Clinical trial NCT05601882
Conditions: Atopic Dermatitis
Keywords: Atopic Dermatitis AD Level-Up Upadacitinib Dupilumab RINVOQ
Sponsor: AbbVie
Start date: 2022-11-28; Completion date: 2024-08-08
Enrollment: 920 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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

Upadacitinib and dupilumab are approved drugs for the treatment of moderate to severe atopic dermatitis (AD). The study is comprised of a 35-day Screening Period, a 16-week treatment Period 1 and a 16-week treatment Period 2. Participants are randomly assigned to 1 of 2 groups called treatment arms to receive upadacitinib Dose A or dupilumab in Period 1. There is a 30-day or 12-week follow-up visit for those on upadacitinib or dupilumab respectively, who will not enter Period 2. In Period 2, participants will receive upadacitinib Dose A or Dose B for 16 weeks, followed by a 30-day follow-up visit. Approximately 880 adolescent and adult participants ages 12 to 64 with moderate to severe AD who are candidates for systemic therapy will be enrolled at up to 330 sites worldwide.

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

Detailed description:

Arms: arm 1: Adult participants received a loading dose of 600 mg dupilumab by subcutaneous (SC) injection at the Baseline visit followed by 300 mg dupilumab SC every other week (EOW) until Week 16.

Adolescents (12 to 17 years of age and weighing at least 40 kg) received treatment according to their body weight. Participants weighing 40 to \< 60 kg received a loading dose of 400 mg dupilumab SC at the Baseline visit followed by 200 mg SC EOW until Week 16. Those weighing 60 kg or more received a loading dose of 600 mg dupilumab SC at the Baseline visit followed by 300 mg dupilumab SC EOW until Week 16. arm 2: Participants received 15 mg upadacitinib orally once a day (QD) up to Week 16. Starting at Week 4, participants had their dose increased to 30 mg QD if they had a \< 50% reduction from Baseline in Eczema Area and Severity Index (EASI 50) response or a \< 4-point improvement from Baseline in Worst Pruritus Numerical Rating Scale (WP-NRS; weekly average). Starting at Week 8, participants had their dose increased to 30 mg QD if they had a \< EASI 75 response. arm 3: At Week 16, participants receiving dupilumab as per its label in Period 1 were reassigned based on their Eczema Area and Severity Index (EASI) response. Those with \< EASI 75 were offered the option to receive oral doses of upadacitinib 15 mg QD in Period 2 up to Week 32. Those with ≥ EASI 75 completed the end of study procedures. Starting at Week 20, participants with \< EASI 75 or a \< 4-point improvement from Baseline in Worst Pruritus Numerical Rating Scale (WP-NRS; weekly average) had their dose increased to 30 mg QD up to Week 32. arm 4: At Week 16, participants receiving upadacitinib in Period 1 were reassigned based on their Eczema Area and Severity Index (EASI) response. Those with \< EASI 75 were allocated or continued to receive upadacitinib 30 mg QD in Period 2. Those with ≥ EASI 75 completed the end of study procedures.
Interventions: intervention 1: Dupilumab intervention 2: Upadacitinib
Intervention descriptions: intervention 1: Dupilumab is administered as a subcutaneous (SC) injection. intervention 2: Extended-release tablet

Protocol documents:
Prot_000.pdf: 


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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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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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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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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STUDY M23-696  |  Version 2.0  |  EudraCT 2022-002482-15
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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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STUDY M23-696  |  Version 2.0  |  EudraCT 2022-002482-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

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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STUDY M23-696  |  Version 2.0  |  EudraCT 2022-002482-15
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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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STUDY M23-696  |  Version 2.0  |  EudraCT 2022-002482-15
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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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CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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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STUDY M23-696  |  Version 2.0  |  EudraCT 2022-002482-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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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STUDY M23-696  |  Version 2.0  |  EudraCT 2022-002482-15
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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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SAP_001.pdf: 
 Upadacitinib 
M23-696 – Statistical Analysis Plan 
Version 4.0 – 11 April 2024 
 
 
1 
 
 
Statistical Analysis Plan for Study 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) 
 
Version 4.0 
 
 
NCT05601882


 Upadacitinib 
M23-696 – Statistical Analysis Plan 
Version 4.0 – 11 April 2024 
 
 
2 
Table of Contents 
1.0 
Introduction ........................................................................... 5 
2.0 
Study Objectives and Design ................................................ 5 
2.1 
Study Objectives, Hypotheses and Estimands ......................................... 5 
2.2 
Study Design Overview .......................................................................... 7 
2.3 
Treatment Assignment and Blinding ....................................................... 9 
2.4 
Sample Size Determination .................................................................. 11 
3.0 
Endpoints ............................................................................. 12 
3.1 
Primary Endpoint ................................................................................. 12 
3.2 
Secondary Endpoints ............................................................................ 12 
3.3 
Additional Efficacy Endpoints .............................................................. 12 
3.4 
Safety Endpoints .................................................................................. 13 
4.0 
Analysis Populations ........................................................... 14 
5.0 
Subject Disposition .............................................................. 15 
6.0 
Study Treatment Duration and Compliance ..................... 16 
7.0 
Subject Characteristics ....................................................... 20 
7.1 
Demographics and Baseline Characteristics .......................................... 20 
7.2 
Medical History and Prior and Concomitant Medications ..................... 21 
7.3 
Protocol Deviations .............................................................................. 22 
8.0 
Handling of Potential Intercurrent Events for the 
Primary and Secondary Endpoints .................................... 23 
9.0 
Efficacy Analyses ................................................................. 23 
9.1 
General Considerations......................................................................... 23 
9.2 
Handling of Missing Data ..................................................................... 24 
9.3 
Primary Efficacy Endpoint and Analyses .............................................. 26 
9.3.1 
Primary Efficacy Endpoint ................................................................... 26 
9.3.2 
Main Analysis of Primary Efficacy Endpoint ........................................ 26 
9.3.3 
Sensitivity and Supplementary Analyses of the Primary Efficacy 
Endpoint ............................................................................................... 27 
9.4 
Secondary Efficacy Endpoints and Analyses ........................................ 28 
9.4.1 
Key Secondary Efficacy Endpoint(s) .................................................... 28 
9.4.2 
Main Analyses of Key Secondary Efficacy Endpoint(s) ........................ 28 
 


 Upadacitinib 
M23-696 – Statistical Analysis Plan 
Version 4.0 – 11 April 2024 
 
 
3 
9.4.3 
Sensitivity and Supplementary Analyses for Key Secondary 
Efficacy Endpoints ............................................................................... 29 
9.5 
Additional Efficacy Endpoints and Analyses ........................................ 29 
9.6 
Efficacy Subgroup Analyses ................................................................. 30 
9.7 
Analysis of Daily Efficacy Measurement for Worst Pruritus NRS ........ 30 
10.0 
Safety Analyses .................................................................... 31 
10.1 
General Considerations......................................................................... 31 
10.2 
Adverse Events..................................................................................... 31 
10.2.1 
Treatment-Emergent Adverse Events.................................................... 32 
10.2.2 
Adverse Event Overview ...................................................................... 33 
10.2.3 
Treatment-Emergent Adverse Events by SOC and/or PT ...................... 33 
10.2.4 
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure .............................................................................................. 35 
10.2.5 
Deaths, Serious Adverse Events, and Adverse Events Leading to 
Study Treatment Discontinuation.......................................................... 35 
10.2.6 
Adverse Events of Special Interest ........................................................ 36 
10.2.7 
Adverse Events of Other Safety Topics of Interest ................................ 37 
10.3 
Analysis of Laboratory Data ................................................................. 37 
10.4 
Analysis of Vital Signs ......................................................................... 38 
10.5 
Other Safety Analyses .......................................................................... 39 
10.6 
Safety Subgroup Analyses .................................................................... 39 
11.0 
Other Analyses .................................................................... 39 
12.0 
Interim Analyses.................................................................. 39 
12.1 
Data Monitoring Committee ................................................................. 39 
13.0 
Overall Type-I Error Control ............................................. 40 
14.0 
Version History ................................................................... 40 
14.1 
Changes to Planned Analyses in the Protocol........................................ 41 
15.0 
References ............................................................................ 42 
 
List of Tables 
Table 1. 
Analyses Populations: ITT Populations and Safety Populations ............ 15 
Table 2. 
Model of Categorical Variables in Period 1 and Period 2 ...................... 24 
 


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M23-696 – Statistical Analysis Plan 
Version 4.0 – 11 April 2024 
 
 
4 
Table 3. 
Summary of the Estimand Attributes Corresponding to the 
Primary Efficacy Objective .................................................................. 27 
Table 4. 
Summary of the Estimand Attributes Corresponding to the Key 
Secondary Efficacy Objectives ............................................................. 29 
Table 5. 
SAP Version History Summary ............................................................ 40 
 
List of Figures 
Figure 1. 
Study Schematic ..................................................................................... 9 
 
List of Appendices 
Appendix A. 
List of SAP Signatories ........................................................................ 43 
Appendix B. 
Definition of Adverse Events of Special Interest ................................... 44 
Appendix C. 
Potentially Clinically Important Criteria for Safety Endpoints .............. 46 
Appendix D. 
Random Seeds ...................................................................................... 48 
Appendix E. 
National Cholesterol Education Program (NCEP) Adult 
Treatment Panel III (ATPIII) for Selected Lipid Parameters ................. 50 
Appendix F. 
Rescue Definition ................................................................................. 51 
Appendix G. 
Definition of Additional Safety Topics ................................................. 52 
Appendix H. 
Non-Responder Imputation Incorporating Multiple Imputation to 
Handle Missing Data Due to COVID-19 Pandemic or Any Other 
Missing Data That Can Be Reasonably Assumed to Be Missing at 
Random for Dichotomized Outcome Variables ..................................... 54 
 
 


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1.0 
Introduction 
This Statistical Analysis Plan (SAP) describes the statistical analyses for ABT-494 
Study M23-696 (Level-Up) 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 (AD). 
Study M23-696 examines the efficacy and safety of ABT-494 in subjects (≥ 12 and 
< 64 years of age weighing at least 40 kg) with moderate to severe atopic dermatitis who 
have inadequate response to systemic therapy. 
The analyses of pharmacokinetic endpoints and pharmacodynamic biomarker endpoints 
will not be covered in this SAP. 
The SAP will not be updated in case of administrative changes or amendments to the 
protocol unless the changes impact the analysis. 
Unless noted otherwise, all analyses will be performed using SAS Version 9.4 
(SAS Institute Inc., Cary, NC 27513) or later under the UNIX operating system. 
2.0 
Study Objectives and Design 
2.1 
Study Objectives, Hypotheses and Estimands 
The primary study 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 and treated at 30 mg QD in subjects with inadequate response to upadacitinib 
in Period 1. The primary efficacy objective is based on the achievement of an at least 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 
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subjects. The secondary efficacy objectives are based on ranked secondary endpoints as 
defined in Section 3.2 (below) with the treatment of upadacitinib compared with 
dupilumab in the ITT Population. 
The hypothesis corresponding to the primary efficacy endpoint (Section 3.1) is: 
The proportion of subjects achieving 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 EASI 90 and WP-NRS 0/1 at 
Week 16 without the use of rescue medication between upadacitinib and dupilumab in 
the adolescents 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. 
Estimands: Difference in proportion of subjects achieving each of ranked secondary 
endpoints without the use of rescue medication between upadacitinib and dupilumab 
in adolescents and adult subjects with moderate to severe AD who have inadequate 
response to systemic therapy. 
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. 
 


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2.2 
Study Design Overview 
This is a global, Phase 3b/4, randomized, open-label, efficacy assessor-blinded, 
multi-center study that will evaluate upadacitinib compared with dupilumab, 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. 
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 30-day or 12-week follow-up visit or 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. 
Sites will have the option to conduct the unscheduled visits/30-day or 12-week follow-up 
visit virtually during the course of the study as needed: 
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 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 
 


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response to dupilumab and treated 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. 
The details for Upadacitinib/Dupilumab arms and the dose adjustment for each treatment 
arm in each study period can be found in Protocol Section 4.1. 
The primary analysis for the study will be performed when all ongoing subjects have 
completed Week 16 or permanently discontinue 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. Additional analyses may be performed as appropriate. 
The schematic of the study is shown in Figure 1. 
 


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Figure 1. 
Study Schematic 
 
 
 
2.3 
Treatment Assignment and Blinding 
All subjects will be assigned a unique identification number by the IRT at the Screening 
Visit. For subjects who rescreen, the screening number assigned by the IRT at the initial 
Screening Visit should be used. The IRT will assign a randomization number that will 
encode the subject's treatment group assignment according to the randomization schedule 
generated by the statistics department at AbbVie. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 


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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 with potential dose escalation to upadacitinib 
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 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: Dose of dupilumab for subcutaneous administration in adolescent patients 
(12 to 17 years of age and weighing at least 40 kg) with AD will be based on body weight 
of subject at Screening Visit and at each visit: 
● 40 to < 60 kg: initial dose: 400 mg (two 200 mg injections) and subsequent 
doses (EOW): 200 mg 
● 60 kg or more: initial dose: 600 mg (two 300 mg injections) and subsequent 
doses (EOW): 300 mg 
 
 


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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 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*. 
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 blinded 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 subjects are considered as escalating dose to upadacitinib 30 mg QD in analysis if the subjects received the 
drug dispensation of upadacitinib 30 mg QD. 
2.4 
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 arm, 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. Sample size calculations were performed using nQuery 
Version 9.1.1.0. 
 


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3.0 
Endpoints 
3.1 
Primary Endpoint 
The primary endpoint is the achievement of both EASI 90 and WP-NRS 0/1 at Week 16. 
3.2 
Secondary Endpoints 
Ranked Secondary Endpoints are as follows. 
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. 
 
3.3 
Additional Efficacy Endpoints 
In addition to the visits for the primary and ranked secondary efficacy endpoints in 
Section 3.1 and Section 3.2, the primary and ranked secondary efficacy endpoints will 
also be evaluated at the other scheduled visits in Period 1 and Period 2. 
 


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The following endpoints will also be evaluated at all scheduled visits in Period 1 and 
Period 2 (if applicable) during which the assessments are measured as noted in the Study 
Activities Table: 
● 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. 
● 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. 
 
3.4 
Safety Endpoints 
The following endpoints will be included in the safety analyses: 
● Treatment emergent adverse events (TEAEs); 
● Serious adverse events (SAEs); 
● Adverse events of special interest (AESIs); 
● Other Safety Topics of Interest; 
● Adverse events (AEs) leading to discontinuation; 
● Vital signs and laboratory tests. 
 
 


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Laboratory assessments will include hematologic parameters, chemistry, liver function 
tests, and lipid parameters. 
4.0 
Analysis Populations 
Significant non-compliance was identified at a site. As a result of this finding, subjects 
enrolled in this site will not be included in any analysis population and data collected from 
this site will not be included in any analysis. 
The following population sets will be used for the analyses. 
● The Intent-to-Treat (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. 
 
The ITT Populations will be used for all efficacy analyses. Subjects will be included in 
the treatment group to which they are randomized. 
The below Safety Populations will be used to provide a comprehensive summary of safety 
based on treatment received in Period 1 and Period 2 respectively. 
● The Safety Population of Period 1 (Safety 1 Population) consists of all 
randomized 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 
randomized subjects who received at least 1 dose of study drug in Period 2. 
● All Upadacitinib treated Population (ALL UPA Population) consist of all 
subjects who received at least one dose of upadacitinib in the study. 
 
For safety analyses, subjects will be analyzed based on the treatment received. 
 


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The analyses populations for efficacy and safety analyses are summarized in the following 
table. 
Table 1. 
Analyses Populations: ITT Populations and Safety Populations 
Analyses Populations 
Study Period 
Analyses Groups 
ITT 1 
Period 1 
Dupilumab 
Upadacitiniba 
ITT 2 
Period 2 
Upadacitinib/Upadacitinib 30 mg 
Dupilumab/Upadacitinibb 
Safety 1 
Period 1 
Dupilumab 
Upadacitinib 15 mgc 
Upadacitiniba 
Safety 2 
Period 2 
Upadacitinib/Upadacitinib 30 mg 
Dupilumab/Upadacitinibb 
ALL UPA 
During the 
upadacitinib 
administration 
Upadacitinib 15 mg 
Upadacitinib 30 mg 
Any UPAd 
a. 
Upadacitinib subjects regardless of the dose level in Period 1. 
b. 
Dupilumab/Upadacitinib subjects regardless of the upadacitinib dose level in Period 2. 
c. 
Upadacitinib 15 mg subjects (who never received UPA 30 mg QD) in Period 1. 
d. 
Subjects who received at least one dose of upadacitinib regardless of the dose level in the study. 
 
5.0 
Subject Disposition 
The number of subjects for each of the following categories will be summarized overall 
and by treatment groups in the ITT 1 Population: 
● Subjects randomized 
● Subjects randomized and took at least one dose of study drug in Period 1 
● Subjects who completed Period 1 
● Subjects who completed study drug in Period 1 
● Subjects who prematurely discontinued study in Period 1 (all reasons and 
primary reason) 
 


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● Subjects who prematurely discontinued study drug in Period 1 (all reasons and 
primary reason) 
● Subjects who were rescued in Period 1 
● Subjects who experienced dose escalation to upadacitinib 30 mg in Period 1 
 
The summary will be provided for Period 2 for each of the following categories for 
overall and by treatment group in the ITT 2 Population: 
● Subjects who enter Period 2 
● Subjects who took at least one dose of study drug in Period 2 
● Subjects who complete Period 2 
● Subjects who complete study drug in Period 2 
● Subjects who prematurely discontinue study in Period 2 (all reasons and 
primary reason) 
● Subjects who prematurely discontinue study drug in Period 2 (all reasons and 
primary reason) 
● Subjects who were rescued in Period 2 
● Subjects who received dupilumab at Baseline and experienced dose escalation 
to upadacitinib 30 mg in Period 2 
 
6.0 
Study Treatment Duration and Compliance 
For Period 1 and Period 2, the duration of treatment will be summarized by treatment 
groups using the Safety 1 and Safety 2 Populations, respectively. 
Study Drug Duration (in Days) in Period 1: 
Duration of upadacitinib in Period 1 is defined for each subject as 
● For subjects who do not continue into Period 2: 
Date of the last dose of study drug in the Period 1 - Date of the first dose of 
study drug in Period 1 + 1 
 
 


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● For subjects who continue into Period 2: 
Minimum of (Date of the first dose of study drug in Period 2 - Date of first 
dose of study drug in Period 1, Date of the last dose of study drug in 
Period 1 - Date of first dose of study drug in Period 1 + 1) 
 
Duration of upadacitinib 15mg for subjects who have never experienced dose escalation 
in Period 1 is defined as 
● Date of the last dose of upadacitinib 15 mg in the Period 1 - Date of the first 
dose of upadacitinib 15 mg in Period 1 + 1 
 
Duration of dupilumab in Period 1 is defined for each subject as 
● For subjects who do not continue into Period 2: 
Last dose date of dupilumab in Period 1 - first dose date of dupilumab in 
Period 1 +14 
● For subjects who continue into Period 2: 
Minimum of (Date of the first dose of upadacitinib in Period 2  Date of first 
dose of dupilumab in Period 1, Date of last dose dupilumab in Period 1  Date 
of first dose of dupilumab in Period 1 + 14) 
 
Study Drug Duration (in Days) in Period 2: 
Duration of upadacitinib in Period 2 is defined for each subject as Date of the last dose of 
study drug in the Period 2 - Date of the first dose of study drug in Period 2 + 1. 
During the administration of upadacitinib (applicable for All UPA Population only): 
Duration of upadacitinib is defined for each subject as the last dose date of 
upadacitinib - first dose date of upadacitinib +1. 
Duration of treatment will be summarized using the number of subjects treated, mean, 
standard deviation, median, minimum, and maximum. In addition, the number and 
percentage of subjects in each treatment duration intervals will be summarized: 
 


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● (≥ 4 weeks, ≥ 8 weeks, ≥ 16 weeks) for Period 1 
● (≥ 4 weeks, ≥ 16 weeks) for Period 2 
● (≥ 4 weeks, ≥ 8 weeks, ≥ 16 weeks, ≥ 20 weeks, and ≥ 32 weeks) for All UPA 
Population 
 
Compliance: 
Treatment compliance will be summarized 
● In Period 1 for Safety 1 Population 
● In Period 2 for Safety 2 Population 
● During the administration of upadacitinib for All UPA Population 
 
Upadacitinib compliance is defined as the number of upadacitinib tablets actually taken 
(i.e., the difference between the number of tablets dispensed and the number of tablets 
returned) by the subject divided by the number of tablets planned to be taken by the 
subject in Period 1, Period 2 and during the administration of upadacitinib (for All UPA 
Population), respectively. 
The planned tablets for upadacitinib defined as follows: 
In Period 1: 
● For subjects who took UPA 15 mg QD, then escalate dose to UPA 30 mg QD 
in Period 1, the number of planned tablets for UPA 15 mg QD will be used 
before dose escalation; the number of planned tablets for UPA 30 mg QD will 
be used after dose escalation, and the number of planned tablets of UPA 30 mg 
QD depends on the tablet types (15 mg or 30 mg depends on the site). 
● For subjects who took UPA 15 mg QD and never received UPA 30 mg QD in 
Period 1, the number of planned tablets for UPA 15 mg QD will be used. 
 
 


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In Period 2: 
● For subjects who took UPA 15 mg QD in Period 1, then took dose to UPA 
30 mg QD in Period 2, the number of planned tablets for UPA 30 mg QD will 
be used in Period 2, and the number of planned tablets of UPA 30 mg QD 
depends on the tablet types (15 mg or 30 mg depends on the site). 
● For subjects who took dupilumab in Period 1, then took UPA 15 mg QD and 
never experience dose escalation in Period 2, the number of planned tablets for 
UPA 15 mg QD will be used in Period 2. 
● For subjects who took dupilumab in Period 1, switched to UPA 15 mg QD at 
the beginning of Period 2 and then escalated dose to UPA 30 mg QD, the 
number of planned tablets for UPA 15 mg QD in Period 2 will be used before 
dose escalation; the number of planned tablets for UPA 30 mg QD in Period 2 
will be used after dose escalation, and the number of planned tablets of UPA 
30 mg QD depends on the tablet types (15 mg or 30 mg depends on the site). 
 
During the administration of upadacitinib for All UPA Population: 
● For subjects who took UPA 15 mg QD, then escalate dose to UPA 30 mg QD, 
the number of planned tablets for UPA 15 mg QD will be used before dose 
escalation; the number of planned tablets for UPA 30 mg QD will be used after 
dose escalation, and the number of planned tablets of UPA 30 mg QD depends 
on the tablet types (15 mg or 30 mg depends on the site). 
● For subjects who took UPA 15 mg QD and never experienced dose escalation, 
the number of planned tablets for UPA 15 mg QD will be used. 
 
Dupilumab compliance is defined as the number of dupilumab injections administered 
during the subject's participation divided by the number of injections planned during the 
subject's participation in Period 1. The number of injections planned for dupilumab group 
in Period 1 is based on protocol Amendment 2.0, i.e., Week 14 dupilumab dose will be 
the last planned dose for all subjects in the dupilumab group if they complete Period 1. 
 


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7.0 
Subject Characteristics 
7.1 
Demographics and Baseline Characteristics 
The following demographic and baseline characteristics will be summarized for each 
treatment and overall in each ITT Population. 
Demographics: 
● Sex (female, male) 
● Age (years) 
● Age categories 1 (12 to < 18; 18 to < 40; ≥ 40 to < 64 years). 
● Age categories 2 (< 18 years, ≥ 18 years) 
● Race (White, Black or African American, Asian, American Indian/Alaska 
Native, Native Hawaiian or Other Pacific Islander, Other, Multiple) 
● Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
● Body Weight (kg) 
● Height (cm) for adolescents 
● Body Mass Index (BMI) (kg/m2) for adolescents and overall 
● BMI categories (< 25 kg/m2, ≥ 25 kg/m2 to < 30 kg/m2, ≥ 30 kg/m2) for 
adolescents and overall 
● Tobacco/Nicotine and Alcohol Use: 
○ Tobacco/Nicotine Use (unknown, never, current, former) 
○ Alcohol Use (unknown, never, current, former) 
 
Baseline Characteristics 
● Baseline EASI (< median, ≥ median) 
● Body Surface Area (BSA) in percentage 
● Baseline vIGA-AD (3, 4) 
● Previous systemic therapy (with and without) 
● EASI overall score and body region scores 
 


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


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● A concomitant medication in Period 1 is defined as any medication that started 
prior to the date of the first dose of study drug in Period 1 and continued to be 
taken after the first dose of study drug in Period 1; or any medications taken 
after the first dose of study drug and within 1 day of the last dose of study drug 
for the subjects on upadacitinib in Period 1, and within 14 days of the last dose 
of study drug for the subjects on dupilumab in Period 1, respectively. 
● A concomitant medication in Period 2 is defined as any medication that started 
prior to the date of the first dose of study drug in Period 2 and continued to be 
taken after the first dose of study drug in Period 2 or any medications, other 
than study drug, taken after the first dose of study drug and within 1 day of the 
last dose of study drug in Period 2. 
 
Concomitant medications will be summarized by periods in each Safety Population. Prior 
medications will be summarized in the Safety Populations. The number and percentage of 
subjects taking medications will be summarized by generic drug name based on the World 
Health Organization (WHO) Drug Dictionary for both prior and concomitant medications. 
7.3 
Protocol Deviations 
Protocol deviations include eligibility criteria violations, receipt of wrong treatment or 
incorrect dose of study treatment, development of withdrawal criteria without being 
withdrawn, and use of prohibited concomitant medications. A listing of subjects with 
protocol deviations will be provided. 
For each of the following protocol deviation categories and across all categories, the 
number and percentage of randomized subjects with at least one protocol deviation will be 
summarized overall and by treatment group in the ITT 1 and ITT 2 Populations: 
● Subject entered the study even though she/he did not satisfy entry criteria, by 
entry criteria. 
● Subject developed withdrawal criteria during the study but was not withdrawn. 
● Subject received wrong treatment or incorrect dose of study treatment. 
● Subject took prohibited concomitant medication. 
 
 


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8.0 
Handling of Potential Intercurrent Events for the 
Primary and Secondary Endpoints 
All efficacy endpoints (defined in Section 3.1, Section 3.2, and Section 3.3) will be 
analyzed based on the ITT 1 Population in Period 1 and ITT 2 Population in Period 2. 
The following combined composite variable strategy and treatment policy strategy 
intercurrent events (ICEs) handling method will be used as the primary approach to 
handle intercurrent events in this study for all efficacy endpoints: 
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) 
9.0 
Efficacy Analyses 
9.1 
General Considerations 
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 tests will be 2-sided at an 
alpha level of 0.05. 
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). 
 


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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 (OC), which is defined in Section 9.2. 
Analysis of Categorical Variables 
Models of Categorical Variables in Period 1 and Period 2 are summarized in Table 2. 
Table 2. 
Model of Categorical Variables in Period 1 and Period 2 
Period 
Type of 
Variables 
ITT 
Populations 
Imputation 
Method 
Intercurrent Events 
Handling 
Analysis Model 
Period 1 
Categorical 
ITT 1 
NRI-MI 
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) 
CMH test stratified 
by vIGA-AD 
categories (3; 4) and 
age (12 to < 18; 18 
to < 40; ≥ 40 to 
< 64 years) 
Period 2 
Categorical 
ITT 2 
OC 
Summarized by 
counts and 
percentages (with 
95% confidence 
interval) 
 
Unless otherwise specified, any subject randomized into an incorrect stratum will be 
analyzed according to the actual stratum the subject belongs to. During derivation, any 
subject not already within the current strata will be included in the nearest stratum. 
9.2 
Handling of Missing Data 
In Period 1, 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). 
 


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● The NRI-MI will categorize any subject who does not have an evaluation 
during a pre-specified visit window (either due to missing assessment or due to 
early withdrawal from the study) as a non-responder for the visit. The only 
exceptions are: 1) when the subject is a responder both before and after the 
visit window, the subject will be categorized as a responder for the visit. 
2) missing data due to COVID-19 infection or logistical restriction or any 
other missing data that can be reasonably assumed to be Missing at Random, 
will be handled by Multiple Imputation. In addition, all assessments after the 
start of rescue medications will not be included in the analyses; as a result, 
subjects will be counted as non-responders thereafter and will not be imputed 
by MI. Random seeds are provided in Appendix D. NRI-MI is the primary 
approach to handle missing data for categorical endpoints in Period 1. 
● Non-responder Imputation (NRI): NRI will be performed in the same way as 
NRI-MI without the exception #2 above. That is, missing due to COVID-19 
infection or logistical restriction or any other missing data that can be 
reasonably assumed to be Missing at Random, will also be counted as non-
responders. The NRI is a missing data handling method in a sensitivity 
analysis for the primary endpoint. 
 
Subjects whose change/percent change from Baseline cannot be calculated because of a 
missing Baseline will be considered as a non-responder at all post-baseline visits in both 
NRI-MI and NRI approaches. 
Multiple Imputation (MI): another missing data handling method performed in a 
sensitivity analysis for the primary endpoint. Markov Chain Monte Carlo (MCMC) will 
be first applied to augment data into monotonic missing pattern and PROC MI will be 
used to generate 30 datasets using the regression method. 
● The imputation is done in two steps for the primary endpoint. 
● Step 1: The EASI 90 and WP-NRS 0/1 (based on weekly average) are imputed 
separately. 
For example, for EASI 90, the variables to be included in the imputation 
model are treatment group, major stratum (vIGA-AD categories and age), 
 


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Baseline, and measurements at each visit in Period 1. The random seed for 
MCMC and the random seed for PROC MI are specified in Appendix D. The 
imputed post-baseline measurements will be rounded to the same precision as 
the observed data before the determination of responder status. WP-NRS 0/1 
will be imputed by the same imputation model as EASI 90. 
● Step 2: After obtained the EASI 90 and WP-NRS 0/1(based on weekly 
average) at Week 16 based on MI imputed values separately, subjects will be 
characterized as responders or non-responders based on MI imputed datasets. 
Using the Cochran-Mantel-Haenszel (CMH) model adjusted by main 
stratification factors (vIGA-AD categories and age), the imputed endpoints 
will be analyzed using each of the 30 datasets. SAS PROC MIANALYZE will 
be used to generate the final inferences of the risk difference between 
upadacitinib and dupilumab. Note that measurements will be considered as 
missing after the first dose of rescue treatment before MI. Regardless of MI 
imputed values, subjects after receiving rescue medications will be counted as 
non-responders. 
 
In Period 2, the primary approach to handle missing data is Observed Cases (OC). 
● The OC analysis will not impute values for missing evaluations, and thus a 
subject who does not have an evaluation at a scheduled visit will not be 
included in the OC analysis for that visit. The OC analysis will be performed 
for all variables and will not include values after more than 1 day after 
discontinuation of study drug. 
 
9.3 
Primary Efficacy Endpoint and Analyses 
9.3.1 
Primary Efficacy Endpoint 
The primary endpoint is the achievement of both EASI 90 and WP-NRS 0/1 at Week 16. 
9.3.2 
Main Analysis of Primary Efficacy Endpoint 
For the primary endpoint, comparisons between upadacitinib and dupilumab will be 
conducted using the CMH test on ITT 1 Population, adjusting for vIGA-AD categories 
 


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(vIGA-AD 3; 4) and age (12 to < 18; 18 to < 40; ≥ 40 to < 64 years). NRI-MI will be the 
primary approach to handle missing values. 
In Period 1, frequencies and percentages will be provided along with 95% CIs. Point 
estimates, 95% CIs and p-values from the CMH test for the difference in proportions 
between upadacitinib and dupilumab will be provided. 
The attributes of the estimand corresponding to the primary efficacy objective are 
summarized in Table 3. 
Table 3. 
Summary of the Estimand Attributes Corresponding to the 
Primary Efficacy Objective 
Estimand 
Label 
Attributes of the Estimand 
Treatment 
Endpoint 
Population 
Handling of 
Intercurrent Events 
Statistical 
Summary 
EASI 90 
and WP-
NRS 0/1 at 
Week 16 
Upadacitinib 
vs. 
dupilumab 
Achievement 
of both 
EASI 90 and 
WP-NRS 0/1 
at Week 16 
Adolescents 
and adult 
subjects 
with 
moderate to 
severe AD 
who have 
inadequate 
response to 
systemic 
therapy. 
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). 
Difference 
in the 
proportion 
of subjects 
treated with 
upadacitinib 
compared 
with those 
treated with 
dupilumab. 
 
9.3.3 
Sensitivity and Supplementary Analyses of the Primary 
Efficacy Endpoint 
Sensitivity analysis of the primary efficacy endpoint will be performed by using MI and 
NRI to handle missing data, respectively. 
Supplementary Analysis: supplementary analysis of the primary endpoint will be 
performed by excluding those subjects whose primary endpoint evaluations were not 
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were accidentally unblinded to treatment information. Please refer to Documentation of 
Key Decision for more details. 
9.4 
Secondary Efficacy Endpoints and Analyses 
9.4.1 
Key Secondary Efficacy Endpoint(s) 
Ranked Secondary Endpoints are as follows. 
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. 
 
9.4.2 
Main Analyses of Key Secondary Efficacy Endpoint(s) 
In Period 1, the ranked secondary efficacy endpoints will be analyzed by comparing 
upadacitinib and dupilumab. The categorical endpoints will be analyzed by CMH test on 
ITT 1 Population, adjusting for vIGA-AD categories (vIGA-AD 3; 4) and age (12 to 
< 18; 18 to < 40; ≥ 40 to < 64 years). 
 


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The attributes of the estimands corresponding to the key secondary efficacy objectives are 
summarized in Table 4. 
Table 4. 
Summary of the Estimand Attributes Corresponding to the Key 
Secondary Efficacy Objectives 
Estimand 
Label 
Attributes of the Estimand 
Treatment 
Endpoint 
Population 
Handling of  
Intercurrent Events 
Statistical 
Summary 
Categorical 
secondary 
endpoints 
Upadacitinib 
vs. 
dupilumab 
Achievement 
of the 
respective 
categorical 
secondary 
endpoint 
Adolescents 
and adult 
subjects 
with 
moderate to 
severe AD 
who have 
inadequate 
response to 
systemic 
therapy. 
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). 
Difference 
in the 
proportion 
of subjects 
treated with 
upadacitinib 
compared 
with those 
treated with 
dupilumab. 
 
9.4.3 
Sensitivity and Supplementary Analyses for Key Secondary 
Efficacy Endpoints 
Supplementary Analysis: supplementary analysis of each ranked secondary endpoint will 
be performed by excluding those subjects whose corresponding ranked secondary 
endpoint evaluations were not completed by blinded efficacy assessor or were completed 
by Blinded Efficacy Assessors who were accidentally unblinded to treatment information. 
Please refer to Documentation of Key Decision for more details. 
9.5 
Additional Efficacy Endpoints and Analyses 
CMH test will be used to analyze categorical variables stratified by vIGA-AD categories 
(vIGA-AD 3; 4) and age (12 to < 18; 18 to < 40; ≥ 40 to < 64 years). NRI-MI will be used 
for handling missing data. All variables in Section 3.1, Section 3.2, and Section 3.3 will 
 


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also be summarized descriptively in Period 2 using the OC approach. Models of 
categorical variables in Period 1 and Period 2 are summarized in Table 2. 
9.6 
Efficacy Subgroup Analyses 
To evaluate the consistency of efficacy over demographic and other Baseline 
characteristics, the primary efficacy endpoint will be analyzed in 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). 
 
Of note, any subgroups with fewer than 10% subjects may be combined with other for 
analyses, and the 10% cutoff may be updated after running the baseline characteristics. 
For any subgroup, if there are zero subjects within a stratum in any treatment group, the 
CMH model will not be adjusted for the stratification factors. For each type of subgroup, 
Breslow-Day test will be performed to test the homogeneity across subgroups. 
9.7 
Analysis of Daily Efficacy Measurement for Worst Pruritus 
NRS 
For daily efficacy assessments of the Worst Pruritus NRS, a rolling weekly average is 
calculated by using handheld device only to represent the corresponding endpoints by 
week in Period 1 and 2. 
The weekly average of the daily values from a maximum of seven days immediately prior 
to the first dose date will be used as the Baseline value. The rolling weekly average score 
is calculated for each Day m, starting from Day 8 through the Week 16 visit as follows. 
Let Pm-6, Pm-5,…, Pm-1, Pm be the daily score from Day m  6 to Day m, and Nm be the 
number of days with non-missing scores from Day m  6 to Day m, then the rolling 
weekly average for Day m is: 
 


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If the values from four or more days of the seven-day period are missing, then the rolling 
weekly average of Day m will be set to missing. If more than one assessment is included 
on the same day, the assessment associated with the worst condition on that day will be 
chosen as the daily score. Analysis value for a given visit will be selected from rolling 
averages based on analysis window conventions. 
For the visits where the questionnaire is completed at the site, scores from single clinic 
visits will be used as the analysis value. However, these analysis values will not be 
included in rolling weekly average calculations. 
10.0 
Safety Analyses 
10.1 
General Considerations 
Safety summaries will be provided using the safety Populations. For the safety analysis, 
subjects are assigned to a treatment group based on the treatment actually received, 
regardless of the treatment randomized. 
Safety analyses will include adverse events, laboratory, and vital sign measurements. 
Missing safety data will not be imputed. 
10.2 
Adverse Events 
The summaries of adverse events will be provided by treatment groups (defined in 
Table 1) in Period 1 for Safety 1 Population, in Period 2 for Safety 2 Population, and 
during the administration of upadacitinib for All UPA Population. 
m
m
m
i
i
N
P
=
6
 


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10.2.1 
Treatment-Emergent Adverse Events 
Treatment-emergent adverse events (TEAEs) are defined as follows: 
● TEAEs in Period 1 are defined as any adverse events that begin or worsen in 
severity after initiation of upadacitinib/dupilumab through the minimum 
(30 days following the last dose of upadacitinib in Period 1 or through 84 days 
following the last dose of dupilumab in Period 1, the start day of Period 2  1). 
● TEAEs in Period 2 are defined as any adverse events that begin or worsen in 
severity after initiation of upadacitinib in Period 2 through 30 days following 
the last dose of upadacitinib in Period 2. 
● TEAEs during the administration of upadacitinib are defined as any adverse 
events that begin or worsen in severity after initiation of upadacitinib through 
30 days following the last dose of upadacitinib. 
 
If a missing or an incomplete onset date is collected for an adverse event, the event will be 
assumed to be treatment-emergent unless there is other evidence that confirms that the 
event is not treatment-emergent (e.g., the event end date is prior to the study drug start 
date). Events where the onset date is the same as the study treatment start date are 
assumed to be treatment-emergent. All treatment-emergent AEs will be summarized 
overall, as well as by primary MedDRA SOC and Preferred Term. The SOCs will be 
presented in alphabetical order, and the PTs will be presented in alphabetical order within 
each SOC. 
The number and percentage of subjects experiencing TEAEs and the number of events per 
100 patient-years of exposure will be summarized. 
TEAEs per 100 patient-years of exposure are defined as the number of TEAEs divided by 
the total exposure in 100 patient-years. See the calculation method below: 
100 * (Number of TEAEs) / (Total Patient Years) 
where total patient years is defined as the sum of the study drug duration (defined in 
Section 6.0) of all subjects normalized by 365.25 and rounded to 1 decimal place. 
 


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10.2.2 
Adverse Event Overview 
The number and percentage of subjects experiencing TEAEs will be summarized for each 
treatment group for the following AE categories.: 
● Any TEAE 
● Any treatment-emergent serious adverse events (SAE) 
● Any TEAE leading to discontinuation of study drug 
● Any severe TEAE (Grade 3 and above according to National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0) 
● Any TEAE related to study drug according to the investigator 
● Any treatment-emergent SAE related to study drug according to the 
investigator 
● TEAEs of Special Interest 
● Other Safety Topics of Interest 
● Any TEAE leading to death 
● All Deaths 
○ Deaths occurring ≤ 30 days after last dose of upadacitinib or ≤ 84 days 
after last dose of dupilumab 
○ Deaths occurring > 30 days after last dose of upadacitinib or > 84 days 
after last dose of dupilumab 
○ Related to COVID-19 
 
10.2.3 
Treatment-Emergent Adverse Events by SOC and/or PT 
TEAEs will be summarized and presented using primary MedDRA version 22.1 or later 
by system organ class (SOC) and preferred terms (PT); by maximum relationship to study 
drug as assessed by the investigator (e.g., reasonable possibility or no reasonable 
possibility) and SOC and PT; by maximum toxicity and SOC and PT. The SOCs will be 
presented in alphabetical order, and the PTs will be presented in alphabetical order within 
each SOC. Subjects reporting more than one adverse event for a given MedDRA preferred 
 


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term will be counted only once for that term (most severe incident for the toxicity tables 
and most related incident for the relationship tables). A subject who reports more than 
1 AE in different SOCs will be counted only once in the overall total. Subjects reporting 
more than one type of adverse event will be counted only once in the overall total. If the 
same adverse event occurs multiple times within a subject, the highest severity and level 
of relationship to investigational product will be reported. 
The following summaries of adverse events will be generated: 
● All TEAEs 
● Treatment-emergent serious adverse events 
● Treatment-emergent severe adverse events 
● TEAEs related to study drug according to the investigator 
● TEAEs leading to discontinuation of study drug 
● TEAEs by maximum relationship to the study drug as assessed by the 
investigator (e.g., reasonable possibility or no reasonable possibility) 
● TEAEs by maximum toxicity 
● TEAEs leading to death 
 
For summaries of AEs by toxicity, each subject is counted only once  according to the 
maximum toxicity level observed. If a subject has an AE with an unknown toxicity, then 
the subject will be counted in the toxicity category of "unknown." The only exception is 
that if the subject has another occurrence of the same AE with the most extreme, non-fatal 
NCI CTCAE toxicity (i.e., grade 4) or is fatal (grade 5). In this case, the subject will be 
counted under grade 4 if non-fatal or 5 if fatal. For tables that look at severity instead of 
toxicity, the subjects that have an unknown NCI CTCAE grade but another occurrence of 
the same AE that is considered severe (grade ≥ 3) will be counted under severe. 
 


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10.2.4 
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure 
AEs occurring during the entire study will be presented by event rate per 100 patient 
years. These will be presented by treatment group for the following AE categories. 
● Any TEAE 
● Any treatment-emergent SAE 
● Any TEAE leading to discontinuations of study drug 
● Any severe TEAE 
● Any TEAE related to study drug according to the investigator 
● Any treatment-emergent SAE related to study drug according to the 
investigator 
● TEAEs of Special Interest 
● Other Safety Topics of Interest; 
● Any TEAE leading to death 
● All Deaths 
○ Deaths occurring ≤ 30 days after last dose of upadacitinib or ≤ 84 days 
after last dose of dupilumab 
○ Deaths occurring > 30 days after last dose of upadacitinib or > 84 days 
after last dose of dupilumab 
○ Related to COVID-19 
 
Additional AEs may be considered for tabulation/summary based on recommendations 
from Clinical and Safety as deemed appropriate. 
10.2.5 
Deaths, Serious Adverse Events, and Adverse Events 
Leading to Study Treatment Discontinuation 
SAEs (including deaths) and AEs leading to study drug discontinuation will be presented 
in listing format. SAEs and AEs leading to study drug discontinuation will be summarized 
by SOC and PT. 
 


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In addition, for each treatment group, the event rate leading to per 100 patient-years of 
exposure will be calculated for each SOC and each PT for each treatment emergent SAE 
and TEAEs leading to discontinuation of study drug. 
10.2.6 
Adverse Events of Special Interest 
Adverse events of special interest will be summarized by SOC and PT and listing format 
and will be based on standard or company MedDRA queries (SMQs or CMQs) 1) from 
Baseline to Week 16 visit and 2) the entire upadacitinib treatment period, respectively. 
Adverse events of special interest are categorized as follows: 
● Serious infections 
● Opportunistic infections excluding tuberculosis and herpes zoster 
● Herpes Zoster 
● Active Tuberculosis 
● Anemia 
● Neutropenia 
● Lymphopenia 
● Renal Dysfunction 
● Hepatic disorder 
● Creatine Phosphokinase Elevations (CPK; adolescents only) 
● Possible Malignancy* 
● Malignancy 
● Non-melanoma skin cancer (NMSC) 
● Malignancy excluding NMSC 
● Lymphoma 
● Adjudicated MACE 
● Adjudicated VTE 
● Adjudicated gastrointestinal perforations 
* 
Possible Malignancy is used for surveillance and safety monitoring for both clinical trial and post marketing data 
and will not be included as AESI in in text tables for any safety document. 
 
 


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Detailed information about the search criteria is provided in Appendix B. 
10.2.7 
Adverse Events of Other Safety Topics of Interest 
Adverse Events of Other Safety Topics of Interest specifically for this study will be 
summarized by SOC and PT and listing format and will be based on standard or company 
MedDRA queries (SMQs or CMQs or selected PTs) in Period 1. Detailed information 
about the search criteria is provided in Appendix G. The listings of Adverse Events of 
Other Safety Topics of Interest will be provided. 
10.3 
Analysis of Laboratory Data 
Data collected from central and local laboratories, including additional laboratory testing 
due to an SAE, will be used in all analyses. The clinical laboratory tests defined in the 
protocol operations manual (e.g., hematology and clinical chemistry) will be summarized. 
For the analysis of laboratory data, values observed up to 30 days after the last dose of 
upadacitinib or 84 days after the last dose of dupilumab will be included. 
Analysis of Quantitative Laboratory Parameters (Hematology, Chemistry and 
Urinalysis) 
Raw values and change from Baseline (percent change if applicable) to each applicable 
post-baseline visit will be summarized for selected laboratory variables. At each visit, the 
following descriptive statistics will be presented by treatment groups: number of 
observations, Baseline mean (Standard deviation, SD), visit mean (SD), change from 
Baseline mean (SD), standard error, and the 95% confidence interval of the mean change 
from Baseline. 
Shift Table Analyses 
Selected laboratory parameters will be tabulated using shift tables from Baseline to the 
worst value by NCI CTCAE in Period 1 for the Safety 1 Population and during the 
administration of upadacitinib for the All UPA Population. Selected lipid parameters will 
 


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


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number of observations, Baseline mean, and visit mean. The change from Baseline mean, 
standard error, and 95% confidence interval will be presented for the mean change from 
Baseline by treatment group in Period 1 and Period 2. 
Vital sign variables will be evaluated based on potentially clinically important (PCI) 
criteria (Appendix C) in Period 1 and for the ALL UPA Population. For each vital signs 
PCI criterion, the number and percentage of subjects who have at least one vital sign 
value meeting the criteria will be summarized. Listings will be provided to summarize 
subject-level vital sign data for subjects meeting PCI criteria. 
10.5 
Other Safety Analyses 
Not applicable. 
10.6 
Safety Subgroup Analyses 
Selected safety summary will be provided for adolescent subgroup, i.e., TEAE overview; 
TEAE, SAE and death by SOC and PT; and AESI. 
11.0 
Other Analyses 
Not applicable. 
12.0 
Interim Analyses 
There will be no interim analyses. 
12.1 
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 
 


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participants. Given the above, it is not necessary to implement an independent Drug 
Monitoring Committee for the conduct of this study. 
13.0 
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-wise error rate is strongly controlled at 0.05. 
14.0 
Version History 
Table 5. 
SAP Version History Summary 
Version 
Date 
Summary 
1.0 
26 January 2023 
Initial version 
2.0 
26 July 2023 
Exclude significant non-compliance site of the study 
3.0 
13 March 2024 
Changes to keep consistent with Protocol V2.0: 
• 
Updated Age strata to "Age <64" throughout the 
text. 
• 
Removed "Other Event of Interest content" in 
Section 3.4, Section 10.2.2, Section 10.2.3, 
Section 10.2.4. 
• 
Added contents about "Other Safety Topics of 
Interest" in Section 3.4, Section 10.2.2, 
Section 10.2.4. 
• 
Updated Definition of Additional Safety Topics in 
Appendix F. 
• 
Added clarification about follow-up visit in 
Section 2.2. 
• 
Added clarification about compliance in Section 6.0. 
 
Changes for clarification/typos: 
• 
Added clarification for duration of upadacitinib 
15 mg in Section 6.0. 
 


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Version 
Date 
Summary 
• 
Added clarification of AESI list in Section 10.2.3, 
Section 10.2.4, Section 10.2.6. 
• 
Added the footnote about random seeds in 
Appendix C. 
• 
Removed "acne adverse events" content in 
Section 10.2.3. 
• 
Removed Covid-19 in AE summary in 
Section 10.2.2. 
• 
Added nQuery version in Section 2.4. 
• 
Added clarification about the additional objective 
related to Study Period 2 in Section 2.1. 
• 
Added clarification about Safety Subgroup analyses 
in Section 10.6. 
4.0 
11 April 2024 
• 
Added superscripts in Table A to match the 
corresponding footnotes in Appendix D. 
• 
Added clarification in Section 9.1 when deriving 
actual stratum: "During derivation, any subject not 
already within the current strata will be included in 
the nearest stratum." 
• 
Added supplementary analysis for primary and 
ranked secondary endpoints by excluding the 
subjects whose efficacy assessments for primary and 
ranked secondary endpoints evaluations were not 
completed by blinded efficacy assessors or were 
completed by blinded efficacy assessors who were 
accidentally unblinded to treatment group 
information, in Section 9.3.3 and Section 9.4.3. 
• 
Moved Breslow-Day test statement from 
Section 9.3.2 to Section 9.6. 
• 
Clarification language in Section 10.2.3, 
Section 10.2.4, Section 10.2.6 regarding AESIs 
which were moved to Appendix B Definition of 
Adverse Events of Special Interest. 
 
14.1 
Changes to Planned Analyses in the Protocol 
 
 


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15.0 
References 
1. 
FDA Guidance on Conduct of Clinical Trials of Medical Products during 
COVID-19 Pandemic - Guidance for Industry, Investigators, and Institutional 
Review Boards. FDA. 2020. 
2. 
Statistical Considerations for Clinical Trials During the COVID-19 Public Health 
Emergency - Guidance for Industry. FDA. 2020. 
3. 
Points to consider on implications of Coronavirus disease (COVID-19) on 
methodological aspects of ongoing clinical trials. EMA. 2020. 
4. 
Graham JW, Olchowski AE, Gilreath TD. How many imputations are really 
needed? Some practical clarifications of multiple imputation theory. Prev Sci. 
2007;8(3):206-13. 
5. 
Rubin DB, Schenker N. Interval estimation from multiply-imputed data: a case 
study using agriculture industry codes. J Am Stat Assoc. 1987;81:366-74. 
6. 
White IR, Royston P, Wood AM. Multiple imputation using chained equations: 
Issues and guidance for practice. Stat Med. 2011;30(4):377-99. 
 
 


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


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Appendix B. 
Definition of Adverse Events of Special Interest 
AEs of Special Interest (AESI) will be identified by the following CMQ, SMQ, and other 
search criteria (Note: for each database lock, the categories of AESIs will follow the latest 
version of Product Safety Statistical Analysis Plan for Upadacitinib, with the exceptions 
of Hepatitis B Reactivation which is not an AESI. AESIs with the corresponding code for 
the MedDRA version in that DBL will be shown in a summary table): 
AESI 
Type of MedDRA 
Query 
Broad or 
Narrow 
Search 
SMQ/CMQ Search Criteria 
Serious Infections 
CMQ 
 
"Infections" - Subset for SAEs 
Opportunistic Infections 
excluding tuberculosis and 
herpes zoster 
CMQ 
 
"Opportunistic Infection 
excluding tuberculosis and herpes 
zoster" 
Possible Malignancy 
SMQ 
Narrow 
"Malignancies" 
Malignancy 
SMQ 
 
"Malignant Tumours" 
Non-Melanoma Skin Cancer 
(NMSC) 
SMQ/CMQ 
SMQ 
Narrow 
Skin Malignant tumours (Narrow 
SMQ) removing Melanoma CMQ 
Malignancy excluding NMSC 
 
 
Malignancy Narrow SMQ and 
removing NMSC output 
Lymphoma 
SMQ 
 
"Malignant Lymphomas" 
Hepatic Disorder (including 
DILI events) 
SMQ 
Narrow 
"Drug Related Hepatic Disorders"  
Adjudicated Gastrointestinal 
Perforations 
Medical review of 
events identified 
by the 
"Gastrointestinal 
Perforation" SMQ 
Narrow search 
 
 
Anemia 
CMQ 
 
"Non-Hemolytic and 
Non-Aplastic Anemias" 
Neutropenia 
CMQ 
 
"Hematological 
Toxicity - Neutropenia" 
Lymphopenia 
CMQ 
 
"Hematological 
Toxicity - Lymphopenia 
(Veliparib Product Specific)" 
Herpes Zoster 
CMQ 
 
"Herpes Zoster" 
 


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AESI 
Type of MedDRA 
Query 
Broad or 
Narrow 
Search 
SMQ/CMQ Search Criteria 
Renal Dysfunction 
SMQ 
Narrow 
"Acute Renal Failure" 
Active Tuberculosis 
CMQ 
 
"Active Tuberculosis" 
Creatine Phosphokinase 
(CPK) Elevations and 
Rhabdomyolysis 
PT 
 
PT of "Blood creatine 
phosphokinase increased"; PT of 
"Rhabdomyolysis" 
Adjudicated cardiovascular 
eventsa 
Output from CAC 
 
 
MACE* 
 
 
 
Cardiovascular Death 
 
 
 
Non-fatal Myocardial 
Infarction 
 
 
 
Non-fatal Stroke 
 
 
 
Other Adjudicated 
Cardiovascular Events 
 
 
 
Undetermined/Unknown 
Cause of Deaths  
 
 
 
Adjudicated Thrombotic 
Events 
Output from CAC 
 
 
VTE** 
 
 
 
Deep Vein Thrombosis 
 
 
 
Pulmonary Embolism 
 
 
 
Other Venous Thrombosis 
 
 
 
Arterial Thromboembolic 
Events (non-cardiac, 
non-neurologic) 
 
 
 
CAC  Cardiovascular Adjudication Committee; CMQ  company MedDRA query; PT  preferred term; 
SMQ  standard MedDRA query 
* 
MACE: Major Adverse Cardiovascular Events, defined as cardiovascular death, non fatal myocardial infarction 
and non fatal stroke. 
** VTE: Venous thromboembolic events, defined as deep vein thrombosis (DVT) and pulmonary embolism (PE) 
(fatal and non fatal). 
a. 
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Appendix C. 
Potentially Clinically Important Criteria for Safety Endpoints 
The criteria for Potentially Clinically Important (PCI) laboratory findings are described in 
Table C-1 and Table C-2, PCI criteria for the liver function tests are described in 
Table C-3, and the PCI criteria for vital sign findings are described in Table C-4. 
Table C-1. 
Criteria for Potentially Clinically Important Hematology Values 
Hematology Variables 
Units 
Definition of Potentially 
Clinically Important 
Very Low 
Hemoglobin 
g/dL 
< 8.0 
Platelets count 
109/L 
< 50.0 
WBC count 
109/L 
< 2.0 
Neutrophils 
109/L 
< 1.0 
Lymphocytes 
109/L 
< 0.5 
 
Table C-2. 
Criteria for Potentially Clinically Important Chemistry Values 
Chemistry Variables 
Units 
Definition of Potentially Clinically Important 
Very Low 
Very High 
ALP 
U/L 
 
> 5.0 × ULN 
SGOT/AST 
U/L 
 
> 5.0 × ULN 
SGPT/ALT 
U/L 
 
> 5.0 × ULN 
Albumin 
g/L 
< 20 
 
Glucose 
mmol/L 
< 2.2 
> 13.9 
Triglycerides 
mmol/L 
 
> 5.7 
Creatinine 
mcmol/L 
 
> 3.0 × ULN 
Potassium 
mmol/L 
< 3.0 
> 6.0 
Calcium 
mmol/L 
< 1.75 
> 3.1 
Sodium 
mmol/L 
< 130 
> 155 
Phosphate 
mmol/L 
< 0.6 
 
CPK 
U/L 
 
> 5.0 × ULN 
Total Cholesterol 
mmol/L 
 
> 10.34 
 
 


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


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Appendix D. 
Random Seeds 
In case of non-convergence, the random seed will be updated by adding 100000 at each 
attempt until convergence of model happens. 
A. Random Seeds for NRI-MI 
Endpoints 
Random Seed 
MCMC procedure 
PROC MI 
EASI 90 and WP-NRS 0/1 at 
Week 16a 
1001 for EASI 90; 
1002 for WP-NRS 
9001 for EASI 90; 
9002 for WP-NRS 
EASI 90 at Week 16 
1003 
9003 
WP-NRS 0/1 at Week 16 among 
subjects with Baseline  
WP-NRS > 1 
1004 
9004 
An improvement (reduction) in 
WP-NRS ≥ 4 at Week 16 among 
subjects with Baseline  
WP-NRS ≥ 4b 
1005 
9005 
WP-NRS 0/1 at Week 4 among 
subjects with Baseline  
WP-NRS > 1c 
1006 
9006 
WP-NRS 0/1 at Week 2 among 
subjects with Baseline  
WP-NRS > 1d 
1007 
9007 
EASI 90 at Week 4e 
1008 
9008 
EASI 75 at Week 2a 
1009 
9009 
EASI 100 at Week 16a 
1010 
9010 
Achievement of 75% reduction in 
EASI in the head and neck region 
from Baseline at Week 2, 4, 8, 
12, 16 
1011 
9011 
Achievement of 75% reduction in 
EASI in the trunk region from 
Baseline at Week 2, 4, 8, 12, 16 
1012 
9012 
 


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Endpoints 
Random Seed 
MCMC procedure 
PROC MI 
Achievement of 75% reduction in 
EASI in the upper extremities 
region from Baseline at Week 2, 
4, 8, 12, 16 
1013 
9013 
Achievement of 75% reduction in 
EASI in the lower extremities 
region from Baseline at Week 2, 
4, 8, 12, 16 
1014 
9014 
Notes: 
a. 
The random seed for the corresponding endpoint at the other visits (i.e., Week 2, 4, 8, 12) will use the random seed 
for that endpoint at Week 16, except EASI 75 where the random seed for this endpoint at the other visits (i.e., 
Week 4, 8, 12, 16) will use the one at Week 2. 
b. 
The random seed for an improvement (reduction) in WP NRS ≥ 4 at the other visits (i.e., Week 1, 2, 3, 4, 5, 6, 7, 8, 
9, 10, 11, 12, 13, 14 and 15) will use the random seed for this endpoint at Week 16. 
c. 
The random seed for WP NRS 0/1 at Week 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15 will use the random seed for this 
endpoint at Week 4. 
d. 
The random seed for WP NRS 0/1 at Week 1 and 3 will use the random seed for this endpoint at Week 2. 
e. 
The random seed for EASI 90 at the other visits (i.e., Week 2, 8 and 12) will use the random seed for this endpoint 
at Week 4. 
 
B. Random Seed for MI 
Endpoints 
Random Seed 
MCMC procedure 
PROC MI 
EASI 90 and WP-NRS 0/1 at 
Week 16 
1015 for EASI 90; 
1016 for WP-NRS 
9015 for EASI 90; 
9016 for WP-NRS 
 
 


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


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


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Appendix G. 
Definition of Additional Safety Topics 
Additional Safety Topics will be identified by the following CMQ, SMQ, or other search 
criteria: 
Additional safety topics 
Search criteria 
Anaphylactic reactions 
Narrow SMQ "anaphylactic reactions" (20000021) 
Hypersensitivity reactions 
Narrow SMQ "hypersensitivity" (20000214) 
Injection site reactions 
CMQ "Injection site reaction" (10000091) 
Suicidal ideation and behavior 
Narrow SMQ "Suicide/self-injury" (20000037) 
Conjunctivitis 
Narrow SMQ "Conjunctival disorders" (20000175) 
Keratitis 
Including the following PTs: 
• 
Allergic keratitis 
• 
Infective keratitis 
• 
Keratitis 
• 
Keratitis bacterial 
• 
Keratitis fungal 
• 
Keratitis interstitial 
• 
Keratitis sclerosing 
• 
Keratitis viral 
• 
Punctate keratitis 
• 
Ulcerative keratitis 
• 
Varicella keratitis 
 


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Additional safety topics 
Search criteria 
Parasitic (Helminth) Infections 
Including the following PTs: 
• 
Arthritis helminthic 
• 
Biliary tract infection helminthic 
• 
Cystitis helminthic 
• 
Endocarditis helminthic 
• 
Enterocolitis helminthic 
• 
Eye infection helminthic 
• 
Gastritis helminthic 
• 
Genital infection helminthic 
• 
Helminthic infection 
• 
Hepatic infection helminthic 
• 
Lymphadenitis helminthic 
• 
Meningoencephalitis helminthic 
• 
Myocarditis helminthic 
• 
Oral helminthic infection 
• 
Pancreatitis helminthic 
• 
Pericarditis helminthic 
• 
Pneumonia helminthic 
• 
Skin infection helminthic 
• 
Splenic infection helminthic 
• 
Upper respiratory tract infection helminthic 
• 
Vulvovaginitis helminthic 
• 
Wound infection helminthic 
Arthralgia 
Including PT arthralgia 
 
 


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Appendix H. 
Non-Responder Imputation Incorporating Multiple Imputation to 
Handle Missing Data Due to COVID-19 Pandemic or Any Other 
Missing Data That Can Be Reasonably Assumed to Be Missing at 
Random for Dichotomized Outcome Variables 
1.0 
Overview 
1.1 
Background and Justification for Missing at Random (MAR) 
Assumption 
The COVID-19 pandemic is interfering with the conduct of many ongoing trials, with 
potential impacts on treatment duration and the collection, analysis and the interpretation 
of clinical trial data. Some protocol-specified visits in the clinical trials may be impacted 
due to COVID-19 infection or logistical restrictions during the pandemic. For example, 
some scheduled visits may be missed due to self-quarantine or local government 
restrictions on travel; some visits may also be delayed or canceled due to healthcare 
resource constraints during the pandemic. Impacted visits due to COVID-19 will be 
recorded in the database. The probability of having missed visits and missing data due to 
COVID-19 infection or logistical restrictions related to the COVID-19 pandemic can be 
reasonably assumed to be unrelated to the unobserved values. Therefore, for the purpose 
of statistical analysis, it is reasonable to assume that these missing data are missing at 
random (MAR) and the statistical models that require MAR assumption are appropriate. 
In some cases, sensitivity analyses may be performed to assess the impact of missing data 
and the robustness of the conclusion. 
1.2 
FDA Guidance 
FDA provided two guidance documents1,2 in March 2020 and June 2020 on the efficacy 
collection and possible changes in the statistical analysis plan: 
"With respect to efficacy assessments, FDA recommends consultation with the 
appropriate review division regarding protocol modifications for the collection of efficacy 
endpoints, such as use of virtual assessments, delays in assessments, and alternative 
collection of research-specific specimens, if feasible. For individual instances where 
 


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efficacy endpoints are not collected, the reasons for failing to obtain the efficacy 
assessment should be documented (e.g., identifying the specific limitation imposed by 
COVID-19 leading to the inability to perform the protocol-specified assessment)." 
"If changes in the protocol will lead to amending data management and/or statistical 
analysis plans, the sponsor should consider doing so in consultation with the applicable 
FDA review division. Prior to locking the database, sponsors should address in the 
statistical analysis plan how protocol deviations related to COVID-19 will be handled for 
the prespecified analyses." 
1.3 
EMA Guidance 
EMA provided guidance3 in March 2020: 
"At this point in time it is not possible to give general applicable advice on how the 
different aspects related to the pandemic should be handled, as implications on clinical 
trials are expected to be manifold. Impact on the data collection, analysis and 
interpretation of results for each trial will need a thorough case-by-case assessment." 
"As a general principle, there are strong scientific reasons to conduct trials as planned and 
implement changes only when there is a convincing scientific reason that it improves 
interpretability of results." 
1.4 
Missing Data Handling for Missing Due to COVID-19 or Any 
Other Missing Data That Can Be Reasonably Assumed to Be 
Missing at Random for Dichotomized Variables 
In this document, a missing data handling method is proposed to handle missing data due 
to COVID-19 infection or logistical restrictions related to the COVID-19 pandemic or any 
other missing data that can be reasonably assumed to be missing at random under the 
general MAR framework. In particular, we explain using multiple imputation (MI) to 
handle missing data due to COVID-19 or any other missing data that can be reasonably 
assumed to be Missing at Random in dichotomized variables in conjunction with non-
responder imputation (NRI) for missing data due to other reasons. 
 


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2.0 
Non-responder Imputation Incorporating Multiple 
Imputation (NRI-MI) 
2.1 
Overall Description of the Method 
For a dichotomized outcome variable with missing data, the NRI-MI will categorize any 
subject who does not have evaluation during a pre-specified visit window as a non-
responder for the visit, with two exceptions: 
If the subject is a responder both before and after the pre-specified visit window in 
Period 1, the subject will be categorized as a responder for the visit. 
If the reason for missing (e.g., missed visits, incomplete visit, out-of-schedule visits, or 
discontinuations of study drug) is due to COVID-19 or any other missing data that can be 
reasonably assumed to be Missing at Random, the information will be captured in the 
database and the subject's response status will be imputed using multiple imputation. 
In addition, subjects whose change/percent change from Baseline cannot be calculated 
because of a missing Baseline will be considered as a non-responder at all post-baseline 
visits unless the post-baseline value is zero. 
Non-responder imputation incorporating multiple imputation (NRI-MI) for missing due to 
COVID-19 or any other missing data that can be reasonably assumed to be Missing at 
Random will be implemented as follows. 
2.2 
Multiple Imputation (MI) and MAR Assumption 
When a dichotomized variable is derived from a continuous scale, for example, EASI 90 
(at least a 90% reduction in EASI relative to Baseline), the multiple imputation will be 
applied to the original scale, EASI (ranges from 0 - 72) assuming multivariate normal 
distribution. Then the dichotomized variable will be derived from the imputed value. 
The MI procedure assumes that the data are missing at random (MAR). That is, for an 
outcome variable Y, the probability that an observation is missing depends only on the 
 


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observed values of other variables, not on the unobserved values of the outcome 
variable Y. Statistical inference from the MI procedure is valid under the MAR 
assumption. 
2.3 
Imputation Algorithm 
It is reasonable to assume the missing values of the longitudinal data for an outcome 
variable (e.g., EASI, the original scale of EASI 90, at each post-baseline visit) follows a 
monotone missing pattern. In practice, the missing data of the outcome variable might 
have an arbitrary (non-monotone) missing data pattern. An extra step may be added 
accordingly, to augment data into a monotone missing pattern. 
For the outcome variable (e.g., EASI at each visit), K 'complete' datasets can be generated 
in two steps: augmentation step and imputation step. K, the number of repetitions, is 
determined below. 
Augmentation Step 
For datasets with non-monotone missing data pattern, the augmentation step will 
first impute enough values to augment the data into a monotonic missing pattern: 
Markov Chain Monte Carlo (MCMC) will be applied to augment the data using PROC MI 
with the MCMC IMPUTE monotone statement, assuming a multivariate normal 
distribution. The augmented data will be used in the subsequent imputation step to 
generate 'complete' datasets. Covariates included in the model are treatment, stratification 
factors (vIGA-AD categories (vIGA-AD 3; 4) and age (12 to < 18; 18 to < 40; ≥ 40 to 
< 64 years)), Baseline, and all post-baseline visits of the outcome variable according to 
the pre-specified order. Of note, categorical variables are included using the form of 
dummy variables. 
Repeat the imputation process K 30 times using the procedure described above to form 
K 30 monotone missing datasets, where K is determined as described in "Repetition of 
Imputations (K)." 
 


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Imputation Step 
For missing data with monotone missing patterns, the choice of multiple imputation using 
a parametric regression model that assumes multivariate normality is appropriate. 
The imputation step is described below: 
The imputation model for the missing data is a regression model, which controls for 
treatment, stratification factors (vIGA-AD categories [vIGA-AD 3; 4]) and age (12 to 
< 18; 18 to < 40; ≥ 40 to < 64 years), Baseline, and all post-baseline visits of the outcome 
variable. The covariates included in the model and the order of these variables are 
consistent with the augmentation step. 
For each monotone missing dataset, using SAS PROC MI with MONOTONE REG model 
statement, the outcome variable at each post-baseline visit with missing values will be 
imputed sequentially with covariates constructed from their corresponding sets of 
preceding variables. 
A 'complete' dataset with imputed values for the missing data is generated after the 
augmentation and imputation steps are completed. 
Repetition of Imputations (K) 
Repetition of imputations, K, must be determined in advance. When estimating the overall 
variance of multiple imputation, the additional sampling variance is the 
between-imputation variance divided by K. This value represents the sampling error 
associated with the overall or average coefficient estimates. It is used as a correction 
factor for using a specific number of imputations. The more imputations (K) are 
conducted, the more precise the parameter estimates will be. For example, with a 1% 
power falloff tolerance in multiple imputation, as compared to an infinite number of 
imputations, multiple imputation requires 20 repetitions of imputation for 30% missing 
information and 40 repetitions for 50% missing information.4 In the usual clinical settings 
expecting less than 30% missing information, K  30 repetitions are deemed sufficient. 
 


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When missingness exceeds 30%, depending on the power falloff tolerance level, number 
of repetitions may need to be increased. Recent research4 suggested that the number of 
repetitions (K) should be at least equal to the percentage of missing.6 
2.4 
Derivation of Response Status and Non-Responder 
Imputation 
For each 'complete' dataset, the imputed post-baseline values will be rounded to the same 
precision as the observed data. Response status (e.g., EASI 90 at each visit) will be 
determined accordingly. 
The imputed response status for missing due to reasons other than COVID-19 or any other 
missing data that can be reasonably assumed to be Missing at Random will be overridden 
by non-responder imputation (Section 9.2) to ensure that multiple imputation is only 
applied to missing due to COVID-19 or any other missing data that can be reasonably 
assumed to be Missing at Random: 
Using NRI approach, all missing due to reasons other than COVID-19 or any other 
missing data that can be reasonably assumed to be Missing at Random will be categorized 
as non-responders. In addition, subjects whose change/percent change from Baseline 
cannot be calculated because of a missing Baseline will be considered as a non-responder 
at all post-baseline visits unless the post-baseline value is zero. 
The only exception is that a subject will be categorized as a responder for the visit if the 
subject is a responder both before and after an SAP-specified visit window in Period 1. 
2.5 
Analysis 
The statistical analysis will use the Cochran-Mantel-Haenszel (CMH) test adjusted by the 
stratification factors derived from actual values. 
 


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2.5.1 
Analysis of Each Dataset 
For each of the K 'complete' datasets, the CMH test will be used to estimate the treatment 
difference (Upadacitinib versus Dupilumab) and the corresponding standard error. 
2.5.2 
Synthesis of Results for Statistical Inference 
The results from the K 'complete' datasets will be synthesized using the SAS procedure 
PROC MIANALYZE, following Rubin's formula,5 to derive the MI estimator of the 
treatment difference for the final inferences. 
Rubin's formula 
We fit the analysis model to the kth 'complete' dataset, denoting the estimate of the 
treatment difference q by 𝜃̃𝑘 from the kth 'complete' dataset, and denoting the 
corresponding estimate of the variance as Vk. 
The MI estimator of q (point estimator obtained from PROC MIANALIZE), 𝜃̃𝑀𝐼, is the 
average of the K individual estimators: 
𝜃̃𝑀𝐼=
1
𝐾∑
𝜃̃𝑘.
𝐾
𝑘=1
  
 
The estimated variance of 𝜃̃𝑀𝐼, is a combination of the between- and within-imputation 
variability as follows: 
𝑉𝑀𝐼= 𝑊+ (1 +
1
𝐾)𝐵 , 
 
where 𝑊=
1
𝐾∑
𝑉𝑘
𝐾
𝑘=1
 is the within-imputation variability and 
𝐵=
1
𝐾−1 ∑
(𝜃̃𝑘−𝜃̃𝑀𝐼)2
𝐾
𝑘=1
 is the between-imputation variance. 
It has been shown1 that the statistic 
 


 Upadacitinib 
M23-696 – Statistical Analysis Plan 
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61 
𝑇=
𝜃̃𝑀𝐼−𝜃
√𝑉𝑀𝐼  
 
has an approximate 𝑡𝑣 distribution where 𝑣= (𝐾−1)(1 +
𝑊
𝐵)2. Statistical inference, 
including hypothesis testing and confidence intervals for the treatment effect, will be 
based on this T-statistic. 
3.0 
Sample SAS Code 
/**********************/ 
/*IMPUTATION ALGORITHM*/ 
/**********************/ 
/*NOTE: THIS APPROACH REQUIRES NO MISSING IN CATEGORICAL COVARIATES AND 
REQUIRES AT LEAST ONE OBSERVATION IN BASELIBE OR ONE OF THE POST
BASELINE VISIT*/ 
 
/*PRE AUGMENTATION  CREATE DUMMY FOR CATEGORICAL VARIABLES*/ 
/********************************************/ 
DATA EASI_2; SET EASI; 
  /*THE MCMC STATMENT BELOW ASSUMES MULTI VARIATE NORMAL*/ 
  /*IF TREATMENT OR ANY COVARIATES ARE CATEGORICAL WITH L>2 LEVELS*/ 
  /*NEED TO CREATE L 1 DUMMY VARIABLES*/ 
  /*HERE, TREATMENT (TRT01PN) HAS 2 LEVELS, SO WE NEED 1 DUMMY 
VARIABLES*/ 
  IF TRT01PN=1 THEN TRT1=1; 
  ELSE TRT1=0; 
RUN; 
 
/*AUGMENTATION STEP 
 TO HAVE 30 MONOTONE MISSING DATASETS*/ 
PROC MI DATA=EASI_2 OUT=EASI_MONO NIMPUTE=30 SEED= 1001 /*RANDOM SEED 
PRE DEFINED*/ 
  ROUND=. . . 0.1 0.1 0.1 0.1 0.1 0.1 /*VALUE ROUND TO 1ST DECIMAL*/ 
  MIN=. . . 0 0 0 0 0 0            /*MINIMUM VALUE OF EASI IS 0*/ 
  MAX=. . . 72 72 72 72 72 72;   /*MAXIMUM VALUE OF EASI IS 72*/ 
  MCMC IMPUTE=MONOTONE ; 
/*NOTE: CATEGORICAL VARIABLES SUCH AS TRT1 ARE DUMMY, CREATED ABOVE*/ 
/*NOTE: ALL OTHER NON DUMMIED COVARIATES MUST BE CONTINUOUS*/ 
/*SUPPOSE STRATAN (NUMERIC VARIABLE FOR STRATA) HAS ONLY 2 LEVELS, NO 
NEED TO CREATE DUMMY*/ 
  VAR TRT1 AGEGR1N VIGAGR1N BASE WK2 WK4 WK8 WK12 WK16; 
/*CAUTION TO USE THE "BY" STATEMENT IN MCMC: */ 
/*MVN MODEL IS FITTED WITHIN EACH 'BY' GROUP, INSTEAD OF ACROSS ALL 
GROUPS*/ 
RUN; 
 
 


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62 
/*IMPUTATION STEP  DETERMINE IMPUTATION DISTRIBUTION AND RANDOMLY 
IMPUTE MISSING VALUE TO GENERATE 'COMPLETE' DATASETS*/ 
/***************************************************/ 
PROC MI DATA=EASI_MONO OUT=EASI_FULL NIMPUTE=1 SEED= 9001  /*RANDOM SEED 
PRE DEFINED*/ 
  ROUND=. . . 0.1 0.1 0.1 0.1 0.1 0.1 /*VALUE ROUND TO 1ST DECIMAL*/ 
  MIN=. . . 0 0 0 0 0 0            /*MINIMUM VALUE OF EASI IS 0*/ 
  MAX=. . . 72 72 72 72 72 72;   /*MAXIMUM VALUE OF EASI IS 72*/ 
  MINMAXITER=1000; 
  CLASS TRT01PN AGEGR1N VIGAGR1N; 
  VAR TRT01PN AGEGR1N VIGAGR1N BASE WK2 WK4 WK8 WK12 WK16; 
  MONOTONE REG (WK2 WK4 WK8 WK12 WK16);  /* IMPUTED SEQUENTIALLY, FROM 
WK 2 TO 16, WITH COVARIATES CONSTRUCTED FROM THE CORRESPONDING PRECEDING 
VARIABLES*/ 
  BY IMPUTATION ;                   /*FOR EACH OF THE 30 MONOTONE 
MISSING DATASETS, IMPUTE A 'COMPLETE' DATASET*/ 
RUN; 
 
 
/*DETERMINE DICHOTOMOUS RESPONSE STATUS, EASI 90*/ 
DATA ALL; SET EASI_FULL; 
  IF 0<=WK2<=0.9*BASE THEN EASI90_2=1; 
    ELSE EASI90 2=0; 
  IF 0<=WK4<=0.9*BASE THEN EASI90_4=1; 
    ELSE EASI90 4=0; 
  IF 0<=WK8<=0.9*BASE THEN EASI90_8=1; 
    ELSE EASI90_8=0; 
  IF 0<=WK12<=0.9*BASE THEN EASI90_12=1; 
    ELSE EASI90_12=0; 
  IF 0<=WK16<=0.9*BASE THEN EASI90_16=1; 
    ELSE EASI90_16=0; 
RUN; 
 
 
/***********************************************************************
*/ 
/*    DATA HANDLING STEPS TO MERGE COVID 19 or Other MAR STATUS OMITTED         
*/ 
/*            PLACE TO ADD DATA HANDLING AND MERGING STEPS              
*/ 
/***********************************************************************
*/ 
 
/*FOR MI, SKIP THE FOLLOWING CODE, PROCEED TO THE CODE AFTER ANALYSIS 
MODEL *//*OVERRIDE MISSING VALUES NOT DUE TO COVID 19 or Other MAR WITH 
TRADITIONAL NRI*/ 
DATA ALLF; SET ALL; 
  /*COVID19_XX='Y' IF MISSING AT WEEK XX IS DUE TO COVID 19 or Other 
MAR; IF NOT, OVERRIDE WITH TRADITIONAL NRI*/ 
 


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  IF COVID19 2 NE 'Y' THEN EASI90 2=EASI90NRI 2; 
  IF COVID19 4 NE 'Y' THEN EASI90 4=EASI90NRI 4; 
  IF COVID19_8 NE 'Y' THEN EASI90_8=EASI90NRI_8; 
  /*VARIABLE EASI90NRI XX: TRADITIONAL NRI DATA AT WEEK XX, WHICH COVERS 
THE SPECIAL HANDLING SUCH AS THE BEFORE AND AFTER EXCEPTION*/ 
  IF COVID19_12 NE 'Y' THEN EASI90_12=EASI90NRI_12; 
  IF COVID19_16 NE 'Y' THEN EASI90_16=EASI90NRI_16; 
RUN; 
PROC SORT DATA=ALLF; BY _IMPUTATION_ SUBJID; RUN; 
 
/****************/ 
/*ANALYSIS MODEL*/ 
/****************/ 
 
/*KEY CODE: ANALYZING EACH 'COMPLETE' DATASET*/ 
/***********************************/ 
/*COMPARE TREATMENT GROUPS 1 (Dupilumab) AND 2 (Upadacitinib) ONLY*/ 
DATA ALL; SET ALL; 
  WHERE TRT01PN IN (1,2); 
RUN; 
 
/*INDIVIDUAL LEVEL DATA 
> # OF RESPONDERS & # OF SUBJECTS, TO BE READ
IN TO PROC STDRATE*/ 
PROC FREQ DATA=ALL; 
  BY IMPUTATION ; 
  TABLES TRT01PN*AGEGR1N*VIGAGR1N*EASI90_16/LIST NOCUM NOPRINT 
OUT=COUNT_TABLE; 
  /*WEEK 16 RESULTS AS AN EXAMPLE*/ 
RUN; 
DATA COUNT_TABLE; SET COUNT_TABLE; 
  DROP PERCENT; 
RUN; 
PROC TRANSPOSE DATA=COUNT_TABLE OUT=FREQ_TABLE PREFIX=RESP; 
ID EASI90 16; 
BY IMPUTATION_ TRT01PN AGEGR1N VIGAGR1N; 
VAR COUNT; 
RUN;   
DATA FREQ TABLE1; SET FREQ_TABLE; 
  CASE=RESP1; 
  SIZE=SUM(RESP0, RESP1); 
  KEEP _IMPUTATION_ TRT01PN AGEGR1N VIGAGR1N CASE SIZE; 
RUN; 
 
/*RE ORDER TO SET 1 (Dupilumab) AS THE REFERENCE GROUP*/ 
DATA FREQ_TABLE2; SET FREQ_TABLE1; 
  IF TRT01PN=2 THEN TRT01PN=0; 
RUN; 
 
/*CALCULATE THE COMMON RISK DIFF FOR EACH COMPLETE DATASET*/ 
 


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PROC STDRATE DATA=FREQ TABLE2 
  METHOD=MH STAT=RISK EFFECT=DIFF; 
  BY _IMPUTATION_; 
  POPULATION GROUP=TRT01PN EVENT=CASE TOTAL=SIZE; 
  STRATA AGEGR1N VIGAGR1N / ORDER=DATA STATS(CL=NONE) EFFECT; 
  ODS OUTPUT EFFECT=EFFECT; 
RUN; 
 
 
/*COMBINING RESULTS USING PROC MIANALYZE*/ 
/****************************************/ 
PROC MIANALYZE DATA=EFFECT; 
  ODS OUTPUT PARAMETERESTIMATES=RISK_DIFF_MH;   
  MODELEFFECTS RISKDIFF; 
  STDERR STDERR; 
RUN;