study visits.  The 
individual activities are described in detail in the Operations Manual (Appendix F).  Allowed 
modifications due to COVID-19 are detailed in the Operations Manual.
Page 57 of 108
 








STUDY M22-000  |  Version 3.0  |  EU CT 2023-504869-23-00  
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX E. PROTOCOL SUMMARY OF CHANGES
Previous Protocol Versions
Protocol
Date
Version 1.0
08 April 2022
Version 2.0
01 February 2022
Administrative Change 1
05 April 2023
The purpose of this version is to update the protocol regarding EU Clinical Trial Regulation requirements, 
and to align the protocol with updated safety standards for upadacitinib study protocols.
The following changes were made for Version 3.0 of this protocol: 
Protocol

Applied administrative change and minor text edits as needed.  

Title page: Updated with EU CT number, updated Sponsor/Emergency Medical Contact 
information.

Section 1 (Synopsis): Updated to align with version 3.0 revisions. 

Section 2.1 (Background and Rationale): Updated approvals for treatment with upadacitinib.

Section 2.2 (Benefits and Risks to Subjects): Added AEs that have been observed in patients 
receiving JAK inhibitors including upadacitinib.

Section 5.2 (Contraception Recommendations): Updated language for females of childbearing 
potential, added section on Contraceptive Counseling.

Section 5.3 (Prohibited Medications and Therapy): 

Updated list of prohibited biological therapies with immunosuppressive potential.

Updated examples of commonly used strong CYP3A inhibitors and inducers.

Section 5.4 (Prior and Concomitant Therapy): 

Added language to indicate that subjects should not have received a COVID-19 vaccination 
in the 7 days prior to randomization or plan to receive a COVID-19 vaccination within the 
first 7 days after initiation of study drug.

Section 5.5 (Withdrawal of Subjects and Discontinuation of Study): 

Updated language indicating that laboratory results or AEs that either meet the criteria for 
discontinuation of study drug, or rule out safe continuation of the study drug, would be 
determined by the investigator.

Updated malignancy language.

Added Section 5.11, Publication Policy.

Section 6.1 (Complaints and Adverse Events):
Page 61 of 108
 


STUDY M22-000  |  Version 3.0  |  EU CT 2023-504869-23-00  
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

Added Malignancy and Hypersensitivity Reactions and corresponding eCRFs.

Added language for SUSAR reporting in the EU.

Added Fractures and Retinal detachment to list of AESIs.

Section 6.2 (Toxicity Management): 

Updated language for management of serious infections, muscle-related symptoms, 
thrombosis events, and COVID-19.

Updated Elective and Emergency Surgeries to indicate that elective surgery prior to study 
primary endpoint must be discussed with the TA MD and performed with TA MD approval.

Section 8.3 (Subject Confidentiality): Added language regarding the documentation of personal 
data breaches.

Section 9 (Source Documents and Case Report Form Completion), Section 10 (Data Quality 
Assurance): Added Regulation [EU] No 536/2014.

Appendix D (Activity Schedule): 

To update the study activities table to allow for ADerm-SS and ADerm-IS PROs to be 
collected at the Baseline visit on the site tablet device).
Operations Manual

Applied administrative changes and minor text edits as needed.  

Section 1 (Contacts): Updated Sponsor/Emergency Medical Contact information.

Section 2.1 (Individual Treatment Period Visit Activities): 

Added review and documentation of compliance with pregnancy avoidance 
recommendations for females of childbearing potential.

Updated Baseline visit with language for Post-Baseline Visits.

Section 3.4 (Adverse Event Assessment): Updated to specify SAEs as protocol-related.

Section 3.5 (Patient-Reported Outcomes): 

Updated to indicate that The PRO instruments to be completed on the site device at 
scheduled study visits should be done before any interaction with site personnel has 
occurred (e.g., before drug administration, clinical assessments, and discussion of AEs or 
any review of laboratory findings) to avoid biasing the subject's response.

Updated to indicate that ADerm-SS and ADerm-IS will be administered on electronic 
handheld devices from Baseline through Week 24.

Section 3.12 (Physical Examinations and Assessments): Updated CXR and Vaccine requirements.

Section 3.14 (Clinical Laboratory Tests): 

Updated to indicate that the investigator will record the laboratory result as an adverse 
event if the out-of-range value results in discontinuation of study drug, or necessitates 
therapeutic medical intervention.
Page 62 of 108
 


STUDY M22-000  |  Version 3.0  |  EU CT 2023-504869-23-00  
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

Added QuantiFERON-TB Gold Plus and Varicella antibody tests to Local Laboratory Tests.

Indicated that results of any HIV antibody testing will be retained by the study site under 
confidential restrictions.

Added language for Beta-D Glucan Testing (for Japan only).

Updated TB testing procedures.

Updated language for indeterminate QuantiFERON-TB Gold Plus test.

Section 4.1 (Methods and Timing of Safety Assessment): Added supplemental eCRFs for 
Malignancy and Hypersensitivity Reactions.

Section 4.2 (Reporting Adverse Events and Intercurrent Illnesses): updated SUSAR language to 
specify as in accordance with global and local requirements.
Page 63 of 108
 

SAP_001.pdf: 
Upadacitinib
M22-000 – Statistical Analysis Plan
Version 2.0 – 27 August 2024
1
Statistical Analysis Plan for Study M22-000
A Phase 3b/4 Randomized, Blinded, Treat-to-Target 
and Dose-Flexibility Study of Upadacitinib in Adult 
Subjects with Moderate to Severe Atopic Dermatitis 
(Flex-Up)
Version 2.0
NCT05507580


Upadacitinib
M22-000 – Statistical Analysis Plan
Version 2.0 – 27 August 2024
2
Table of Contents
1.0
Introduction...........................................................................5
2.0
Study Objectives and Design ................................................5
2.1
Study Objectives, Hypotheses and Estimands......................................... 5
2.2
Study Design Overview.......................................................................... 6
2.3
Treatment Assignment and Blinding....................................................... 8
2.4
Sample Size Determination .................................................................... 9
3.0
Endpoints...............................................................................9
3.1
Primary Endpoint ................................................................................... 9
3.2
Secondary Endpoints.............................................................................. 9
3.3
Additional Efficacy Endpoints.............................................................. 10
3.4
Safety Endpoint(s)................................................................................ 12
4.0
Analysis Populations ...........................................................13
5.0
Subject Disposition..............................................................15
6.0
Study Treatment Duration and Compliance .....................16
7.0
Subject Characteristics .......................................................17
7.1
Demographics and Baseline Characteristics.......................................... 17
7.2
Medical History and Prior and Concomitant Medications ..................... 19
7.3
Protocol Deviations .............................................................................. 20
8.0
Handling of Potential Intercurrent Events for the 
Primary and Secondary Endpoints ....................................21
9.0
Efficacy Analyses.................................................................21
9.1
General Considerations......................................................................... 21
9.2
Handling of Missing Data..................................................................... 22
9.3
Primary Efficacy Endpoint(s) and Analyses.......................................... 22
9.3.1
Primary Efficacy Endpoint ................................................................... 22
9.3.2
Main Analysis of Primary Efficacy Endpoint........................................ 23
9.3.3
Sensitivity and Supplementary Analyses of the Primary Efficacy 
Endpoint............................................................................................... 23
9.4
Secondary Efficacy Endpoints and Analyses ........................................ 23
9.4.1
Secondary Efficacy Endpoints.............................................................. 23
9.4.2
Main Analyses of Secondary Efficacy Endpoints.................................. 24


Upadacitinib
M22-000 – Statistical Analysis Plan
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3
9.4.3
Sensitivity and Supplementary Analyses for Secondary Efficacy 
Endpoints ............................................................................................. 25
9.5
Additional Efficacy Endpoints and Analyses ........................................ 25
9.6
Efficacy Subgroup Analyses................................................................. 25
9.7
Analysis of Daily Efficacy Measurement.............................................. 26
10.0
Safety Analyses....................................................................26
10.1
General Considerations......................................................................... 26
10.2
Adverse Events..................................................................................... 27
10.2.1
Treatment-Emergent Adverse Events.................................................... 27
10.2.2
Adverse Event Overview...................................................................... 28
10.2.3
Treatment-Emergent Adverse Events by SOC and/or PT ...................... 29
10.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure .............................................................................................. 30
10.2.5
Deaths, Serious Adverse Events, and Adverse Events Leading to 
Study Treatment Discontinuation.......................................................... 30
10.2.6
Adverse Events of Special Interest........................................................ 31
10.3
Analysis of Laboratory Data................................................................. 32
10.4
Analysis of Vital Signs......................................................................... 33
10.5
Safety Topics of Interest....................................................................... 34
10.6
Other Safety Analyses .......................................................................... 34
10.7
Safety Subgroup Analyses.................................................................... 34
11.0
Other Analyses ....................................................................34
12.0
Interim Analyses..................................................................34
12.1
Data Monitoring Committee................................................................. 35
13.0
Overall Type-I Error Control.............................................35
14.0
Version History ...................................................................35
14.1
Changes to Planned Analyses in the Protocol........................................ 35
15.0
References............................................................................36
List of Tables
Table 1.
Analyses Populations: ITT Populations and Safety Populations ............ 15
Table 2.
Analysis Models and Imputation Methods ............................................ 21


Upadacitinib
M22-000 – Statistical Analysis Plan
Version 2.0 – 27 August 2024
4
Table 3.
Summary of the Estimand Attributes Corresponding to the 
Primary Efficacy Objective .................................................................. 23
Table 4.
Summary of the Estimand Attributes Corresponding to the 
Secondary Efficacy Objectives ............................................................. 25
Table 5.
SAP Version History Summary ............................................................ 35
List of Figures
Figure 1.
Study Schematic..................................................................................... 8
List of Appendices
Appendix A.
List of SAP Signatories ........................................................................ 37
Appendix B.
Definition of Adverse Events of Special Interest................................... 38
Appendix C.
Rescue Definition................................................................................. 41
Appendix D.
Potentially Clinically Important Criteria for Safety Endpoints .............. 42
Appendix E.
National Cholesterol Education Program (NCEP) Adult 
Treatment Panel III (ATPIII) for Selected Lipid Parameters ................. 44


Upadacitinib
M22-000 – Statistical Analysis Plan
Version 2.0 – 27 August 2024
5
1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for ABT-494 
Study M22-000 (Flex-Up) "A Phase 3b/4 Randomized, Blinded, Treat-to-Target and 
Dose-Flexibility Study of Upadacitinib in Adult Subjects with Moderate to Severe Atopic 
Dermatitis (Flex-Up)."
This study aims to provide descriptive data on the efficacy and safety of dose escalation to 
upadacitinib 30 mg once daily (QD) and dose reduction to upadacitinib 15 mg QD based 
on a clinical response after 12 weeks of treatment. This data will inform the clinical 
management for subjects with moderate to severe AD treated with both approved doses of 
upadacitinib.
The analyses of pharmacodynamic biomarker endpoints will not be covered in this SAP.
The SAP will not be updated in case of administrative changes or amendments to the 
protocol unless the changes impact the analysis.
Unless noted otherwise, all analyses will be performed using SAS Version 9.4 (SAS 
Institute Inc., Cary, NC  27513) or later under the UNIX operating system.
2.0
Study Objectives and Design
2.1
Study Objectives, Hypotheses and Estimands
The primary study objectives are:
1.
Sub-Study 1 (SS1):  The primary study objective for SS1 is to evaluate the 
efficacy and safety of dose escalation to upadacitinib 30 mg QD in subjects who 
do not achieve Eczema Area and Severity Index (EASI) 90 on upadacitinib 15 mg 
QD after 12 weeks.
2.
Sub-Study 2 (SS2):  The primary study objective for SS2 is to evaluate the 
efficacy and safety of dose reduction to upadacitinib 15 mg QD in subjects who 
achieve EASI 90 on upadacitinib 30 mg QD after 12 weeks.


Upadacitinib
M22-000 – Statistical Analysis Plan
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6
The additional objective is to generate evidence on patient impact (patient reported 
outcomes [PROs]) with upadacitinib treatment based on a clinical response target 
(EASI 90) (Treat-to-Target).
No hypothesis testing will be performed in this study.
The estimand corresponding to the primary endpoint is defined as:
●
The proportion of subjects who achieve EASI 90 at Week 24, regardless of 
treatment discontinuation, with upadacitinib treatments (upadacitinib 15 mg or 
30 mg QD) in adult subjects with moderate to severe AD.
2.2
Study Design Overview
This is a Phase 3b/4, randomized, blinded, treat-to-target, dose-flexibility, multi-center 
study that will evaluate upadacitinib, as monotherapy, in approximately 454 adult subjects 
(≥ 18 and < 65 years of age) with moderate to severe AD who are candidates for systemic 
therapy.
The study is comprised of a 35-day Screening Period, a 12-week double-blind period and 
a 12-week single-blind period. During the single-blind period, subjects will be blinded to 
the upadacitinib dose and EASI score evaluations.
The study treatment duration will be 24 weeks.
After the last study visit, a 30-day follow-up visit (or phone call if a visit is not possible) 
will be completed to determine the status of any new or ongoing AEs/SAEs and 
concomitant medications.
Subjects who meet the eligibility criteria will be randomized in a 1:1 ratio to enter SS1 to
receive oral doses of upadacitinib 15 mg QD at Baseline or SS2 to receive oral doses of 
upadacitinib 30 mg QD at Baseline.


Upadacitinib
M22-000 – Statistical Analysis Plan
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7
●
SS1:
○
Subjects randomized to enter the SS1 at Baseline will receive oral doses of 
upadacitinib 15 mg QD during the 12-week double-blind period.
○
At Week 12, subjects from SS1 receiving upadacitinib 15 mg QD will be 
reassigned based on their EASI response, which is calculated based on the 
observed EASI value regardless of use of rescue medications:
●
Subjects achieving a < 90% reduction in EASI (< EASI 90) will be 
allocated to receive oral doses of upadacitinib 30 mg QD. This 
constitutes the Study Cohort 1 (SC1).
●
Subjects achieving a ≥ 90% reduction in EASI (≥ EASI 90) will 
continue to receive oral doses of upadacitinib 15 mg QD. This 
constitutes the Study Cohort 2 (SC2).
●
SS2:
○
Subjects randomized to enter SS2 at Baseline will receive oral doses of 
upadacitinib 30 mg QD during the 12-week double-blind period.
○
At Week 12, subjects from SS2 receiving upadacitinib 30 mg QD will be 
reassigned based on their EASI response, which is calculated based on the 
observed EASI value regardless of use of rescue medications:
●
Subjects achieving < EASI 90 will continue to receive oral doses of 
upadacitinib 30 mg QD. This constitutes the Study Cohort 3 (SC3).
●
Subjects achieving ≥ EASI 90 will be allocated to receive oral doses of 
upadacitinib 15 mg QD. This constitutes the Study Cohort 4 (SC4).
The final and only database lock will occur at the end of the study.
The schematic of the study is shown in Figure 1.


Upadacitinib
M22-000 – Statistical Analysis Plan
Version 2.0 – 27 August 2024
8
Figure 1.
Study Schematic
2.3
Treatment Assignment and Blinding
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 study will be randomized 
in a 1:1 ratio to one of the 2 treatment groups:
●
Upadacitinib 15 mg QD
●
Upadacitinib 30 mg QD
The study will be stratified by Baseline vIGA-AD categories (3; 4) and prior use of 
dupilumab (yes; no).


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M22-000 – Statistical Analysis Plan
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9
During the 12-week double-blind period, study sites and subjects will remain blinded. 
During the single blind period, only the subjects will be blinded to the upadacitinib dose 
and the EASI score evaluations. 
2.4
Sample Size Determination
By Assuming:
●
In SS1, 54% of subjects would be EASI 90 non-responder at Week 12.
●
In SS2, 65% of the subjects would be EASI 90 responder at Week 12.
●
There would be no more than 8% dropouts every 12 weeks.
A total sample size of 454 subjects will result in at least 96 subjects in SC1 and SC4, to 
ensure the half width of 95% CI will be within 10% for EASI 90 response estimation at 
Week 24.
3.0
Endpoints
3.1
Primary Endpoint
The primary endpoint is:
●
Achievement of EASI 90 at Week 24.
3.2
Secondary Endpoints
The secondary endpoints are:
●
Achievement of EASI 75/100 at Week 24.
●
Achievement of EASI 75/90/100 at Week 12.
●
Achievement of EASI 90 and a Worst Pruritus NRS of 0 or 1 for subjects with 
Worst Pruritus NRS > 1 at Baseline at Week 12 and Week 24.
●
Achievement of vIGA-AD of 0 or 1 at Week 12.
●
Achievement of vIGA-AD of 0 or 1 at Week 24


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●
Achievement of an improvement (reduction) in Worst Pruritus NRS ≥ 4 for 
subjects with Worst Pruritus NRS ≥ 4 at Baseline at Week 12.
●
Achievement of an improvement (reduction) in Worst Pruritus NRS ≥ 4 for 
subjects with Worst Pruritus NRS ≥ 4 at Baseline at Week 24. 
●
Achievement of Worst Pruritus NRS of 0 or 1 for subjects with Worst Pruritus 
NRS > 1 at Baseline at Week 12.
●
Achievement of Worst Pruritus NRS of 0 or 1 for subjects with Worst Pruritus 
NRS > 1 at Baseline at Week 24.
●
Achievement of an improvement (reduction) from Baseline in DLQI ≥ 4 for 
subjects with DLQI ≥ 4 at Baseline at Week 12. 
●
Achievement of an improvement (reduction) from Baseline in DLQI ≥ 4 for 
subjects with DLQI ≥ 4 at Baseline at Week 24. 
●
Achievement of DLQI 0/1 for subjects with DLQI > 1 at Baseline at Week 12.
●
Achievement of DLQI 0/1 for subjects with DLQI > 1 at Baseline at Week 24.
3.3
Additional Efficacy Endpoints
All variables listed as primary or secondary endpoints will be analyzed at all applicable 
visits other than those listed above. In addition, the following endpoints will be evaluated 
at all applicable visits unless otherwise specified. Additional Efficacy Endpoints are:
●
Experience of a loss of response after Week 12 until Week 24 (defined as a 
loss of at least 50% of the EASI improvement gained from Baseline to 
Week 12) among subjects who had an EASI 90 response at Week 12.
●
Achievement of EASI score < 7 / < 3 / < 1.
●
Achievement of Worst Pruritus NRS of 0 for subjects with Worst Pruritus 
NRS >0 at Baseline.
●
Achievement of an improvement (reduction) in Patient Oriented Eczema 
Measure (POEM) ≥ 4 from Baseline for subjects with POEM ≥ 4 at Baseline.
●
Achievement of POEM ≤ 2 /  0 for subjects with POEM > 2 / > 0 at Baseline, 
respectively.


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●
Achievement of POEM Itch item score of 0 for subjects with POEM Itch item 
score >0 at Baseline.
●
Achievement of POEM Sleep item score of 0 for subjects with POEM Sleep 
item score > 0 at Baseline.
●
Change and percent change from Baseline in Patient Global Impression of 
Severity (PGIS).
●
Achievement of "Minimal" or "Absent" on the PGIS for subjects who are 
"Mild" or worse on the PGIS at Baseline.
●
Achievement of "Absent" on the PGIS for subjects who are "Minimal" or 
worse on the PGIS at Baseline.
●
Change and percent change from Baseline in Patient Global Impression of 
Treatment (PGIT).
●
Achievement of "Extremely satisfied" or "Very satisfied" on the PGIT for 
subjects who are "Somewhat satisfied" or worse on the PGIT at Baseline.
●
Achievement of "Extremely Satisfied" on the PGIT for subjects who are "Very 
satisfied" or worse on the PGIT at Baseline.
●
Achievement of an improvement (reduction) in Atopic Dermatitis Impact 
Scale (ADerm-IS) Sleep ≥ 12 from Baseline for subjects with ADerm-IS Sleep 
≥12 at Baseline.
●
Achievement of an improvement (reduction) in ADerm-IS Emotional State 
≥11 from Baseline for subjects with ADerm-IS Emotional State ≥11 at 
Baseline.
●
Achievement of an improvement (reduction) in ADerm-IS Daily Activities 
≥14 from Baseline for subjects with ADerm-IS Daily Activities ≥ 14 at 
Baseline.
●
Achievement of ADerm-IS Sleep ≤3 /
0 for subjects with ADerm-IS Sleep 
> 3/> 0 at Baseline, respectively.
●
Achievement of ADerm-IS Daily Activities ≤2 /
0 for subjects with 
ADerm-IS Daily Activities > 2/> 0 at Baseline, respectively.
●
Achievement of ADerm-IS Emotional State ≤2 /
0 for subjects with 
ADerm-IS Emotional State > 2/> 0 at Baseline, respectively.


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●
Achievement of an improvement (reduction) in Atopic Dermatitis Symptom 
Scale (ADerm-SS) Skin Pain ≥ 4 from Baseline for subjects with ADerm-SS 
Skin Pain ≥ 4 at Baseline.
●
Achievement of ADerm-SS Skin Pain ≤1 /  0 for subjects with ADerm-SS 
Skin Pain > 1/> 0 at Baseline, respectively.
●
Achievement of an improvement (reduction) in ADerm-SS 7-item total 
symptom score (TSS-7) ≥28 from Baseline for subjects with ADerm-SS 
TSS-7 ≥ 28 at Baseline.
●
Achievement of ADerm-SS TSS-7 ≤11 / ≤1 for subjects with ADerm-SS 
TSS-7 > 11 / > 1 at Baseline, respectively.
●
Achievement of EASI 75 / 90, for subjects who experienced an inadequate 
response to previous treatment with dupilumab for AD as reported by the 
investigator
●
Achievement of EASI 90 and a Worst Pruritus NRS of 0 or 1, for subjects with 
Worst Pruritus NRS > 1 at Baseline and experienced an inadequate response to 
previous treatment with dupilumab for AD as reported by the investigator.
●
Achievement of EASI 75 / 90, for subjects who were previously treated with 
dupilumab for AD.
●
Achievement of EASI 90 and a Worst Pruritus NRS of 0 or 1, for subjects with 
Worst Pruritus NRS > 1 at Baseline and were previously treated with 
dupilumab for AD.
●
For subjects participating in the Wearable Tool Substudy:
○
Change from Baseline in average nightly nocturnal scratch: total scratch 
time and number of scratch events.
○
Change from Baseline in the following sleep parameters: total sleep time, 
wake after sleep onset, sleep efficiency, and sleep onset latency.
3.4
Safety Endpoint(s)
The following endpoints will be included in the safety analyses:
●
Treatment emergent adverse events (TEAEs);


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●
Serious adverse events (SAEs);
●
Adverse events of special interest (AESIs);
●
Adverse events (AEs) leading to discontinuation;
●
Vital signs and laboratory tests.
Laboratory assessments will include hematologic parameters, chemistry, liver function 
tests, and lipid parameters.
4.0
Analysis Populations
For simplicity, the double-blind period and the single-blind period are denoted by DB 
period and SB period respectively. The following population sets will be used for the 
analyses.
The Intent-to-Treat (ITT) Populations for the efficacy analyses are defined as:
●
ITT Population of SS1 in DB Period (ITT 1 SS1 Population) includes all 
subjects who are randomized into SS1.
●
ITT Population of SS1 in SB Period (ITT 2 SS1 Population) includes all 
subjects who are randomized into SS1 at Baseline and continued into SB 
Period.
●
ITT Population of SS2 in DB Period (ITT 1 SS2 Population) includes all 
subjects who are randomized into SS2.
●
ITT Population of SS2 in SB Period (ITT 2 SS2 Population) includes all 
subjects who are randomized into SS2 at Baseline and continued into SB 
Period.
The Safety Populations for the safety analyses are defined as:
●
Safety Population of SS1 in DB Period (Safety 1 SS1 Population) consists of 
all subjects who are randomized into SS1 and received at least 1 dose of study 
drug in DB Period.


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●
Safety Population of SS1 in SB Period (Safety 2 SS1 Population) consists of 
all subjects who received at least 1 dose of study drug in SB Period of SS1.
●
Safety Population of SS2 in DB Period (Safety 1 SS2 Population) consists of 
all subjects who are randomized into SS2 and received at least 1 dose of study 
drug in DB Period.
●
Safety Population of SS2 in SB Period (Safety 2 SS2 Population) consists of 
all subjects who received at least 1 dose of study drug in SB Period of SS2.
●
Safety Population for all upadacitinib treatment (ALL UPA Population) 
consists of all subjects who received at least 1 dose of upadacitinib in the 
study. This population includes two cohorts: All UPA 15 mg and All UPA 
30 mg. All UPA 15 mg cohort consists of all subjects who received at least 1 
dose of upadacitinib 15 mg in SS1 and SS2 (only count exposure to 15 mg). 
All UPA 30 mg consists of all subjects who received at least 1 dose of 
upadacitinib 30 mg in SS1 and SS2 (only count exposure to 30 mg). All safety 
analysis based on ALL UPA Population will be summarized by the above two 
cohorts.
These populations will be used to provide a comprehensive summary of safety based on 
treatment received regardless of randomization. 


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Table 1.
Analyses Populations: ITT Populations and Safety Populations
Analyses Populations
Study Period
Analyses Groups
ITT 1 SS1
DB Period
UPA 15 mg QD
ITT 1 SS2
UPA 30 mg QD
ITT 2 SS1
SB Period
UPA 15/15 mg QD
UPA 15/30 mg QD
ITT 2 SS2
UPA 30/15 mg QD
UPA 30/30 mg QD
Safety 1 SS1
DB Period
UPA 15 mg QD
Safety 1 SS2
UPA 30 mg QD
Safety 2 SS1
SB Period
UPA 15/15 mg QD
UPA 15/30 mg QD
Safety 2 SS2
UPA 30/15 mg QD
UPA 30/30 mg QD
ALL UPA
During the upadacitinib 
administration
All UPA 15 mg QD
All UPA 30 mg QD
5.0
Subject Disposition
In the DB Period, the number of subjects for each of the following categories will be 
summarized overall and by the two sub-studies in the ITT 1 Populations:
●
Subjects randomized
●
Subjects randomized and dosed in DB Period
●
Subjects who completed DB Period
●
Subjects who completed study drug in DB Period
●
Subjects who prematurely discontinued study in DB Period 
●
Subjects who prematurely discontinued study drug in DB Period
●
Subjects who initiated rescue medications in DB Period


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The summary will be provided for SB Period for each of the following categories by the 
four study cohorts in the ITT 2 Populations:
●
Subjects who entered SB Period
●
Subjects dosed in SB Period
●
Subjects who completed SB Period
●
Subjects who completed study drug in SB Period
●
Subjects who prematurely discontinued study in SB Period
●
Subjects who prematurely discontinued study drug in SB Period
●
Subjects who initiated the rescue medications in SB Period
6.0
Study Treatment Duration and Compliance
For the DB Period and the SB Period, the duration of treatment will be summarized by 
sub-studies and treatment groups using Safety 1 and Safety 2 Populations, respectively. 
DB Period:
●
For subjects who did not continue into SB Period:
○
Date of last dose of study drug in DB Period
Date of first dose of study 
drug in DB Period + 1.
●
For subjects who continued into SB Period: 
○
Minimum of (Date of first dose of study drug in SB Period Date of first 
dose of study drug in DB Period, Date of last dose of study drug in DB 
Period Date of first dose of study drug in DB Period + 1.)
SB Period:
For subjects who continued into SB Period:
●
Date of last dose of study drug in SB Period Date of first dose of study drug 
in SB Period + 1.


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ALL UPA:
Study drug duration during the administration of study drug in ALL UPA Population is 
defined as follows.
For All UPA 15mg cohort:
●
Date of last dose of upadacitinib 15mg Date of first dose of upadacitinib 
15 mg + 1.
For All UPA 30mg cohort:
●
Date of last dose of upadacitinib 30mg Date of first dose of upadacitinib 
30 mg + 1.
Duration of treatment will be summarized using the number of subjects treated, mean, 
standard deviation, median, minimum and maximum. In addition, the number and 
percentage of subjects in each treatment duration intervals (≥ 4 weeks, ≥ 12 weeks, 
≥16 weeks, and achieving 24 weeks) will be summarized for Safety 1, Safety 2, and 
All UPA Populations.
Treatment compliance for DB Period and SB Period will be summarized by treatment 
groups for Safety 1, and Safety 2 Populations. Treatment compliance is defined as the 
number of tablets actually taken divided by the number of tablets that should have been 
taken. For subjects who prematurely discontinued the study drug, the planned tablets will 
only be counted prior to that scheduled visit of discontinuation. Percent compliance will 
be summarized.
7.0
Subject Characteristics
7.1
Demographics and Baseline Characteristics
The following demographic and baseline characteristics will be summarized for each 
treatment in each ITT 1 Population.


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Demographics:
●
Sex (female, male)
●
Age (years)
●
Age categories (18 to < 40; ≥ 40 to < 65 years).
●
Race (White, Black or African American, Asian, American Indian/Alaska 
Native, Native Hawaiian or Other Pacific Islander)
●
Ethnicity (Hispanic or Latino, Not Hispanic or Latino)
●
Body Weight (kg)
●
Tobacco/Nicotine and Alcohol Use:
○
Tobacco/Nicotine Use (unknown, never, current, former)
○
Alcohol Use (unknown, never, current, former)
Baseline Characteristics
●
Baseline EASI (< median; ≥median)
●
Baseline EASI (<21; ≥21)
●
EASI overall score and body region scores
●
Body Surface Area (BSA) 
●
Baseline vIGA-AD (3, 4)
●
Previous systemic therapy for AD (with and without)
●
Prior Atopic Dermatitis Treatment
●
Worst Pruritus NRS (Weekly Average)
●
DLQI, POEM, PGIS, PGIT
●
ADerm-IS sleep domain, daily activity domain, and emotional state domain
●
ADerm-SS Skin pain and TSS-7
●
Prior use of dupilumab
●
Disease duration since diagnosis (years)
●
Disease duration since symptoms started (years)
●
Duration between symptoms and diagnosis (years)


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Clinical Test at Screening
●
TB Status: Tuberculin PPD skin test result, QuantiFERON-TB Gold test result, 
Latent TB (Yes/No)
●
Hepatitis B Virus (HBV)/Hepatitis C Virus (HCV)
●
Chest x-ray
○
Normal, Abnormal
○
Calcified granulomas (Absent, Present)
○
Pleural scarring (Absent, Present)
○
Pleural thickening (Absent, Present)
○
Indicative of previous TB infection (Yes, No)
7.2
Medical History and Prior and Concomitant Medications
Medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The actual version of the MedDRA coding dictionary will be noted in the 
statistical tables and clinical study report. The number and percentage of subjects in each 
medical history category (by MedDRA system organ class (SOC) and preferred term) will 
be summarized overall and by treatment group for the safety 1 Populations. The SOC will 
be presented in alphabetical order, and the preferred terms will be presented in 
alphabetical order within each SOC. Subjects reporting more than one condition/diagnosis 
will be counted only once in each row (SOC or preferred term).
A prior medication is defined as any medication taken prior to the date of the first dose of 
study drug. Prior medications will be summarized in the ITT 1 Populations.
Concomitant medications will be summarized by periods in each Safety 1 and Safety 2
Populations.
●
A concomitant medication in DB Period is defined as any medication that 
started prior to the date of the first dose of study drug in DB Period and 
continued to be taken after the first dose of study drug in DB Period; or any 


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medications taken after the first dose of study drug and within 1 day of the last 
dose of study drug in DB Period.
●
A concomitant medication in SB Period is defined as any medication that 
started prior to the date of the first dose of study drug in SB Period and 
continued to be taken after the first dose of study drug in SB Period or any 
medications, other than study drug, taken after the first dose of study drug and 
within 1 day of the last dose of study drug in SB Period.
The number and percentage of subjects taking medications will be summarized by generic 
drug name based on the World Health Organization (WHO) Drug Dictionary for both 
prior and concomitant medications.
7.3
Protocol Deviations
Protocol deviations include eligibility criteria violations, receipt of wrong treatment or 
incorrect dose of study treatment, development of withdrawal criteria without being 
withdrawn, and use of prohibited concomitant medications. A listing of subjects with 
protocol deviations will be provided.
For each of the following protocol deviation categories and across all categories, the 
number and percentage of randomized subjects with at least one protocol deviation will be 
summarized overall and by the treatment groups in the ITT 1 Population:
●
Subject entered into the studies or cohorts even though did not satisfy entry 
criteria;
●
Subject developed withdrawal criteria during the study but was not withdrawn;
●
Subject received wrong treatment or incorrect dose of study treatment;
●
Subject took prohibited concomitant medication.


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8.0
Handling of Potential Intercurrent Events for the 
Primary and Secondary Endpoints
For all the endpoints, no intercurrent event will be considered in the primary approach 
(treatment strategy policy), i.e., all observed data will be included in the analyses.
9.0
Efficacy Analyses
9.1
General Considerations
The efficacy analysis will be conducted in the ITT 1 and ITT 2 Populations in DB Period 
and SB Period descriptively and no statistical testing will be performed in this study.
Categorical endpoints will be summarized by counts and percentages, as well as 95% 
confidence interval (CI) of the percentage. Continuous variables will be analyzed by the 
number of observations, mean, standard deviation, median, minimum, maximum, as well 
as 95% confidence intervals (CIs) of the mean values. The primary missing data handling 
approach for efficacy summary is As Observed (AO).
Table 2.
Analysis Models and Imputation Methods
Period
Type of 
Variables
Imputation 
Method
Intercurrent Events 
Handling
Analysis Model
DB
Categorical
AO (primary)
The treatment policy 
strategy is used in this 
study, i.e., the occurrence 
of the intercurrent events
(e.g., treatment 
discontinuation, rescue 
etc.) are considered 
irrelevant in defining the 
treatment effect of interest.
Under this strategy, all
values for the variables of 
interest are used regardless 
of the intercurrent events.
Descriptive summary
Continuous
AO (primary)
ANCOVA including DB 
treatment groups, baseline, 
stratification factors (vIGA-
AD categories [3; 4] and 
prior use of dupilumab [yes; 
no]) in the model. 
SB
Categorical
AO (primary)
Descriptive summary
Continuous
AO (primary)
ANCOVA including SB
treatment groups, baseline, 
stratification factors (vIGA-
AD categories [3; 4] and 
prior use of dupilumab [yes; 
no]) in the model.
Note:
Sensitivity analysis for the primary endpoint will use multiple imputation to handle missing data.


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9.2
Handling of Missing Data
All efficacy endpoints will be analyzed using AO approach:
●
The AO analysis will not impute values for missing evaluations, and thus a 
subject who does not have an evaluation at a scheduled visit will not be 
included in the AO analysis for that visit.
Another missing data handling method performed as a sensitivity analysis for the primary 
endpoint only is Multiple Imputation (MI) approach, which defined as below:
●
MI approach: Markov Chain Monte Carlo (MCMC) will be first applied to 
augment data into monotonic missing pattern and PROC MI will be used to 
generate 30 datasets using the regression method. The imputation is done in 
two steps for the primary endpoint.
Step 1: Missing EASI scores will be imputed. The variables to be included in the 
imputation model are treatment groups, actual stratification factors (vIGA-AD categories 
(3; 4) and prior use of dupilumab (yes; no)), baseline, and measurements at each visit. The 
random seed for MCMC and the random seed for PROC MI are set as 1005 and 9015. 
The imputed post-baseline measurements will be rounded to the same precision as the 
observed data before the determination of responder status.
Step 2: After obtaining the EASI 90 at Week 24 based on MI imputed values, subjects 
will be characterized as responders or non-responders based on MI imputed datasets. The 
primary endpoint will be analyzed using each of the 30 datasets. SAS PROC 
MIANALYZE will be used to generate the final inferences of the EASI 90 percentages, 
the standard errors as well as 95% CIs.
9.3
Primary Efficacy Endpoint(s) and Analyses
9.3.1
Primary Efficacy Endpoint
The Primary endpoint is the achievement of EASI 90 at Week 24.


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9.3.2
Main Analysis of Primary Efficacy Endpoint
Frequencies and percentages will be provided along with 95% CIs. The AO approach will 
be used as the primary approach for handling the missing data. The attributes of the 
estimand corresponding to the primary efficacy objective are summarized in Table 3.
Table 3.
Summary of the Estimand Attributes Corresponding to the 
Primary Efficacy Objective
Estimand
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling of
Intercurrent Events
Statistical 
Summary
EASI 90 at 
Week 24
Upadacitinib
15 mg or 
30 mg
Achievement 
of EASI 90 at 
Week 24
Subjects 
with 
moderate to 
severe 
atopic 
dermatitis
The treatment policy 
strategy is used in this 
study. All the values for 
the variable of interest 
will be used regardless 
of Intercurrent Events.
Counts and
percentages 
will be 
provided 
along with 
95% CIs.
Analysis of the primary endpoint will be conducted on the ITT 2 SS1 and ITT 2 SS2 
Populations.
9.3.3
Sensitivity and Supplementary Analyses of the Primary 
Efficacy Endpoint
The primary endpoint will be summarized using the Multiple Imputation (MI) to handle 
missing data.
9.4
Secondary Efficacy Endpoints and Analyses
9.4.1
Secondary Efficacy Endpoints
The secondary endpoints are:
●
Achievement of EASI 75/100 at Week 24.
●
Achievement of EASI 75/90/100 at Week 12.
●
Achievement of EASI 90 and a Worst Pruritus NRS of 0 or 1 for subjects with 
Worst Pruritus NRS > 1 at Baseline at Week 12 and Week 24.


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●
Achievement of vIGA-AD of 0 or 1 at Week 12.
●
Achievement of vIGA-AD of 0 or 1 at Week 24.
●
Achievement of an improvement (reduction) in Worst Pruritus NRS ≥ 4 for 
subjects with Worst Pruritus NRS ≥ 4 at Baseline at Week 12.
●
Achievement of an improvement (reduction) in Worst Pruritus NRS ≥ 4 for 
subjects with Worst Pruritus NRS ≥ 4 at Baseline at Week 24.
●
Achievement of Worst Pruritus NRS of 0 or 1 for subjects with Worst Pruritus 
NRS > 1 at Baseline at Week 12.
●
Achievement of Worst Pruritus NRS of 0 or 1 for subjects with Worst Pruritus 
NRS > 1 at Baseline at Week 24.
●
Achievement of an improvement (reduction) from Baseline in DLQI ≥ 4 for 
subjects with DLQI ≥ 4 at Baseline at Week 12.
●
Achievement of an improvement (reduction) from Baseline in DLQI ≥ 4 for 
subjects with DLQI ≥ 4 at Baseline at Week 24.
●
Achievement of DLQI 0/1 for subjects with DLQI > 1 at Baseline at Week 12.
●
Achievement of DLQI 0/1 for subjects with DLQI > 1 at Baseline at Week 24.
9.4.2
Main Analyses of Secondary Efficacy Endpoints
Frequencies and percentages will be provided along with 95% CIs based on ITT 1 and 
ITT 2 populations using the AO approach. The attributes of the estimands corresponding 
to the secondary efficacy objectives are summarized in Table 4.


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Table 4.
Summary of the Estimand Attributes Corresponding to the 
Secondary Efficacy Objectives
Estimand
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling of 
Intercurrent Events
Statistical 
Summary
Categorical 
secondary 
endpoints
Upadacitinib 
15 mg or 
30 mg
Achievement 
of each 
respective 
categorical 
endpoint
Subjects 
with 
moderate 
severe 
atopic 
dermatitis
The treatment policy 
strategy is used in this 
study. All the values for 
the variable of interest 
will be used regardless 
of Intercurrent Events.
Counts and 
percentages 
will be 
provided 
along with 
95% CIs
9.4.3
Sensitivity and Supplementary Analyses for Secondary 
Efficacy Endpoints
There is no sensitivity or supplementary analysis for secondary efficacy endpoints.
9.5
Additional Efficacy Endpoints and Analyses
The additional efficacy endpoints listed in Section 3.3 will be analyzed as below. The 
categorical endpoints will be summarized by ITT 1 and ITT 2 populations using the AO 
approach. For the categorical endpoints, counts and percentages will be provided along 
with 95% CIs, by visit and by treatment group. For the continuous endpoints, Least 
Square (LS) mean, 95% CI and standard error (SE) will be provided using ANCOVA 
including treatment, baseline, stratification factors (vIGA-AD categories [3; 4] and prior 
use of dupilumab [yes; no]) in the model.
9.6
Efficacy Subgroup Analyses
The primary endpoint will be also summarized by the following subgroups using the AO 
approach:
●
Baseline vIGA-AD (3; 4),
●
Baseline EASI score (<21; ≥21), and
●
Baseline EASI score (<median; ≥median).


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●
Prior Use of Dupilumab (Yes; No)
9.7
Analysis of Daily Efficacy Measurement
For daily efficacy assessments of the Worst Pruritus NRS, ADerm-IS sleep domain, and 
ADerm-SS skin pain, a rolling weekly average is calculated by using handheld device 
only to represent the corresponding endpoints by week in DB Period and SB Period.
The weekly average of the daily values from a maximum of 7 days immediately prior to 
the first dose date will be used as the Baseline value. The rolling weekly average score is 
calculated for each Day m, starting from Day 8 through the Week 24 visit as follows. Let 
Pm-6, Pm-5, …, Pm-1, Pm be the daily score from Day m
6 to Day m, and Nm be the number 
of days with non-missing scores from Day m
6 to Day m, then the rolling weekly 
average for Day m is:
If the values from four or more days of the 7-day period are missing, then the rolling 
weekly average of Day m will be set to missing. If more than one assessment is included 
on the same day, the assessment associated with the worst condition on that day will be 
chosen as the daily score. Analysis value for a given visit will be selected from rolling 
averages based on analysis window conventions.
10.0
Safety Analyses
10.1
General Considerations
Safety summaries will be provided using the safety Populations. For the safety analysis, 
subjects are assigned to a treatment group based on the treatment actually received, 
regardless of the treatment randomized.
m
m
m
i
i
N
P
=
6


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Safety analyses will include adverse events, laboratory, and vital sign measurements.
Missing safety data will not be imputed.
10.2
Adverse Events
The summaries of adverse events will be provided by treatment groups in DB Period for 
Safety 1 Population, in SB Period for Safety 2 Population, and during the administration 
of upadacitinib for All UPA Population.
10.2.1
Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are defined as follows:
●
TEAEs in DB Period are defined as any adverse events that begin or worsen in 
severity after initiation of upadacitinib through the minimum (30 days 
following the last dose of upadacitinib in DB Period, or the start day of SB 
Period  1).
●
TEAEs in SB Period are defined as any adverse events that begin or worsen in 
severity after initiation of upadacitinib in SB Period through 30 days following 
the last dose of upadacitinib in SB Period.
●
TEAEs during the administration of upadacitinib are defined as any adverse 
events that begin or worsen in severity after initiation of upadacitinib through 
30 days following the last dose of upadacitinib.
If a missing or an incomplete onset date is collected for an adverse event, the event will be 
assumed to be treatment-emergent unless there is other evidence that confirms that the 
event is not treatment-emergent (e.g., the event end date is prior to the study drug start 
date). Events where the onset date is the same as the study treatment start date are 
assumed to be treatment-emergent.
All TEAEs will be summarized overall, as well as by primary MedDRA SOC and 
Preferred Term. The SOCs will be presented in alphabetical order, and the PTs will be 
presented in alphabetical order within each SOC.


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The number and percentage of subjects experiencing TEAEs and the number of events per 
100 patient-years of exposure will be summarized.
TEAEs per 100 patient-years of exposure are defined as the number of TEAEs divided by 
the total exposure in 100 patient-years. See the calculation method below:
100 * (Number of TEAEs) / (Total Patient Years)
where total patient years is defined as the sum of the study drug duration (defined in 
Section 6.0) of all subjects normalized by 365.25 and rounded to 1 decimal place.
10.2.2
Adverse Event Overview
The number and percentage of subjects experiencing TEAEs will be summarized for each
treatment group for the following AE categories:
●
Any TEAE
●
Any treatment-emergent serious adverse events (SAE)
●
Any TEAE leading to discontinuation of study drug
●
Any severe TEAE (Grade 3 and above according to National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE), 
version 5.0)
●
Any TEAE with reasonable possibility of being drug related
●
Any treatment-emergent SAE with reasonable possibility of being drug related 
●
Any TEAE leading to death
●
All Deaths
○
Deaths occurring ≤ 30 days after last dose of upadacitinib
○
Deaths occurring > 30 days after last dose of upadacitinib
○
Related to COVID 19
In addition, a separate overview of AESIs and overview of AESIs per 100 patient-years of 
exposure will be provided for the categories in Section 10.2.6.


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10.2.3
Treatment-Emergent Adverse Events by SOC and/or PT
TEAEs will be summarized and presented using primary MedDRA version 26.0 by 
system organ class (SOC) and preferred terms (PT); by maximum relationship to study 
drug as assessed by the investigator (e.g., reasonable possibility or no reasonable 
possibility) and SOC and PT; by maximum toxicity and SOC and PT. The SOCs will be 
presented in alphabetical order, and the PTs will be presented in alphabetical order within 
each SOC. Subjects reporting more than one adverse event for a given MedDRA preferred 
term will be counted only once for that term (most severe incident for the toxicity tables 
and most related incident for the relationship tables). A subject who reports more than 
1 AE in different SOCs will be counted only once in the overall total. Subjects reporting 
more than one type of adverse event will be counted only once in the overall total. If the 
same adverse event occurs multiple times within a subject, the highest severity and level 
of relationship to investigational product will be reported.
The following summaries of adverse events will be generated:
●
All TEAEs
●
Treatment-emergent serious adverse events
●
Treatment-emergent severe adverse events
●
TEAEs with reasonable possibility of being drug related 
●
TEAEs leading to discontinuation of study drug
●
TEAEs by maximum toxicity 
●
TEAEs of Special Interest
●
TEAEs leading to death
For summaries of AEs by toxicity, each subject is counted only once 
according to the 
maximum toxicity level observed. If a subject has an AE with an unknown toxicity, then 
the subject will be counted in the toxicity category of "unknown." The only exception is 
that if the subject has another occurrence of the same AE with the most extreme, non-fatal 
NCI CTCAE toxicity (i.e., grade 4) or is fatal (grade 5). In this case, the subject will be 
counted under grade 4 if non-fatal or 5 if fatal. For tables that look at severity instead of 


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toxicity, the subjects that have an unknown NCI CTCAE grade but another occurrence of 
the same AE that is considered severe (grade ≥ 3) will be counted under severe.
10.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure
AEs occurring during the entire study will be presented by event rate per 100 patient 
years. These will be presented by treatment group for the following AE categories.
●
Any TEAE
●
Any treatment-emergent SAE
●
Any TEAE leading to discontinuation of study drug
●
Any severe TEAE
●
Any TEAE with reasonable possibility of being drug related
●
Any treatment-emergent SAE with reasonable possibility of being drug related 
●
TEAEs of Special Interest
●
Any TEAE leading to death
●
All Deaths
○
Deaths occurring ≤ 30 days after last dose of upadacitinib
○
Deaths occurring > 30 days after last dose of upadacitinib
○
Related to COVID 19
Additional AEs may be considered for tabulation/summary based on recommendations 
from Clinical and Safety as deemed appropriate.
10.2.5
Deaths, Serious Adverse Events, and Adverse Events 
Leading to Study Treatment Discontinuation
SAEs (including deaths) and AEs leading to study drug discontinuation will be presented 
in listing format. SAEs and AEs leading to study drug discontinuation will be summarized 
by SOC and PT.


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In addition, for each treatment group, the event rate leading to per 100 patient-years of 
exposure will be calculated for each SOC and each PT for each treatment emergent SAE 
and TEAEs leading to discontinuation of study drug.
10.2.6
Adverse Events of Special Interest 
Adverse events of special interest will be summarized by SOC and PT and listing format 
and will be based on standard or company MedDRA queries (SMQs or CMQs).
Adverse events of special interest are categorized as follows:
●
Serious infections
●
Opportunistic infection excluding tuberculosis and herpes zoster
●
Herpes Zoster
●
Active Tuberculosis
●
Anemia
●
Neutropenia
●
Lymphopenia
●
Renal Dysfunction
●
Hepatic disorders (including DILI)
●
Malignancy
●
Non-melanoma skin cancer (NMSC)
●
Malignancy excluding NMSC
●
Lymphoma
●
Adjudicated MACE 
●
Adjudicated VTE
●
Adjudicated gastrointestinal perforations
●
Bone fractures
●
Retinal detachment
●
Serious hypersensitivity reactions


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Detailed information about the search criteria is provided in Appendix B.
Tabular listings of selected adverse events of special interest will be provided. Possible 
malignancy will only be listed.
Information on the extent of herpes zoster infection involvement will be summarized as 
collected in the respective AE form.
10.3
Analysis of Laboratory Data
Data collected from central and local laboratories, including additional laboratory testing 
due to an SAE, will be used in all analyses, except for Baseline where SAE-related 
laboratory assessments on or before the first dose of study drug will be excluded. The 
clinical laboratory tests defined in the protocol operations manual (e.g., hematology and 
clinical chemistry) will be summarized.
For the analysis of laboratory data, values observed up to 30 days after the last dose of 
upadacitinib will be included.
Analysis of Quantitative Laboratory Parameters (Hematology, Chemistry and 
Urinalysis)
Raw values and change from Baseline (percent change if applicable) to each applicable 
post-baseline visit will be summarized for selected laboratory variables in the Safety 1 
and Safety 2 Populations. At each visit, the following descriptive statistics will be 
presented by treatment groups: number of observations, Baseline mean (Standard 
deviation, SD), visit mean (SD), medium, change from Baseline mean (SD), standard 
error, and the 95% confidence interval of the mean change from Baseline.
Shift Table Analyses
Selected laboratory parameters will be tabulated using shift tables from Baseline to the 
worst value by NCI CTCAE in DB Period for the Safety 1, in SB Period for the Safety 2 
Population and during the administration of upadacitinib for the All UPA Population. 


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Selected lipid parameters will be summarized using National Cholesterol Education 
Program (NCEP) Adult Treatment Panel III (ATPIII) guidelines and details can be found 
in Appendix E. Similar shift tables will be provided to summarize shifts from Baseline to 
the final post-baseline value in DB Period for the Safety 1, in SB Period for the Safety 2 
Population and during the administration of upadacitinib for the All UPA Population. 
Here, the Upadacitinib Baseline is defined as the last observation prior to the first dose of 
upadacitinib. The criteria in shift table are defined using CTCAE 4.03. 
Potentially Clinically Important Laboratory Values
Laboratory abnormalities will be evaluated based on Potentially Clinically Important 
(PCI) criteria (NCI CTCAE V4.03 criteria of Grade 3 or above) in DB Period for the 
Safety 1, in SB Period for the Safety 2 Population and during the administration of 
upadacitinib for the All UPA Population. For each laboratory PCI criterion, the number 
and percentage of subjects who have a laboratory value meeting the criteria will be 
summarized. Listings will be provided to summarize subject-level laboratory data for 
subjects meeting PCI criteria. The PCI criteria are defined in Appendix D using CTCAE 
4.03.
Liver Function Tests
For the purpose of assessing for potential Hy's law cases, the frequencies and percentages 
of subjects with post-baseline liver function test values that meet the PCI criteria (defined 
in Appendix D) will be presented in DB Period for the Safety 1 Population, in SB Period 
for the Safety 2 Population and during the administration of upadacitinib for the 
ALL UPA Population. A listing of possible Hy's Law cases will be provided.
10.4
Analysis of Vital Signs
Vital sign measurements of systolic and diastolic blood pressure, pulse rate, respiratory 
rate and body temperature will be summarized.


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Each vital sign variable will be summarized for all time points (starting with Baseline) 
with the number of non-missing observations, mean and standard deviation, median, 
minimum and maximum. Mean change from Baseline to each applicable post-baseline 
visit in both DB Period and SB Period will be summarized for each vital sign variable, 
with the number of observations, Baseline mean, and visit mean. The change from 
Baseline mean, standard error, and 95% confidence interval will be presented for the 
mean change from Baseline within each treatment group in Safety 1 and Safety 2 
Populations.
Vital sign variables will be evaluated based on potentially clinically important (PCI) 
criteria (Appendix D) for the Safety 1, Safety 2 and the ALL UPA Population. For each 
vital signs PCI criterion, the number and percentage of subjects who have at least one 
vital sign value meeting the criteria will be summarized. Listings will be provided to 
summarize subject-level vital sign data for subjects meeting PCI criteria.
10.5
Safety Topics of Interest
Not applicable.
10.6
Other Safety Analyses
Not applicable.
10.7
Safety Subgroup Analyses
Not applicable.
11.0
Other Analyses
Not applicable.
12.0
Interim Analyses
There will be no interim analyses.


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12.1
Data Monitoring Committee
Given no subjects participating in the study will receive placebo or other active 
comparators, the causality of any AEs reported in the participants can be adequately 
assessed in the context of upadacitinib treatment. The study team will monitor and 
evaluate any AEs to identify findings that could put the study participants at risk and then 
make clinical decisions regarding the study conduct, which could include modification or 
termination of the study. This can adequately safeguard the participants. Given the above, 
it is not necessary to implement an independent Data Monitoring Committee for the 
conduct of this study.
13.0
Overall Type-I Error Control
No hypothesis testing will be performed in this study. Overall type-1 error control is not 
considered.
14.0
Version History
Table 5.
SAP Version History Summary
Version
Date
Summary
1.0
11 July 2023
Initial version
2.0
27 August 2024
1. The other events of interest in version 1 have been re-
classified into the AESI category. These events include 
Bone fractures, Retinal detachment, and Serious 
hypersensitivity reactions (in Section 3.4, 10.2.3, 10.2.4, 
10.2.6 and Appendix B). These changes are due to the 
release of the PSSAP version 8.0 on Aug. 20, 2024. 
2. Added the Rescue Definition as Appendix C.
3. Made some minor changes, including typo corrections. 
14.1
Changes to Planned Analyses in the Protocol
Not applicable


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15.0
References
1.
Graham JW, Olchowski AE, Gilreath TD. How many imputations are really 
needed? Some practical clarifications of multiple imputation theory. Prev Sci. 
2007;8(3):206-13.
2.
Rubin DB, Schenker N.  Interval estimation from multiply-imputed data: a case 
study using agriculture industry codes. J Am Stat Assoc. 1987;81:366-74.
3.
White IR, Royston P, Wood AM. Multiple imputation using chained equations: 
Issues and guidance for practice. Stat Med. 2011;30(4):377-99.


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Appendix A.
List of SAP Signatories
Name
Title
Role/Functional Area
Author
Statistical Sciences
Statistical Sciences
Statistical Programming
Medical Monitor


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Appendix B.
Definition of Adverse Events of Special Interest
Adverse Events of Special Interest (AESI) will be identified using the following search 
criteria (Note: for each database lock, the categories of AESIs will follow the latest 
version of Product Safety Statistical Analysis Plan for Upadacitinib, with the exceptions 
of Hepatitis B Reactivation which is not an AESI. AESIs with the corresponding code for 
the current MedDRA version in that DBL will be shown in a summary table):


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AESI
Type of MedDRA 
Query
Broad or 
Narrow 
Search
SMQ/CMQ Search Criteria
Serious Infections
CMQ
"Infections" – Subset for SAEs
Opportunistic Infection 
excluding tuberculosis and 
herpes zoster
CMQ
"Opportunistic Infection 
excluding tuberculosis and 
herpes zoster" 
Possible malignancy
SMQ
Narrow
"Malignancies"
Malignancy
SMQ
Narrow
"Malignant Tumours"
Non-Melanoma Skin Cancer 
(NMSC)
SMQ/CMQ
SMQ Narrow
Skin Malignant Tumours
(Narrow SMQ) removing 
Melanoma CMQ
Malignancy excluding NMSC
Malignancy Tumours Narrow
SMQ and removing NMSC 
output
Lymphoma
SMQ
Broad
"Malignant Lymphomas"
Hepatic Disorder
SMQ
Narrow
"Drug Related Hepatic 
Disorders" 
Adjudicated Gastrointestinal 
Perforations
Medical review of 
events identified 
by the 
"Gastrointestinal 
Perforation" SMQ 
Narrow search
Anemia
CMQ
"Non-Hemolytic and Non-
Aplastic Anemias" 
Neutropenia
CMQ
"Hematological Toxicity –
Neutropenia"
Lymphopenia
CMQ
"Hematological Toxicity –
Lymphopenia (Upadacitinib
Product Specific)"
Herpes Zoster
CMQ
"Herpes Zoster"
Renal Dysfunction
SMQ
Narrow
"Acute Renal Failure"


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AESI
Type of MedDRA 
Query
Broad or 
Narrow 
Search
SMQ/CMQ Search Criteria
Active Tuberculosis
CMQ
"Active Tuberculosis"
Adjudicated cardiovascular 
eventsa
Output from CAC
MACE*
Cardiovascular Death
Non-fatal Myocardial 
Infarction
Non-fatal Stroke
Other Adjudicated 
Cardiovascular Events
Undetermined/Unknown 
Cause of Deaths 
Adjudicated Thrombotic 
Events
Output from CAC
VTE**
Deep Vein Thrombosis 
Pulmonary Embolism 
Other Venous Thrombosis
Arterial Thromboembolic 
Events (non-cardiac, non-
neurologic)
CAC  Cardiovascular Adjudication Committee; CMQ  company MedDRA query; PT  preferred term; 
SMQ
standard MedDRA query
*
MACE:  Major Adverse Cardiovascular Events, defined as cardiovascular death, non fatal myocardial infarction 
and non fatal stroke.
**
VTE:  Venous thromboembolic events, defined as deep vein thrombosis (DVT) and pulmonary embolism (PE) 
(fatal and non fatal).
a.
Reviewed and adjudicated by an independent Cardiovascular Adjudication Committee in a blinded manner.


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Appendix C.
Rescue Definition
The topical medications for AD therapy are coded to the following drug classes. Among 
these AD medications, the potential AD rescue medications are determined through a 
medical review process.
1.
Plain Topical Corticosteroids
2.
High Potency Topical Corticosteroids
3.
Medium Potency Topical Corticosteroids
4.
Low Potency Topical Corticosteroids
5.
Topical Calcineurin Inhibitor Therapy
6.
Other Topical therapy (not including moisturizers/emollients)
Concomitant medications that are categorized as "potential AD rescue" per medical
review AND in categories 1 - 6 above are considered as rescue medications in Period 1
and Period 2.
The medical review process is documented in the Rescue Medication Medical Review
Process - Upadacitinib AD.


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Appendix D.
Potentially Clinically Important Criteria for Safety Endpoints
The criteria for Potentially Clinically Important (PCI) laboratory findings are described in 
Table D-1 and Table D-2, PCI criteria for the liver function tests are described in 
Table D-3, and the PCI criteria for vital sign findings are described in Table D-4.
Table D-1.
Criteria for Potentially Clinically Important Hematology Values
Hematology Variables
Units
Definition of Potentially 
Clinically Important
Very Low
Hemoglobin
g/dL
< 8.0
Platelets count
109/L
< 50.0
WBC count
109/L
< 2.0
Neutrophils
109/L
< 1.0
Lymphocytes
109/L
< 0.5
Table D-2.
Criteria for Potentially Clinically Important Chemistry Values
Chemistry Variables
Units
Definition of Potentially Clinically Important
Very Low
Very High
ALP
U/L
> 5.0 × ULN
SGOT/AST
U/L
> 5.0 × ULN
SGPT/ALT
U/L
> 5.0 × ULN
Albumin
g/L
< 20
Glucose
mmol/L
< 2.2
> 13.9
Triglycerides
mmol/L
> 5.7
Creatinine
mcmol/L
> 3.0 × ULN
Potassium
mmol/L
< 3.0
> 6.0
Calcium
mmol/L
< 1.75
> 3.1
Sodium
mmol/L
< 130
> 155
Phosphate
mmol/L
< 0.6
CPK
U/L
> 5.0 × ULN
Total Cholesterol
mmol/L
> 10.34


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Table D-3.
Criteria for Potentially Clinically Important Liver Function Tests
Variables
Units
Definition of Potentially Clinically Important
Very High
AST
U/L
≥ 3 × ULN
≥ 5 × ULN
≥ 10 × ULN
≥ 20 × ULN
ALT
U/L
≥ 3 × ULN
≥ 5 × ULN
≥ 10 × ULN
≥ 20 × ULN
Total Bilirubin
UMOL/L
≥ 2 × ULN
Alkaline phosphatase
U/L
≥ 1.5 × ULN
ALT (U/L) and/or AST (U/L) 
and concurrent TBL
(UMOL/L)
ALT and/or AST ≥ 3 × ULN and concurrent TBL 
≥1.5 × ULN
ALT and/or AST ≥ 3 × ULN and concurrent TBL 
≥2 × ULN
Table D-4.
Criteria for Potentially Clinically Important Vital Sign Values
Vital Sign
Category
Criteria for Potential Clinically Significant Vital Signs
Systolic blood pressure
Low
Value ≤ 90 mmHg and decrease ≥ 20 mmHg from Baseline
High
Value ≥ 160 mmHg and increase ≥ 20 mmHg from Baseline
Diastolic blood 
pressure
Low
Value ≤ 50 mmHg and decrease ≥ 10 mmHg from Baseline
High
Value ≥ 100 mmHg and increase ≥ 10 mmHg from Baseline
Pulse
Low
Value ≤ 50 bpm and decrease ≥ 15 bpm from Baseline
High
Value ≥ 120 bpm and increase ≥ 15 bpm from Baseline
Weight (adults)
High
> 7% increase from Baseline
Low
> 7% decrease from Baseline
Weight (Adolescents)
Low
> 7% decrease from Baseline


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Appendix E.
National Cholesterol Education Program (NCEP) Adult Treatment 
Panel III (ATPIII) for Selected Lipid Parameters
●
LDL cholesterol (< 3.36, ≥ 3.36 and < 4.14, ≥ 4.14 mmol/L)
●
HDL cholesterol (< 1.03, ≥ 1.03 mmol/L)
●
Total cholesterol (< 5.17, ≥ 5.17 and < 6.21, ≥ 6.21 mmol/L)
●
Triglycerides (< 1.69, ≥ 1.69 and < 2.26, ≥ 2.26 mmol/L)