A Phase 3b/4 Randomized, Open-label, Efficacy Assessor Blinded Study, Comparing the Safety and Assessor Blinded Efficacy of Upadacitinib to Dupilumab in Subjects With Moderate to Severe Atopic Dermatitis (Level-Up)
Phase: PHASE3
Conditions: Atopic Dermatitis
Sponsor: AbbVie



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Sponsor emergency medical contact:
 MD
 Global Medical Affairs 
AbbVie
1 North Waukegan Road 
North Chicago, IL 60064
Mobile:
Email:
EMERGENCY 24 hour Number: +1 973-784-6402
For Non-EU Countries: 
AbbVie 
1 North Waukegan Road
North Chicago, IL 60064
United States of America
For EU Countries:
AbbVie Deutschland GmbH & Co. KG (AbbVie)
Knollstrasse 50
67061 Ludwigshafen
Germany
* For European Union countries: the sponsor is AbbVie Deutschland GmbH & Co. KG. The specific 
contact details of the AbbVie legal/regulatory entity (person) within the relevant country are provided 
within the clinical trial agreement with the Investigator/Institution and in the Clinical Trial Application 
with the Competent Authority. Additional study contact information can be found in the Operations 
Manual (Appendix F).
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TABLE OF CONTENTS
1
SYNOPSIS
6
2
INTRODUCTION
10
2.1
BACKGROUND AND RATIONALE
10
2.2
BENEFITS AND RISKS TO SUBJECTS
11
3
OBJECTIVES AND ENDPOINTS
14
3.1
OBJECTIVES, HYPOTHESES, AND ESTIMANDS
14
3.2
PRIMARY ENDPOINT
15
3.3
SECONDARY ENDPOINTS
15
3.4
ADDITIONAL EFFICACY ENDPOINTS
15
3.5
SAFETY ENDPOINTS
16
3.6
BIOMARKER RESEARCH ENDPOINTS
16
4
INVESTIGATIONAL PLAN
16
4.1
OVERALL STUDY DESIGN AND PLAN
16
4.2
DISCUSSION OF STUDY DESIGN
19
5
STUDY ACTIVITIES
20
5.1
ELIGIBILITY CRITERIA
20
5.2
CONTRACEPTION RECOMMENDATIONS
25
5.3
PROHIBITED MEDICATIONS AND THERAPY
28
5.4
PRIOR AND CONCOMITANT THERAPY
31
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
33
5.6
FOLLOW-UP AFTER SUBJECT DISCONTINUATION OF STUDY DRUG OR FROM STUDY
35
5.7
STUDY DRUG
36
5.8
RANDOMIZATION/DRUG ASSIGNMENT
38
5.9
PROTOCOL DEVIATIONS
38
5.10 DATA MONITORING COMMITTEE
38
5.11 PAPER DIARY CARDS FOR SITES IN CHINA ONLY
38
6
SAFETY CONSIDERATIONS
39
6.1
COMPLAINTS AND ADVERSE EVENTS
39
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6.2
TOXICITY MANAGEMENT
45
7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
49
7.1
STATISTICAL AND ANALYTICAL PLANS
49
7.2
DEFINITION FOR ANALYSIS POPULATIONS
50
7.3
HANDLING POTENTIAL INTERCURRENT EVENTS FOR THE PRIMARY AND RANKED SECONDARY ENDPOINTS
50
7.4
STATISTICAL ANALYSES FOR EFFICACY
50
7.5
STATISTICAL ANALYSES FOR SAFETY
51
7.6
STATISTICAL ANALYSIS OF OPTIONAL BIOMARKER DATA
52
7.7
INTERIM ANALYSIS
52
7.8
OVERALL TYPE I ERROR CONTROL
52
7.9
SAMPLE SIZE DETERMINATION
52
7.10 INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD (IEC/IRB)
52
7.11 ETHICAL CONDUCT OF THE STUDY
53
7.12 SUBJECT CONFIDENTIALITY
53
8
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
53
9
DATA QUALITY ASSURANCE
53
10 START AND COMPLETION OF THE STUDY
53
11 REFERENCES
53
LIST OF TABLES
TABLE 1.
EXAMPLES OF COMMONLY USED STRONG CYP3A INHIBITORS AND INDUCERS
30
TABLE 2.
DESCRIPTION OF STUDY DRUG
37
TABLE 3.
SPECIFIC TOXICITY MANAGEMENT GUIDELINES FOR ABNORMAL LABORATORY VALUES
47
LIST OF FIGURES
FIGURE 1.
STUDY SCHEMATIC
19
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LIST OF APPENDICES
APPENDIX A.
STUDY-SPECIFIC ABBREVIATIONS AND TERMS
56
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
59
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
60
APPENDIX D.
ACTIVITY SCHEDULE
61
APPENDIX E.
PROTOCOL SUMMARY OF CHANGES
66
APPENDIX F.
OPERATIONS MANUAL
69
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required for any subject who initiates commercially available upadacitinib or 
dupilumab upon the study Completion Visit or Premature Discontinuation 
visit.
The study is comprised of two periods:

Period 1: A 16-week open-label, efficacy assessor blinded treatment 
period to evaluate the efficacy and safety of upadacitinib, initiated 
at 15 mg QD and dose adjusted based on clinical response starting 
after 4 weeks of treatment, compared with dupilumab as per its 
label.
Subjects who meet eligibility criteria will be randomized in a 1:1 
ratio to receive either upadacitinib 15 mg QD or dupilumab as per 
its label. During Period 1, subjects randomized to upadacitinib 15 
mg QD will have their dose increased to 30 mg QD if any of the 
following parameters is met:

Starting at Week 4, subject has a < EASI 50 response. 

Starting at Week 4, subject has a < 4-point improvement from 
Baseline in WP-NRS (weekly average).

Starting at Week 8, subject has a < EASI 75 response.

Period 2: An extension period to evaluate the efficacy and safety of 
upadacitinib, initiated at 15 mg QD and dose adjusted based on 
clinical response, in subjects with inadequate response to 
dupilumab, and treatment at 30 mg QD in subjects with inadequate 
response to upadacitinib in Period 1. 
At Week 16 subjects from both treatment arms in Period 1 with a 
< EASI 75 response will enter Period 2; subjects from the dupilumab 
arm will be offered the option to receive upadacitinib 15 mg QD 
while subjects from the upadacitinib arm will either continue (if 
already receiving 30 mg QD) or be escalated to upadacitinib 30 mg 
QD (if receiving 15 mg QD) until Week 32.

During Period 2, subjects receiving upadacitinib 15 mg QD will 
have their dose increased to 30 mg QD if any of the following 
parameters is met:
o
Starting at Week 20, subject has a < EASI 75 response. 
o
Starting at Week 20, subject has a < 4-point improvement 
from Baseline in WP-NRS (weekly average) 
Rescue Therapy
Period 1
Upadacitinib arm: Starting four weeks following dose escalation to 
upadacitinib 30 mg QD in Period 1, subjects with a < EASI 50 response or < 4-
point improvement from Baseline in WP-NRS (weekly average) will have the 
option to add topical therapy (except for topical JAK inhibitors) as rescue 
therapy.
Dupilumab arm: Starting at Week 4 of Period 1 with dupilumab as per its 
label, subjects with a < EASI 50 response or < 4 point improvement from 
Baseline in WP-NRS (weekly average), will have the option to add topical 
therapy (except for topical JAK inhibitors) as rescue therapy.
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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.2-5 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, interferon (IFN)-γ, which are known contributors to inflammatory disorders. It 
also blocks the signaling of IL-4, IL-13, IL-31, IL-22, IFNγ, and thymic stromal lymphopoietin (TSLP) 
cytokines that play an important role in the pathogenesis of atopic dermatitis (AD). To date, upadacitinib 
has been approved in at least one country for rheumatoid arthritis (RA), psoriatic arthritis (PsA), 
ankylosing spondylitis (AS), non-radiographic axial spondyloarthritis (nr-axSpA), ulcerative colitis (UC), 
Crohn's disease (CD), and atopic dermatitis (AD). Upadacitinib is also being investigated for patients with 
giant cell arteritis (GCA), Takayasu arteritis, polyarticular course juvenile idiopathic arthritis (pcJIA), 
systemic juvenile idiopathic arthritis (sJIA), pediatric AD, pediatric UC, nonsegmental vitiligo, hidradenitis 
suppurativa (HS), alopecia areata and systemic lupus erythematosus (SLE).
Additional information regarding indications under study can be found in the current edition of the 
upadacitinib Investigator's Brochure. 
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, multicenter studies (MEASURE UP 1, MEASURE UP 2 and AD UP),6-8
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 (EU), Japan, Canada, and the United States (US), with some differences in the 
indications or posologies.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 based on the 
clinical response were assessed. 
In addition, the efficacy and safety of upadacitinib 30 mg QD versus dupilumab for the treatment of 
adult subjects with moderate to severe AD who were candidates for systemic therapy was assessed in a 
head-to-head, Phase 3b, multicenter, randomized, double-blinded, double-dummy, active-controlled 
clinical trial (HEADS UP).10,11 However, the 15 mg QD dose for upadacitinib was not assessed in that trial. 
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Dupilumab is a recombinant human IgG4 monoclonal antibody that inhibits interleukin-4 and 
interleukin-13 signaling. Dupilumab inhibits IL-4 signaling via the Type I receptor (IL-4Rα/γc), and both IL-
4 and IL-13 signaling through the Type II receptor (IL-4Rα/IL-13Rα). 
Dupilumab has been approved in at least one country for the treatment of moderate to severe AD, 
moderate to severe asthma, chronic rhinosinusitis with nasal polyposis, eosinophilic esophagitis, and 
prurigo nodularis.
In AD, dupilumab 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, and for the treatment of 
severe AD in children 6 to 11 years old who are candidates for systemic therapy in the EU and for the 
treatment of adult and pediatric patients aged 6 months and older with moderate-to-severe AD whose 
disease is not adequately controlled with topical prescription therapies or when those therapies are not 
advisable in the United States (US).12
The efficacy and safety of dupilumab as monotherapy and with concomitant topical corticosteroids (TCS) 
were evaluated in three pivotal randomized, double-blind, placebo-controlled, multicenter studies 
(SOLO 1, SOLO 2, and CHRONOS)13,14 in 2,119 patients 18 years of age and older with moderate to severe 
AD. The efficacy and safety of dupilumab monotherapy in adolescent patients was evaluated in a 
randomized, double-blind, placebo-controlled, multicenter study (AD-1526)15 in 251 adolescent patients 
12 to 17 years of age with moderate-to-severe AD.
This study aims to provide data on the efficacy and safety of upadacitinib initiated at 15 mg QD and dose 
escalated based on the clinical response, compared with dupilumab as per its label, after 16 weeks of 
treatment. 
Additionally, this study aims to provide data on the efficacy and safety of upadacitinib initiated at 15 mg 
QD and dose adjusted based on clinical response in subjects with inadequate response to dupilumab.
Clinical Hypothesis
The primary hypothesis is that upadacitinib, initiated at 15 mg QD and dose escalated based on clinical 
response will demonstrate superior efficacy compared to dupilumab and will be well tolerated in adult 
and adolescent subjects with moderate to severe AD who have inadequate response to a systemic 
therapy.
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
The recommended dose is upadacitinib 15 mg or 30 mg QD based on individual patient presentation. A 
dose of 15 mg QD is recommended for patients with risk factors for venous thromboembolism, major 
adverse cardiovascular events (MACE), and malignancy. A dose of 30 mg QD may be appropriate for 
patients with high disease burden who have no known risk factors for venous thromboembolism, MACE, 
and malignancy, or for patients with an inadequate response to 15 mg QD. The lowest effective dose for 
maintenance should be used.9
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For patients ≥ 65 years of age the recommended dose is upadacitinib 15 mg QD.9 The recommended 
dose of upadacitinib for adolescents (from 12 to 17 years of age) weighing at least 30 kg is 
upadacitinib 15 mg QD.9 The above indication and posology correspond to the European Union and may 
vary within different jurisdictions.
In the US USPI, upadacitinib has been approved for adults and pediatric patients 12 years of age and 
older with refractory, moderate to severe AD whose disease is not adequately controlled with other 
systemic drug products, including biologics, or when the use of those therapies are inadvisable. 
Upadacitinib is not recommended for use in combination with other JAK inhibitors, biologic 
immunomodulators, or with other immunosuppressants.
The recommended dosage for pediatric patients 12 years of age and older weighing at least 40 kg and 
adults less than 65 years of age is to initiate treatment with 15 mg once daily. If an adequate response is 
not achieved, consider increasing the dosage to 30 mg once daily. Discontinue upadacitinib if an 
adequate response is not achieved with the 30 mg dose. Use the lowest effective dose needed to 
maintain response.
The efficacy and safety of upadacitinib 15 mg and 30 mg QD was assessed in 3 Phase 3 randomized, 
double-blind, multicenter studies (MEASURE UP 1, MEASURE UP 2, and AD UP) in a total of 2584 
subjects (12 years of age and older).6-8 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, Eczema Area and Severity Index (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 (WP-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 reactivation, 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 fracture, and some laboratory abnormalities have been 
observed in patients receiving JAK inhibitors including upadacitinib. 
An increased risk of infections including opportunistic infections (e.g., mucosal candida infections) and 
herpes zoster, non-melanoma skin cancer (NMSC), and abnormal laboratory changes (e.g., elevations of 
serum transaminases, lipids, creatine phosphokinase [CPK], and reductions in hemoglobin and white 
blood cells [WBC]) have been observed with upadacitinib therapy. 
In ORAL Surveillance, a study of a different JAK inhibitor, tofacitinib, in RA patients 50 years of age and 
older with at least one cardiovascular risk factor, higher rates of all-cause mortality, malignancies, MACE 
and thrombosis (overall thrombosis, deep vein thrombosis, and pulmonary embolism) were seen in 
patients treated with tofacitinib versus TNF blockers.7,16 These higher rates were primarily observed in 
patients 65 years of age and older, patients with a history of atherosclerotic cardiovascular disease, and 
current or past long-time smokers. Although upadacitinib clinical trial data to date 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 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 
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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.
Dupilumab 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, and for the treatment of severe AD in 
children 6 to 11 years old who are candidates for systemic therapy in the EU17 and for the treatment of 
adult and pediatric patients aged 6 months and older with moderate-to-severe AD whose disease is not 
adequately controlled with topical prescription therapies or when those therapies are not advisable in 
the United States (US).12
Although dupilumab addresses the needs of some patients with moderate to severe AD, a large unmet 
need still exists in this population since, in the dupilumab Phase 3 studies (even when combined with 
topical corticosteroids [TCS]), fewer than 40% of the adult patients achieved 0 or 1 on the Investigator's 
Global Assessment (IGA) scale.13,14 This percentage was lower for adolescents, as 24.4 % of subjects 
included in the study achieved a 0 or 1 on the IGA at Week 16.
Therefore, a large proportion of patients continued to experience significant symptoms on dupilumab 
therapy. Nearly 50% of dupilumab adult subjects who were IGA 0 or 1 responders at Week 16 became 
nonresponders by Week 52.17 Dupilumab is generally well-tolerated, and the most common adverse 
events (AEs) are injection site reaction, conjunctivitis, and blepharitis.
Considering the coronavirus – 2019 (COVID-19) pandemic and based on the information to date, it is 
unknown whether study participants treated with upadacitinib may be at an increased risk for COVID-19 
or experience more serious illness if infected. The data thus far do not show that patients on 
upadacitinib treatment have worse outcomes of COVID.
For further details, please see findings from completed studies, including safety data in the current 
upadacitinib Investigator's Brochure.18,19
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3 OBJECTIVES AND ENDPOINTS
3.1 Objectives, Hypotheses, and Estimands
Objectives
Primary
The primary study objective, related to Study Period 1, is to assess the efficacy and safety of 
upadacitinib, initiated at 15 mg once daily (QD) and dose adjusted based on clinical response, compared 
with dupilumab as per its label.
An additional objective, related to Study Period 2, is to assess the efficacy and safety of upadacitinib, 
initiated at 15 mg QD and dose adjusted based on clinical response, in subjects with inadequate 
response to dupilumab.
The primary efficacy objective is based on the achievement of a composite endpoint of at least a 90% 
reduction in EASI from baseline (EASI 90) and a Worst Pruritus Numerical Rating Scale of 0 or 1 (WP-NRS 
0/1) at Week 16 with the treatment of upadacitinib compared with dupilumab per its label in the Intent-
to-Treat (ITT) Population, which consists of all randomized subjects (Section 7.2). 
Secondary 
The secondary efficacy objectives are based on ranked secondary endpoints as defined in Section 3.3
with the treatment of upadacitinib compared with dupilumab in the ITT Population. 
Hypotheses and Estimands for the Primary and Ranked Secondary Endpoints
The hypothesis corresponding to the primary efficacy endpoint (Section 3.2) is: 

The proportion of subjects achieving both EASI 90 and WP-NRS 0/1 at Week 16 in those treated 
with upadacitinib is greater than those treated with dupilumab. 
The estimand corresponding to the primary endpoint is defined using the composite variable strategy, 
as follows:

Difference in the proportion of subjects achieving both EASI 90 and WP-NRS 0/1 at Week 16 
without the use of rescue medication, regardless of treatment discontinuation, between 
upadacitinib and dupilumab in the adolescent and adult subjects with moderate to severe AD 
who have inadequate response to systemic therapy.
The hypotheses and estimands corresponding to the ranked secondary endpoints are summarized 
below.

Hypotheses: the proportion of subjects achieving each ranked endpoint in those treated with 
upadacitinib is greater than those treated with dupilumab
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
Estimands: Difference in proportion of subjects achieving each of ranked secondary endpoints 
without the use of rescue medication, regardless of treatment discontinuation, between 
upadacitinib and dupilumab in the adolescent and adult subjects with moderate to severe AD 
who have inadequate response to systemic therapy. 
3.2 Primary Endpoint
The primary endpoint is the achievement of a composite endpoint of both EASI 90 and WP-NRS 0/1 at 
Week 16.
3.3 Secondary Endpoints
Ranked Secondary Endpoints 
1.
Achievement of EASI 90 at Week 16.
2.
Achievement of WP-NRS 0/1 at Week 16 among subjects with Baseline WP-NRS > 1.
3.
Achievement of an improvement (reduction) in WP-NRS ≥4 at Week 16 among subjects with
Baseline WP-NRS ≥4.
4.
Achievement of WP-NRS 0/1 at Week 4 among subjects with Baseline WP-NRS > 1.
5.
Achievement of WP-NRS 0/1 at Week 2 among subjects with Baseline WP-NRS > 1.
6.
Achievement of EASI 90 at Week 4.
7.
Achievement of EASI 75 at Week 2.
8.
Achievement of EASI 100 at Week 16.
3.4 Additional Efficacy Endpoints
In addition to Week 16 assessments, the primary and ranked secondary efficacy endpoints will be 
evaluated at all scheduled visits in Period 1 and Period 2 as noted in the Study Activities Table 
(Appendix D) during which the assessments are measured.
The following endpoints will also be evaluated at all scheduled visits in Period 1 and Period 2 during 
which the assessments are measured as noted in the Study Activities Table (Appendix D):

Achievement of EASI 75/90/100 at Week 32 for subjects who received dupilumab/upadacitinib 
in Period 1 and did not achieve EASI 75 at Week 16.

Achievement of EASI 90 AND WP-NRS 0/1 at Week 32 for subjects who received 
dupilumab/upadacitinib in Period 1 and did not achieve EASI 90 AND WP-NRS 0/1 at Week 16.

Achievement of an improvement (reduction) in WP-NRS ≥ 4 at Week 32 for subjects who had 
WP-NRS ≥ 4 at Baseline and who received dupilumab/upadacitinib in Period 1 and did not 
achieve WP-NRS reduction ≥ 4 at Week 16.
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
Achievement of WP-NRS 0/1 at Week 32 for subjects who had WP-NRS > 1 at Baseline and who 
received dupilumab/upadacitinib in Period 1 and did not achieve WP-NRS 0/1 at Week 16.

Achievement of 75% reduction in EASI in each body region from Baseline;

Achievement of 75% reduction in EASI in the head and neck body region at Week 32 for subjects 
who received dupilumab/upadacitinib in Period 1 and did not achieve 75% reduction in EASI in 
the head and neck body region at Week 16.
3.5 Safety Endpoints
Safety will be assessed by AE monitoring, physical examination, vital signs, imaging, and clinical 
laboratory testing during the study. Laboratory assessments will include hematologic parameters, 
chemistry, liver function tests, and lipid parameters. Tanner Stage assessments will be included for 
adolescent subjects. 
3.6 Biomarker Research Endpoints
Optional biospecimens (e.g., skin biopsies, whole blood for plasma, serum, and DNA) 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, 
cellular populations, and/or metabolites, either free or in association with particular cell types. The 
analyses may include but are not limited to: serum and plasma proteomic and genomic evaluations, 
transcriptomic, genetic, and histologic analysis to evaluate biomarker endpoints related to safety, 
disease state, response to treatment, and target pathway. The biomarker research results may not be 
included with the clinical study report. Further details regarding the biomarker research and collection 
time points are located in the Operations Manual Section 2.1, and Section 3.7.
Optional biospecimens will not be collected from sites where local regulations do not allow for the 
collection, use, and storage of samples as described.
No biomarker samples will be collected in China.
4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
This is a global, Phase 3b/4, randomized, open-label, efficacy assessor-blinded, multicenter study that 
will evaluate upadacitinib compared with dupilumab per its label, as monotherapy, in adolescents and 
adult subjects (≥12 and < 64 years of age weighing at least 40 kg) with moderate to severe AD who have 
inadequate response to systemic therapy. Eligible subjects must have a documented history of 
inadequate response to at least one systemic treatment for AD prior to the Baseline Visit or for whom 
other systemic treatments are otherwise medically inadvisable.
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
The study will consist of a 35-day Screening Period; Period 1, a 16-week randomized, open-label, efficacy 
assessor blinded treatment period for all subjects, and a 30-day or 12-week follow-up visit for subjects 
on upadacitinib or dupilumab respectively, who will not enter the Period 2; Period 2, a 16-week open-
label, efficacy assessor blinded extension period for those subjects with a < EASI 75 response at Week 16 
(total duration 32 weeks) and a 30-day follow-up visit. 
The study is comprised of two periods:

Period 1: A 16-week open-label, efficacy assessor blinded treatment period designed to evaluate 
the efficacy and safety of upadacitinib, initiated at 15 mg QD and dose adjusted based on clinical 
response starting after 4 weeks of treatment, compared with dupilumab as per its label. 
Subjects who meet eligibility criteria will be randomized in a 1:1 ratio to receive either 
upadacitinib 15 mg QD or dupilumab as per its label. 

Period 2: An open-label, efficacy assessor blinded extension period to evaluate the efficacy and 
safety of upadacitinib, initiated at 15 mg QD and dose adjusted based on clinical response in 
subjects with inadequate response to dupilumab, and treatment at 30 mg QD in subjects with 
inadequate response to upadacitinib in Period 1. At Week 16, subjects from both treatment 
arms with a < EASI 75 response will enter Period 2; subjects from the dupilumab arm will be 
offered the option to receive upadacitinib 15 mg QD while subjects from the upadacitinib arm 
will either continue (if already receiving 30 mg) or be escalated to upadacitinib 30 mg QD (if 
receiving 15 mg QD) until Week 32.
During Period 1, subjects who meet eligibility criteria will be randomized in a 1:1 ratio to one of the two 
arms as shown below:

Upadacitinib arm (N = 440): Daily oral doses of upadacitinib 15 mg QD from the Baseline visit 
until the Week 16 visit. During Period 1, subjects randomized to upadacitinib 15 mg QD will have 
their dose increased to 30 mg QD if any of the following parameters is met:

Starting at Week 4, subject has a < EASI 50 response

Starting at Week 4, subject has a < 4-point improvement from Baseline in WP-NRS (weekly 
average)

Starting at Week 8, subject has a < EASI 75 response
At Week 16, subjects receiving upadacitinib 15 mg QD or 30 mg QD, will be reassigned based on 
their EASI response:

< EASI 75 will be allocated or continue to receive oral doses of upadacitinib 30 mg QD in 
Period 2

≥ EASI 75 will complete end of study procedures. 

Dupilumab arm (N = 440):

Adults: Dupilumab 600 mg (2 × 300 mg dupilumab SC injection) administered at the Baseline 
visit, followed by dupilumab 300 mg SC injection EOW until the Week 16 visit. 

Adolescents: Adolescents (12 to 17 years of age and weighing at least 40 kg).
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Dose of dupilumab for subcutaneous administration in adolescent patients 12 to 17 years of age 
with AD.
Body weight of subject at Screening Visit and at each visit: 
1.
40 to < 60 kg: 

Initial dose: 400 mg (two 200 mg injections)

Subsequent doses (EOW): 200 mg
2.
60 kg or more: 

Initial dose: 600 mg (two 300 mg injections) 

Subsequent doses (EOW): 300 mg

At Week 16, subjects receiving dupilumab as per its label will be reassigned based on their EASI 
response:

< EASI 75 will be offered the option to receive oral doses of upadacitinib 15 mg QD and 
enter Period 2

≥ EASI 75 will complete end of study procedures

During Period 2, subjects randomized to upadacitinib 15 mg QD will have their dose increased to 
30 mg QD if any of the following parameters is met:

Starting at Week 20, subject has a < EASI 75 response 

Starting at Week 20, subject has a < 4-point improvement from Baseline in WP-NRS (weekly 
average)
An unscheduled visit may be used for this purpose if necessary for dose escalation.
Any subject treated for at least 8 weeks with upadacitinib 30 mg QD with a < EASI 50 response 
(reduction from Baseline) after rescue with topical corticosteroid treatment for at least 1 week must be 
discontinued.
Randomization will be stratified by baseline disease severity (moderate validated Investigator Global 
Assessment for AD [vIGA-AD 3] vs. severe [vIGA-AD 4]) and age categories (12 to < 18; 18 to < 40; ≥ 40 to 
< 64 years).
During Period 1 and Period 2 which are open-label, only the efficacy assessor will be blinded to the 
subject's treatment assignment. Subjects and other study site personnel will be aware of the subject's 
treatment assignment.
Further details regarding study procedures are located in the Operations Manual. See Section 5 for 
information regarding eligibility criteria.
The primary analysis for the study will be performed when all ongoing subjects have completed Week 16 
or permanently discontinue Period 1. This analysis is the final and only analysis for the primary and 
ranked secondary endpoints. Additional analyses may be performed as appropriate.
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Figure 1.
Study Schematic
BL = Baseline; EOW = every other week; EASI 50/75 = Eczema Area and Severity Index 50/75; QD = once daily; 
SC= subcutaneous; vIGA-AD = Validated Investigator's Global Assessment for Atopic Dermatitis
4.2 Discussion of Study Design
Choice of Control Group
Dupilumab is a systemic therapy approved in the US, EU, and elsewhere for treatment of adult and 
adolescent patients with moderate to severe AD. One upadacitinib Phase 3b study (HEADS UP)10,11 in a 
similar patient population showed superior results for upadacitinib 30 mg QD versus dupilumab 300 mg 
every other week (EOW) at Week 16. This study is being performed to evaluate the hypothesis of 
potential superiority of upadacitinib, initiated at 15 mg QD and dose escalated based on clinical 
response versus dupilumab as per its label.
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. Other than the biomarker analyses which are exploratory, all clinical and 
laboratory procedures in this study are standard and generally accepted.
Care should be taken to minimize the pain and discomfort of laboratory procedures. 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 
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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 adolescent and adult AD population with 
moderate to severe disease activity with documented history of inadequate response to at least one 
prior systemic treatment for AD. Adolescent and adult subjects ≥12 and < 64 years of age and weighing 
at least 40 kg 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).
This study is also assessing 2 doses of dupilumab, which will be used according to its current label 
dosage for both adults and adolescents (≥ 40 kg).
All subjects in the upadacitinib arm will receive 15 mg QD as the starting dose. The dose will be adjusted 
based on clinical response starting after 4 weeks of treatment when needed and according with the 
protocol criteria.
The dose selection was informed by the two doses studied in the pivotal trials to support the approvals 
of market authorizations of moderate to severe AD in several jurisdictions, including but not limited to 
the EU, Japan, US, and Canada. Both doses showed a positive benefit-risk and the objective of this study 
is to generate data that will help inform the use of both approved doses.
All the current available pharmacokinetic (PK), pharmacodynamic, safety, and efficacy data from 
upadacitinib studies were used to support the selection of these doses.
Exposures associated with upadacitinib 30 mg or 15 mg QD using the once daily formulation are 
predicted to be efficacious in treatment of subjects with moderate to severe AD with limited effects on 
laboratory parameters.
The selection of the dupilumab doses was based on the approved posology in moderate to severe AD 
subjects, initial dose of 600 mg (two 300 mg injections), followed by 300 mg given EOW administered as 
subcutaneous injection for adults, initial dose of 400 mg (two 200 mg injections), followed by 200 mg 
EOW administered as subcutaneously (SC) injection for adolescents 12 to 17 years of age weighing 
between 30 kg and less than 60 kg, and initial dose of 600 mg (two 300 mg injections), followed by 
300 mg given EOW administered as subcutaneous injection for adolescents 12 to 17 years of age 
weighing 60 kg or more.17,20
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):
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Consent
1. Adult subjects ≥ 18 years of age at Screening Visit or their legally authorized representative 
must voluntarily sign and date an informed consent, approved by an independent ethics 
committee (IEC)/institutional review board (IRB), prior to the initiation of any screening or 
study-specific procedures and comply with the requirements of this study protocol.
2. For subjects ≥ 12 and < 18 years of age at Screening Visit: Parent or legal guardian, as 
required, has voluntarily signed and dated an informed consent form, approved by an IEC, after 
the nature of the study has been explained and the subject's parent or legal guardian has had 
the opportunity to ask questions. Subjects will be included in all discussions in order to obtain 
verbal/and or written assent. Parent/legal guardian and subject must comply with the 
requirements of this study protocol. If a subject becomes of legal age during the course of the 
study, that subject will need to be consented using the approved informed consent form.
Demographics and Laboratory Assessments
3. Subjects must be at least ≥ 12 years old and < 64 years old at Screening Visit. Adolescent 
subjects (between ≥ 12 and < 18 years of age and weighing ≥ 40 kg) may be enrolled only if 
there is local approval for dupilumab in this age group. Subject must not turn 65 years old 
before completing the study.
4. Body weight must be ≥ 40 kg at the Baseline Visit for subjects between ≥ 12 and < 18 years of 
age, unless there are higher weight requirements per the local approved label for dupilumab, in 
which case the more restricted requirement must be followed.
5. 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 for adult subjects and adolescent 
subjects (12 - 17 years of age);

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.
AD Disease history
6. Chronic AD with onset of symptoms at least 3 years prior to baseline and subject meets 
Hanifin and Rajka criteria.21
7. Subject meets the following disease activity criteria:
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
EASI score ≥16; vIGA-AD score ≥3 and ≥10% BSA of AD involvement at theBaseline Visit;

Baseline weekly average of daily WP-NRS ≥ 4. Note: The baseline weekly average of daily 
WP-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.

Documented history of inadequate response to previous systemic treatment defined as 
documented history of previous inadequate response to at least one prior systemic 
treatment for AD OR for whom other systemic treatments are otherwise medically 
inadvisable (e.g., because of important side effects or safety risks).

Subject has applied a topical emollient (an additive-free, bland emollient moisturizer) twice 
daily for at least 7 days before the Baseline Visit and for the duration of the study. Note: 
Subject may use prescription moisturizers or moisturizers containing ceramide, urea, 
filaggrin degradation products or hyaluronic acid if such moisturizers were initiated before 
the Screening visit.
Subject History
8. Subject is judged to be in good health as determined by the Principal Investigator, based upon 
the results of the Screening assessments and medical history. 
9. No history of clinically significant (per investigator's judgment) drug or alcohol abuse within 
the last 6 months.
10. Subject must have no current or past history of infection including:

Other active skin diseases or skin infections (bacterial, fungal, or viral) requiring systemic 
treatment within 4 weeks of the Baseline Visit or would interfere with the appropriate 
assessment of AD lesions;

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 tuberculosis (TB) or meet TB exclusionary parameters (specific requirements for TB 
testing are provided in the Operations Manual);

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-19, 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 
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since the COVID-19 positive test result (whichever comes last). Subjects may be rescreened 
if deemed appropriate by the investigator based upon the subject's health status.

Subjects must not have evidence of:

HBV: hepatitis B surface antigen (hepatitis B [HB] Ag) positive (+) test or detectable hepatitis 
B virus (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);

HCV: detectable HCV ribonucleic acid (RNA) in any subject with anti-HCV antibody (HCV Ab).

For Japan: Positive result of beta-D-glucan (screening for Pneumocystis jirovecii infection) or 
two consecutive indeterminate results of beta-D-glucan during the Screening Period. 
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;

Any other unstable clinical condition which, in the opinion of the investigator, would put the 
subject at risk by participating in the protocol;

Diagnosed active parasitic infection; suspected or high risk of parasitic infection, unless 
clinical and (if necessary) laboratory assessment have ruled out active infection before 
randomization;

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;

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. 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.
13. For France, 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).
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Contraception
14. A negative serum pregnancy test for all female subjects considered to be of childbearing 
potential (as defined in Section 5.2) at the Screening Visit and a negative urine pregnancy test at 
baseline prior to the first dose of study drug.
15. If female of childbearing potential (as defined in Section 5.2), must be practicing at least 1 
protocol-specified method of birth control, that is effective from Study Day 1 (or earlier) through 
at least 30 days or 12 weeks after the last dose of study drug (for upadacitinib or dupilumab, 
respectively).
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). Subjects with a urine pregnancy test at Baseline that is 
borderline or ambiguous must have a serum pregnancy test. In such cases, the participant must 
be excluded from participation if the serum pregnancy result is positive.
17. Female subjects of childbearing potential must practice at least 1 protocol-specified method 
of birth control that is effective from Study Day 1 through at least 30 days after the last dose of 
study drug (local practices may require 2 methods of birth control). Female subjects of non-
childbearing potential do not need to use birth control.
18. Female subjects must not be pregnant, breastfeeding, or considering becoming pregnant 
during the study and through at least 30 days or 12 weeks after the last dose of study drug (for 
upadacitinib or dupilumab, respectively).
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®], fedratinib 
[Inrebic®], and deucravacitinib [Sotyktu™]).
20. No prior exposure to dupilumab, tralokinumab, or lebrikizumab.
21. Subjects must not have used the following AD treatments within the specified time frame
prior to Baseline Visit:

Systemic therapy for AD, including but not limited to corticosteroids, methotrexate, 
cyclosporine, azathioprine, phosphodiesterase type 4 (PDE4)-inhibitors, IFN-γ and 
mycophenolate mofetil within 4 weeks;

Topical treatments including but not limited to TCS, TCIs, or topical PDE-4inhibitors within 7 
days.

Targeted biologic treatments within 5 half-lives [if known] or within 12 weeks, whichever is 
longer
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
Phototherapy treatment, laser therapy, tanning booth, or extended sun exposure that could 
affect disease severity or interfere with disease assessments within 4 weeks;

Oral or parenteral traditional Chinese medicine within 4 weeks.
22. Subject must not have been treated with any investigational drug of chemical or biologic 
nature within a minimum of 30 days or five half-lives (whichever is longer) prior to the first dose 
of study drug or is currently enrolled in another interventional clinical study.
23. 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 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.
24. Subject must not have received any live vaccine with replicating potential within 30 days (or 
longer if required locally) prior to the first dose of study drug, or have expected need of 
vaccination with any live vaccine with replicating potential during study participation including
at least 30 days or 12 weeks (or longer if required locally) after the last dose of study drug (for 
upadacitinib or dupilumab, respectively). 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: 
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.
3.
Premenarchal female (have not met the definition of childbearing potential below). 
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
Females who are Tanner Stage 1 or 2 who have not experienced menarche (at least one 
menstrual period). Tanner Stage must be established and documented through 
investigator-or delegated, trained medical professional assessment.

Females of Childbearing Potential
Females who have experienced menarche, or who are Tanner Stage 3 or higher who have not 
experienced menarche will be considered to be of childbearing potential. Tanner Stage must be 
established and documented through investigator-or delegated, trained medical professional 
assessment.
Females that are not postmenopausal and not premenopausal with permanent sterility or 
permanent infertility (as per the definition of a female of non-childbearing potential above) are 
considered females of childbearing potential. 
Females of childbearing potential must avoid pregnancy while taking study drug and for at least 
30 days or 12 weeks after the last dose of study drug (for upadacitinib or dupilumab, 
respectively). Females must commit to use a highly effective method of contraception listed 
below (failure rate of <1% per year, when used consistently and correctly) plus a barrier 
method, if indicated below or required per local practice:

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. Importantly, periodic abstinence [e.g., calendar, ovulation, symptothermal, 
post-ovulation methods] and withdrawal are not acceptable). 
Contraception recommendations related to 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.
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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.
FOR ADOLESCENTS (≥12 YEARS TO <18 YEARS OF AGE)
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:
1.
Premenarchal female who has not met the definition of childbearing potential below

Females who are Tanner Stage 1 or 2 who have not experienced menarche (at least one 
menstrual period). Tanner Stage must be established and documented through 
investigator-or delegated, trained medical professional assessment.
2.
Female with permanent infertility due to one of the following: 

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.
Females, of Childbearing Potential

Females who have experienced menarche, or who are Tanner Stage 3 or higher who have not 
experienced menarche will be considered to be of childbearing potential. Tanner Stage must be 
established by an investigator-or delegated, trained medical professional assessment.

Females of childbearing potential must avoid pregnancy while taking study drug and for at least 
30 days or 12 weeks after the last dose of study drug (for upadacitinib or dupilumab, 
respectively). 

Females must commit to use a highly effective method of contraception listed below (failure 
rate of <1% per year, when used consistently and correctly) plus a barrier method, if indicated 
below: 

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).

Oral, intravaginal, and transdermal combined (estrogen and progestogen-containing) OR 
oral or injectable progestogen-only hormonal birth control associated with inhibition of 
ovulation initiated at least 30 days prior to study Baseline 

PLUS a barrier method (preferably a male condom with or without spermicide; other 
barrier options are female condom, cap, diaphragm, or sponge with spermicide). 

Implantable progestogen-only hormonal birth control associated with inhibition of ovulation 
initiated at least 30 days prior to study Baseline 
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
Intrauterine device (IUD). 

Intrauterine hormone-releasing system (IUS). 
Contraception recommendations related to use of concomitant therapies prescribed should be based on 
the local label.
Change in Female Subject's Childbearing Potential or Pregnancy Risk During the Study
If the subject's childbearing potential changes after start of the study (e.g., a premenarchal female 
participant reaches Tanner 3 and/or menarche), or the risk of pregnancy changes (e.g., a female who is 
not heterosexually active becomes active), the participant and/or their legally authorized representative 
must discuss this with the investigator, who should determine if a female participant must begin a highly 
effective method of contraception. If reproductive status is questionable, additional evaluation should 
be considered. The discussion should be documented in the subject's source records.
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.
5.3 Prohibited Medications and Therapy
Biologic Therapies
Current and concomitant biologic therapies and biosimilar versions of biologic drugs that are considered 
immune modulating (or immune suppressing) are prohibited during treatment with the study drug. 
Subjects must have discontinued biologic therapies with immunosuppressive potential prior to the first 
dose of study drug as specified in the washout procedures (Eligibility Criterion 20, Protocol Section 5.1), 
OR at least five times the mean terminal elimination half-life of the medication prior to the first dose of 
study drug. No minimum washout prior to Baseline is required for a biologic therapy if an undetectable 
drug level measured by a commercially available assay is documented.
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
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
Golimumab

Guselkumab

Infliximab

Ixekizumab

Lebrikizumab

Natalizumab

Nemolizumab

Risankizumab

Rituximab

Secukinumab

Tocilizumab

Tralokinumab

Ustekinumab

Vedolizumab
Other Non-Biologic Systemic Therapy
Concomitant treatment with systemic non-steroidal systemic 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 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.
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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.
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
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.
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Topical Therapy
No topical treatments for AD should be started for the duration of the treatment with study drug except 
for rescue treatment (see Rescue Concomitant Medications and Therapy, Section 5.4). This includes but 
is not limited to calcineurin inhibitors, corticosteroids, and phosphodiesterase-4 inhibitors. Prescription 
moisturizers or moisturizers containing additives such as ceramide, hyaluronic acid, urea, or filaggrin are 
prohibited unless initiated prior to Screening. Additive-free, bland topical emollient treatments are 
allowed per Eligibility Criteria. 
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 TA MD or Therapeutic Area Scientific Director (TA SD).
Other Medications Prohibited during the Study
Oral and topical JAK inhibitors (e.g., commercial upadacitinib [Rinvoq®], tofacitinib [Xeljanz®], ruxolitinib 
[Jakafi® or Opzelura®], baricitinib [Olumiant®], peficitinib [Smyraf®], abrocitinib [Cibinqo®], filgotinib 
[Jyseleca®], fedratinib [Inrebic ®], 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 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 on the subject paper diary cards 
(see Section 5.11).
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 12 weeks for upadacitinib or dupilumab, respectively (or 
longer if required locally) after the last dose of study drug. If a subject requires to receive a live vaccine 
with replicating potential, this subject should permanently discontinue the study participation prior to 
receiving the live vaccine. Varicella (chicken pox) vaccination status will be recorded as part of a 
subject's medical history. Examples of live vaccines with replicating potential include, but are not limited 
to, the following:

Monovalent live influenza A (H1N1) (intranasal);
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
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 or monkeypox vaccine capable of replicating (ACAM2000®);

Yellow fever;

Bacille Calmette-Guérin (BCG);

Typhoid (oral).
If the live herpes zoster vaccine is to 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 infection (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.
For Japan only: 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) vaccines. 
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.
Rescue Concomitant Medications and Therapy
Period 1
Upadacitinib arm: Starting four weeks following dose escalation to upadacitinib 30 mg QD in Period 1, 
subjects with a < EASI 50 response or < 4-point improvement from Baseline in WP-NRS (weekly average) 
will have the option to add topical therapy (except for topical JAK inhibitors) as rescue therapy.
Dupilumab arm: Starting at Week 4 of Period 1 with dupilumab as per its label, subjects with a < EASI 50 
response or < 4-point improvement from Baseline in WP-NRS (weekly average), will have the option to 
add topical therapy (except for topical JAK inhibitors) as rescue therapy.
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Period 2
Starting four weeks following dose escalation to upadacitinib 30 mg QD in Period 2, subjects with a < 
EASI 75 response from Baseline or < 4-point improvement from Baseline in WP-NRS (weekly average) 
will have the option to add topical therapy (except for topical JAK inhibitors) as rescue therapy.
All Periods
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 subject should be discontinued from the study.
Efficacy and safety assessments should be conducted (e.g., disease severity scores, safety labs) before 
administering any rescue treatment. An unscheduled visit may be used for this purpose if necessary. 
If there are any questions regarding concomitant or prior therapies, the AbbVie TA SD should be 
contacted who will then discuss it with the AbbVie Therapeutic Area Medical Director (TA MD) and
provide a recommendation.
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 his/her site if 
he/she has 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 infection (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.
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
Confirmed diagnosis of deep vein thrombosis (DVT), pulmonary embolus or non-cardiac, non-
neurologic arterial thrombosis.

Subject is non-compliant with TB prophylaxis (if applicable) or develops active TB at any time 
during the study.

Subject develops any malignancy, except for developing a localized NMSC or a carcinoma in-situ 
of the cervix if this can be successfully treated at its localization.

Subject develops a gastrointestinal (GI) perforation (other than due to appendicitis or 
mechanical injury).

The subject experiences a serious hypersensitivity reaction without an alternative etiology.

The subject experiences an anaphylactic reaction or other severe systemic reaction that is 
related to study drug.

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.

Subject is significantly non-compliant with study visits/study drug administration.

Initiation of any prohibited systemic therapy for AD.

Initiation of phototherapy.

Treatment with a live (attenuated) vaccine with replicating potential.

Any subject treated for at least 8 weeks with upadacitinib 30 mg QD with a < EASI 50 response 
(reduction from Baseline) after rescue with topical corticosteroid treatment for at least 1 week 
must be discontinued.
Additional requirements related to abnormal laboratory values and selected adverse events of special
interest (AESIs) are located in Protocol Section 6.2 (Toxicity Management).
COVID-19 Pandemic-Related Acceptable Protocol Modification
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.
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5.6 Follow-Up After Subject Discontinuation of Study Drug or from 
Study
Discontinuation of Study Drug
Subjects who prematurely discontinue study drug treatment will be discontinued from study
participation entirely. 
Following discontinuation of study drug, the subject should be treated in accordance with the 
investigator's best clinical judgment based on available approved treatment options. 
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, an End of Treatment Follow-up Visit after
the last dose of study drug is required to ensure all treatment-emergent AEs/SAEs have been resolved.
The 30-day or 12-week follow-up phone call (for subjects on upadacitinib or dupilumab, respectively) 
following the last dose of study drug will not be required for any subject who initiates commercially 
available upadacitinib or dupilumab upon the study Completion Visit or Premature Discontinuation 
visit. The End of Treatment Follow-up Visit is defined as:

For subjects on upadacitinib, a 30-day follow-up visit (or phone call if a visit is not possible) after 
the last study drug dose will be completed to determine the status of any new or ongoing 
AEs/SAEs and concomitant medications.

For subjects receiving dupilumab, a 12-week follow-up visit (or phone call if a visit is not 
possible) after the last study drug injection will be completed to determine the status of any 
new or ongoing AEs/SAEs and concomitant medications.
For subjects who prematurely discontinued study participation, this visit may be a telephone call if a site 
visit is not possible.
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 
subject is willing, a 30-day or 12 week follow-up phone call or visit after the last dose of study drug (for 
upadacitinib and dupilumab, respectively) may be completed to ensure all treatment-emergent 
AEs/SAEs have been resolved.
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.
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In the event a subject withdraws consent from the clinical study, biomarker research will continue 
unless the subject explicitly requests analysis to be stopped. When AbbVie is informed the subject has 
withdrawn and no longer wishes biomarker research to continue, samples will not be analyzed, and 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.
5.7 Study Drug
Upadacitinib will be taken orally daily, beginning on Day 1 (Baseline), and should be taken at 
approximately the same time each day, with or without food.
Dupilumab will be administered subcutaneously (SC) at the Baseline visit, followed by SC injection EOW. 
Subjects will continue their disease-related concomitant medications therapy as allowed per protocol. 
AbbVie will not supply any disease-related concomitant medication therapy taken during the course of 
the study.
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 supply upadacitinib and dupilumab (Table 2). AbbVie provided study drug should not be 
substituted or alternately sourced unless otherwise directed by AbbVie.
Upadacitinib must be stored at controlled room temperature (15° to 25°C/59° to 77°F). Dupilumab must 
be stored at refrigerated temperature (2° to 8°C/35° to 46°F). 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.
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 performed according to instructions from the sponsor and according to 
local regulations following completion of drug/device accountability procedures.
During the COVID-19 pandemic or geo-political crisis in Ukraine, 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.
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Table 2.
Description of Study Drug
Investigational Product
Investigational Product
Investigational Product
Investigational
product name
Upadacitinib (ABT-494)
Upadacitinib (ABT-494)
Dupilumab pre-filled syringe
Mode/Route of 
Administration
(ROA)
Oral
Oral
SC
Formulation
15 mg
30 mg
200 mg
300 mg
Dosage Form
Extended-release
tablets
Extended-release tablets
Solution for injection in pre-filled 
syringe
Masking
Open-label
Open-label
Open-label
Frequency of 
administration
QD
QD
Adults: Dupilumab 600 mg (2 × 300 
mg dupilumab SC injection) 
administered at the Baseline visit, 
followed by dupilumab 300 mg SC 
injection every other week
Adolescents (12 to 17 years of age 
weighing at least 40 kg): Dose of 
dupilumab for subcutaneous 
administration in adolescent 
subjects 12 to 17 years of age with 
atopic dermatitis
Body weight of subject:
1.
40 to <60 kg:

Initial dose: 400 mg (two 200 
mg injections)

Subsequent doses (EOW): 
200 mg
2.
60 kg or more:

Initial dose: 600 mg (two 300 
mg injections)

Subsequent doses (EOW): 
300 mg
Storage Conditions 
15° to 25° C
15° to 25° C
2° to 8° C
Manufacturer
AbbVie
AbbVie
Sanofi, Genzyme
(Regeneron) or other
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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.
Randomization for the study is described in Section 4.1. Randomization will be stratified by baseline 
vIGA-AD categories [3;4] and age categories (12 to < 18; 18 to < 40; ≥ 40 to < 64 years).
The efficacy assessor will remain blinded to each subject's treatment through Week 32. Subjects and 
other study site personnel will be aware of the subject's treatment assignment. The IRT will provide 
access to unblinded subject treatment information in the case of medical emergency.
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), the investigator is responsible for notifying independent 
ethics committee (IEC)/independent review board (IRB), regulatory authorities (as applicable), and 
AbbVie.
In Japan, the investigator will record all protocol deviations in the appropriate medical records at the 
site.
5.10 Data Monitoring Committee
Given that the study is only assessor blinded and no subjects participating in the study will receive 
placebo, the causality of any AEs reported in the participants can be adequately assessed in the context 
of upadacitinib or dupilumab 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 Drug Monitoring 
Committee for the conduct of this study.
5.11 Paper Diary Cards for Sites in China Only
For sites in China only, a paper diary card for recording adverse events, concomitant medications, and 
dosing will be provided at Baseline and subjects will be trained on how to complete the diary cards by 
site staff during the visit. If subjects require re-training during the study, the site staff will accommodate 
this requirement. 
All subjects should complete their paper diary cards throughout the entire study. Subjects will be 
instructed to bring their paper diary cards back to the site to be reviewed and collected at each visit, 
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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 site should collect the paper 
diary card at the next on-site visit. Subjects will be instructed to record the date and time each dose of 
study drug is taken, indicating if any doses of study drug are missed.
Subjects will also be instructed to record adverse events 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 adverse event, drug administration, and concomitant medication as applicable. At 
each visit after Baseline, including the Final/Premature Discontinuation 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/Premature Discontinuation 
Visit), the subject will be provided 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 and eCRF forms, 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.
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 
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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 adverse events 
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
An adverse event 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 adverse event 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 adverse event or not. Any worsening of a pre-existing condition or 
illness is considered an adverse event. Worsening in severity of a reported adverse event should be 
reported as a new adverse event. Laboratory abnormalities and changes in vital signs are considered to 
be adverse events if they are clinically significant, such as resulting in discontinuation from the study, 
necessitating therapeutic medical intervention, meeting protocol-specific criteria (see Section 6.2
regarding toxicity management), and/or if the investigator considers them to be adverse events. Any 
clinically significant change from baseline per investigator judgment in the study safety evaluations 
should be reported as an adverse event. 
The investigators will monitor each subject for clinical and laboratory evidence of adverse events on a 
routine basis throughout the study. All adverse events will be followed to a satisfactory conclusion.
An elective surgery/procedure scheduled to occur during a study will not be considered an adverse 
event 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 adverse event.
If any of the following events are reported, then the following supplemental report must be completed.
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Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that results in 
fetal loss.
Persistent or Significant 
Disability/Incapacity
An event that results in a condition that substantially interferes with 
the activities of daily living of a study subject. Disability is not 
intended to include experiences of relatively minor medical 
significance such as headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle).
Important Medical Event 
Requiring Medical or Surgical 
Intervention to Prevent 
Serious Outcome
An important medical event that may not be immediately life-
threatening or result in death or hospitalization, but based on 
medical judgment may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the outcomes 
listed above (i.e., death of subject, life threatening, hospitalization, 
prolongation of hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity). Additionally, any elective or 
spontaneous abortion or stillbirth is considered an important 
medical event along with any suspected transmission of an 
infectious agent via a medicinal product if no other serious criterion 
is applicable. 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 or 5 half-lives, 
whichever is longer, after discontinuation of study drug administration will be collected, whether 
solicited or spontaneously reported by the subject. 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 drug (Rinvoq), all adverse events reported by healthcare professionals or the patient, will 
be captured as postmarketing 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 drug. Similarly, if a subject prematurely discontinues study participation and begins 
commercially available dupilumab drug (Dupixent), all adverse events reported by the healthcare 
professionals or the patient, will be captured as postmarketing reports. The 84-day (12 week) follow-up 
phone call following the last dose of dupilumab study drug during the study will not occur for subjects 
who begin commercially available dupilumab drug. 
The following definitions will be used for Serious Adverse Reactions (SAR) and Suspected Unexpected 
Serious Adverse Reaction (SUSAR):
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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 Suspected Unexpected Serious Adverse Reactions (SUSAR) reporting for 
the Investigational Medicinal Product (IMP) in accordance with global and local requirements.
Adverse events will be monitored throughout the study to identify any of special interest that may 
indicate a trend or risk to subjects.
Adverse Events of Special Interest
The following 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

Elevated creatine phosphokinase (CPK; adolescents only)

Adjudicated Gastrointestinal perforations

Adjudicated cardiovascular events (e.g., major adverse cardiovascular event [MACE])

Adjudicated embolic and thrombotic events (non-cardiac, non-CNS)
In addition to the AESIs listed above, the following adverse events will also be monitored during the 
study:

Bone Fracture

Retinal Detachment

Hypersensitivity Reactions

Conjunctivitis
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
Keratitis

Parasitic (Helminth) Infections

Arthralgia
Adverse Event Severity and Relationship to Study Drug
The investigator 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 selfcare 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 adverse event 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.
Recording of Adverse Events Symptoms on the Subject Paper Diary Cards: 
For sites in China only, subjects are asked to record adverse event symptoms on the subject paper diary 
cards (see Section 5.11, Paper Diary Cards for Sites in China Only, for description of paper diary cards).
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Cardiovascular Adjudication Committee 
An independent committee of physician experts in cardiovascular adjudication will be utilized to assess 
potential cardiovascular, cerebrovascular, embolic, and thrombotic AEs in a blinded manner as defined 
by the Cardiovascular Adjudication Committee (CAC) charter. A CAC charter will be prepared separate 
from the protocol that will describe the objective, scope, frequency, and triggers for data reviews.
Gastrointestinal Perforation Adjudication Committee 
An internal gastrointestinal perforation committee will identify and adjudicate adverse events of 
spontaneous GI perforation. The internal committee will be comprised of at least two 
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.
Pregnancy
Pregnancy in a study subject is not considered an adverse event. However, 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 pregnancy outcome,
will be collected. 
Female subjects should avoid pregnancy throughout the course of the study, starting with the Screening 
Visit through 30 days or 12 weeks after the last study drug administration (for upadacitinib or 
dupilumab, respectively). 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 
the study. (Protocol Section 5.5: Withdrawal of Subjects and Discontinuation of Study).
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 of the site becoming aware of the 
event. 
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 serious 
infection has been successfully treated. Subjects who develop active TB must be permanently 
discontinued from study drug.
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Herpes zoster: If a subject develops herpes zoster, consider temporarily interrupting study drug until the 
episode resolves.
Gastrointestinal Perforation: If a diagnosis of GI 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 
continuation, and discuss with the TA MD whether it is appropriate to continue study drug.
Malignancy: Subjects who develop malignancy other than 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, pulmonary embolus or non-cardiac, non-
neurologic arterial thrombosis is confirmed, the subject must be discontinued from study drug.
Hypersensitivity: If a systemic hypersensitivity reaction (immediate or delayed) occurs, including 
anaphylaxis, serum sickness, angioedema, urticaria, rash, erythema nodosum, and erythema 
multiforme, administration of study drug should be discontinued immediately and appropriate therapy 
initiated.
Helminth infection: Patients with pre-existing helminth infections should be treated before initiating 
study drug. If patients become infected while receiving treatment with study drug and do not respond 
to anti-helminth treatment, treatment with study drug should be interrupted until infection resolves, at 
the discretion of the PI.
Conjunctivitis and keratitis related events: Study subjects receiving study drug should be advised to 
report new onset or worsening eye symptoms to the PI. Subjects dosed with study drug who develop 
conjunctivitis that does not resolve following standard treatment or signs and symptoms suggestive of 
keratitis should undergo ophthalmological examination.
Eosinophilic conditions: Cases of eosinophilic pneumonia and cases of vasculitis consistent with 
eosinophilic granulomatosis with polyangiitis (EGPA) have been reported with dupilumab in adult 
patients who participated in the asthma development program. Cases of vasculitis consistent with EGPA 
have been reported with dupilumab and placebo in adult patients with co-morbid asthma in the chronic 
rhinosinusitis with nasal polyposis development program. Physicians should be alert to vasculitic rash, 
worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients 
with eosinophilia.
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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 local laboratory abnormalities which may require data entry into an eCRF, an additional local 
lab 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 × Baseline value.
For the above serum creatinine elevation scenario, complete the appropriate 
supplemental renal eCRF(s).
Creatine Phosphokinase
If a subject experiences any symptoms suggestive of myositis or 
rhabdomyolysis, blood for measuring CPK and aldolase levels should be 
drawn with clinical management as deemed appropriate by the 
investigator.
If confirmed CPK value ≥ 4 × ULN and there are no symptoms suggestive of 
myositis or rhabdomyolysis, the subject may continue study drug at the 
investigator's discretion after evaluation.
If CPK value ≥ 4 × ULN accompanied by symptoms suggestive of myositis or 
rhabdomyolysis, interrupt study drug and contact AbbVie TA MD.
For above CPK elevation scenarios, complete supplemental CPK eCRF.
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 before the primary endpoint 
visit has been completed must be discussed with the TA MD and only 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.
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 ranked secondary 
endpoints analyses. Complete and specific details of the statistical analysis will be described in the 
Statistical Analysis Plan (SAP).
The statistical analyses will be performed using SAS (SAS Institute Inc., Cary, North Carolina, USA).
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The primary analysis will be conducted after all ongoing subjects have completed the Week 16 visit or 
permanently discontinued Period 1, and all data pertaining to Period 1 are cleaned. This analysis is the 
final and only analysis for the primary and ranked secondary endpoints.
7.2 Definition for Analysis Populations
The ITT Population of Period 1 (ITT_1 population) consists of all subjects who were randomized at 
Baseline. The ITT Population of Period 2 (ITT_2 population) consists of all subjects who were randomized 
at Baseline and continue in Period 2. Subjects will be included in the treatment group to which they are 
randomized. The ITT Populations will be used for all efficacy analyses.
The Safety Population of Period 1 (Safety_1 population) consists of all subjects who received at least 1 
dose of study drug in Period 1. The Safety Population of Period 2 (Safety_2 population) consists of all 
subjects who received at least 1 dose of study drug in Period 2. The populations will be used to provide a 
comprehensive summary of safety based on treatment received in Period 1 and Period 2 respectively.
7.3 Handling Potential Intercurrent Events for the Primary and Ranked 
Secondary Endpoints
The following combined composite variable strategy and treatment policy strategy for intercurrent 
events (ICEs) handling method will be used:
Subjects will be considered as non-responders after the initiation of rescue medication (composite 
variable strategy); and the value for the variable of interest is used regardless of treatment 
discontinuation (treatment policy strategy). No other intercurrent event is considered.
7.4 Statistical Analyses for Efficacy
All primary and secondary endpoints will be analyzed in the ITT_1 population to test the superiority of 
upadacitinib over dupilumab in Period 1. All efficacy endpoints will be summarized descriptively using 
ITT_2 population in Period 2. Subjects will be included in the treatment group to which they are 
randomized.
In Period 1, categorical endpoints will be analyzed using Cochran-Mantel-Haenszel (CMH) test stratified 
by vIGA-AD categories (vIGA-AD 3; 4) and age (12 to < 18; 18 to < 40; ≥ 40 to < 64 years). For categorical 
endpoints, missing values and visits after the rescue will be handled by non-responder imputation (NRI) 
except for missing values due to COVID-19 or any other missing data that can be reasonably assumed to 
be Missing at Random, which will be handled by multiple imputation (NRI-MI).
In Period 2, categorical endpoints will be summarized by counts and percentages, as well as 95% 
confidence interval (CI) of the percentage. The primary approach to handle missing data is Observed 
Cases.
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Summary and Analysis of the Primary Endpoints
Analysis of the primary endpoint will be conducted on the ITT_1 population based on treatment as 
randomized. The difference in the proportion of responders will be used to compare upadacitinib group 
and dupilumab group using the CMH test, stratified by vIGA-AD categories and age (12 to < 18; 18 to 
< 40; ≥ 40 to < 64 years). NRI-MI will be the primary approach for handling missing data. 
The NRI approach and the multiple imputation approach will be used as the sensitivity analysis of the 
primary endpoint.
Summary and Analysis of Secondary Endpoints
Summary and Analysis of Ranked Secondary Endpoints
Secondary endpoints will be analyzed in the ranked order as outlined in Section 3.3. All secondary 
categorical variables will be analyzed using CMH test, stratified by vIGA-AD categories and age (12 to 
< 18; 18 to < 40; ≥ 40 to < 64 years). NRI-MI will be the primary approach for handling missing data.
Summary and Analysis of Additional Efficacy Endpoints
CMH test will be used to analyze categorical variables stratified by vIGA-AD categories and age (12 to 
< 18; 18 to < 40; ≥ 40 to < 64 years). NRI-MI will be used for handling missing data.
Subgroup Analysis for Efficacy
The primary endpoints will be analyzed by the following subgroups:

Baseline vIGA-AD (3; 4),

Baseline EASI score (< 21; ≥ 21),

Baseline EASI score (< median; ≥ median), and

Age (12 to < 18; 18 to < 40; ≥ 40 to < 64 years).
7.5 Statistical Analyses for Safety
The safety analyses will be carried out using the Safety Population and will be based on treatments the 
subjects actually received. Safety will be assessed by AEs, physical examination, laboratory assessments, 
and vital signs. Note that missing safety data will not be imputed. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Treatment-emergent adverse events (TEAEs) are defined as those that began or worsened in severity 
after the first dose of study drug and no more than 5 half-lives of the drug after the last dose of study 
drug. Specifically, 30 days will be used for upadacitinib, and 84 days (12 weeks) will be used for 
dupilumab. The number and percentage of subjects experiencing TEAEs will be tabulated using system 
organ class and preferred term, overall and by severity and by relationship to the study drug as assessed 
by the investigator by the Period using the Safety_1 population and Safety_2 population, respectively. 
Summaries (including percentages and events per 100 patient years) of TEAEs, AESIs, SAEs, deaths, and 
AEs leading to discontinuation will be provided in both Periods.
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For laboratory tests and vital signs, mean change from baseline and percentage of subject with 
evaluations meeting pre-defined Potentially Clinically Important criteria will be summarized in both 
Periods. For selected lab parameters, a listing of all subjects with any laboratory value above Grade 3 of 
Common Toxicity Criteria will be provided. Additional details for the safety analysis will be provided in 
the SAP.
7.6 Statistical Analysis of Optional Biomarker Data
Analysis may be conducted on optional biomarker data for the purpose of identification of prognostic, 
predictive, surrogate, and pharmacodynamic biomarkers associated with efficacy or safety. The 
association of biomarkers to the efficacy or safety endpoints may be explored for each biomarker one at 
a time, and also for combinations of biomarkers via some multivariate predictive modeling approaches.
7.7 Interim Analysis
No interim analysis is planned for this study.
7.8 Overall Type I Error Control
The statistical comparisons of upadacitinib versus dupilumab for the primary efficacy endpoint and the 
ranked secondary endpoints will be carried out in the hierarchical order under a 2-sided significance 
level of 0.05. This means that statistically significant results for the comparison in the higher rank 
(primary, then ranked secondary endpoints) are necessary to initiate the testing of the next comparison 
in the lower rank. Since a step-down procedure is used, each comparison will be tested at a significance 
level of 0.05 and the family-wised error rate is strongly controlled at 0.05.
7.9 Sample Size Determination
Approximately 880 subjects will be randomized to upadacitinib or dupilumab in a 1:1 ratio. Assuming a 
response rate of 12% in achieving both EASI 90 and WP-NRS 0/1 at Week 16 in the dupilumab group, 
this sample size will provide more than 90% power to detect the treatment difference of 17% 
(upadacitinib versus dupilumab), using a two-sided significant level of 0.05.
7.10 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.
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7.11 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.
7.12 Subject Confidentiality
To protect subjects' confidentiality, all subjects and their associated samples will be assigned numerical 
study identifiers or "codes." No identifiable information will be provided to AbbVie.
8 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 Good Clinical Practice (GCP), and applicable local regulatory 
requirement(s).
9 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.
10
START AND COMPLETION OF THE STUDY
The start-of-study is defined as the date of the first site activated.
The end-of-study is defined as the date of the last subject's last visit or the actual date of follow-up 
contact, whichever is later; and in the last country where the study was conducted.
11
REFERENCES
1.
Murray PJ. The JAK-STAT signaling pathway: input and output integration. J Immunol. 
2007;178(5):2623-9.
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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.
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.
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 (supplement). 
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. Blauvelt A, Teixeira HD, Simpson EL, et al. Efficacy and Safety of Upadacitinib vs Dupilumab in Adults 
With Moderate-to-Severe Atopic Dermatitis: A Randomized Clinical Trial. JAMA Dermatol. 
2021;157(9):1047-55.
11. Blauvelt A, Teixeira HD, Simpson EL, et al. Efficacy and Safety of Upadacitinib vs Dupilumab in Adults 
With Moderate-to-Severe Atopic Dermatitis: A Randomized Clinical Trial (supplement). JAMA 
Dermatol. 2021;157(9):1047-55.
12. Dupixent. Tarrytown, NY; Regeneron Pharmaceuticals, 2020.
13. Simpson EL, Bieber T, Guttman-Yassky E, et al. Two phase 3 trials of dupilumab versus placebo in 
atopic dermatitis. N Engl J Med. 2016;375(24):2335-48.
14. Blauvelt A, de Bruin-Weller M, Gooderham M, et al. Long-term management of moderate-to-severe 
atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 
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1-year, randomised, double-blinded, placebo-controlled, phase 3 trial. Lancet. 
2017;389(10086):2287-303.
15. Simpson E, Paller AS, Siegfried EC, et al. . Efficacy and Safety of Dupilumab in Adolescents With 
Uncontrolled Moderate to Severe Atopic Dermatitis A Phase 3 Randomized Clinical Trial. JAMA 
Dermatol. 2020;156(1):44-56.
16. 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.
17. European Medicines Agency. Dupixent (dupilumab) SmPC London, England2018 [Available from: 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/004390/huma
n_med_002158.jsp&mid=WC0b01ac058001d124.
18. Sidbury R, Davis DM, Cohen DE, et al. Guidelines of care for the management of atopic dermatitis: 
section 3. Management and treatment with phototherapy and systemic agents. J Am Acad 
Dermatol. 2014;71(2):327-49.
19. Wollenberg A, Barbarot S, Bieber T, et al. Consensus-based European Guidelines for Treatment of 
Atopic Eczema (Atopic Dermatitis) in Adults and Children:  Part II. J Eur Acad Dermatol Venereol. 
2018;32(6):850-78.
20. Dupixent (dupilumab) injection, for subcutaneous use [prescribing information]. Bridgewater, NJ; 
Sanofi-Aventis, 2017.
21. Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol. 1980;92 
(suppl):44-7.
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APPENDIX A. STUDY-SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
Ab
Antibody
AD
atopic dermatitis
ADL
activities of daily living
AE
Adverse event
AESI
adverse event of special interest
Ag
antigen
ALC
absolute lymphocyte count
ALT
alanine transaminase
ANC
Absolute neutrophil count
AST
aspartate transaminase
BCG
Bacille Calmette-Guérin
CAC
Cardiovascular Adjudication Committee
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
CPK
creatine phosphokinase
CTEP
Cancer Treatment Evaluation Program
CXR
chest x-ray
CYP3A
cytochrome P450 3A
DL
detection limit
DLQI
Dermatology Life Quality Index
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DVT
deep vein thrombosis
EASI
Eczema Area and Severity Index
ECG
Electrocardiogram
eCRF
electronic case report form
EDC
Electronic data capture
eow
every other week
EU
European Union
FSH
follicle-stimulating hormone
GCP
Good clinical practice
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GFR
glomerular filtration rate
GI
gastrointestinal
HB
hepatitis B
HBV
hepatitis B virus
HCV
hepatitis C virus
HCV Ab
HCV antibody
HIV
Human immunodeficiency virus
HIV Ab
HIV antibody
ICEs
intercurrent events
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
IGA
Investigator's Global Assessment
IL
interleukin
IMP
Investigational Medicinal Product
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
JAK1
Janus kinase 1
JAK2
Janus kinase 2
MACE
major adverse cardiovascular event
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MI
myocardial infarction
Min
minimum
mRNA
messenger ribonucleic acid
NCI
National Cancer Institute
NMSC
non-melanoma skin cancer
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NRI
Non-responder imputation
NRI-MI
Non-Responder Imputation incorporating multiple imputation to handle missing data 
due to COVID-19 or any other missing data that can be reasonably assumed to be 
Missing at Random
OR
odds ratio
PCR
polymerase chain reaction
PD Visit
Premature Discontinuation visit
PDE4
phosphodiesterase type 4
PK
pharmacokinetic 
PsA
psoriatic arthritis
PUVA
psoralen and ultraviolet A
QD
once a day
RNA
ribonucleic acid
SAE
Serious adverse event
SAP
Statistical analysis plan
SAR
serious adverse reaction
SC
subcutaneously
SmPC
Summary of Product Characteristics
SUSAR
Suspected unexpected serious adverse reactions
TB
tuberculosis
TCS
topical corticosteroids
TEAE
treatment-emergent adverse event
TNF
tumor necrosis factor
TSLP
Thymic stromal lymphopoietin
TYK2
tyrosine kinase 2
ULN
upper limit of normal
US
United States
USPI
United States package insert
UV
Ultra-violet
vIGA-AD
validated Investigator´s Global Assessment for AD
vs.
versus
WBC
white blood cells
WP-NRS
Worst Pruritus-Numerical Rating Scale
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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M23-696: A Phase 3b/4 Randomized, Open-label, Efficacy Assessor Blinded Study, Comparing the Safety 
and Assessor Blinded Efficacy of Upadacitinib to Dupilumab in Subjects with Moderate to Severe Atopic Dermatitis 
(Level-Up)
Protocol Date: 02 May 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 one (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 the trial protocol that has the 
potential to affect the following:

Rights, safety, physical or mental integrity of the subjects in the clinical trial

Scientific value of the clinical trial, reliability or robustness of data generated
10. Providing direct access to source data documents for study-related monitoring, audits, IEC/IRB review, 
and regulatory inspection(s).
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
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APPENDIX C. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
Medical Affairs
Medical Affairs
Statistics 
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APPENDIX D. ACTIVITY SCHEDULE
The following table shows the required activities for the study. The individual activities are described in 
detail in the Operations Manual (Appendix F).
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APPENDIX E. PROTOCOL SUMMARY OF CHANGES
Previous Protocol Versions
Protocol
Date
Version 1.0
10 August 2022
Administrative Change 1 (China Only)
05 December 2022
Administrative Change 2 (China Only)
10 January 2023
Version 1.1 (France Only)
13 January 2023
Version 1.2 (Japan Only)
28 February 2023
The purpose of this version is to correct minor clerical errors for consistency throughout the protocol in 
addition to the following:

To update Sponsor emergency contact information and list of protocol signatories.

To update current upadacitinib treatment indications in (Section 2.1).

To add the references for the pivotal studies in atopic dermatitis mentioned in Section 2.1 and 
Section 2.2 and to add references to another important study information in Section 2.1 per 
France EC request.

To align with known AEs, and additional detail for current research based on ORAL surveillance 
study results (Section 2.2).

To clarify the estimand definition and the handling rule of the intercurrent events (Section 3.1
and Section 7.3).

To clarify the primary endpoint (Section 3.2).

To include additional detail for safety assessments, and Tanner Stage assessments included for 
adolescent subjects required by regulatory agencies (Section 3.5).

To include that the permanent discontinuation from the study will be mandatory in any subject 
who has been treated for at least 8 weeks with upadacitinib 30 mg QD and has not achieved an 
EASI 50 response from Baseline after rescue with topical corticosteroid treatment for at least 1 
week (Section 4.1) per FDA request.

Figure 1 updated for clarification.

To clarify the eligibility criteria language to enroll subjects < 64 to ensure no subject 65 or older 
is enrolled (Section 4.1 and Section 5.1).

To update eligibility criteria for laboratory values specific to pediatric studies, include detail for 
COVID-19 which better reflects situation post-pandemic, clarify requirements for serum and 
urine pregnancy tests, to update prior and concomitant medications, to distinguish between live 
vaccines with replicating potential and those without, and to clarify contraception 
recommendations (Section 5.1). 
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
To add an eligibility criterion specific to France that requires subjects to be registered with a 
social security scheme, and to specify that they not fall within the scope of Article L1121-6 or 
Article L1121-8 of the French Public Health Code (Section 5.1).

To include the rationale for the collection of race and ethnic origin as part of subject 
demographics (Operations Manual Section 3.2) per France EC request. 

To update the estimated glomerular filtration rate eligibility criterion (Section 5.1) per German 
CA request.

To clarify that topical treatment with emollient should be applied for 7 days before Baseline Visit 
and throughout the study duration (Section 5.1).

To clarify that topical anti-infectives, topical antihistamines, and bleach baths are allowed per 
investigator discretion for the duration of the study (Section 5.3).

To clarify that females who have experienced menarche, or who are Tanner Stage 3 or higher 
who have not experienced menarche will be considered to be of childbearing potential and 
update pregnancy avoidance recommendations (Section 5.2).

To update prohibited medications and therapy to reflect prohibited medications used in 
indications currently being studied (Section 5.3).

To align with currently approved options of live vaccines and to highlight country-specific 
requirements (Section 5.4).

To remove language that the AbbVie TA MD may mandate individual subject discontinuation
clarify malignancy language and clarify malignancy language (Section 5.5).

To clarify that for subjects on dupilumab, last dose of dupilumab will be at Week 14 instead of 
Week 16. Dupilumab dose removed from Week 16 for dupilumab responders because the Week 
16 dose would be considered as a Period 2 dose. (Section 5.6).

To clarify that the 12 week follow up includes the 2 weeks after last dose of dupilumab plus 10 
weeks after the Week 16 visit (Section 5.6).

To align with relevant PK guidelines, removed language that study drug should be taken at 
approximately the same time each day, with or without food.

To add the use of subject paper diary cards for sites in China only to collect AE symptoms, 
concomitant therapy, and IP administration (Section 5.11).

Included Japan specific details regarding: subject history (Section 5.1), bilateral tubal 
occlusion/litigation (Section 5.2), live herpes zoster vaccine (Section 5.4 and Operations Manual 
Section 3.11), protocol deviations (Section 5.9), GCP compliance (Section 7.11), beta-D-glucan 
testing for pneumocystis jirovecii infection (Appendix D and Operations Manual Section 2.1 & 
Section 3.13), added section to include information for which safety information is reported in 
Japan (Operations Manual 5.4). Note that historical height from Japan Protocol Version 1.2 
(Operations Manual Section 2.1 & Section 3.9) is no longer required for this study due to the 
study design.

To update complaints and adverse events to include adverse events (AEs) known to be related 
to dupilumab treatment, and clarity that any clinically significant change in the study safety 
evaluations should be reported as an adverse event (Section 6.1) per FDA request.
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
To add cardiac events, AEs of retinal detachment and bone fracture, clarify that CPK monitoring 
is optional and update pregnancy protocol AE language (Section 6.1).

To clarify toxicity management language (Section 6.2).

Clarified height requirements for adults at Baseline (Appendix D and Operations Manual).

To update CXR requirements to include clarification to reduce exposure to X-rays in subjects 
with low TB risk (negative TB testing/assessment) (Appendix D and Operations Manual).

To clarify when at home pregnancy tests are dispensed (Appendix D and Operations Manual).

To relabel the Study Activities Table header in Appendix D to include "Week 8" to align with 
table content rows.

To update the study activities table to allow for TB testing every 6 months if it is locally required 
(Appendix D).
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