Clinical trial NCT03738397
Conditions: Atopic Dermatitis
Keywords: Upadacitinib ABT-494 Dupilumab Atopic Dermatitis
Sponsor: AbbVie
Start date: 2019-02-21; Completion date: 2020-12-09
Enrollment: 673 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate upadacitinib compared to dupilumab (Dupixent®) in adults with moderate to severe atopic dermatitis (AD) who are candidates for systemic therapy.

Detailed description:
The study is comprised of a 35-day screening period, a 24-week double-blinded treatment period, and a follow-up visit 12 weeks after the last dose. Participants who complete Week 24 have the option to enroll into an open-label study (Study M19-850; NCT04195698) of upadacitinib 30 mg once daily and receive treatment with upadacitinib for an additional 52 weeks.

Participants who meet eligibility criteria will be randomized in a 1:1 ratio to receive either upadacitinib or dupilumab. Randomization will be stratified by Baseline disease severity (Validated Investigator Global Assessment scale for Atopic Dermatitis \[vIGA-AD\] score of moderate \[3\] versus severe \[4\]) and age (\<40, ≥ 40 to \< 65, ≥ 65 years).

Arms: arm 1: Participants will receive 30 mg upadacitinib orally once a day (QD) up to Week 24 and placebo to dupilumab by subcutaneous injection every other week from Baseline to Week 22. arm 2: Participants will receive a loading dose of 600 mg dupilumab by subcutaneous (SC) injection on Day 1 followed by 300 mg dupilumab SC every other week (EOW) until Week 22 and placebo to upadacitinib orally QD up to Week 24.
Interventions: intervention 1: Upadacitinib intervention 2: Dupilumab intervention 3: Placebo to dupilumab intervention 4: Placebo to upadacitinib
Intervention descriptions: intervention 1: Extended release tablet intervention 2: Dupilumab is administered as a subcutaneous (SC) injection intervention 3: Placebo administered as a subcutaneous injection intervention 4: Tablet

Protocol documents:
Prot_000.pdf: 
NCT03738397


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TABLE OF CONTENTS
1
SYNOPSIS
5
2
INTRODUCTION
8
2.1
BACKGROUND AND RATIONALE
8
2.2
BENEFITS AND RISKS TO SUBJECTS
9
3
STUDY OBJECTIVES AND ENDPOINTS
11
3.1
OBJECTIVES
11
3.2
PRIMARY ENDPOINT
11
3.3
SECONDARY ENDPOINTS
11
3.4
ADDITIONAL ENDPOINTS
12
3.5
SAFETY ENDPOINTS
12
3.6
BIOMARKER SAMPLES
12
4
INVESTIGATIONAL PLAN
12
4.1
OVERALL STUDY DESIGN AND PLAN
12
4.2
DISCUSSION OF STUDY DESIGN
14
5
STUDY ACTIVITIES
15
5.1
ELIGIBILITY CRITERIA
15
5.2
CONTRACEPTION RECOMMENDATIONS
19
5.3
PROHIBITED MEDICATIONS AND THERAPY
20
5.4
PRIOR AND CONCOMITANT THERAPY
24
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
26
5.6
FOLLOW-UP FOR SUBJECT WITHDRAWAL FROM STUDY
27
5.7
STUDY DRUG
28
5.8
RANDOMIZATION/DRUG ASSIGNMENT
30
5.9
PROTOCOL DEVIATIONS
32
5.10 OTHER STUDY PROCEDURES
32
6
SAFETY CONSIDERATIONS
45
6.1
COMPLAINTS AND ADVERSE EVENTS
45
6.2
TOXICITY MANAGEMENT
52


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6.3
DATA MONITORING COMMITTEE AND CARDIOVASCULAR ADJUDICATION COMMITTEE
56
6.4
OTHER SAFETY DATA COLLECTION
57
6.5
SUSAR REPORTING
57
7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
57
7.1
STATISTICAL AND ANALYTICAL PLANS
57
7.2
DEFINITION FOR ANALYSIS POPULATIONS
57
7.3
STATISTICAL ANALYSES FOR EFFICACY
57
7.4
STATISTICAL ANALYSES FOR SAFETY
58
7.5
STATISTICAL ANALYSIS OF OPTIONAL PROTEOMIC BIOMARKER DATA
59
8
ETHICS
59
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD (IEC/IRB)
59
8.2
ETHICAL CONDUCT OF THE STUDY
59
8.3
SUBJECT CONFIDENTIALITY
59
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
59
10 DATA QUALITY ASSURANCE
60
11 COMPLETION OF THE STUDY
60
12 REFERENCES
61
LIST OF TABLES
TABLE 1.
EXAMPLES OF COMMONLY USED STRONG CYP3A INHIBITORS AND INDUCERS
24
TABLE 2.
DESCRIPTION OF STUDY DRUG AND PLACEBO
28
TABLE 3.
SPECIFIC TOXICITY MANAGEMENT GUIDELINES FOR ABNORMAL LABORATORY VALUES
54
LIST OF FIGURES
FIGURE 1.
STUDY SCHEMATIC
14
FIGURE 2.
INTERPRETATION AND MANAGEMENT OF HBV SEROLOGIC TEST RESULTS
43


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LIST OF APPENDICES
APPENDIX A.
STUDY SPECIFIC ABBREVIATIONS AND TERMS
63
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
67
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
68
APPENDIX D.
ACTIVITY SCHEDULE
69
APPENDIX E.
PROTOCOL SUMMARY OF CHANGES
73
APPENDIX F.
OPERATIONS MANUAL
74








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2 INTRODUCTION
2.1 Background and Rationale
Why This Study Is Being Conducted
Atopic dermatitis (AD) is an inflammatory, pruritic, chronic or chronically relapsing skin disease.  The 
adult phase of AD begins at puberty and frequently continues into adulthood.  In adults, disease typically 
involves flexural folds, face, neck, upper arms and back, and dorsal surfaces of the hands and feet.1,2
Management of AD primarily consists of trigger avoidance, careful attention to skin care, and both 
pharmacologic and nonpharmacologic treatment.3  The 2006 PRACTALL Consensus Report recommends 
treatment by addition of agents in a stepwise fashion based on disease severity, starting with topical 
corticosteroids of increasing potency and/or a topical calcineurin inhibitor and escalating to systemic 
therapy for recalcitrant, severe disease.4  Systemic immunomodulatory agents used to treat AD include 
cyclosporin A, azathioprine, methotrexate (MTX), mycophenolate mofetil, interferon gamma, systemic 
corticosteroids, and dupilumab, a monoclonal antibody that inhibits interleukin (IL)-4 and IL-13 
signaling.5-7  Despite these systemic therapies, an unmet need continues to exist for patients who are 
non-responders or partial responders to these agents.
The Janus kinases or JAKs are a family of intracellular tyrosine kinases that function as dimers in the 
signaling process of many cytokine receptors.  The JAKs play a critical role in both innate and adaptive 
immunity, making them attractive targets for the treatment of inflammatory diseases.  Targeting the JAK 
signaling pathway for AD is supported by the involvement of various pro-inflammatory cytokines that 
signal via JAK pathways in the pathogenesis of AD.  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 AD and other inflammatory disorders.8,9
Upadacitinib is an oral, reversible JAK1 selective inhibitor.  JAK1 inhibition blocks the signaling of many 
important pro-inflammatory cytokines, including IL-2, IL-6, IL-7, and IL-15, which are known contributors 
to inflammatory disorders.  Through modulation of these proinflammatory cytokine pathways, 
upadacitinib offers the potential for effective treatment of inflammatory and autoimmune disorders 
such as AD, rheumatoid arthritis (RA), psoriatic arthritis (PsA), Crohn's disease (CD), ulcerative colitis 
(UC), axial spondyloarthritis (AxSpA), and Giant Cell Arteritis.  In the upadacitinib Phase 2 AD study, a 
statistically significant difference in the mean percent change from Baseline in Eczema Area and Severity 
Index (EASI) score at Week 16 (primary endpoint) was observed for 7.5 mg (–39.4%; P = 0.032 vs 
placebo), 15 mg (–61.7%; P < 0.001 vs placebo), and 30 mg (–74.4%; P < 0.001 vs placebo) groups 
compared with placebo (–23.0%).  Through Week 16 (Period 1), the percentages of subjects with 
adverse events (AEs), serious adverse events (SAEs), severe AEs, and AEs leading to discontinuation were 
similar across treatment groups.  There were no deaths reported during Period 1.
Additionally, upadacitinib was studied in rheumatoid arthritis with the results of two Phase 2 studies 
and two Phase 3 studies available as peer-reviewed manuscripts.10-13  Results from the Phase 2 study in 
AD showed that upadacitinib doses of 15 mg and 30 mg per day had an efficacy and safety profile that 
can benefit patients with moderate to severe AD.


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Clinical Hypothesis
Based on the differentiated selectivity profile for JAK1 inhibition, upadacitinib could demonstrate an 
improved benefit-risk profile compared to other therapeutic strategies for patients with inflammatory 
diseases.
Upadacitinib is expected to provide better efficacy compared to dupilumab and is expected to be well 
tolerated in adult subjects with moderate to severe AD.
Additional information regarding indications under study can be found in the current edition of the 
upadacitinib Investigator's Brochure.14
2.2 Benefits and Risks to Subjects
Treatment of AD in adolescent and adult subjects depends on the extent and severity of disease.  
Topical agents alone are commonly used for mild to moderate cases.  The most commonly used topical 
agents are corticosteroids, calcineurin inhibitor agents, and moisturizers.  The most common adverse 
events (AEs) of topical corticosteroids occur when used as monotherapy for prolonged periods and 
include skin thinning, acne, pigmentation, and striae.  Common AEs associated with use of topical 
calcineurin inhibitors are transient warmth, burning, itching, or stinging at the application site.2,15  When 
topical therapies are insufficient for treating the signs and symptoms of AD, systemic therapy or 
phototherapy are generally added to topical agents.2,15
Treatment guidelines developed by the American Academy of Dermatology recommend the use of 
systemic immunomodulatory agents for subjects in whom optimized topical regimens and/or 
phototherapy do not adequately control the signs and symptoms of disease.5,16  These guidelines 
recognize that insufficient data exist to firmly recommend optimal dosing, duration of therapy, and 
precise monitoring protocols for any systemic immunomodulating medication.  Importantly, in addition 
to the lack of well-controlled efficacy data supporting their use in moderate to severe AD, the duration 
of use of many traditional systemic immunomodulatory agents are limited due to cumulative toxicity.5,16
More recently, dupilumab, a monoclonal antibody that inhibits IL-4 and IL-13 signaling, was approved 
for the treatment of moderate to severe AD in adults in the European Union (EU)17 and United States 
(US)18 in 2017.  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 patients achieved 0 or 1 on the 
Investigator's Global Assessment (IGA) scale; therefore, 60% or more of patients continued to 
experience significant symptoms on dupilumab therapy.6,7  Nearly 50% of dupilumab 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 AEs are injection site reaction, conjunctivitis, and blepharitis.5,16
At this time very few systemic agents are approved for AD and, of those, cyclosporin A and oral 
prednisone are not suitable for long-term use.5,16  Thus, there is a high unmet need for a significant 
number of patients with an inadequate response to currently available agents.  While not approved for 
AD, other systemic treatments may also be utilized including methotrexate, mycophenolate mofetil, and
azathioprine.5,16


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These systemic agents all have immunomodulating properties leading to potential AEs.  The most 
common AEs associated with use of cyclosporin are abnormal renal function tests (e.g., increased 
creatinine or proteinuria), hyperlipidemia, hypertension, headache, and hypertrichosis.5,16  The most 
common AEs associated with methotrexate use are gastrointestinal disorders (e.g., stomatitis, oral 
ulcers, dyspepsia, abdominal pain, nausea, diarrhea) and abnormal liver function tests (e.g., increased 
aspartate transaminase [AST] or increased alanine transaminase [ALT]).5,16  The most common AEs 
associated with use of mycophenolate mofetil and azathioprine are gastrointestinal disorders 
(e.g., nausea, vomiting, abdominal pain, cramping, bloating, anorexia) and occasional leukopenia, 
anemia, and thrombocytopenia.5,16
Taken together, these agents may generally increase the risk of infections and cytopenias, 
gastrointestinal disorders, and may impact renal and/or liver function.5,16  Rarely, lymphoproliferative 
disorders, lymphoma, and other malignancies are associated with these agents.5,16  Thus, there is a high 
unmet need for a significant number of patients with an inadequate response to currently available 
agents.
Upadacitinib is a novel selective orally available JAK1 inhibitor with the potential to decrease Th2 
mediated skin inflammation and itch while having minimal inhibitory effects on JAK2 and JAK3.  This 
could potentially minimize some of the reported safety concerns with non-selective JAK inhibition which 
are thought to be mediated by inhibition of JAK2 and JAK3 signaling pathways.19,20
Primary results from the ongoing Phase 2 study demonstrated superior efficacy of upadacitinib with an 
acceptable safety profile at the selected doses for Phase 3 (15 mg and 30 mg once daily [QD]) compared 
to placebo in subjects with moderate to severe AD.  Taken together, the efficacy and safety data from 
the Phase 2 AD study and cumulative safety data from ongoing Phase 2 and 3 programs in other disease 
indications support further development of upadacitinib in subjects with moderate to severe AD.
Adverse events such as infections, herpes zoster reactivation, malignancies, and hematologic AEs have 
been observed with JAK inhibition.  Events of deep vein thrombosis and pulmonary embolism have been 
reported in patients receiving JAK inhibitors including upadacitinib.  Malignancies have been reported in 
the RA clinical studies for upadacitinib.  Based on the integrated data from the Phase 3 RA studies, there 
were comparable incidence rates of malignancies other than non-melanoma skin cancer (NMSC) 
between the upadacitinib 15 mg QD and 30 mg QD groups with long-term treatment.  NMSC is a 
common malignancy in the general population.  Although the incidence rate of NMSC was higher in the 
upadacitinib 30 mg group compared to the upadacitinib 15 mg group in the integrated analysis data, the 
risk of patients experiencing a NMSC when receiving upadacitinib 15 mg and 30 mg in the Phase 3 RA 
studies did not appear to increase over time.  Based on review of the data available, no pattern of the 
types of malignancies was noted, the malignancies are expected for a population of patients with 
moderately to severely active RA, and the standardized incidence rate is within the expected range for 
the general population.  The safety profile specific to upadacitinib is evolving, with safety results to date 
consistent with those known to be associated with JAK inhibition, with non-serious infections 
(e.g., upper respiratory tract infection or nasopharyngitis) being the most commonly reported AEs.  In 
addition, laboratory changes observed with upadacitinib include elevations of serum transaminases, 
lipids, creatinine, and creatine phosphokinase; both increased and reduced hemoglobin, depending on 
Baseline inflammatory burden; and reductions in white blood cell counts, including natural killer (NK) 
cells.


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The results of all 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.14
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 autoimmune/inflammatory conditions.
3 STUDY OBJECTIVES AND ENDPOINTS
3.1 Objectives
The objective of this study is to evaluate the efficacy and safety of upadacitinib versus dupilumab for the 
treatment of adult subjects with moderate to severe atopic dermatitis who are candidates for systemic 
therapy.
3.2 Primary Endpoint
The primary endpoint is the proportion of subjects achieving a 75% reduction in EASI (EASI 75) from 
Baseline at Week 16.
3.3 Secondary Endpoints
Ranked Secondary Endpoints:
1.
Percent change from Baseline to Week 16 in Worst Pruritus Numerical rating scale (NRS)
2.
Proportion of subjects achieving a 100% reduction in EASI (EASI 100) from Baseline at Week 16
3.
Proportion of subjects achieving a 90% reduction in EASI (EASI 90) from Baseline at Week 16
4.
Percent change from Baseline to Week 4 in Worst Pruritus NRS
5.
Proportion of subjects achieving a 75% reduction in EASI (EASI 75) from Baseline at Week 2
6.
Percent change from Baseline to Week 1 in Worst Pruritus NRS
7.
Proportion of subjects achieving an improvement (reduction) in Worst Pruritus NRS ≥ 4 from 
Baseline at Week 16 for subjects with Worst Pruritus NRS ≥4 at Baseline


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3.4 Additional Endpoints
All variables listed as primary or secondary endpoints will be analyzed at all visits other than those listed 
above.  In addition, the following variables will be analyzed at all visits:
!
Proportion of subjects achieving a 75% reduction in EASI in the head and neck body region from 
Baseline
!
Proportion of subjects achieving a 75% reduction in EASI in each body region (other than head 
and neck) from Baseline
!
Proportion of subjects achieving an improvement (reduction) in Daily Worst Pruritus NRS ≥4 
from Baseline for subjects with Daily Worst Pruritus NRS ≥4 at Baseline by day up to Day 28
3.5 Safety Endpoints
The following safety evaluations will be performed during the study:  treatment-emergent AEs (TEAEs), 
SAEs, AEs of special interest (AESI), AEs leading to discontinuation; vital signs, and laboratory tests.
3.6 Biomarker Samples
Optional biospecimens (e.g., blood, serum, plasma, and skin biopsies) will be collected at specified time 
points (Appendix D) throughout the study to evaluate known and/or novel disease-related or drug-
related biomarkers.  Types of biomarkers may include nucleic acids, proteins, lipids, and/or metabolites.  
This research may be exploratory in nature and the results may not be included with the clinical study 
report.
The analyses of optional biomarker samples may include but are not limited to genetic markers that will 
help to understand the subject's disease and response to upadacitinib.  Genes of interest may include 
those associated with pharmacokinetics (drug metabolizing enzymes, drug transport proteins), genes 
within the target pathway (JAK, Tyk2, TNF), or other genes believed to be related to AD and other 
inflammatory diseases (Filaggrin [FLG], Claudin 1 [CLDN1], Human Leukocyte Antigen [HLA]).  Research 
may also include epigenetic changes in DNA that may associate with the subject's response to treatment 
or disease.  Samples for RNA and proteomics will be used to research if any genetic variants result in 
changes to gene expression or protein concentrations.  For any samples collected in Germany, the 
research will be restricted to upadacitinib and AD.
4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
This is a Phase 3b, randomized, double-blind, double-dummy, active comparator-controlled multicenter 
study that will evaluate the safety and efficacy of upadacitinib versus dupilumab in adults (≥ 18 to 
≤75 years of age) with moderate to severe AD who are candidates for systemic therapy.  Eligible 
subjects must have a documented history of inadequate response to treatment with topical AD 


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treatments or documented use of systemic treatment for AD within 6 months prior to the Baseline Visit 
or for whom topical treatments are otherwise medically inadvisable.
The study is comprised of a 35-day Screening Period, a 24-week double-blind treatment period, and an 
End-of-Treatment Follow-up Visit.  Subjects who complete Study M16-046 will have the option to enroll 
into an open-label study of oral upadacitinib 30 mg QD in which they will be treated for an additional
52 weeks.  The End-of-Treatment Follow-up Visit will be 12 weeks after the last injection for subjects 
who do not enroll into the open-label study.
Subjects who meet eligibility criteria will be randomized in a 1:1 ratio to one of the two arms as shown 
below:
!
Treatment A (N = 325):  Daily oral doses of upadacitinib 30 mg from the Baseline visit until the 
Week 24 visit, and placebo pre-filled syringe administered at the baseline visit (2 subcutaneous 
[SC] injections), followed by placebo pre-filled syringe (1 injection) every other week until the 
Week 22 visit.
!
Treatment B (N = 325):  Dupilumab 600 mg (2 × 300 mg dupilumab SC injection) administered at 
the Baseline visit, followed by dupilumab 300 mg SC injection every other week until the 
Week 22 visit and daily oral doses of placebo tablets from the Baseline visit until the Week 24 
visit.
Randomization will be stratified by baseline disease severity (moderate validated Investigator Global 
Assessment for atopic dermatitis [vIGA-AD 3] vs. severe [vIGA-AD 4]) and age (< 40, ≥ 40 to < 65, 
≥65 years).  The subject's age at baseline will be used for randomization and throughout the duration of 
the study.
Information on the Data Monitoring Committee (DMC) and Cardiovascular Adjudication Committee 
(CAC) is described in Section 6.3.
The schematic of the study is shown in Figure 1.  Further details regarding study procedures are located 
in Section 5.10.
See Section 5.1 for information regarding eligibility criteria.
The study sites and subjects will remain blinded to treatment assignments for the duration of the study.  
A Week 24 database lock will occur after all ongoing subjects have completed the Week 24 visit; the 
Primary Analysis will be performed based on this database lock, which is the only and final analysis for 
efficacy.  A final database lock will be performed at the end of the study.


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Figure 1.
Study Schematic
BL = Baseline; SC = subcutaneous
*
Dupilumab 300 mg SC injection will be administered every other week starting at the Week 2 visit and until the Week 22 
visit, after an initial dose of 600 mg at the Baseline visit.
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 patients 
with moderate to severe AD.  Indirect comparison of the upadacitinib Phase 2 study results with 
published results from the dupilumab Phase 3 studies shows superior nominal results for upadacitinib 
30 mg QD versus dupilumab 300 mg every other week, in a similar patient population.  This study is 
being performed to evaluate the hypothesis of potential superiority of upadacitinib.
Appropriateness of Measurements
Standard clinical and laboratory procedures will be utilized in this study.  All efficacy measurements in 
this study are standard for assessing disease activity in subjects with AD.  Other than the biomarker 
analyses which are exploratory, all clinical and laboratory procedures in this study are standard and 
generally accepted.
Suitability of Subject Population
Eligible subjects have a documented history of inadequate response to treatment with topical or 
systemic AD treatments or they are subjects for whom topical treatments are otherwise medically 
inadvisable.  As a result, these subjects have an unmet need for adequate control of their AD.  Results in 


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the Phase 2 study that evaluated upadacitinib treatment for AD demonstrated superior efficacy of 
upadacitinib with an acceptable safety profile at the selected dose (30 mg QD) compared to placebo in 
subjects with moderate to severe AD.  Therefore, this subject population is considered appropriate for 
treatment and for evaluating a treatment difference between upadacitinib and dupilumab.
Selection of Doses in the Study
This study will evaluate upadacitinib (30 mg QD).  The selection of this dose was informed by the 
analysis of the 16-week safety, efficacy, and exposure-response data of the Period 1 of the Phase 2 AD 
Study M16-048, which evaluated 3 doses of upadacitinib (7.5 mg, 15 mg, and 30 mg QD) versus placebo.  
In addition, all of the currently available pharmacokinetic, pharmacodynamic, safety, and efficacy data 
from upadacitinib studies were used to support the selection of these doses.
Study M16-048 Period 1 results demonstrated superior efficacy of upadacitinib with an acceptable 
safety profile at the selected dose (30 mg QD) compared to placebo in subjects with moderate to severe 
AD.  A statistically significant difference in the mean percent change from Baseline in EASI score at 
Week 16 (primary endpoint) was observed for 7.5 mg (–39.4%; P = 0.032 vs placebo), 15 mg (–61.7%; 
P < 0.001 vs placebo), and 30 mg (–74.4%; P < 0.001 vs placebo) groups compared with placebo 
(–23.0%).  Through Week 16 (Period 1), the percentages of subjects with AEs, SAEs, severe AEs, and AEs 
leading to discontinuation were similar across treatment groups.  There were no deaths reported during 
Period 1.  Preliminary exposure-response analyses for Period 1 of the Phase 2b study show that the 
percentage of subjects achieving EASI 75, EASI 90, or IGA 0/1 increased with increasing upadacitinib 
plasma exposures.
In addition, indirect comparison of the Phase 2 study results with published results from the dupilumab 
Phase 3 studies shows superior nominal results for upadacitinib 30 mg QD versus dupilumab 300 mg 
every other week, in a similar patient population.  This study is being performed to confirm the 
hypothesis of potential superiority raised by this indirect comparison.
In summary, exposures associated with upadacitinib 30 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 dose was based on the approved posology in moderate to severe atopic 
dermatitis subjects [initial dose of 600 mg (two 300 mg injections), followed by 300 mg given every 
other week administered as subcutaneous injection].17,18
5 STUDY ACTIVITIES
5.1 Eligibility Criteria
Subjects must meet all of the following criteria in order to be included in the study.  Anything other than 
a positive response to the questions below will result in exclusion from study participation.
Consent and Demographics
1. Subject must be ≥ 18 years old and ≤ 75 years old at Screening Visit.


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2. Subjects and/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.
3. Subject is judged to be in general good health (other than AD) as determined by the Principal 
Investigator, based upon the results of medical history, laboratory profile, physical examination, 
chest x-ray (CXR), and a 12-lead electrocardiogram (ECG) performed during Screening.
AD Disease Activity
4. Chronic AD with onset of symptoms at least 3 years prior to baseline and subject meets 
Hanifin and Rajka criteria.21
5. Subject meets all of the following disease activity criteria:
!
EASI score ≥ 16 at the Screening and Baseline Visits;
!
vIGA-AD score ≥ 3 at the Screening and Baseline Visits;
!
≥ 10% body surface area (BSA) of AD involvement at the Screening and Baseline Visits;
!
Baseline weekly average of daily Worst Pruritus NRS ≥ 4.  Note:  The baseline weekly 
average of daily Worst Pruritus NRS will be calculated from the 7 consecutive days 
immediately preceding the Baseline Visit.  A minimum of 4 daily scores out of the 7 days is 
needed.
6. Subject has applied a topical emollient (moisturizer) twice daily for at least 7 days before the 
Baseline Visit.  Note:  Subject may use prescription moisturizers or moisturizers containing 
ceramide, urea, filaggrin degradation products or hyaluronic acid if such moisturizers were 
initiated before the screening visit.
7. Documented history (within 6 months of the Baseline Visit) of inadequate response to TCS or 
topical calcineurin inhibitors (TCI) OR documented systemic treatment for atopic dermatitis 
within 6 months prior to the Baseline Visit, OR for whom topical treatments are otherwise 
medically inadvisable (e.g., because of important side effects or safety risks).
Contraception
8. Females of childbearing potential must have a negative serum pregnancy test at the 
Screening Visit and must have a negative urine pregnancy test at the Baseline Visit prior to study 
drug dosing.  Note:  subjects with borderline pregnancy test at Screening must have a serum 
pregnancy test ≥ 3 days later to determine eligibility (refer to Section 5.10 for details).
9. If female, subject must be postmenopausal OR permanently surgically sterile OR for females 
of childbearing potential practicing at least one protocol specified method of birth control (refer 
to Section 5.2) that is effective from the Baseline Visit through at least 12-weeks after the last 
injection.
10. Female subject must not be pregnant, breastfeeding or considering becoming pregnant 
during the study or for approximately 12 weeks after the last injection.


STUDY M16-046  |  Version 4.0  |  EudraCT 2018-002264-57
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
11. Additional local requirements may apply.  Refer to Section 5.10.
Prior and Concomitant Therapy
12. No prior exposure to any JAK inhibitor (including but not limited to ruxolitinib, tofacitinib, 
baricitinib, upadacitinib, abrocitinib [PF-04965842], and filgotinib).
13. No prior exposure to dupilumab.
14. Subjects must not have used the following AD treatments within the specified timeframe 
prior to Baseline Visit:
!
Systemic therapy for AD, including but not limited to corticosteroids, methotrexate, 
cyclosporine, azathioprine, phosphodiesterase type 4 (PDE4)-inhibitors, interferon-gamma 
(IFN-γ) and mycophenolate mofetil within 4 weeks;
!
Targeted biologic treatments (refer to Section 5.3) within 5 half-lives [if known] or within 
12 weeks, whichever is longer;
!
Phototherapy treatment, laser therapy, tanning booth, or extended sun exposure that 
could affect disease severity or interfere with disease assessments within 4 weeks;
!
Oral or parenteral traditional Chinese medicine within 4 weeks;
!
Marijuana use within 2 weeks;
!
Topical treatments (with the exception of topical emollient treatments, described in 
Eligibility Criterion 6), including but not limited to TCS, TCIs, or topical PDE-4 inhibitors 
within 7 days.
15. Subjects must not have received any live vaccine within 4 weeks (or longer if required 
locally) prior to the first dose of study drug, or expected need of live vaccination during study 
participation including at least 12 weeks (or longer if required locally) after the last injection.
16. No systemic use of known strong cytochrome P450 (CYP)3A inhibitors or strong CYP3A 
inducers from Screening through the end of the study (refer to Table 1 in Section 5.3 for 
examples of commonly used strong CYP3A inhibitors and inducers).
17. No treatment with any investigational drug of chemical or biologic nature within 4 weeks or 
five half-lives of the drug (whichever is longer) prior to Baseline Visit or is currently enrolled in 
another clinical study.
Medical History
18. Laboratory values must not meet the following criteria within the Screening Period prior to 
the first dose of study drug:
!
Serum aspartate transaminase (AST) > 2 × upper limit of normal (ULN);
!
Serum alanine transaminase (ALT) > 2 × ULN;
!
Estimated glomerular filtration rate (GFR) of < 40 mL/min/1.73 m2 by simplified 4-variable 
Modification of Diet in Renal Disease (MDRD) formula;
!
Total white blood cell count (WBC) < 2,500/μL;


STUDY M16-046  |  Version 4.0  |  EudraCT 2018-002264-57
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
!
Absolute neutrophil count (ANC) < 1,500/μL;
!
Platelet count < 100,000/μL;
!
Absolute lymphocyte count < 800/μL;
!
Hemoglobin < 10 g/dL.
19. 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;
!
History of recurrent herpes zoster, or one or more episodes of disseminated herpes zoster;
!
History of one or more episodes of disseminated herpes simplex (including eczema 
herpeticum);
!
History of known invasive infection (e.g., listeriosis and histoplasmosis);
!
Human immunodeficiency virus (HIV) infection, defined as confirmed positive anti-HIV 
antibody (HIV Ab) test;
!
Active Tuberculosis (TB) or meets TB exclusionary parameters (refer to Section 5.10 for 
specific requirements for TB testing);
!
Non-skin related active infection(s) requiring treatment with parenteral anti-infectives 
within 30 days, or oral anti-infectives within 14 days prior to the Baseline Visit;
!
Chronic recurring infection and/or active viral infection that, based on the investigator's 
clinical assessment, makes the subject an unsuitable candidate for the study;
!
Active hepatitis B virus (HBV) or hepatitis C virus (HCV):
!
HBV:  hepatitis B surface antigen (HBs Ag) positive (+) or detected sensitivity on the 
HBV DNA polymerase chain reaction (PCR) qualitative test for hepatitis B core antibody 
(HBc Ab) positive (+) subjects (and for hepatitis B surface antibody positive [+] where 
mandated per local requirements);
!
HCV:  HCV ribonucleic acid (RNA) detectable in any subject with anti-HCV antibody 
(HCV Ab).
20. Subject must have no current or past history of the following medical conditions:
!
Any of the following cardiovascular conditions:
!
Recent (within past 6 months) cerebrovascular accident, myocardial infarction, 
coronary stenting or moderate to severe congestive heart failure (New York Heart 
Association Class III or IV);
!
A confirmed systolic blood pressure > 160 mmHg or diastolic blood pressure 
> 100 mmHg;
!
Any other unstable clinical condition which, in the opinion of the investigator, would put 
the subject at risk by participating in the protocol.  Diagnosed active endoparasitic 
infections; suspected or high risk of endoparasitic infection, unless clinical and (if 
necessary) laboratory assessment have ruled out active infection before randomization.


STUDY M16-046  |  Version 4.0  |  EudraCT 2018-002264-57
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
!
Subject has been a previous recipient of an organ transplant which requires continued 
immunosuppression;
!
History of gastrointestinal (GI) perforation (other than due to appendicitis or mechanical 
injury), diverticulitis or significantly increased risk for GI perforation per investigator 
judgment;
!
Conditions that could interfere with drug absorption including but not limited to short 
bowel syndrome;
!
History of any malignancy except for successfully treated NMSC or localized carcinoma in 
situ of the cervix;
!
History of clinically significant medical conditions or any other reason, which in the opinion 
of the investigator, would interfere with the subject's participation in this study or would 
make the subject an unsuitable candidate to receive study drug or would put the subject at 
risk by participating in the study.
Miscellaneous
21. No history of an allergic reaction or significant sensitivity to constituents of the study drugs 
(or its excipients) and/or other products in the same class.
22. No history of clinically significant (per investigator's judgment) drug or alcohol abuse within 
the last 6 months preceding the Baseline Visit.
5.2 Contraception Recommendations
Contraception Recommendations 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:
!
Postmenopausal, age > 55 years with no menses for 12 or more months without an 
alternative medical cause.
!
Postmenopausal, age ≤ 55 years with no menses for 12 or more months without an 
alternative medical cause AND a follicle stimulating hormone (FSH) level > 40 IU/L.
!
Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy, or 
hysterectomy).
!
Females who have not experienced menarche (at least one menstrual period).
!
Females of Childbearing Potential
!
Females of childbearing potential must avoid pregnancy while taking study drug and for at least 
12 weeks after the last injection.  Females must commit to one of the following methods of 
highly effective birth control:


STUDY M16-046  |  Version 4.0  |  EudraCT 2018-002264-57
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
!
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 Day 1.
!
Progestogen-only hormonal birth control (oral, injectable, implantable) associated with 
inhibition of ovulation initiated at least 30 days prior to study Baseline Day 1.
!
Bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a hysterosalpingogram 
confirms success of the procedure).
!
Intrauterine device (IUD).
!
Intrauterine hormone-releasing system (IUS).
!
Vasectomized sexual partner (the partner has received medical confirmation of the surgical 
success of the vasectomy and is the sole sexual partner of the trial subject).
!
Practice true abstinence (unless not acceptable per local practices), defined as:  refraining 
from heterosexual intercourse when this is in line with the preferred and usual lifestyle of 
the subject (periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation 
methods] and withdrawal are not acceptable).
If required per local practices, females of child bearing potential must commit to using 2 methods of 
contraception (either 2 highly effective methods or 1 highly effective method combined with 1 effective 
method).  Effective methods of birth control are the following:
!
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary 
mode of action, initiated at least 30 days prior to Study Day 1.
!
Male or female condom with or without spermicide.
!
Cap, diaphragm, or sponge with spermicide.
!
A combination of male condom with a cap, diaphragm, or sponge with spermicide (double 
barrier method).
Contraception recommendations related to use of concomitant therapies prescribed per standard of 
care should be based on the local label.
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
JAK Inhibitors
Prior and concomitant oral and topical exposure to any other JAK inhibitors including the investigational 
drug, upadacitinib (including but not limited to ruxolitinib [Jakafi®], tofacitinib [Xeljanz®], baricitinib, 
abrocitinib [PF-04965842], and filgotinib) is not allowed.


STUDY M16-046  |  Version 4.0  |  EudraCT 2018-002264-57
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Targeted Biologic Therapies
Current and concomitant biologic therapies and biosimilar versions of biologic drugs are prohibited 
during treatment with the study drug.  Examples of biologic therapies include but are not limited to the 
following:
!
abatacept
!
adalimumab
!
anakinra
!
belimumab
!
certolizumab
!
efalizumab
!
etanercept
!
golimumab
!
guselkumab
!
infliximab
!
ixekizumab
!
natalizumab
!
omalizumab
!
rituximab
!
secukinumab
!
tocilizumab
!
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: 
!
corticosteroids
!
methotrexate
!
cyclosporine
!
azathioprine
!
PDE4-Inhibitors (e.g., apremilast)
!
mycophenolate mofetil


STUDY M16-046  |  Version 4.0  |  EudraCT 2018-002264-57
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
See also Rescue Therapy in Section 5.4 for further details on allowed rescue.
Corticosteroids
Concomitant treatment with systemic corticosteroids (oral, intravenous, intramuscular) and intralesional 
corticosteroids is prohibited during treatment with study drug.
Inhaled, ophthalmic drops and nasal corticosteroid formulations are allowed throughout the study.
See Rescue Therapy in Section 5.4 for further details on allowed rescue.
Investigational Drugs
Subjects who have been treated with any investigational drug within 4 weeks or five half-lives of the 
drug (whichever is longer) prior to the first dose of study drug are excluded from participation in this 
study.  Investigational drugs are also prohibited during 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 for 
at least 4 weeks prior to the Baseline visit and during the study are not allowed.  Tanning booth use or 
extended sun exposure that could affect disease severity or interfere with disease assessments for at 
least 4 weeks prior to the Baseline visit and during treatment with study drug.
Topical Therapy
No topical treatments for AD should be started for the duration of the treatment with study drug except 
for rescue treatment (see Rescue Therapy in Section 5.4).  This includes but is not limited to calcineurin 
inhibitors, corticosteroids, prescription moisturizers or moisturizers containing additives such as 
ceramide, hyaluronic acid, urea, or filaggrin.  Topical emollient treatments are allowed per Eligibility 
Criteria.
Topical anti-infectives, topical antihistamines, and bleach baths are not prohibited during the study if 
they are used for reasons other than AD.  Topical anti-infectives, topical antihistamines, and bleach 
baths may be used in the first 16 weeks of the study for AD if they were used in the 6 months prior to 
the Screening visit.
If there is any question regarding whether a concomitant medication may be used during the study, the 
study site should contact the AbbVie Therapeutic Area Scientific Director (TA SD).
Vaccines
If the subject and investigator choose to receive/administer live vaccines, these vaccinations must be 
completed (per local label) at least 4 weeks (or longer if locally required) before first dose of study drug.  
Live vaccinations are prohibited during study participation until at least 12 weeks after the last injection.
If the live herpes zoster vaccine is to be administered and there is no known history of primary varicella 
(chicken pox), preexisting immunity to varicella should be confirmed with antibody testing at or prior to 
Screening and prior to administration of the herpes zoster vaccine.  If screening varicella antibody 
testing is negative, the live herpes zoster vaccine should not be administered.


STUDY M16-046  |  Version 4.0  |  EudraCT 2018-002264-57
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Examples of live vaccines include, but are not limited to, the following:
!
Monovalent live influenza A (H1N1) (intranasal);
!
Seasonal trivalent live influenza (intranasal);
!
Zostavax (herpes zoster, live attenuated);
!
Rotavirus;
!
Varicella (chicken pox);
!
Measles-mumps-rubella or measles-mumps-rubella-varicella;
!
Oral polio vaccine;
!
Smallpox;
!
Yellow fever;
!
Bacille Calmette-Guérin (BCG);
!
Typhoid (oral).
See Section 5.4 for information about permitted vaccines and recommendations for vaccines.
Cannabis
Use of medicinal and recreational marijuana is prohibited during the study and subjects must have 
discontinued use at least 2 weeks prior to Baseline.
Traditional Chinese Medicine
Traditional oral or parenteral Chinese medicine is not permitted during the study as these may interfere 
with upadacitinib metabolism and exposure and may impact efficacy and safety of upadacitinib 
treatment.  Subjects must have discontinued oral or parenteral traditional Chinese medicine at least 
4 weeks prior to the first dose of study drug.
Strong CYP3A Inhibitors or Inducers
Systemic use of known strong CYP3A inhibitors or strong CYP3A inducers is excluded from the Screening 
Visit through the end of the study.  The most common strong CYP3A inhibitors and inducers are listed in 
Table 1.


STUDY M16-046  |  Version 4.0  |  EudraCT 2018-002264-57
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Table 1.
Examples of Commonly Used Strong CYP3A Inhibitors and Inducers
Strong CYP3A Inhibitors
Strong CYP3A Inducers
Boceprevir
Avasimibe
Clarithromycin
Carbamazepine
Cobicistat
Phenytoin
Conivaptan
Rifampin (Rifampicin)
Grapefruit (fruit or juice)
Rifapentine
Indinavir
St. John's Wort
Itraconazole
Ketoconazole
Lopinavir/Ritonavir
Mibefradil
Nefazodone
Nelfinavir
Posaconazole
Ritonavir
Saquinavir
Telaprevir
Telithromycin
Troleandomycin
Voriconazole
Elective and Emergency Surgeries
Elective surgery will not be allowed during the study.
If the subject must undergo emergency surgery, the study drug should be interrupted at the time of the 
surgery.  See Section 5.7 for allowed study drug interruption parameters.
5.4 Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins and/or herbal 
supplements) 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 atopic dermatitis 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.


STUDY M16-046  |  Version 4.0  |  EudraCT 2018-002264-57
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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.
Vaccines
Vaccines recommended by local guidelines should be considered.  If the investigator chooses to 
administer a vaccine, this should be completed before first dose of study drug with appropriate 
precautions and time interval.  It is recommended that subjects be up to date for recommended 
inactivated, toxoid or biosynthetic vaccines, such as injectable flu vaccine, pneumococcal, and pertussis 
(Tdap).  It is recommended that the live herpes zoster vaccine should be considered for administration 
at least 4 weeks before first dose of study drug or administered at least 12 weeks after the last injection.  
If the herpes zoster vaccine is to be administered, and there is no known history of primary varicella 
(chicken pox), pre-existing 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 herpes zoster vaccine should not be administered.  See Prohibited 
Medications/Therapy for a list of commonly used live vaccines that are prohibited during study 
participation.
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), and pertussis (Tdap) vaccines.
Required Concomitant Medications
Beginning at the screening visit, twice daily use of an additive-free, bland emollient is required for at 
least 7 days prior to Baseline and 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.
Rescue Therapy
Rescue treatment for AD may be provided, if medically necessary at the discretion of the investigator.
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 [MTX], mycophenolate mofetil, azathioprine) or phototherapy, study drug 
should be permanently discontinued prior to the initiation of rescue systemic agent or phototherapy.
Subjects who permanently discontinue study drug are encouraged to continue to participate in the
study (no study drug given) and complete the schedule of study visits and assessments.


STUDY M16-046  |  Version 4.0  |  EudraCT 2018-002264-57
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Investigators should conduct efficacy and safety assessments (e.g., disease severity scores, safety labs) 
before administering any rescue treatment.  An unscheduled visit may be used for this purpose if 
necessary.
5.5 Withdrawal of Subjects and Discontinuation of Study
Subjects may withdraw from the study completely (withdrawal of informed consent) for any reason at 
any time.  Subjects who discontinue the study prematurely after randomization will not be replaced.  
Subjects may discontinue study drug treatment but may choose to continue to participate in the study.  
A subject who discontinues one treatment (injection or tablet) will be discontinued from the other 
treatment (tablet or injection).
Subjects can request to be discontinued from participating in the study at any time for any reason 
including, but not limited to, disease progression or lack of response to treatment.  The investigator may 
discontinue any subject's participation at any time for any reason, including but not limited to, disease 
progression, lack of response to treatment, an AE, safety concerns, or failure to comply with the 
protocol.  Refer to Section 6.2 for additional discontinuation criteria relating to Toxicity Management of 
serious infections, gastrointestinal perforation, cardiovascular and thromboembolic events, malignancy, 
ECG abnormality, and select laboratory abnormalities.
Subjects will have study drug discontinued immediately if any of the following occur:
!
Rescue treatment is administered outside of the parameters described in Section 5.4 (Rescue 
Therapy).
!
Initiation of any systemic rescue therapy for AD.
!
Permanent discontinuation from study drug will be mandatory after Week 4 for any subject with 
an EASI score worsening of 25% or more compared with their Baseline EASI score at any 
2 consecutive scheduled study visits after Week 4 (after a trial of rescue treatment, if 
appropriate; see Rescue Therapy in Section 5.4).  For example, permanent study drug 
discontinuation would apply at Week 8 if EASI score worsening criteria are met at Week 4 and 
Week 8 without rescue therapy given at Week 4.  Permanent study drug discontinuation would 
apply at Week 12 if EASI score worsening criteria are met at Week 8 and Week 12 with rescue 
therapy given at Week 4.  This rule applies similarly to later timepoints.
!
Anaphylactic reaction or other severe systemic or local reaction to study drug injection.
!
Abnormal laboratory results or AEs that neither meet the criteria for discontinuation of study 
drug, as stated in Section 6.2 or determined by the investigator and the AbbVie TA MD or TA SD 
rule out safe continuation of the study drug.
!
The investigator believes it is in the best interest of the subject.
!
The subject requests withdrawal from the study.
!
Eligibility criteria violation was noted after the subject started study drug, when continuation of 
the study drug would place the subject at risk as determined by the AbbVie TA MD or TA SD.
!
Introduction of prohibited medications or dosages when continuation of the study drug would 
place the subject at risk, as determined by the AbbVie TA MD or TA SD.


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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
!
Subject is non-compliant with TB prophylaxis (if applicable) or develops active TB at any time 
during the study.
!
The subject becomes pregnant or plans to become pregnant while on study drug.
!
Malignancy, except for localized NMSC or carcinoma in-situ of the cervix.
!
Subject develops a GI perforation.
!
Subject is significantly non-compliant with study procedures which would put the subject at risk 
for continued participation in the trial in consultation with the AbbVie TA MD or TA SD.
!
An ECG change considered clinically significant and with reasonable possibility of relationship to 
study drug, OR a confirmed absolute Fridericia's correction formula (QTcF ) value > 500 msec in 
adults OR a change of QT interval corrected (QTc) interval > 60 msec from baseline.
!
Confirmed diagnosis of deep vein thrombosis, pulmonary embolus, or non-cardiac, 
non-neurologic arterial thrombosis.
The study will be discontinued or terminated in case of an unacceptable risk, any relevant toxicity, or a 
negative change in the risk:benefit assessment.  This might include the occurrence of AEs with a 
character, severity, or frequency that is new in comparison to the existing risk profile.  In addition, any 
data deriving from other clinical trials or toxicological studies that negatively influence the risk:benefit 
assessment may cause discontinuation or termination of the study.
AbbVie may terminate this study prematurely, either in its entirety or at any site.  The investigator may 
also stop the study at his/her site if he/she has safety concerns.  If AbbVie terminates the study for 
safety reasons, AbbVie will promptly notify the investigator.
For subjects to be considered lost to follow-up, reasonable attempts must be made to obtain 
information on the subject's final status.  At a minimum, 2 telephone calls must be made and 1 certified 
letter must be sent and documented in the subject's source documentation.
5.6 Follow-Up for Subject Withdrawal from Study
Discontinuation of Study Drug and Continuation of Study Participation
In order to minimize missing data for efficacy and safety assessments, subjects who prematurely 
discontinue study drug treatment or study participation should complete a Premature Discontinuation 
visit (PD visit).  All attempts must be made to determine the date of the last study drug dose and the 
primary reason for discontinuation of study drug or study participation.
Subjects who prematurely discontinue study drug but continue study participation should complete a PD 
visit as soon as possible, preferably within 2 weeks.  Afterwards, subjects should follow the regular visit 
schedule as outlined in Appendix D and should adhere to all study procedures except for dispensing 
study drug.  Once the subject has discontinued study drug, all rescue and efficacy driven discontinuation 
criteria no longer apply.  If at any point a subject no longer wants to provide assessments (withdrawal of 
informed consent) following discontinuation of study drug, a second PD visit is not required.  The End-
End-of-Treatment Follow-up visit is not applicable for subjects who discontinued study drug and 


STUDY M16-046  |  Version 4.0  |  EudraCT 2018-002264-57
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
continued study participation and completed at least one study visit at least 12 weeks after the last 
injection.
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.  In addition, if subject is willing, an End-of-Treatment Follow-up visit 
or phone call may be completed 12 weeks after the last injection to ensure all treatment-emergent AEs 
and SAEs have been resolved.
Biomarker Research:
In the event a subject withdraws consent from the clinical study, biomarker research will continue 
unless the subject explicitly requests analysis to be stopped.  When AbbVie is informed that samples are 
withdrawn from research, samples will not be analyzed, no new biomarker analysis data will be 
collected for the withdrawn subject or added to the existing data or database(s).  Data generated for 
biomarker research before subject withdrawal of consent will remain part of the study results.
5.7 Study Drug
The individual study drug information is presented in Table 2.
Table 2.
Description of Study Drug and Placebo 
Investigational Product
Mode of 
Administration
Formulation
Strength
Manufacturer
Upadacitinib tablet
oral
Film-coated tablet
30 mg
AbbVie
Placebo tablet
oral
Film-coated tablet
NA
AbbVie
Dupilumab pre-filled syringe
SC
Solution for injection 
in pre-filled syringe
300 mg
Sanofi, 
Genzyme 
(Regeneron)
Placebo pre-filled syringe
SC
Solution for injection 
in pre-filled syringe
NA
AbbVie
The type and amount of kits dispensed will be managed by the Interactive Response Technology (IRT).
AbbVie will not supply drugs other than upadacitinib and dupilumab.
Storage and Disposition of Study Drug
Upadacitinib and placebo tablets must be stored at controlled room temperature (15° to 25°C/59° to 
77°F).
Dupilumab and placebo pre-filled syringe must be stored refrigerated at 2°C to 8°C and protected from 
light, as specified on the label.


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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
The investigational products are for investigational use only and are to be used only within the context 
of this study.  The investigational products supplied for this study must be maintained under adequate 
security and stored under the conditions specified on the label until dispensed for subject use or 
destroyed on site as appropriate.
Upon receipt, study drugs 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 drugs to be dispensed at the subject's 
corresponding study visit.  Study drugs must not be dispensed without contacting the IRT system.  Study 
drugs will only be used for the conduct of this study.
Packaging and Labeling
Upadacitinib and placebo tablets will be packaged in bottles with quantities sufficient to accommodate 
the study design.  Each bottle will be labeled per local requirements.  The labels must remain affixed to 
the bottles.  Each kit label will contain a unique kit number.
Dupilumab and placebo pre-filled syringes will be packaged in cartons with quantities sufficient to 
accommodate the study design.  Each pre-filled syringe and carton will be labeled as required per 
country requirements.  Labels must remain affixed to the syringe and carton.  Each kit label will contain 
a unique kit number.
Dispense Study Drug
The type and amount of kits dispensed will be managed by the IRT.  Dupilumab and placebo pre-filled 
syringe will be dispensed through IRT every 2 weeks, and upadacitinib and placebo tablets will be 
dispensed through IRT every 4 weeks.
Upadacitinib and placebo tablets will be dispensed to subjects beginning at baseline (Day 1) and as 
specified in Appendix D.  The first dose of study drug will be administered after all other baseline (Day 1) 
procedures are completed.  At the visits specified, the site personnel will review returned study drug kits 
and empty study drug packaging to verify compliance.
Each site will be responsible for maintaining drug accountability records including product description, 
manufacturer, and lot numbers for all non-investigational products dispensed by the site.
Study Drug Administration
Upadacitinib or placebo tablets will be taken orally once daily beginning on Day 1 (Baseline) and should 
be taken at approximately the same time each day.  The study drug can be taken with or without food.  
If a subject should forget to take upadacitinib or placebo tablet dose at their regularly scheduled dosing 
time, they should take the forgotten dose as soon as they remember as long as it is at least 10 hours 
before their next scheduled dose.  Otherwise they should take the next dose at the next scheduled 
dosing time.  Upadacitinib and placebo tablets should be swallowed whole and should not be split, 
crushed, or dissolved.
Dupilumab or placebo pre-filled syringe will be administered by SC injection at study visits on Day 1 and 
every other week at the study visits specified in Appendix D until Week 22.


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The subject will be instructed to return all drug containers (even if empty) to the study site personnel at 
each study visit.  The study site personnel will document compliance.
For allowed study drug interruption due to elective and emergency surgeries, the following rules apply:
1.
If the subject must undergo emergency surgery, the study drug should be interrupted at the 
time of the surgery.  After emergency surgery, allow re-introduction of study drug once the 
physician has examined the surgical site and determined that it has healed and there is no sign 
of infection.
2.
Elective surgery, and interruption of study drug for such a surgery, will not be allowed during 
the study.
5.8 Randomization/Drug Assignment
All subjects will be assigned a unique identification number by the IRT at the Screening Visit.  For 
subjects who rescreen, the screening number assigned by the IRT at the initial screening visit should be 
used.  The IRT will assign a randomization number that will encode the subject's treatment group 
assignment according to the randomization schedule generated by the statistics department at AbbVie.
Subjects will be randomized in a 1:1 ratio to one of two treatment groups:
!
Treatment A:  Upadacitinib 30 mg + placebo pre-filled syringe (N = 325)
!
Treatment B:  Dupilumab 300 mg + placebo tablets (N = 325)
Randomization will be stratified by baseline disease severity (moderate [vIGA-AD 3] vs. severe 
[vIGA-AD 4]) and age (< 40, ≥ 40 to 65, ≥ 65 years).
Blinding
All AbbVie personnel with direct oversight of the conduct and management of the trial, with the 
exception of AbbVie Drug Supply Management Team, will remain blinded until the Week 24 database 
lock.  All study site personnel involved in the study and the subjects will remain blinded to the subject's 
treatment throughout the study.  To maintain the blind, the upadacitinib tablets and placebo tablets 
provided for the study will be identical in appearance.  In addition, dupilumab pre-filled syringe and 
placebo pre-filled syringe will be administered to the subjects at the investigative site.  Both types of 
pre-filled syringes will be provided in identical cartons.  The cartons are sealed with tamper-evident 
seals.  The study site personnel must not break the seals and open the cartons throughout the conduct 
of the study.  The investigator will designate an unblinded administrator to administer the injection to 
the subject.  The designated unblinded administrator must not have involvement with any other study-
related activities.
To maintain the blind for the study, only the designated unblinded administrator will be allowed to 
break the tamper-evident seals of the cartons just prior to administration.  If a kit of dupilumab/placebo 
is dispensed by IRT, it should remain sealed until the time of drug administration.  If for any reason the 
study drug administration is not performed, the carton should remain sealed, and should be accounted 
and prepared for destruction without breaking the tamper evident seal, maintaining the blind of the 
study.  Other study site personnel, including safety and efficacy evaluators, must not be involved with 


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administration of the injectable dosage forms.  To maintain the blind for the subject, appropriate 
measures must be taken to ensure the subjects do not see the study drug syringe or subcutaneous 
administration of study drug.  The investigational sites must take appropriate precautions, including, but 
not limited to, blindfolding the subject, creating a barrier between the subject and administrator or 
administration site, or by any other means of blinding the subjects.  The unblinded administrator will 
immediately discard the syringe in an appropriate container after conducting administration and prior to 
removing the barrier between administrator and the subject.
Empty cartons without the syringe should be retained along with the unopened cartons for 
accountability.  If the carton with the syringe has been opened (the tamper-evident seal broken) and the 
unblinded administrator is not able to administer study drug syringe for any reason, then the 
administrator must document the kit number and a reason(s) for not administering a specific kit.  The 
unblinded administrator will immediately discard the syringe in an appropriate container after 
documenting accountability of such kit and prior to removing the barrier between administrator and the 
subject.
Other site personnel besides an unblinded administrator will not be made aware of the subject 
treatment assignments except in the event of an emergency where identification of the study drug is 
required for therapeutic measures.  The IRT will provide access to unblinded subject treatment 
information in the case of a medical emergency.
In the event of a medical situation that requires unblinding of the study drug assignment, the 
investigator is requested to contact the AbbVie TA MD prior to breaking the blind.  However, if an 
urgent therapeutic intervention is necessary which warrants breaking the blind prior to contacting the 
AbbVie TA MD, the investigator can directly access the IRT system to break the blind without AbbVie 
notification or agreement.  Unblinding is available in the IRT system via the Unblinded Subject 
transaction, which is available only to the investigator.  If the IRT system is unavailable, unblinding may 
occur by contacting the technical support of the IRT vendor via either phone (preferred) or email 
(support@endpointclinical.com).  For country-specific phone numbers, please see the following website:  
http://www.endpointclinical.com/helpdesk/.
In the event that the blind is broken before notification to the AbbVie TA MD, the AbbVie TA MD should 
be notified within 24 hours of the blind being broken.  The date and reason that the blind was broken 
must be conveyed to AbbVie and recorded on appropriate eCRF.
Treatment Compliance
The investigator or his/her designated and qualified representatives will administer/dispense study drug 
only to subjects enrolled in the study in accordance with the protocol.  The study drug must not be used 
for reasons other than that described in the protocol.
Dupilumab and placebo pre-filled syringe dosing will be recorded on the designated eCRF.  Subjects will 
be instructed to return all drug containers (even if empty) to the study site personnel at each clinic visit.  
The study site personnel will document compliance in the study source documents, and the 
accountability of the Study Drug/Placebo will be recorded in IRT.


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5.9 Protocol Deviations
The investigator is responsible for complying with all protocol requirements, written instructions, and 
applicable laws regarding protocol deviations.  Protocol deviations are prohibited except when 
necessary to eliminate an immediate hazard to study subjects.  If a protocol deviation occurs (or is 
identified), the investigator is responsible for notifying independent ethics committee (IEC)/independent 
review board (IRB), regulatory authorities (as applicable), and AbbVie.
5.10 Other Study Procedures
Subject Information and Informed Consent
The investigator or his/her representative will explain the nature of the study to the subject and answer 
all questions regarding this study.  Prior to any study-related screening procedures being performed on 
the subject or any medications being discontinued by the subject in order to participate in this study, 
the informed consent statement will be reviewed, signed, and dated by the subject or their legally 
authorized representative, the person who administered the informed consent, and any other 
signatories according to local requirements.  A copy of the signed informed consent will be given to the 
subject and the original will be placed in the subject's medical record.  An entry must also be made in 
the subject's dated source documents to confirm that informed consent was obtained prior to any 
study-related procedures and that the subject received a signed copy.
Information regarding benefits for subjects and information regarding provisions for treating and/or 
compensating subjects who are harmed as a consequence of participation in the study can be found in 
the informed consent form.
Optional biomarker research samples will only be collected if the subject has voluntarily signed and 
dated a written consent form describing the exploratory research.  The written consent may be part of 
the main consent form.  If the subject does not consent to providing optional samples, the subject will 
still be allowed to participate in the study.
Screening and Re-Screening Procedures
Within 35 days prior to the Baseline Visit, subjects will receive a full explanation of the study design and 
study procedures, provide a written informed consent, and undergo the screening procedures outlined 
in Operations Manual Section 2.1.  With the exception of the QuantiFERON TB-Gold and purified protein 
derivative (PPD) tests (Tuberculosis Testing/Tuberculosis Prophylaxis below), otherwise exclusionary 
laboratory values can be re-tested once during the Screening Period.  If the re-tested laboratory value(s) 
remain(s) exclusionary, the subject will be considered a screen failure.  Redrawing samples if previous 
samples were unable to be analyzed would not count as a retest since previous result was never 
obtained.
Subjects who initially screen-fail for the study are permitted to re-screen once following re-consent.  For 
additional re-screening, AbbVie TA MD or TA SD approval is required.  As appropriate, sites are 
encouraged to contact the AbbVie TA MD/SD to confirm if subjects should or should not be re-screened.  
All screening procedures with the possible exceptions noted below will be repeated during re-screening.  


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The subject must meet all eligibility criteria at the time of re-screening in order to qualify for the study.  
There is no minimum period of time a subject must wait to re-screen for the study.
If the subject had a complete initial screening evaluation including the following assessments, these 
tests will not be required to be repeated for re-screening, provided the conditions noted in Section 5.1
of the protocol are met, there are no changes in the subject's medical history that would warrant 
re-testing, and no more than 90 days have passed:
!
HBV, HCV and HIV serology
!
QuantiFERON Tuberculosis [TB] Gold or equivalent and/or a PPD test (or both if required per 
local guidelines)
!
CXR
!
Electrocardiogram (ECG)
Medical History
A complete non-AD medical history, including demographics, history of tobacco, alcohol, and nicotine 
use, will be taken at Screening.  Additionally, a list of each subject's specific AD-related medical history 
should be recorded at Screening.  History of clinical herpes zoster, herpes zoster vaccination, and 
hepatitis B vaccination status will be recorded as part of the medical history.
The subject's medical history will be updated prior to study drug administration at the Study Day 1 visit.  
This updated medical history will serve as the baseline for clinical assessment and to ensure the subject 
is still eligible for enrollment.
A detailed medical history with respect to TB risk factors will be documented in the study source 
documentation.  This information will include Bacille Calmette-Guérin (BCG) vaccination, cohabitation 
with individuals who have had TB, and travel to, reside in, or work in TB endemic locations.
Drug and Alcohol Screen
Subjects should have no history of clinically significant (per investigator's judgment) drug or alcohol 
abuse within the last 6 months.
Urine specimens will be tested at the screening visit for the presence of drugs of abuse.  The panel for 
drugs of abuse will minimally include the drugs listed below.  Any positive result must be assessed for 
clinical significance.  These analyses will be performed by the certified central laboratory chosen for the 
study.
!
Opiates
!
Barbiturates
!
Amphetamines
!
Cocaine
!
Benzodiazepines
!
Alcohol


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Phencyclidine
!
Propoxyphene
!
Methadone
Adverse Event Assessment
The subjects will undergo physical examination for any active AEs and AEs that have occurred and 
resolved since the last visit as well as be interviewed for AEs that are not apparent in a physical 
examination.  SAEs and protocol related nonserious AEs that occur after a subject signs the informed 
consent will be collected, prior to the first dose of study drug.  Please refer to Section 6.1.
Patient-Reported Outcomes
Subjects will complete the self-administered patient-reported outcome (PRO) instrument (when allowed 
per local regulatory guidelines).  Subjects should be instructed to follow the instructions provided with 
the instrument and to provide the best possible response to each item.  Site personnel shall not provide 
interpretation or assistance to subjects other than encouragement to complete the tasks.  Subjects who 
are functionally unable to read any of the instruments may have site personnel read the questionnaire 
to them.  Site personnel will encourage completion of the instrument at all specified visits and will 
ensure that a response is entered for all items.
Subjects will complete the following questionnaires (described below) as specified in Operations Manual 
Section 2.1:  Worst Pruritus NRS; ADerm-IS; Head and Neck - Patient Global Impression of Severity (HN-
PGIS), and Oral vs Injectable Questionnaire (only for the United States).  The subject should complete 
the questionnaires before site personnel perform any clinical assessments and preferably before any 
interaction with site personnel has occurred to avoid biasing the subject's response.
A validated translation will be provided in their local language, as applicable.  All PROs are collected 
electronically.
For the Worst Pruritus NRS, ADerm-IS, and HN-PGIS, the PRO instrument should be completed prior to 
drug administration on Day 1.  All PRO instruments should be completed prior to any discussion of 
adverse events or any review of laboratory findings.
Worst Pruritus Numerical Rating Scale (NRS)
The Worst Pruritus NRS is an assessment tool that subjects use to report the intensity of their pruritus 
during a daily recall period.  Subjects are asked the question:  "On a scale of 0 to 10, with 0 being no itch 
and 10 being the worst imaginable itch, how would you rate your itch at its worst during the past 
24 hours?"  The Worst Pruritus NRS will be administered daily from Screening through Week 16 using an 
electronic hand-held device that will be given to subjects to take home at Screening.  Hand-held device 
usage ends at the Week 16 visit (subjects should provide their response on the site's tablet at the 
Week 16 study visit).  Starting at the Week 16 visit, the frequency of administration will be reduced from 
daily assessments to assessments only at scheduled site visits using a tablet at the site.
Evaluation of the psychometric properties and assessment of the measurement validity of the Worst 
Pruritis NRS is pending Phase 3 data.


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Atopic Dermatitis Impact Scale (ADerm-IS)
The ADerm-IS is a 10-item PRO questionnaire designed to assess a variety of impacts that subjects 
experience from their AD across both a 24-hour recall period (the daily items 1 to 3) and 7-day recall 
period (the weekly items 4 to 10).  Daily items are related to sleep, and include difficulty falling asleep, 
impact on sleep, and waking at night.  Weekly items include household activities (e.g., washing dishes, 
sweeping, doing laundry), physical activities (e.g., walking, exercising), social activities, concentration, 
self-consciousness, embarrassment, and sadness.  All items of the ADerm-IS are scored on an 11-point 
NRS from 0 (no impact) to 10 (extreme impact).
The ADerm-IS will be administered on electronic hand held devices from Screening through Baseline; 
devices will be given to subjects to take home at Screening.
Head and Neck Patient Global Impression of Severity (HN-PGIS)
The HN-PGIS asks subjects to describe the severity of their head and neck AD symptoms right now.  
Subjects rate their head and neck AD symptoms on a 7-point scale ranging from 0 = Absent (no 
symptoms) to 6 = Very Severe (cannot be ignored and markedly limits my daily activities).  The HN-PGIS 
will be administered on the tablet at site visits throughout the study.
Oral vs Injectable Questionnaire (only in the United States)
The Oral vs Injectable Questionnaire is an assessment tool designed to assess subject preferences 
regarding route of administration (oral QD vs injection Q2 weeks) for medications for AD.  The 
Questionnaire is administered at Week 24 at the site visit.  Subjects provide responses to up to 
5 questions using the electronic tablet device.
Investigator Assessment
The investigator assessments will be recorded on paper worksheets and entered into the eCRF and 
conducted at the study visits specified in Operations Manual Section 2.1.  If possible, the investigator 
assessments should be performed by an independent and blinded assessor who should not perform any 
other study related procedures.  In order to minimize variability, the same assessor should evaluate the 
subject at each visit for the duration of the study.  A back-up assessor should be identified.  The assessor 
must be a qualified medical professional (e.g., nurse, physician's assistant, or physician).  Any assessor 
must be trained and competent in performing such assessments.  It is the responsibility of the 
investigator to ensure that all assessors are qualified and trained to perform assessments and that all 
training is documented.  If the primary assessor is not available, the pre-identified back-up assessor 
should perform such assessments.
Validated Investigator's Global Assessment for Atopic Dermatitis (vIGA-AD)
The vIGA-AD is a validated assessment instrument used in clinical studies to rate the severity of AD 
globally, based on a 5-point scale ranging from 0 (clear) to 4 (severe).
Eczema Area and Severity Index (EASI)
The EASI is a validated measure used in clinical practice and clinical trials to assess the severity and 
extent of AD. The EASI is a composite index with scores ranging from 0 to 72.  Four AD disease 
characteristics (erythema, thickness [induration, papulation, edema], scratching [excoriation], and 


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lichenification) will each be assessed for severity by the investigator or designee on a scale of "0" 
(absent) through "3" (severe).  In addition, the area of AD involvement will be assessed as a percentage 
by body area of head, trunk, upper limbs, and lower limbs, and converted to a score of 0 to 6.  In each 
body region, the area is expressed as 0, 1 (1% to 9%), 2 (10% to 29%), 3 (30% to 49%), 4 (50% to 69%), 
5 (70% to 89%), or 6 (90% to 100%).
Body Surface Area Involvement of Atopic Dermatitis (BSA, %)
A qualified investigator or designee should select the subject's right or left hand as the measuring 
device.  For purposes of clinical estimation, the total surface of the palm plus five digits will be assumed 
to be approximately equivalent to 1%.  Measurement of the total area of involvement by the 
investigator is aided by imagining if scattered plaques were moved so that they were next to each other 
and then estimating the total area involved.  The site should make every attempt to have the same 
qualified investigator or designee perform all BSA assessments on a given subject throughout the study.
Vaccines
Vaccines recommended by local guidelines should be considered.  If the investigator chooses to 
administer a vaccine, this should be completed before first dose of study drug with appropriate 
precautions and time interval.  It is recommended that subjects be up to date for recommended 
inactivated, toxoid or biosynthetic vaccines, such as injectable flu vaccine, pneumococcal, and Tdap.  It is 
recommended that the live herpes zoster vaccine should be considered for administration at least 
4 weeks before first dose of study drug or administered at least 12 weeks after the last injection.  If the 
herpes zoster vaccine is to be administered, and there is no known history of primary varicella (chicken 
pox), pre-existing 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 herpes zoster vaccine should not be administered.  See Prohibited 
Medications/Therapy for a list of commonly used live vaccines that are prohibited during study 
participation.
See Section 5.3 (Prohibited Medications and Therapy) for a list of commonly used live vaccines that are 
prohibited during study participation.
Tuberculosis Testing/Tuberculosis Prophylaxis
The TB screening tests provide diagnostic test results to be interpreted in the context of the subject's 
epidemiology, history, exam findings, etc., and it is the responsibility of the investigator to determine if a 
subject has previous, active, or latent TB.  Expert consultation for the evaluation and/or management of 
TB may be considered per investigator discretion.
At Screening, all subjects will be assessed for evidence of increased risk for TB by a risk questionnaire 
(Operations Manual Section 3.2) and tested for TB infection by QuantiFERON-TB Gold test.  The site staff 
will complete the TB risk questionnaire for all subjects regardless of TB test results and enter the data 
into the appropriate eCRF.  One or more "yes" response on the TB risk questionnaire indicates increased 
risk of TB.
If a subject had a negative PPD test within 90 days prior to Screening and a QuantiFERON-TB Gold test 
cannot be performed by the central laboratory at Screening and source documentation is available, TB 
testing by PPD Skin Test (also known as a TB Skin Test or Mantoux Test) does not need to be repeated 


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provided nothing has changed in the subject's medical history to warrant a repeat test.  These cases may 
be discussed with the AbbVie TA MD.  The results of the TB test(s) will be retained at the site as the 
original source documentation.
The results of the TB test(s) will be retained at the site as the original source documentation.
Subjects with a negative TB test and CXR not suggestive of active TB or prior TB exposure may be 
enrolled.
Subjects with a positive TB test must be assessed for evidence of active TB versus latent TB, including 
signs and symptoms and CXR.  Subjects with no signs or symptoms and a CXR not suggestive of active TB 
may be enrolled after initiation of TB prophylaxis (see below).
Subjects with evidence of active TB must not be enrolled.
For subjects with a negative TB test result at Screening or the most recent evaluation, an annual TB 
follow-up test will be performed.
If an annual TB test is newly positive (seroconversion), a CXR needs to be performed as soon as possible 
to aid in distinguishing active versus latent TB and subsequent annual TB follow-up tests are not 
required.  Any positive TB test after the patient has started the study should be reported as an AE of 
latent TB or active TB (as applicable).
If the subject is experiencing signs or symptoms suspicious for TB or something has changed in the 
subject's medical history to warrant investigation and a repeat test before the next scheduled annual TB 
retest, the case (including the TB test results) should be discussed with the AbbVie TA MD.
TB test
!
The QuantiFERON-TB Gold test (or equivalent) should be performed at Screening on all subjects.  
The PPD skin test should be utilized when the QuantiFERON-TB Gold test (or equivalent) is not 
possible or if both tests are required per local guidelines.
!
Subjects with documentation of prior positive result of QuantiFERON-TB Gold Test and/or PPD 
skin test are not required to repeat either test at Screening or during the study and should be 
considered positive.
!
For regions that require both PPD and QuantiFERON-TB Gold testing, both will be performed.  If 
either PPD or QuantiFERON-TB Gold is positive, the TB test is considered positive.
!
The PPD Skin Test should be utilized only when a QuantiFERON-TB Gold Test is not possible for 
any reason (unless both tests are required per local guidelines).
!
If only a PPD is placed at Screening, then the TB test to be used for the remainder of the study 
for that subject is the PPD.  Similarly, if a subject enters the study with a QuantiFERON-TB Gold 
test alone, then the subject should have their annual TB test performed with a QuantiFERON-TB 
Gold test.
!
If the QuantiFERON-TB Gold Test is NOT possible (or if both the QuantiFERON-TB Gold Test and 
the PPD are required per local guidelines) the PPD will be performed.  The PPD should be read 
by a licensed healthcare professional between 48 and 72 hours after administration.  A subject 


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who does not return within 72 hours will need to be rescheduled for another skin test.  The 
reaction will be measured in millimeters (mm) of induration and induration ≥5 mm is 
considered a positive reaction.  The absence of induration will be recorded as "0 mm" not 
"negative."
!
Subjects who have an ulcerating reaction to PPD in the past should not be re-exposed and the 
PPD should be considered positive.
!
If the QuantiFERON-TB Gold test is indeterminate, then the investigator should perform a local 
QuantiFERON-TB Gold test (or through the central laboratory if not locally available) to rule out 
a positive test result.  If testing remains indeterminate or is positive, then the subject is 
considered to be positive for the purpose of this study.  If the testing result is negative, then the 
patient is considered to be negative.
!
In cases where the QuantiFERON-TB Gold test by the central laboratory is positive and the 
investigator considers the subject at low risk for TB and has no clinical suspicion of TB, the 
investigator may perform a local QuantiFERON-TB Gold test (or repeat testing through the 
central laboratory if not locally available) to confirm the positive test result.  If the repeat testing 
result is negative, the investigator may consider the test to be negative based on his/her clinical 
judgment; if the repeat testing result is positive, the test is considered positive.
!
An equivalent Interferon Gamma Release Assay (IGRA) (such as T-SPOT TB test) may be 
substituted for the QuantiFERON-TB Gold.
TB prophylaxis
Note:  Rifampicin and Rifapentine are not allowed for TB prophylaxis.
At Screening, if the subject has evidence of latent TB infection, prophylactic treatment must be initiated 
at least 2 weeks prior to administration of study drug (or per local guidelines, whichever is longer).  At 
least 6 months of prophylaxis must be completed; however, the full course of prophylaxis does not need 
to be completed prior to the first dose of study drug.
Subjects with a prior history of latent TB that have documented completion of a full course of anti-TB 
therapy will be allowed to enter the study provided nothing has changed in the subject's medical history 
to warrant repeat treatment.  For subjects with completion of a full course of anti-TB therapy, but 
insufficient documentation, the investigator should consult with the AbbVie TA MD.
During the study, subjects with new evidence of latent TB must initiate prophylactic treatment 
immediately per local guidelines and complete at least 6 months of prophylaxis.  Study drug should not 
be withheld.  Two to four weeks later, the subject should be re-evaluated (unscheduled visit) for signs 
and symptoms as well as laboratory assessment of toxicity to TB prophylaxis.
Newly initiated prophylactic treatment and prior therapy should be captured in the eCRF.
Chest X-Ray
CXR (posterior-anterior and lateral views) is required:


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!
For all subjects at Screening to rule out the presence of TB or other clinically relevant findings.  
The CXR will not be required if the subject had a previous normal CXR (posterior-anterior and 
lateral views) within 90 days of Screening, provided all source documentation is available at the 
site, as outlined below and provided nothing has changed in the subject's medical history to 
warrant a repeat test.
Subjects can have a repeat CXR at any time during the study as warranted based on the opinion of the 
Investigator.
A radiologist or pulmonologist must perform and document an assessment of the CXR.  The Principal 
Investigator will indicate the clinical significance of any findings and will sign and date the report.  In the 
assessment of the CXR, the Principal Investigator or their delegate must indicate the presence or 
absence of (1) calcified granulomas, (2) pleural scarring/thickening, and (3) signs of active TB.  If the CXR 
demonstrates changes suggestive of previous TB (e.g., calcified nodule, fibrotic scar, apical or basilar 
pleural thickening) or other findings that are clinically significant, the Principal Investigator should 
contact the AbbVie TA MD before enrolling the subject.
12-Lead Electrocardiogram
A 12-lead ECG will be performed at Screening (Operations Manual Section 2.1).  The ECG should be 
performed prior to blood collection.
The ECGs will be evaluated by an appropriately trained physician at the site ("local reader").  The local 
reader from the site will sign and date all ECG tracings and will provide his/her global interpretation as a 
written comment on the tracing using the following categories:
!
Normal ECG
!
Abnormal ECG – not clinically significant
!
Abnormal ECG – clinically significant
Biomarker Sampling
Optional biospecimens (blood, serum, plasma, and skin biopsies) will be collected for biomarker
research at visits detailed in Appendix D.  All biomarker samples should be labeled and shipped as 
outlined in the study-specific laboratory manual.  AbbVie (or people or companies working with AbbVie) 
will store the samples and data in a secure storage space with adequate measures to protect 
confidentiality.  The samples may be retained while research on upadacitinib (or drugs of this class) or 
atopic dermatitis and related conditions continues, but for no longer than 20 years after study 
completion, or per local requirement.
Height and Body Weight
Height and body weight will be measured without shoes at visits specified in Appendix D.  All 
measurements will be recorded in imperial or metric units where applicable.


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Vital Signs
Vital sign determinations of systolic and diastolic blood pressure, pulse rate, and body temperature will 
be obtained at visits specified in Appendix D.  Blood pressure and pulse rate should be measured after 
the subject has been sitting for at least 3 minutes.  For additional guidance on conventional office blood 
pressure measurements, please refer to the 2018 European Society of Cardiology (ESC)/European 
Society of Hypertension (ESH) guidelines.22
Physical Examination
A complete physical examination will be performed at visits specified in Appendix D.  The physical 
examination performed on Study Day 1 will serve as the baseline physical examination for the entire 
study.  Physical examination abnormalities noted by the investigator at Baseline prior to the first dose of 
study drug will be recorded in the subject's medical history; abnormalities noted after the first dose of 
study drug will be evaluated and documented by the investigator as to whether or not the abnormality 
is an AE.  All findings, whether related to an AE or part of each subject's medical history, will be captured 
on the appropriate eCRF page.
At any time, a symptom-directed physical examination can be performed as deemed necessary by the 
investigator.
Clinical Laboratory Tests
Blood and urine samples will be collected following a minimum 8-hour fast.  If a subject is not able to 
fast when necessary (except during Screening visit), due to unforeseen circumstances, the non-fasting 
status will be recorded in study source documentation.
A certified laboratory will be utilized to process and provide results for the clinical laboratory tests.  
Laboratory reference ranges will be obtained prior to the initiation of the study.
Instructions regarding the collection, processing, and shipping of these samples will be provided by the 
central laboratory.
A urine dipstick macroscopic urinalysis will be completed by the central laboratory at all required visits.  
A microscopic analysis will be performed in the event the dipstick results show leukocytes, nitrite, 
protein, ketones, or blood greater than negative or glucose greater than normal.
If a laboratory test value is outside the reference range and the investigator considers the laboratory 
result to be clinically significant, the investigator will:
!
repeat the test to verify the out-of-range value;
!
follow the out-of-range value to a satisfactory clinical resolution.
A laboratory test value that requires a subject to be discontinued from the study drug or requires a 
subject to receive treatment will be recorded as an AE.  The central laboratory chosen for this study will 
provide instructions regarding the collection, processing and shipping of these samples.  The baseline 
laboratory test results for clinical assessment for a particular test will be defined as the last 
measurement prior to the initial dose of study drug.


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Clinical Laboratory Tests
Hematology
Clinical Chemistry
Other Tests
Hematocrit 
Hemoglobin
RBC count
WBC count
Neutrophils
Bands
Lymphocytes
Monocytes 
Basophils 
Eosinophils 
Platelet count
BUN 
Creatinine
Total bilirubin
INR (reflex only)a
Albumin
ALT
AST
Alkaline phosphatase
CPK 
Sodium 
Potassium 
Bicarbonate/CO2
Chloride
Calcium
Inorganic phosphorus
Uric acid 
Total protein 
Glucose 
Cholesterol 
LDL-C
HDL-C
Triglycerides
Central Lab Tests:
Estimated glomerular filtration rate (eGFR) 
International normalized ratio (INR) 
Serum pregnancy (beta human chorionic 
gonadotropin [bHCG]) test
Hepatitis Screening:
Hepatitis B surface antigen (HBs Ag) 
Hepatitis B surface antibody (HBs Ab)
Hepatitis B core antibody (HBc Ab)
Hepatitis B virus deoxyribonucleic acid 
polymerase chain reaction (HBV DNA 
PCR [reflex only])
Hepatitis C virus antibody (HCV Ab) 
Hepatitis C virus ribonucleic acid (HCV RNA 
[reflex only]) 
Human immunodeficiency virus antibody 
(HIV Ab) 
QuantiFERON-TB Gold
High-sensitivity C-reactive protein (hsCRP) 
Follicle stimulating hormone (FSH)b 
Drug and alcohol screen
Local Lab Tests:
Urine pregnancy test
Varicella antibody, if indicated
PPD test/T-SPOT TB
Urinalysis
Specific gravity
Ketones
pH 
Protein 
Blood Glucose
Urobilinogen 
Bilirubin 
Leukocytes 
Nitrites
Microscopic examination, if 
needed
Ab = antibody; ALT = alanine aminotransferase; AST = aspartate aminotransferase; bHCG = beta human chorionic gonadotropin; 
BUN = blood urea nitrogen; CO2 = carbon dioxide; CPK = creatine phosphokinase; DNA = deoxyribonucleic acid; FSH = follicle-
stimulating hormone; HBc Ab = hepatitis B core antibody; HBs Ab = hepatitis B surface antibody; HBs Ag = hepatitis B surface 
antigen; HBV = hepatitis B virus; HCV Ab = hepatitis C virus antibody; HDL-C = high-density lipoprotein cholesterol; HIV = human 
immunodeficiency virus; hsCRP = high sensitivity C-reactive protein; INR = international normalized ratio; LDL-C = low-density 
lipoprotein cholesterol; PCR = polymerase chain reaction; RBC = red blood cell; RNA = ribonucleic acid; TB = tuberculosis;
WBC = white blood cell
a.
INR will only be measured if ALT and/or AST > 3 × upper limit of normal (ULN).
b.
At screening only for female < 55 years old.
Pregnancy Tests (Serum and Urine)
A serum pregnancy test will be performed for female of childbearing potential at the Screening Visit.  
The serum pregnancy test will be sent to and performed by the central laboratory.  If the serum 
pregnancy test is positive the subject is considered a screen failure.  If the serum pregnancy test is 
borderline, it should be repeated ≥ 3 days later to determine eligibility.  If the repeat serum pregnancy 
test is:
!
Positive, the subject is considered a screen failure;
!
Negative, the subject can be enrolled into the trial;


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!
Still borderline ≥ 3 days later, the subject is considered a screen failure.
A urine pregnancy test will be performed for all female of childbearing potential at the Baseline Visit 
prior to the first dose of study drug and at minimum at monthly intervals at study visits.  More frequent 
pregnancy tests will be performed throughout the study if required per local requirements.  If the End-
of-Treatment follow up period is longer than 30 days, female subjects should perform monthly 
pregnancy tests at home, and the results of the monthly at home tests should be communicated to the 
site.
!
If the baseline urine pregnancy test performed at the site is negative, then dosing with study 
drug may begin.
!
If the baseline or post-baseline urine pregnancy test performed at the site is positive, dosing 
with study drug must be withheld and a serum pregnancy test is required.  The serum pregnancy 
test will be performed by the central laboratory.  If the serum pregnancy test is negative, study 
drug may be started or resumed.  If the serum pregnancy test is positive, study drug must be 
permanently discontinued.  In the event a pregnancy test comes back borderline, a repeat test is 
required (≥ 3 days later) to document a negative result.  If the repeat serum pregnancy test is:
!
Positive, the subject must be discontinued;
!
Negative, the subject can continue in the trial;
!
Still borderline ≥ 3 days later, the subject must be discontinued.
If during the course of the study a female becomes surgically sterile or post-menopausal and complete 
documentation as described in Contraception Recommendations for Female is available, pregnancy 
testing is no longer required.
A pregnant or breastfeeding female will not be eligible to enter the study or be allowed to continue 
study drug.
Clinical Chemistry
A minimum 8-hour fast will be necessary for blood samples to be drawn for chemistry.  If a subject is not 
able to fast when necessary due to unforeseen circumstances, the nonfasting status will be recorded in 
study source documentation.
Urinalysis
Dipstick urinalysis will be completed by the central laboratory at all required visits.  Specified abnormal 
macroscopic urinalyses defined as leukocytes, nitrite, protein, ketones, or blood greater than negative, 
or glucose greater than normal will be followed up with a microscopic analysis at the central laboratory.
Hepatitis Screen
All subjects will be tested for the presence of HBV and HCV at Screening.
Hepatitis B Virus (HBV):
Subjects will be tested for the presence of HBV at Screening using the following tests:


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!
HBs Ag (Hepatitis B surface antigen)
!
HBc Ab/anti-HBc (Hepatitis B core antibody)
!
HBs Ab/anti-HBs (Hepatitis B surface antibody)
A positive result for HBs Ag will be exclusionary.
A negative result for HBs Ag will trigger automatic reflex testing for HBc Ab and surface antibodies (HBs 
Ab).
!
A negative test result for HBc Ab does not require HBV DNA PCR qualitative testing and the 
subject may be enrolled (Figure 2, Scenarios A and B).
!
For a subject who has had a HBV vaccination (should document in the medical history), a 
positive test result for HBs Ab is expected, the HBV DNA PCR qualitative testing is not required 
and the subject may be enrolled (Figure 2, Scenario B).*
!
For subjects without a history of HBV vaccination (and where mandated by local requirements) a 
positive result for HBs Ab requires HBV DNA PCR testing (automatic reflex testing; Figure 2, 
Scenario B).
!
A positive test result for HBc Ab requires HBV DNA PCR testing (automatic reflex testing) 
(Figure 2, Scenarios C and D).  A result for HBV DNA that exceeds detection sensitivity will be 
considered positive.
Figure 2.
Interpretation and Management of HBV Serologic Test Results
*
A positive test result for HBs Ab is expected for subjects who have had a HBV vaccination.  For subjects without a history of
HBV vaccination (and where mandated by local requirements) a positive result for HBs Ab requires HBV DNA PCR testing.  
**
Where mandated by local requirements; subjects with HBs Ab+ and/or HBc Ab+ and negative HBV DNA at Screening 
should have HBV DNA PCR testing performed every 12 weeks.  HBV DNA PCR testing every 12 weeks is not necessary when 
the subject has a history of HBV vaccine and HBs Ab+ and HBc Ab.
!
A positive result for HBV DNA or a result that exceeds detection sensitivity will be 
exclusionary.


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!
A subject with a negative result for HBV DNA testing may be enrolled.
!
Where mandated by local requirements:  A positive result for HBs Ab requires HBV DNA PCR 
testing.
!
A result that exceeds detection sensitivity by central laboratory will be considered a positive 
result for HBV DNA and will be exclusionary.
!
A subject with a negative result for HBV DNA may be enrolled.
!
For subjects with HBs Ab+ and/or HBc Ab+ and negative HBV DNA at screening, HBV DNA 
PCR test should be performed every 12 weeks.  HBV DNA PCR testing every 12 weeks is not 
necessary when the subject has a history of HBV vaccine and HBs Ab+, HBc Ab–.
!
Subjects with HBc Ab+ (irrespective of HBs Ab status) and negative HBV DNA at screening 
who develop a positive result for HBV DNA PCR testing during the study accompanied by the 
following should be referred to a hepatologist within one week for consultation and 
recommendation regarding subsequent treatment, and immediate study drug interruption 
will be required (or per local guidelines):
!
an ALT > 5 × ULN OR
!
ALT or AST > 3 × ULN and either a total bilirubin > 2 × ULN or INR > 1.5 OR
!
ALT or AST > 3 × ULN along with clinical signs of possible hepatitis.
Hepatitis C Virus (HCV)
Blood samples for HCV serology will be obtained at the Screening Visit.  A positive HCV Ab will trigger a 
HCV RNA test.  A subject will not be eligible for study participation if test results indicate active Hepatitis 
C (HCV RNA detectable in any subject with anti-HCV Ab). 
Human Immunodeficiency Virus (HIV)
Subjects with HIV infection (positive HIV test) are excluded from study participation.  An anti-HIV 
antibody (Ab) test will be performed at Screening, unless prohibited by local regulations.  The 
investigator must discuss any local reporting requirements to local health agencies with the subject.  The 
site will report confirmed positive results to their health agency per local regulations, if necessary.  If a 
subject has a confirmed positive result, the investigator must discuss with the subject the potential 
implications to the subject's health and subject should receive or be referred for clinical care promptly.  
AbbVie will not receive results from the testing and will not be made aware of any positive result.
Discontinuation of Study Drug and Subjects Withdrawal
All attempts must be made to determine the date of the last study drug dose and the primary reason for 
discontinuation of study drug or study participation.  The information will be recorded on the 
appropriate eCRF page.  However, these procedures should not interfere with the initiation of any new 
treatments or therapeutic modalities that the investigator feels are necessary to treat the subject's 
condition.  Following discontinuation of study drug, the subject should be treated in accordance with 
the investigator's best clinical judgment irrespective of whether the subject decides to continue 
participation in the study.


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Discontinuation of Study Drug and Continuation of Study Participation
Subjects may discontinue study drug treatment but may choose to continue to participate in the study.  
A subject who discontinues one treatment (injection or tablet) will be discontinued from the other 
treatment (tablet or injection).  Subjects who prematurely discontinue study drug should complete a 
Premature Discontinuation visit (PD visit) as soon as possible, preferably within 2 weeks.  Afterwards, 
subjects should follow the regular visit schedule as outlined in Appendix D and should adhere to all 
study procedures except for annual TB testing, dispensing study drug, and blood sample collection for 
optional exploratory research and validation studies.  Once the subject has discontinued study drug, all 
rescue and efficacy driven discontinuation criteria no longer apply, and subjects should be treated per 
standard of care.  If at any point a subject no longer wants to provide assessments (withdrawal of 
informed consent) following discontinuation of study drug, a second PD visit is not required. 
Premature Discontinuation of Study (Withdrawal of Informed Consent)
Subjects may withdraw from the study completely (discontinuation of study drug treatment and study 
participation; withdrawal of informed consent) for any reason at any time.  If a subject prematurely 
discontinues study participation, the procedures outlined for the PD visit should be completed as soon 
as possible, preferably within 2 weeks of study drug discontinuation.  In addition, an End-of-Treatment 
Follow-up visit or phone call may be completed 12 weeks after the last injection to determine the status 
of any ongoing AEs/SAEs or the occurrence of any new AEs/SAEs.  Subjects who discontinue the study 
prematurely after randomization will not be replaced.
All attempts must be made to determine the date of the last study drug dose and the primary reason for 
discontinuation of study drug or study participation.  The information will be recorded on the 
appropriate eCRF page.  However, these procedures should not interfere with the initiation of any new 
treatments or therapeutic modalities that the investigator feels are necessary to treat the subject's 
condition.
Following discontinuation of study drug, the subject will be treated in accordance with the investigator's 
best clinical judgment, irrespective of whether or not the subject decides to continue participation in the 
study.
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).


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For a product this may include, but is not limited to, damaged/broken product or packaging, product 
appearance whose color/markings do not match the labeling, labeling discrepancies/inadequacies in the 
labeling/instructions (e.g., printing illegible), missing components/product, device not working properly, 
or packaging issues.
Product complaints concerning the investigational product and/or device must be reported to AbbVie 
within 1 business day of the study site's knowledge of the event.  Product complaints occurring during 
the study will be followed up to a satisfactory conclusion.
Medical Complaints/Adverse Events and Serious Adverse Events
An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not the event is considered causally related to the use of the 
product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as well as from 
accidental or intentional overdose, drug abuse, or drug withdrawal.  Any worsening of a pre-existing 
condition or illness is considered an AE.  Worsening in severity of a reported AE should be reported as a 
new AE.  Laboratory abnormalities and changes in vital signs are considered to be AEs only if they result 
in discontinuation from the study drug, necessitate therapeutic medical intervention, meets protocol 
specific criteria (see Section 6.2 regarding toxicity management) and/or if the investigator considers 
them to be AEs.
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.
If any of the following events are reported, then the following supplemental report must be completed:




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Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any length 
of time or prolongs the subject's hospital stay.  This does not include 
an emergency room visit or admission to an outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that results in 
fetal loss.
Persistent or Significant 
Disability/Incapacity
An event that results in a condition that substantially interferes with 
the activities of daily living of a study subject.  Disability is not 
intended to include experiences of relatively minor medical 
significance such as headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle).
Important Medical Event 
Requiring Medical or Surgical 
Intervention to Prevent 
Serious Outcome
An important medical event that may not be immediately life-
threatening or result in death or hospitalization, but based on 
medical judgment may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the outcomes 
listed above (i.e., death of subject, life threatening, hospitalization, 
prolongation of hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity).  Additionally, any elective or 
spontaneous abortion or stillbirth is considered an important 
medical event.  Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or 
drug abuse.
All adverse events reported from the time of study drug administration until 12 weeks after the last 
injection will be collected, whether solicited or spontaneously reported by the subject.  Subjects who 
discontinue study drug treatment but continue to participate in the study will have AEs collected for the 
remainder of study participation.  In addition, serious adverse events and protocol-related non-serious 
adverse events will be collected from the time the subject signs the study-specific informed consent.
Additionally, in order to assist the adjudication process, additional information on any potential major 
adverse cardiovascular events will be collected, if applicable.


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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 AEs of special interest for upadacitinib will be monitored during the study:
!
Serious infections
!
Opportunistic infections
!
Herpes zoster
!
Active Tuberculosis
!
Malignancy (all types)
!
Adjudicated Gastrointestinal perforations
!
Adjudicated cardiovascular events (e.g., major adverse cardiovascular event [MACE])
!
Anemia
!
Neutropenia
!
Lymphopenia
!
Increased serum creatinine and renal dysfunction
!
Hepatic events and increased hepatic transaminases
!
Elevated creatine phosphokinase (CPK)
!
Adjudicated embolic and thrombotic events (non-cardiac, non-Central nervous system [CNS])
Adverse Event Severity and Relationship to Study Drug
The investigators will rate the severity of each AE according to the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
If no grading criteria are provided for the reported event, then the event should be graded as follows:
Mild (Grade 1)
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated
Moderate (Grade 2)
Minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL)


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Severe (Grade 3 - 5)
Grade 3
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self care ADL (Self care ADL refers to bathing, dressing and 
undressing, feeding self, using the toilet, taking medications, and not 
bedridden)
Grade 4
Life-threatening consequences; urgent intervention indicated
Grade 5
Death related to AE
The investigator will use the following definitions to assess the relationship of the AE to the use of study 
drug:
Reasonable Possibility – After consideration of factors including timing of the event, biologic plausibility, 
clinical judgment, and potential alternative causes, there is sufficient evidence (information) to suggest 
a causal relationship.
No Reasonable Possibility – After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is insufficient evidence 
(information) to suggest a causal relationship.
For causality assessments, events assessed as having a reasonable possibility of being related to the 
study drug will be considered "associated."  Events assessed as having no reasonable possibility of being 
related to study drug will be considered "not associated."  In addition, when the investigator has not 
reported a causality or deemed it not assessable, AbbVie will consider the event associated.
If an investigator's opinion of no reasonable possibility of being related to study drug is given, an Other 
cause of event must be provided by the investigator for the SAE.
Pregnancy
While not an adverse event, pregnancy in a study subject must be reported to AbbVie within 1 working 
day after the site becomes aware of the pregnancy.  If a pregnancy occurs in a study subject information 
regarding the pregnancy and the outcome will be collected.
Female subjects should avoid pregnancy throughout the course of the study, starting with the Screening 
Visit through 12 weeks after the last injection.  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 
(Section 5.5).
The pregnancy outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a SAE and must be reported to AbbVie within 24 hours after the site becomes aware of the 
event.






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infection or a serious opportunistic infection.  A subject who develops a new infection during treatment 
with study drug should undergo prompt diagnostic testing appropriate for an immunocompromised 
subject.  As appropriate, antimicrobial therapy should be initiated, and the subject should be closely 
monitored.  Study drug may be restarted once the infection has been successfully treated.  Subjects who 
develop active TB must be permanently discontinued from study drug.
Management of Herpes Zoster
If a subject develops herpes zoster, consider temporarily interrupting study drug until the episode 
resolves.
Management of Serious Gastrointestinal Events
Subjects presenting with the onset of signs or symptoms of a gastrointestinal perforation should be 
evaluated promptly for early diagnosis and treatment.  If the diagnosis of gastrointestinal perforation is 
confirmed, the subject must be discontinued from study drug.
Management of Thrombosis Events
Subjects who develop symptoms of thrombosis should be promptly evaluated and treated 
appropriately.  If the diagnosis of deep vein thrombosis, pulmonary embolus or non-cardiac, 
non-neurologic arterial thrombosis is confirmed, the subject must be discontinued from study drug.
Management of Malignancy
Subjects who develop malignancy other than NMSC or carcinoma in-situ of the cervix must be 
discontinued from the study drug.  Information including histopathological results should be queried for 
the confirmation of the diagnosis.  Periodic skin examination is recommended for patients who are at 
increased risk for skin cancer.
Management of ECG Abnormality
Subjects must be discontinued from study drug for an ECG change considered clinically significant and 
with reasonable possibility of relationship to study drug, OR a confirmed absolute Fridericia's correction 
formula (QTcF) value > 500 msec, OR a change of QTc interval > 60 msec from baseline.
Management of Select Laboratory Abnormalities
For any given laboratory abnormality, the investigator should assess the subject, apply the standard of 
care for medical evaluation and treatment following any local guidelines.  Specific toxicity management 
guidelines for abnormal laboratory values are described in Table 3 and may require a supplemental eCRF 
to be completed (see Protocol Section 6.1 [Complaints and Adverse Events]).  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 must occur as soon as possible.


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Table 3.
Specific Toxicity Management Guidelines for Abnormal Laboratory Values
Laboratory 
Parameter
Toxicity Management Guideline
Hemoglobin
!
If hemoglobin < 8 g/dL interrupt study drug dosing and confirm by repeat testing with 
new sample
!
If hemoglobin decreases ≥ 3.0 g/dL from baseline, without an alternative etiology, 
interrupt study drug dosing and confirm by repeat testing with new sample.
!
If hemoglobin decreases ≥ 3.0 g/dL from baseline and an alternative etiology is known, 
the subject may remain on study drug at the investigator's discretion.
!
If confirmed, continue to withhold study drug until hemoglobin value returns to 
normal reference range or its baseline value.
Absolute 
neutrophil count 
(ANC)
!
If confirmed < 1000/μL by repeat testing with new sample, interrupt study drug dosing 
until ANC value returns to normal reference range or its baseline value.
!
Discontinue study drug if confirmed < 500/μL by repeat testing with new sample.
Absolute 
lymphocyte 
counts (ALC)
!
If confirmed < 500/μL by repeat testing with new sample, interrupt study drug dosing 
until ALC returns to normal reference range or its baseline value.
Total white blood 
cell count 
!
If confirmed < 2000/μL by repeat testing with new sample, interrupt study drug dosing 
until white blood cell count returns to normal reference range or its baseline value.
Platelet count 
!
If confirmed < 50,000/μL by repeat testing with new sample, interrupt study drug 
dosing until platelet count returns to normal reference range or its baseline value.


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Laboratory 
Parameter
Toxicity Management Guideline
AST or ALT
!
Interrupt study drug if confirmed ALT or AST > 3 × ULN by repeat testing with new 
sample and either a total bilirubin > 2 × ULN or an international normalized ratio (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.
!
Interrupt study drug if confirmed ALT or AST > 3 × ULN by repeat testing with new 
sample along with new appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (> 5% increase from baseline).
!
Interrupt study drug if confirmed ALT or AST > 5 × ULN by repeat testing with new 
sample for more than 2 weeks.
!
Interrupt study drug if confirmed ALT or AST > 8 × ULN by repeat testing with new 
sample.
•
Subjects with HBc Ab+ (irrespective of HBs Ab status) and negative HBV DNA PCR 
testing at Screening who develop the following should have HBV DNA PCR testing 
performed within one week (based on initial elevated value):
!
ALT> 5 × ULN OR
!
ALT or AST > 3 × ULN if an alternate cause is not readily identified.
!
A separate blood sample for HBV DNA PCR testing will be needed at the time of 
repeat testing for ALT or AST.  As with INR, a separate tube is needed.
A positive result for HBV DNA PCR testing will require immediate interruption of study 
drug (unless not acceptable by local practices) and a hepatologist consultation should 
occur within 1 week for recommendation regarding subsequent treatment.
Subjects who meet any of the above criteria should be evaluated for an alternative 
etiology of the ALT or AST elevation and managed as medically appropriate.  The 
investigator should contact the AbbVie TA MD to discuss the management of a subject 
when an alternative etiology has been determined.  The alternative etiology should be 
documented appropriately in the eCRF; study drug should be discontinued if no alternative 
etiology can be found and ALT or AST elevations persist.
For any confirmed ALT or AST elevations > 3 ULN, complete the appropriate supplemental 
hepatic eCRF(s).
Serum Creatinine
!
If serum creatinine is > 1.5 × the Baseline value and > ULN, repeat the test for serum 
creatinine (with subject in an euvolemic state) to confirm the results.  If the results of 
the repeat testing still meet this criterion, then interrupt study drug and re-start study 
drug once serum creatinine returns to ≤ 1.5 × Baseline value and ≤ ULN.
For the above serum creatinine elevation scenario, complete the appropriate 
supplemental renal eCRF(s).


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Laboratory 
Parameter
Toxicity Management Guideline
Creatine 
Phosphokinase
!
If confirmed CPK value ≥ 4 × ULN and there are no symptoms suggestive of myositis or 
rhabdomyolysis, the subjects may continue study drug at the investigator's discretion.
!
If CPK ≥ 4 × ULN accompanied by symptoms suggestive of myositis or rhabdomyolysis, 
interrupt study drug and contact AbbVie TA MD.
For the above CPK elevation scenarios, complete supplemental increased CPK eCRF.
Ab = antibody; ALC = absolute lymphocyte counts; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
CPK = creatine phosphokinase; DNA = deoxyribonucleic acid; eCRF = electronic case report form; HB = hepatitis B; 
HBc Ab+ = Hepatitis B core antibody positive; HBs Ab = Hepatitis B surface antibody; HBV = hepatitis B virus; 
INR = international normalized ratio; PCR = polymerase chain reaction; TA MD = Therapeutic Area Medical Director; 
ULN = upper limit of normal
6.3 Data Monitoring Committee and Cardiovascular Adjudication 
Committee
An external DMC comprised of persons independent of AbbVie and with relevant expertise in their field 
will review unblinded safety and if necessary, efficacy data from the ongoing study.  The DMC members 
consist of two clinicians and one biostatistician with one clinician being an expert in the management of 
subjects with AD.  The primary responsibility of the DMC will be to protect the safety of the subjects 
participating in this study.
The operation of the DMC data review involves data preparation by AbbVie (for blinded data) and an 
independent CRO (Axio Research for unblinded data to DMC), DMC review of the data at a prespecified 
schedule (every 4 months) or ad hoc if needed, DMC report with recommendations provided to the 
AbbVie Contact, and triage of the recommendations the AbbVie Contact to the appropriate parties 
(AbbVie Study Management Team or Internal Review Committee).  The first DMC meeting is expected to 
occur approximately 4 months after the first subject first dose date.
A separate DMC charter will be prepared outside of the protocol and will describe the roles and 
responsibilities of the DMC members, frequency of data reviews, and relevant safety data to be 
assessed.
Communications from the DMC to the Study Teams will not contain information that could potentially 
unblind the team to subject treatment assignments.  In addition, the treatment outcomes will not be 
communicated from the DMC to the Study Teams.
An independent committee of physician experts in cardiovascular adjudication will be utilized to assess 
potential cardiovascular and thromboembolic AEs in a blinded manner as defined by the Cardiovascular 
Adjudication Committee charter.


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6.4 Other Safety Data Collection
Specific manifestations of AD (i.e., itching, excoriations, oozing, crusting, erythema, etc.) should not be 
reported as individual AEs if they are considered to be a worsening of the underlying disease; instead, 
worsening of atopic dermatitis should be reported as the AE.
6.5 SUSAR Reporting
AbbVie will be responsible for SUSAR reporting for the IMP in accordance with global and local 
guidelines and Appendix A of the Investigator Brochure will serve as the Reference Safety Information 
(RSI).  The RSI in effect at the start of a DSUR reporting period serves as the RSI during the reporting 
period.  For follow-up reports, the RSI in place at the time of occurrence of the 'suspected' Serious 
Adverse Reaction will be used to assess expectedness.
7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
7.1 Statistical and Analytical Plans
The objective of the statistical analyses is to evaluate the efficacy and safety of upadacitinib for the 
treatment of adult subjects with moderate to severe AD who are candidates for systemic therapy.
Complete and specific details of the statistical analysis will be described and fully documented in the 
Statistical Analysis Plan (SAP).  The SAP will be finalized prior to the Week 24 database lock.  The 
statistical analyses will be performed using SAS (SAS Institute Inc., Cary, North Carolina, USA).
7.2 Definition for Analysis Populations
The Intent-to-Treat (ITT) Population consists of all randomized subjects and will be used for the efficacy 
analyses.  A Per-Protocol Population may be defined if deemed necessary to exclude subjects with 
protocol violations that will affect the primary endpoint.  If defined, the criteria to determine the 
Per-Protocol Population will be detailed in the SAP.  List of subjects to be excluded from the 
Per-Protocol Population will be finalized before database lock and blind break.  The Per-Protocol 
Population, if defined, will be used to analyze the primary efficacy endpoint.
The Safety Population consists of all randomized subjects who received at least 1 dose of study drug 
including placebos.
7.3 Statistical Analyses for Efficacy
All efficacy endpoints will be analyzed in the ITT population to test the superiority of upadacitinib over 
dupilumab.  In addition, the primary efficacy endpoints will be analyzed in the Per Protocol Population, if 
defined.  Subjects will be included in the treatment group to which they are randomized.


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Categorical variables will be analyzed using Cochran-Mantel-Haenszel (CMH) test, stratified by vIGA-AD 
categories (vIGA-AD 3 or 4).  Continuous variables will be analyzed using mixed-effect model with 
repeated measures (MMRM).
Missing values and visits after the rescue will be handled by non-responder imputation (NRI) for 
categorical variables (except for missing values due to COVID-19, which will be handled by multiple 
imputation, NRI-C) or MMRM for continuous variables.
Primary Analysis
The primary endpoint is the proportion of subjects achieving EASI 75 at Week 16.
Comparison of the primary endpoint will be made between the upadacitinib group and the dupilumab 
group using the CMH test, stratified by vIGA-AD categories.  NRI-C will be the primary approach to 
handle missing values, with multiple Imputation (MI) as the sensitivity approach to handle missing 
values.  Per-protocol analysis, if defined, will be used as another sensitivity analysis.
Secondary endpoints will be analyzed in the ranked order as outlined in Section 3.3.
Sample Size Estimation
Approximately 650 subjects (18 - 75 years old) will be randomized to upadacitinib 30 mg or dupilumab in 
a ratio of 1:1 (325 subjects per treatment group).  Assuming an EASI 75 response rate of at most 50% in 
the dupilumab arm, this sample size will provide more than 80% power to detect at least a 12% 
treatment difference using two-sided test at a 0.05 significant level.  The assumption of dupilumab 
response rate for EASI 75 at Week 16 and 12% treatment difference were based on the pooled response 
rates of dupilumab Phase 3 monotherapy studies (SOLO 1 and SOLO 2) and the response rate of 
upadacitinib 30 mg in the upadacitinib AD Phase 2b study.23
7.4 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.  Analysis details will be specified in 
the SAP.
Adverse events will be coded using MedDRA.  Treatment-emergent AEs (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 the MedDRA SOC and preferred term (PT), by severity, and by relationship to the 
study drug as assessed by the investigator.  Summaries (including percentages and events per 
100 patient-years) of SAEs, deaths, AEs leading to discontinuation and AESIs will be provided as well.  
Pre-treatment AEs will be summarized separately.
For laboratory and vital signs, mean change from Baseline and percentage of subject with evaluations 
meeting criteria for pre-defined Potentially Clinically Significant values will be summarized.


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7.5 Statistical Analysis of Optional Proteomic Biomarker Data
Analysis may be conducted on optional proteomic 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.
8 ETHICS
8.1 Independent Ethics Committee/Institutional Review Board 
(IEC/IRB)
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the IEC/IRB for review and approval.  Approval of both the protocol and the informed 
consent form(s) must be obtained before any subject is enrolled.  Any amendment to the protocol will 
require review and approval by the IEC/IRB before the changes are implemented to the study.  In 
addition, all changes to the consent form(s) will be IEC/IRB approved.
8.2 Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, Operations Manual, International Council 
for Harmonisation (ICH) guidelines, applicable regulations, and guidelines governing clinical study 
conduct and the ethical principles that have their origin in the Declaration of Helsinki.  Responsibilities of 
the investigator are specified in Appendix B.
8.3 Subject Confidentiality
To protect subjects' confidentiality, all subjects and their associated samples will be assigned numerical 
study identifiers or "codes."  No identifiable information will be provided to AbbVie.
9 SOURCE DOCUMENTS AND CASE REPORT FORM 
COMPLETION
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported.  All source documents should be attributable, legible, contemporaneous, original, 
accurate, and complete to ensure accurate interpretation of data.  Clinical site monitoring is conducted 
to ensure that the rights and well-being of human subjects are protected, that the reported trial data 
are accurate, complete, and verifiable, 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).


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Electronic Patient Reported Data
Patient reported data must be completed for each subject screened/enrolled in this study.  Some of 
these data are being collected with an Electronic Patient Reported Outcome (ePRO) system called 
Trialmax, provided by the technology vendor CRF Health of Plymouth Meeting, PA, USA.  The ePRO 
system is in compliance with Title 21 CFR Part 11.  The documentation related to the system validation 
of the ePRO system is available through the vendor, CRF Health, while the user acceptance testing of the 
study-specific patient reported outcome design will be conducted and maintained at AbbVie.
The subject will be entering the data on an electronic device; these data will be uploaded to a server.  
The data on the server will be considered source, and maintained and managed by CRF Health.  Daily 
Worst Pruritus NRS and daily and weekly ADerm-IS ePROs will be collected from subjects electronically 
every evening via a hand-held device provided to the subject at Screening.  Hand-held device usage 
stops at the Week 16 visit.  The Week 16 and subsequent NRS will be completed electronically via an 
onsite tablet device.  ADerm-IS will be collected only during the Screening period and at the Baseline 
Visit.  The hand-held electronic device will be programmed to allow data entry once per day.  The ePRO 
data of HN-PGIS will be collected electronically via an onsite tablet device into which the subject will 
directly enter the required pieces of information at visits specified in the Operations Manual Section 2.1 
(Individual Treatment Period Visit Activities).  The Oral vs Injectable Questionnaire will be collected 
electronically from subjects via the onsite tablet device at the Week 24 visit (only performed in the 
United States).  The electronic tablet device will be programmed to allow data entry for only the visits 
specified in the protocol and will not allow for subjects to complete more than one of the same 
assessments at any one visit.  All data entered on the devices will be immediately stored to the devices 
itself and automatically uploaded to a central server administrated by CRF Health.  The investigator and 
delegated staff will be able to access all uploaded subject entered data via a password protected 
website, up until the generation, receipt and confirmation of the study archive.
Internet access to the ePRO data will be provided by CRF Health for the duration of the study.  This 
access will be available for the duration of the study to the site investigator, as well as delegated 
personnel.  Such access will be removed from investigator sites following the receipt of the study 
archive.  Data from the ePRO system will be archived on appropriate data media (CD-ROM, etc.) and 
provided to the investigator at that time as a durable record of the site's ePRO data.  It will be possible 
for the investigator to make paper print-outs from that media.
10
DATA QUALITY ASSURANCE
AbbVie will ensure that the clinical trial is conducted with a quality management system that will define 
quality tolerance limits in order to ensure human subject protection and reliability of study results.  Data 
will be generated, documented, and reported in compliance with the protocol, ICH GCP, and applicable 
regulatory requirements.
11
COMPLETION OF THE STUDY
The end-of-study is defined as the date of the last subject's last visit. 


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12
REFERENCES
1.
Kunz B, Oranje AP, Labrèze L, et al.  Clinical validation and guidelines for the SCORAD index:  
consensus report of the European Task Force on Atopic Dermatitis.  Dermatology.  
1997;195(1):10-9.
2.
Wollenberg A, Barbarot S, Bieber T, et al.  Consensus-based European guidelines for treatment 
of atopic eczema (atopic dermatitis) in adults and children:  part I.  J Eur Acad Dermatol 
Venereol.  2018;32(5):657-82.
3.
Krakowski AC, Eichenfield LF, Dohil MA.  Management of atopic dermatitis in the pediatric 
population.  Pediatrics.  2008;122(4):812-24.
4.
Akdis CA, Akdis M, Bieber T, et al.  Diagnosis and treatment of atopic dermatitis in children and 
adults:  European Academy of Allergoly and Clinical Immunology/American Academy of Allergy, 
Asthma and Immunology/PRACTALL Consensus Report.  Allergy.  2006;61(8):969-87.
5.
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.
6.
Blauvelt A, de Bruin-Weller M, Gooderham M, et al.  Long-term management of moderate-to-
severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD 
CHRONOS):  a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial.  Lancet.  
2017;389(10086):2287-303.
7.
Simpson EL, Bieber T, Guttman-Yaasky E, et al.  Two phase 3 trials of dupilumab versus placebo 
in atopic dermatitis.  N Engl J Med.  2016;375(24):2335-48.
8.
Chung-Ching C, Di Meglio P, Nestle FO.  Harnessing dendritic cells in inflammatory skin diseases.  
Semin Immunol.  2011;23(1):28-41.
9.
Nobbe S, Dziunycz P, Muhleisen B, et al.  IL-31 expression by inflammatory cells is preferentially 
elevated in atopic dermatitis.  Acta Derm Venereol.  2012;92(1):24-8.
10. Genovese MC, Smolen JS, Weinblatt ME, et al.  Efficacy and Safety of ABT-494, a Selective JAK-1 
Inhibitor, in a Phase IIb Study in Patients With Rheumatoid Arthritis and an Inadequate 
Response to Methotrexate.  Arthritis Rheumatol.  2016;68(12):2857-66.
11. Kremer JM, Emery P, Camp HS, et al.  A Phase IIb Study of ABT-494, a Selective JAK-1 Inhibitor, in 
Patients With Rheumatoid Arthritis and an Inadequate Response to Anti–Tumor Necrosis Factor 
Therapy.  Arthritis Rheumatol.  2016;68(12):2867-77.
12. Genovese MC, Fleischmann R, Combe B, et al.  Safety and efficacy of upadacitinib in patients 
with active rheumatoid arthritis refractory to biologic disease-modifying anti-rheumatic drugs 
(SELECT-BEYOND):  a double-blind, randomised controlled phase 3 trial.  Lancet Online.  
2018;391(10139):2513-24.
13. Burmester GR, Kremer JM, Van den Bosch F, et al.  Safety and efficacy of upadacitinib in patients 
with rheumatoid arthritis and inadequate response to conventional synthetic disease-modifying 
anti-rheumatic drugs (SELECT-NEXT):  a randomised, double-blind, placebo-controlled phase 3 
trial.  Lancet Online.  2018;391(10139):2503-12.


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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
14. AbbVie.  Upadacitinib Investigator's Brochure Edition 10.  19 August 2019.
15. Eichenfield LF, Tom WL, Berger TG, et al.  Guidelines of care for the management of atopic 
dermatitis:  section 2.  Management and treatment of atopic dermatitis with topical therapies.  
J Am Acad Dermatol.  2014;71(1):116-32.
16. 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.
17. Dupixent [summary of product characteristics].  Paris, France:  Sanofi-Aventis Groupe.  2017.
18. Dupixent [package insert].  Tarrytown, NY:  Regeneron Pharmaceuticals, Inc; 2017.
19. 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.
20. Norman P.  Selective JAK1 inhibitor and selective Tyk2 inhibitor patents.  Expert Opinion on 
Therapeutic Patents.  2012;22(10):1233-49.
21. Hanifin JM, Rajka G.  Diagnostic features of atopic dermatitis.  Acta Derm Venereol.  
1980;944-47.
22. Williams B, Mancia G, Spiering W, et al.  2018 ESC/ESH guidelines for the management of 
arterial hypertension.  Eur Heart J.  2018;39(33):3021-104.
23. Simpson EL, Bieber T, Guttman-Yassky E, at al.  SOLO 1 and SOLO 2 Investigators.  Two Phase 3 
trials of dupilumab versus placebo in atopic dermatitis.  NEJM.  2016;375(24):2335-48.


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APPENDIX A. STUDY SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
Ab
Antibody
AD
Atopic dermatitis
ADerm-IS
Atopic dermatitis impact scale
ADL
Activities of daily living
AE
Adverse event
AESI
Adverse events of special interest
ALC
Absolute lymphocyte count
ALT
Alanine transaminase
ANC
Absolute neutrophil count
AST
Aspartate transaminase
AxSpA
Axial spondyloarthritis
BCG
Bacille Calmette-Guérin
BSA
Body surface area
BUN
blood urea nitrogen
CAC
Cardiovascular adjudication committee
CD
Crohn's disease
CFR
Code of Federal Regulations
CLDN1
Claudin 1
CMH
Cochran-Mantel-Haenszel
CNS
Central nervous system
CPK
Creatine kinase
CRO
Contract Research Organization
CTCAE
Common Terminology Criteria for Adverse Events
CXR
Chest x-ray
CYP
Cytochrome P450
CYP3A
Cytochrome P450 3A
DMC
Data monitoring committee
DNA
deoxyribonucleic acid
EASI
Eczema Area and Severity Index
EASI 75/90/100
75%/90%/100% reduction in Eczema Area and Severity Index


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ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
eGFR
estimated glomerular filtration rate
ePRO
Electronic patient reported outcome
EU
European Union
EudraCT
European Clinical Trials Database
FLG
Filaggrin
FSH
Follicle-stimulating hormone
GCP
Good clinical practice
GFR
Glomerular filtration rate
GI
Gastrointestinal
HBc
Anti-hepatitis B core antibodies
HBc Ab
Hepatitis B core antibodies
HBs
Anti-hepatitis B surface antibody
HBs Ab
Anti-hepatitis B surface antibody
HBs Ag
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HCV Ab
Hepatitis C antibody
HDL-C
high-density lipoprotein cholesterol
HIV
Human immunodeficiency virus
HIV Ab
HIV antibody
HLA
Human Leukocyte Antigen
hsCRP
High-sensitivity C-reactive protein
ICH
International Council for Harmonisation
IEC
Independent ethics committee
IEC/IRB
Independent Ethics Committee/Institutional Review Board
IFN
interferon
IFN-γ
Interferon gamma
IGA
Investigator's Global Assessment
IgE
Immunoglobulin E
IGRA
Interferon-gamma release assay
IL
Interleukin


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IMP
Investigational Medicinal Product
INR
international normalized ratio
IRB
Institutional review board
IRT
Interactive response technology
ITT
Intent-to-Treat
IU
International Unit
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
JAK
Janus kinase
LDL-C
low-density lipoprotein cholesterol
MACE
Major adverse cardiovascular event
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multiple imputation
MMRM
mixed-effect model with repeated measures
MTX
Methotrexate
NCI
National Cancer Institute
NK
Natural killer
NMSC
Non-melanoma skin cancer
NRI
Non-responder imputation
NRI-C
Non-Responder Imputation incorporating Multiple Imputation to handle missing 
data due to COVID-19
NRS
Numerical rating scale
PCR
Polymerase chain reaction
PD
Premature discontinuation
PDE4
Phosphodiesterase type 4
PGIS
Patient Global Impression of Severity
PPD
Purified protein derivative
PRO
patient-reported outcome
PsA
Psoriatic arthritis
PT
Preferred term
PUVA
Psoralen and ultraviolet A
QD
Once daily
QTc
QT interval corrected


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QTcF
Friedericia's correction formula
RA
Rheumatoid arthritis
RBC
red blood cell
RNA
ribonucleic acid
RSI
Reference safety information
SAE
Serious adverse event
SAP
Statistical analysis plan
SC
Subcutaneous(ly)
SOC
System organ classes
SUSAR
Suspected Unexpected Serious Adverse Reaction
TA MD
Therapeutic Area Medical Director
TA SD
Therapeutic Area Scientific Director
TB
Tuberculosis
TCI
Topical calcineurin inhibitor
TCS
Topical corticosteroids
Tdap
Tetanus-diphtheria-acellular pertussis
TEAE
Treatment emergent adverse event
TNF
tumor necrosis factor
Tyk2
Tyrosine kinase 2
UC
Ulcerative colitis
ULN
Upper limit of normal
US
United States
UV
Ultra violet
vIGA-AD
Validated Investigator Global Assessment for atopic dermatitis
WBC
White blood cell


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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M16-046:  A Phase 3b Multicenter, Randomized, Double-Blind, Double-Dummy, Active 
Controlled Study Comparing the Safety and Efficacy of Upadacitinib to Dupilumab in Adult Subjects with 
Moderate to Severe Atopic Dermatitis
Protocol Date:  10 November 2020
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation 
(ICH) Good Clinical Practices (GCP) and local regulations and guidelines governing the study at the site 
location.  In signing the Investigator Agreement, the investigator is agreeing to the following:
1.
Conducting the study in accordance with ICH GCP, the applicable regulatory requirements, 
current protocol and operations manual, and making changes to a protocol only after notifying 
AbbVie and the appropriate Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC), except when necessary to protect the subject from immediate harm.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed consent and 
ethics committees (e.g., IEC or IRB) review and approval of the protocol and its amendments.
4.
Reporting complaints that occur in the course of the investigation(s) to AbbVie.
5.
Reading the information in the Investigator's Brochure/safety material provided, including the 
instructions for use and the potential risks and side effects of the investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the study about 
their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making those records 
available for inspection by representatives of AbbVie and/or the appropriate regulatory agency, 
and retaining all study-related documents until notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and approved the initial 
clinical protocol and all of its amendments.
9.
Reporting promptly, all changes in the research activity and all unanticipated problems involving 
risks to human subjects or others, to the appropriate individuals (e.g., coordinating investigator, 
institution director) and/or directly to the ethics committees and AbbVie.
10. Providing direct access to source data documents for study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s).
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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APPENDIX C. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
Clinical Program Development
Immunology Clinical Development
Immunology Clinical Development
Data and Statistical Sciences 
Data and Statistical Sciences
Pharmacovigilance & Patient Safety
Immunology Translational Science 
Medical Writing


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APPENDIX D. ACTIVITY SCHEDULE
The following table shows the required activities.  The individual activities are described in detail in the 
Operations Manual Section 2.1.








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APPENDIX E. PROTOCOL SUMMARY OF CHANGES
Protocol
Date
Version 1.0
17 October 2018
Version 1.1 (VHP Countries:  Czech Republic, Denmark, 
Finland, Germany, Hungary, Italy, Norway, Poland, 
Spain, Sweden, United Kingdom)
18 February 2019
Version 1.2 (Ireland only)
18 February 2019
Administrative Change 1
31 May 2019
Version 1.3 (United States only)
25 June 2019
Version 2.0
13 March 2020
Version 2.1 (Ireland only)
13 March 2020
Version 2.2 (VHP countries)
31 July 2020
Version 3.0
28 October 2020
Version 2.2.1 (VHP countries)
29 October 2020
Summary of Protocol Changes:
!
Section 4.1 Overall Study Design and Plan
!
Specified that a Week 24 database lock will be conducted to perform the Primary Analysis.
Rationale:  To clarify the timing of the Primary Analysis.
!
Section 5.8 Randomization/Drug Assignment
!
Clarified that AbbVie personnel will remain blinded until the Week 24 database lock.
Rationale:  To be consistent with Section 4.1.
!
Section 7.1 Statistical and Analytical Plans
!
Specified that the SAP will be finalized prior to the Week 24 database lock.
Rationale:  To be consistent with Section 4.1.


STUDY M16-046  |  Version 4.0  |  EudraCT 2018-002264-57
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX F. OPERATIONS MANUAL

SAP_001.pdf: 
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Statistical Analysis Plan for Study M16-046
A Multicenter, Randomized, Double-Blind, Double-
Dummy, Active Controlled Study Comparing the 
Safety and Efficacy of Upadacitinib to Dupilumab in 
Adult Subjects with Moderate to Severe Atopic 
Dermatitis
Date: 02 November 2020
Version 2.0
NCT03738397


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Table of Contents
1.0
Introduction .............................................................................5
2.0
Study Design and Objectives..................................................5
2.1
Objectives and Hypotheses ........................................................................5
2.2
Study Design Overview .............................................................................5
2.3
Treatment Assignment and Blinding .........................................................7
2.4
Sample Size Determination........................................................................8
3.0
Endpoints..................................................................................8
3.1
Primary Endpoint.......................................................................................8
3.2
Secondary Endpoints .................................................................................8
3.3
Other Efficacy Endpoints...........................................................................9
3.4
Safety Endpoints ........................................................................................9
4.0
Analysis Populations ...............................................................9
5.0
Subject Disposition................................................................11
6.0
Study Drug Duration and Compliance................................12
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ....................14
7.1
Demographics and Baseline Characteristics............................................14
7.2
Medical History .......................................................................................16
7.3
Prior and Concomitant Medications ........................................................16
8.0
Efficacy Analyses...................................................................17
8.1
General Considerations............................................................................17
8.1.1
Analysis of Efficacy Endpoints by Variable Type...................................18
8.1.2
Analysis of Daily Efficacy Measurements...............................................19
8.2
Handling of Missing Data........................................................................20
8.2.1
Categorical Endpoints..............................................................................21
8.2.2
Continuous Endpoints..............................................................................22
8.3
Primary Efficacy Endpoint and Analyses ................................................22
8.3.1
Primary Efficacy Endpoint ......................................................................22
8.3.2
Handling of Missing Data for the Primary Efficacy Endpoint ................23
8.3.3
Primary Efficacy Analysis .......................................................................23
8.3.4
Additional Analyses of the Primary Efficacy Endpoint...........................23


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8.4
Secondary Efficacy Analyses...................................................................23
8.4.1
Key Secondary Efficacy Analyses...........................................................23
8.4.2
Supportive Secondary Efficacy Analyses ................................................25
8.5
Additional Efficacy Analyses ..................................................................25
8.6
Efficacy Subgroup Analyses....................................................................25
9.0
Safety Analyses ......................................................................26
9.1
General Considerations............................................................................26
9.2
Adverse Events ........................................................................................26
9.2.1
Treatment-Emergent Adverse Events ......................................................26
9.2.2
Adverse Events of Special Interest for Upadacitinib...............................31
9.2.3
Adverse Events of Other Safety Topics of Interest..................................31
9.3
Analysis of Laboratory Data....................................................................31
9.4
Analysis of Vital Signs ............................................................................36
10.0
Interim Analyses....................................................................36
10.1
Data Monitoring Committee....................................................................36
11.0
Overall Type-I Error Control ..............................................37
12.0
Version History......................................................................38
13.0
References...............................................................................38
List of Tables
Table 1.
Model of Continuous Variables...............................................................19
Table 2.
List of Laboratory Values ........................................................................33
Table 3.
SAP Version History Summary...............................................................38
List of Figures
Figure 1.
Study Schematic.........................................................................................7
List of Appendices
Appendix A.
Protocol Deviations..................................................................................39
Appendix B.
Definition of Adverse Events of Special Interest ....................................40


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Appendix C.
Potentially Clinically Important Criteria for Safety Endpoints ...............42
Appendix D.
National Cholesterol Education Program (NCEP) Adult 
Treatment .................................................................................................45
Appendix E.
Random Seeds..........................................................................................46
Appendix F.
Non-Responder Imputation Incorporating Multiple Imputation to 
Handle Missing Data Due to COVID-19 Pandemic for 
Dichotomized Outcome Variables...........................................................47
Appendix G.
Rescue Definition.....................................................................................59
Appendix H.
EASI Scoring Algorithm..........................................................................60
Appendix I.
Patient Report Outcome Scoring .............................................................63
Appendix J.
Definition of Additional Safety Topics....................................................65


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1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for upadacitinib 
Study Protocol M16-046, A Multicenter, Randomized, Double-Blind, Double-Dummy, 
Active Controlled Study Comparing the Safety and Efficacy of Upadacitinib to 
Dupilumab in Adult Subjects with Moderate to Severe Atopic Dermatitis. 
Study M16-046 examines the efficacy and safety of upadacitinib in subjects with 
moderate to severe atopic dermatitis.
The analyses of biomarker and pharmacokinetic 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.
This SAP includes changes to analyses described in the protocol.  Details are outlined in 
Section 12.0.
2.0
Study Design and Objectives
2.1
Objectives and Hypotheses
The objective of this study is to evaluate the efficacy and safety of upadacitinib versus 
dupilumab for the treatment of adult subjects with moderate to severe atopic dermatitis 
(AD) who are candidates for systemic therapy.
2.2
Study Design Overview
This is a Phase 3b, randomized, double-blind, double-dummy, active comparator-
controlled multicenter study that will evaluate the safety and efficacy of upadacitinib 
versus dupilumab in adults (≥ 18 to ≤ 75 years of age) with moderate to severe AD who 


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are candidates for systemic therapy. Eligible subjects must have a documented history of 
inadequate response to treatment with topical AD treatments or documented use of
systemic treatment for AD within 6 months prior to the Baseline Visit or for whom topical 
treatments are otherwise medically inadvisable.
The study is comprised of a 35-day Screening Period, a 24-week double-blind treatment 
period, and an End-of-Treatment Follow-up Visit. The End-of-Treatment Follow-up Visit 
will be 12 weeks after the last injection. Subjects who meet eligibility criteria will be 
randomized in a 1:1 ratio to one of the two arms as shown below:
●
Treatment A (N = 325): Daily oral doses of upadacitinib 30 mg from the 
Baseline visit until the Week 24 visit, and placebo pre-filled syringe 
administered at the baseline visit (2 subcutaneous [SC] injections), followed by 
placebo pre-filled syringe (1 injection) every other week until the Week 22 
visit.
●
Treatment B (N = 325): Dupilumab 600 mg (2 × 300 mg dupilumab SC 
injection) administered at the Baseline visit, followed by dupilumab 300 mg SC 
injection every other week until the Week 22 visit and daily oral doses of 
placebo tablets from the Baseline visit until the Week 24 visit.
Randomization will be stratified by baseline disease severity (moderate validated 
Investigator Global Assessment for atopic dermatitis [vIGA-AD 3] vs. severe [vIGA-AD 
4]) and age (< 40, ≥ 40 to < 65, ≥ 65 years). The subject's age at baseline will be used for 
randomization and throughout the duration of the study.
The schematic of the study is shown in Figure 1.


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Figure 1.
Study Schematic
BL = Baseline; SC = subcutaneous
*
Dupilumab 300 mg SC injection will be administered every other week starting at the Week 2 visit and until the 
Week 22 visit, after an initial dose of 600 mg at the Baseline visit.
2.3
Treatment Assignment and Blinding
Subjects will be randomized to upadacitinib or dupilumab in a 1:1 ratio.  Randomization 
will be stratified by baseline disease severity (moderate [vIGA-AD 3] vs. severe [vIGA-
AD 4]), and age (< 40, ≥ 40 - < 65, ≥ 65).
The AbbVie study team, study site personnel, and subjects will be blinded to treatment 
assignment until the primary analysis.  Thereafter, all study site personnel involved in the 
study and subjects will remain blinded to the subject's treatment throughout the study.  
The exception to this is the designated unblinded site staff responsible for administration 
of the injectable study drug who are unblinded for the entirety of the study.  


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2.4
Sample Size Determination
Approximately 650 subjects (18 - 75 years old) will be randomized to upadacitinib 30 mg 
or dupilumab in a ratio of 1:1 (325 subjects per treatment group).  Assuming an EASI 75 
response rate of at most 50% in the dupilumab arm, this sample size will provide more 
than 80% power to detect at least a 12% treatment difference using two-sided test at a 
0.05 significant level.  The assumption of dupilumab response rate for EASI 75 at Week 
16 and 12% treatment difference were based on the pooled response rates of dupilumab 
Phase 3 monotherapy studies (SOLO 1 and SOLO 2) and the response rate of upadacitinib 
30 mg in the upadacitinib AD Phase 2b study.
3.0
Endpoints
3.1
Primary Endpoint
The primary endpoint is:
●
Proportion of subjects achieving a 75% reduction in EASI from Baseline 
(EASI 75) at Week 16.
3.2
Secondary Endpoints
Ranked Secondary Endpoints:
●
Percent change in Worst Pruritus numerical rating scale (NRS) from Baseline at 
Week 16
●
Proportion of subjects achieving a 100% reduction in EASI (EASI 100) at 
Week 16
●
Proportion of subjects achieving a 90% reduction in EASI (EASI 90) at 
Week 16
●
Percent change in Worst Pruritus NRS from Baseline to Week 4
●
Proportion of subjects achieving a 75% reduction in EASI (EASI 75) from 
Baseline at Week 2
●
Percent change in Worst Pruritus NRS from Baseline to Week 1


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●
Proportion of subjects achieving an improvement (reduction) in Worst Pruritus 
NRS ≥ 4 from Baseline at Week 16.
3.3
Other Efficacy Endpoints
All variables listed as primary or secondary endpoints will be analyzed at all visits other 
than Week 16. In addition, the following variables will be analyzed at all visits:
●
Proportion of subjects achieving 75% reduction in EASI in the head and neck 
body region from Baseline
●
Proportion of subjects achieving 75% reduction in EASI in each body region 
(other than head and neck) from Baseline
Proportion of Subjects Achieving an Improvement (Reduction) in Daily Worst Pruritus 
NRS ≥ 4 from Baseline for Subjects with Daily Worst Pruritus NRS ≥4 at Baseline by 
Day Up to Day 28
3.4
Safety Endpoints
The following safety evaluations will be performed during the study:
●
Treatment-emergent AEs (TEAEs); 
●
Serious adverse events (SAEs);
●
Adverse events of special interest (AESIs); 
●
Other Safety Topics of Interest.
●
AEs leading to discontinuation of study drug;
●
Vital signs and laboratory tests
4.0
Analysis Populations
The following populations will be used for the analyses.


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The Intent-to-Treat (ITT) Population includes all randomized subjects.  The ITT 
Population will be used for all efficacy analyses.  Subjects will be included in the analysis 
according to the treatment groups that they are randomized to.
The Per-Protocol (PP) Population will include ITT subjects which excludes subjects with 
major protocol deviations that potentially affect the primary efficacy endpoint.  The final 
criteria and the exclusion of subjects from the per-protocol population will be finalized 
before unblinding data for the Primary Analysis.
The Per-Protocol Population will exclude the subjects who violate any of the following 
criteria: 
●
Receive 80% of planned study drug, per randomization, before Week 16
●
Have an EASI assessment post-baseline on or before Week 16
●
Meet all the following disease activity criteria:
○
EASI score ≥ 16 at the Baseline Visits;
○
vIGA-AD score ≥ 3 at the Baseline Visits;
○
≥10% BSA of AD involvement at the Baseline Visits;
○
Baseline weekly average of daily worst pruritus NRS ≥ 4. Note:  The 
baseline weekly average of daily worst pruritus NRS will be calculated 
from the 7 consecutive days immediately preceding the Baseline Visit.  A 
minimum of 4 daily scores out of the 7 days is needed.
●
Must not have used the following AD treatments within the specified timeframe 
prior to Baseline Visit, per assessment of eligibility criterion 16 in the protocol:
○
Systemic therapy for AD, including but not limited to corticosteroids, 
methotrexate, cyclosporine, azathioprine, phosphodiesterase type 4 
(PDE4)-inhibitors, interferon-gamma (IFN-γ) and mycophenolate mofetil 
within 4 weeks; 
○
Targeted biologic treatments (refer to Section 5.3 of the protocol) 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; 
○
Marijuana use within 2 weeks; 
○
Topical treatments (with the exception of topical emollient treatments, 
described in Eligibility Criterion 8), including but not limited to TCS, 
TCIs, or topical PDE-4 inhibitors within 7 days.
Per-protocol Population will be fully defined in the classification plan and the exclusion 
of subjects from the Per-protocol Population will be finalized before blind break.
The Safety Population consists of all subjects who received at least 1 dose of study drug 
including matching placebo.  For the safety population, subjects are assigned to a 
treatment group based on the "as treated" treatment group, regardless of the treatment 
randomized.  The "as treated" is determined by the treatment the subject received during 
the majority of the subject's drug exposure time in the analysis period if any mis-dosing 
occurs.
5.0
Subject Disposition
The total number of subjects who were screened, enrolled (randomized), and reasons for 
exclusion, including screen failure, will be summarized.
The number of subjects for each of the following categories will be summarized for each 
treatment group in the ITT Population:
●
Subjects enrolled (randomized) in the study;
●
Subjects who took at least one dose of study drug;
●
Subjects who took at least one dose of active study drug;
●
Subjects who completed protocol-specified treatment;
●
Subjects who prematurely discontinued study drug (all reasons and primary 
reason);


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●
Subjects who prematurely discontinued study (all reasons and primary reason);
●
Subjects who completed the study
●
Subjects who were rescued in the study
●
Subjects who enrolled to M19-850 
Number and percentage of subjects who discontinued study drug and who discontinued 
from study will be summarized by reason (primary reason and all reasons) for each 
treatment group and overall.  Subjects with multiple reasons for premature discontinuation 
will be counted once in the calculation of the number and percentage of total 
discontinuations.
In addition, a disposition table of the below categories will be summarized:
!
Subjects who took at least one dose of study drug before Week 16; 
!
Subjects who took at least one dose of active study drug before Week 16;
!
Subjects who completed Week 16;
!
Subjects who prematurely discontinued study drug (all reasons and primary 
reason) before Week 16;
!
Subjects who prematurely discontinued study (all reasons and primary reason) 
before Week 16;
!
Subjects who were rescued in the study before Week 16
6.0
Study Drug Duration and Compliance
Study Drug Duration (in Days):
Summary of study drug duration and study drug compliance will be provided for each 
treatment group for the Safety Population 1) from Baseline to Week 16 visit and 2) the 
entire treatment period, respectively. Study drug duration (days) will be summarized 
using the number of subjects, mean, standard deviation, minimum, median and maximum 
for each treatment group.


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1.
From Baseline to Week 16:
●
Duration of upadacitinib is defined for each subject as 
○
The minimum (last dose date of upadacitinib, Week 16 visit date -1) minus 
first dose date of upadacitinib +1 if the Week 16 visit date is non-missing, 
and 
○
The minimum (last dose date of upadacitinib, nominal Week 16 visit date-
1) minus first dose date of upadacitinib +1 if the Week 16 visit date is 
missing.  Here nominal Week 16 visit date is defined as first dose date of 
upadacitinib + 112.
●
Duration of dupilumab is defined for each subject as the last dose date of 
dupilumab before Week 16) minus first dose date of dupilumab +14.  The last 
dose of dupilumab before Week 16 is defined as the last dose date of 
dupilumab within 105 days (the upper bound of Week 14 dupilumab 
administration window) of the first dose date of dupilumab. 
2.
The entire treatment period:
●
Duration of upadacitinib is defined for each subject as last dose date of 
upadacitinib minus first dose date of upadacitinib +1, 
●
Duration of dupilumab is defined for each subject as last dose date of 
dupilumab minus first dose of dupilumab date +14.
Compliance:
Treatment compliance will be summarized by treatment group in the Safety Population 
for 1) from Baseline to Week 16 visit and 2) the entire treatment period, respectively.
1.
From Baseline to Week 16:
●
Upadacitinib compliance is defined as the number of upadacitinib (or placebo 
for upadacitinib) actually taken prior to Week 16 (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 
during the first 16 weeks. 


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●
Dupilumab compliance is defined as the number of dupilumab (or placebo for 
dupilumab) injections administered during the subject's participation prior to 
Week 16 by the subject divided by the number of injections planned during the 
subject's participation during the first 16 weeks.
2.
The entire treatment period:
●
Upadacitinib compliance is defined as the number of upadacitinib (or placebo 
for upadacitinib) 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 during the study.
●
Dupilumab compliance is defined as the number of dupilumab (or placebo for 
dupilumab) injections administered during the subject's participation up to 
Week 22 by the subject divided by the number of injections planned during the 
subject's participation during the study.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications
Demographics, baseline or disease characteristics, and medical history will be 
summarized for ITT overall and by treatment group. Categorical variables will be 
summarized with the number and percentage of subjects; percentages will be calculated 
based on the number of non-missing observations. Continuous variables will be 
summarized with descriptive statistics (number of non-missing observations, mean and 
standard deviation, median, minimum and maximum). Prior and concomitant 
medications will be summarized for the Safety Population overall and by treatment group.
7.1
Demographics and Baseline Characteristics
Subject Demographics
The following demographic and Baseline parameters will be summarized.


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Subject Demographics
●
Sex (Male, Female)
●
Age (Years)
●
Age Group (< 40 years, ≥ 40 – < 65 years, ≥ 65 years)
●
Race (White, Black, American Indian/Alaska Native, Native Hawaiian or Other 
Pacific Islander, Asian, Other)
●
Ethnicity (Hispanic or Latino, not Hispanic or Latino)
●
Body weight (kg)
●
Height (cm)
●
BMI (kg/m2)
●
BMI (normal:  < 25, overweight:  ≥ 25 – < 30, obese:  ≥ 30)
●
Geographic Region (US/Puerto Rico/Canada and Other)
●
Tobacco/Nicotine and Alcohol Use
○
Tobacco/Nicotine Use (unknown, never, current, former)
○
Alcohol Use (unknown, never, current, former)
Baseline Characteristics
●
Baseline vIGA-AD (< 4, 4)
●
Baseline EASI (< median, ≥ median)
●
HS CRP (< median, ≥ median)
●
Immunoglobulin E (IgE)
●
Previous systemic therapy (with and without)
●
EASI overall score and body region scores
●
Body Surface Area (BSA) in percentage
●
Worst Pruritus NRS (Weekly Average)
●
Worst Pruritus NRS (Daily Score)
●
Head and Neck Patient Global Impression of Severity (HN-PGIS)
●
Atopic Dermatitis Impact Scale (ADerm-IS)


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●
Disease duration since diagnosis (years)
●
Disease duration since symptoms started (years)
●
Duration between symptoms and diagnosis (years)
●
Prior Atopic Dermatitis Treatment
●
TB Status:  Tuberculin PPD skin test result, QuantiFERON-TB Gold test result, 
Latent TB(Yes/No)
●
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
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 and preferred term) will be 
summarized overall and by treatment group. The system organ class (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).
Medical history will be summarized in the ITT Population.
7.3
Prior and Concomitant Medications
Prior and concomitant medications will be summarized by generic name. A prior 
medication is defined as any medication taken prior to the date of the first dose of study 
drug. A concomitant medication is defined as any medication that started prior to the date 
of the first dose of study drug and continued to be taken after the first dose of study drug 


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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 for the subjects on upadacitinib, and within 14 
days of the last dose of study drug for the subjects on dupilumab, respectively. 
Medications taken on the day of the first dose of study drug are counted as concomitant 
medications. 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.
Prior and concomitant medications will be summarized in the Safety Population.
8.0
Efficacy Analyses
8.1
General Considerations
The Primary Analysis will be performed after all ongoing subjects have completed the 
Week 24 visit and the database has been locked.  This will be the only and final analysis 
for the primary and key secondary efficacy endpoints as well as all other efficacy 
endpoints. All efficacy analyses will be conducted in the ITT Population. In addition, 
Per-protocol analysis for primary endpoint will be performed. All tests will be 2-sided at 
an alpha level of 0.05.
Categorical variables and continuous variables will be analyzed using Cochran-Mantel-
Haenszel (CMH) and Mixed-Effect Model Repeat Measurement (MMRM) method,
respectively.
"Baseline" refers to the last non-missing observation before the first administration of 
study drug or randomization if no study drug is given. When analyzing rolling-average-
based endpoints, Baseline refers to the last available rolling average before the date of 
first administration of study drug.


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8.1.1
Analysis of Efficacy Endpoints by Variable Type
Analysis of Categorical Variables
For ITT Population, frequencies and percentages will be summarized along with 95% 
confidence interval (CI) based on normal approximation.  For ITT Population, pairwise 
comparisons of upadacitinib vs. dupilumab will be made using CMH test using 
stratification factor as baseline vIGA-AD categories (vIGA-AD 3 or 4).  Point estimates, 
-value, and 95% CIs for the difference in proportions between upadacitinib and 
dupilumab will be provided.  Construction of CIs for the common risk difference will be 
based on the Mantel-Haenszel estimate adjusting for stratification factors.  Breslow-Day 
test will be performed to test the homogeneity between strata.
NRI-C will be the primary approach for categorical endpoints (Section 8.2).  In addition, 
the primary endpoint and all key secondary categorical endpoints will be analyzed using 
MI defined in Section 8.2 as the sensitivity approach.  All categorical endpoints will be 
analyzed using NRI-NC defined in Section 8.2 as the sensitivity approach.
Analysis of Continuous Variables
For ITT Population, the Baseline and visit means will be presented for each treatment 
group who have both Baseline and post-baseline visit values.  For ITT Population, Percent 
change from Baseline in the treatment groups will be compared using MMRM model as 
described in Table 1.  Point estimates, SE, and 95% CIs of LS mean change from Baseline 
within treatment groups, and these statistics along with -value between upadacitinib 
group and dupilumab will be provided.


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Table 1.
Model of Continuous Variables
Population
Model
Adjust for Stratification Factor(s)
ITT
MMRM model includes the 
categorical fixed effects of 
treatment, visit and treatment-by-
visit interaction, and the continuous 
fixed covariates of Baseline 
measurement.
vIGA-AD categories at 
randomization 
All efficacy endpoints will be analyzed overall and within each stratum of the 
stratification factors: baseline vIGA-AD categories and age group Analysis model within 
each stratum will not be adjusted for stratification factors.
8.1.2
Analysis of Daily Efficacy Measurements
For daily efficacy assessments including the Worst Pruritus NRS, a rolling weekly 
average is calculated by using handheld device only to represent the corresponding 
endpoints by week on and before Week 16.
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 or Study Day 
120 as follows.  Let Pm-6, Pm-5,…, Pm-1, Pm be the daily score from Day m – 6 to Day m, 
and Nm be the number of days with non-missing scores from Day m – 6 to Day m, then the 
rolling weekly average for Day m is:
If the values from four or more days of the 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 
m
m
m
i
i
N
P
∀
#
∃
6


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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.
8.2
Handling of Missing Data
Missing data could occur due to various reasons, including missing visits/assessments, 
early withdrawal from the study, or missing due to COVID-19 infection or logistic 
restriction.
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.  
Sensitivity analyses will be performed to assess the impact of missing data and the 
robustness of the conclusion.
Handling of intercurrent events and missing data for the efficacy analyses is described 
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8.2.1
Categorical Endpoints
●
The primary approach for handling missing data in the analysis of categorical 
endpoints (including the primary endpoint) will use Non-Responder Imputation 
while incorporating Multiple Imputation (MI) to handle missing data due to 
COVID-19 (NRI-C).
The NRI-C 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 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. NRI-C 
will not be applied to the endpoint of improvement of daily Worst Pruritus 
NRS ≥4 up to Day 28.
●
A sensitivity analysis for categorical endpoints will use NRI with No special 
data handling for missing due to COVID-19 (NRI-NC).
NRI-NC will be performed in the same way as NRI-C without the 
exception #2 above. That is, missing due to COVID-19 infection or logistical 
restriction will also be counted as non-responders.
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-C and NRI-NC approaches. NRI-NC will be 
primary approach for the efficacy endpoint of improvement of daily Worst 
Pruritus NRS ≥4 up to Day 28.
●
Multiple Imputation (MI), a sensitivity analysis for the primary endpoint and
key secondary categorical endpoints:  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 
variables to be included in the imputation model are:  treatment group, stratum 
(vIGA-AD categories), gender, Baseline, and measurements at each visit up to 
the end of the analysis period. The random seed for MCMC and the random 


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seed for PROC MI are specified in Appendix E.  The imputed post-baseline 
measurements will be rounded to the same precision as the observed data 
before the determination of responder status.  Subjects will be characterized as
responders or non-responders based on MI imputed datasets.  Using the CMH 
model adjusted by the stratification factor (vIGA-AD categories), 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 group and dupilumab group.  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.
8.2.2
Continuous Endpoints
For continuous endpoints, missing data will be handled using Mixed-Effect Model Repeat 
Measurement (MMRM).
●
The MMRM will be conducted using mixed model including observed 
measurements at all visits, except that measurements after any rescue 
medication will be excluded.  The mixed model includes the fixed effects of 
categorical variable of treatment, visit and treatment-by-visit interaction, main 
stratification factor at randomization (baseline vIGA-AD categories), and the 
continuous variable of Baseline measurement.  An unstructured variance 
covariance matrix (UN) will be used.  If the model cannot converge, an 
appropriate covariance structure matrix (e.g., autoregressive (1) or compound 
symmetry) will be used.  The parameter estimations are based on the method of 
restrictive maximum likelihood (REML).  The fixed effects will be used to 
report model-based means at corresponding visits.
8.3
Primary Efficacy Endpoint and Analyses
8.3.1
Primary Efficacy Endpoint
The primary endpoint for the primary analysis of efficacy is:


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●
Proportion of subjects achieving at least a 75% reduction in Eczema Area and 
Severity Index from Baseline (EASI 75) at Week 16;
Hypotheses corresponding to the primary objective and endpoint is:
●
The proportion of subjects with EASI 75 treated with upadacitinib for Atopic 
Dermatitis is greater than that of dupilumab at Week 16.
8.3.2
Handling of Missing Data for the Primary Efficacy Endpoint
The NRI-C will be the primary approach for missing data handling in the analyses of the 
primary efficacy endpoint.  The NRI-NC and MI approaches will be used as sensitivity 
analyses.
8.3.3
Primary Efficacy Analysis
For ITT Population, comparisons between each upadacitinib group and the dupilumab
group will be conducted using the CMH test, adjusting for vIGA-AD categories. NRI-C 
will be the primary approach to handle missing values.  The NRI-NC and MI approaches 
will be used as sensitivity analyses.
8.3.4
Additional Analyses of the Primary Efficacy Endpoint
The primary efficacy analysis will be performed on PP Population as a sensitivity analysis 
of the primary endpoint.  The definition of PP Population can be found in Section 4.0.  
The per-protocol analysis will be based on the NRI-C approach.
8.4
Secondary Efficacy Analyses
8.4.1
Key Secondary Efficacy Analyses
The secondary endpoints for the primary analysis of efficacy are:
●
Percent change in Worst Pruritus NRS from baseline to Week 16 


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●
Proportion of subjects achieving at least a 100% reduction in Eczema Area and 
Severity Index from Baseline (EASI 100) at Week 16;
●
Proportion of subjects achieving at least a 90% reduction in Eczema Area and 
Severity Index from Baseline (EASI 90) at Week 16;
●
Percent change in Worst Pruritus NRS from Baseline to Week 4;
●
Proportion of subjects achieving a 75% reduction in EASI (EASI 75) from 
Baseline at Week 2;
●
Percent change in Worst Pruritus NRS from Baseline to Week 1
●
Proportion of subjects achieving an improvement (reduction) in Worst Pruritus 
NRS ≥ 4 from Baseline at Week 16
Hypotheses corresponding to the endpoints are:
●
The percent change in Worst Pruritus NRS from baseline in subjects treated 
with upadacitinib for Atopic Dermatitis is greater than that of dupilumab at 
Week 16.
●
The proportion of subjects with EASI 100 treated with upadacitinib for Atopic 
Dermatitis is greater than that of dupilumab at Week 16.
●
The proportion of subjects with EASI 90 treated with upadacitinib for Atopic 
Dermatitis is greater than that of dupilumab at Week 16.
●
The percent change in Worst Pruritus NRS from baseline in subjects treated 
with upadacitinib for Atopic Dermatitis is greater than that of dupilumab at 
Week 4.
●
The proportion of subjects with EASI 75 treated with upadacitinib for Atopic 
Dermatitis is greater than that of dupilumab at Week 2.
●
The percent change in Worst Pruritus NRS from baseline in subjects treated 
with upadacitinib for Atopic Dermatitis is greater than that of dupilumab at 
Week 1.
●
The proportion of subjects with an improvement (reduction) in Worst Pruritus 
NRS ≥ 4 with upadacitinib for Atopic Dermatitis is greater than that of 
dupilumab at Week 16.


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Secondary efficacy endpoints will be analyzed by comparing upadacitinib treatment group 
and dupilumab. The categorical endpoints and continuous endpoint will be analyzed by 
CMH and MMRM, respectively, and the corresponding analyses are specified in 
Section 8.1.
Worst Pruritus NRS will be analyzed based on weekly rolling averages of daily scores.
8.4.2
Supportive Secondary Efficacy Analyses
The NRI-C will be the primary approach for missing data handling in the analyses of the 
binary secondary efficacy endpoints.  The NRI-NC approach will be used as sensitivity 
analyses. MMRM will be the primary and the only approach for continuous endpoint.
8.5
Additional Efficacy Analyses
For ITT Population, additional efficacy endpoints will be compared between the 
upadacitinib and dupilumab treatment groups.  The categorical endpoints will be analyzed 
by CMH, and the corresponding analyses are specified in Section 8.1.  
8.6
Efficacy Subgroup Analyses
To evaluate the consistency of the efficacy over demographic and other Baseline 
characteristics, the primary endpoint will be analyzed in the following subgroups.
●
Age Group (< 40 years, ≥ 40 – < 65 years, ≥ 65 years)
●
Sex (male, female)
●
BMI (normal:  < 25, overweight:  ≥ 25 – < 30, obese:  ≥ 30)
●
Race (White, Asian, Black, and Other)
●
Weight (< median, ≥ median)
●
Geographic regions (US/PR/Canada, Other)
●
Baseline vIGA-AD (moderate or milder [vIGA-AD ≤3], severe [vIGA-AD 4])
●
Baseline EASI (< median, ≥ median)
●
hsCRP (< median, ≥ median)
●
Previous systemic therapy (with and without)


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Any RACE subgroups with fewer than 10% subjects will be combined with Other for 
analyses.  Age ≥ 65 years or BMI ≥ 30 subgroups will be combined with their adjacent 
subgroup when having fewer than 10% subjects.  For any subgroup, if there are zero 
subjects within a stratum in any treatment group, the CMH model will not be adjusted by
the stratification factors.
9.0
Safety Analyses
9.1
General Considerations
Safety data will be summarized for the Safety Population. Safety summaries will be 
presented by treatment group and total. For the safety analysis, subjects are assigned to a 
treatment group based on the treatment actually received, regardless of the treatment 
randomized.
A subject's actual treatment will be determined by the most frequent dose regimen 
received.
Safety analyses will include adverse events, laboratory, and vital sign measurements.  
Missing safety data will not be imputed.
9.2
Adverse Events
9.2.1
Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are defined as any adverse events that begin 
or worsen in severity after initiation of upadacitinib/dupilumab through 30 days following 
the last dose of upadacitinib or 84 days following the last dose of dupilumab, regardless of 
any study drug interruption.  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).


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Pre-treatment AEs are defined as AEs that occurred before the first dose of 
upadacitinib/dupilumab. Post-treatment AEs are defined as AEs that occurred beyond 30 
days after the last dose of upadacitinib or 84 days after the last dose of dupilumab.
Adverse event data will be coded using the Medical Dictionary for Drug Regulatory 
Activities (MedDRA) version 22.1 or most up to date version.
Summary tables will be presented as follows:
1. Adverse Event Overview
An overview of AEs will be presented consisting of the number and percentage of 
subjects experiencing at least one event for each of the following AE categories 1) from 
Baseline to Week 16 visit and 2) the entire treatment period, respectively:
●
Any treatment-emergent AE
●
Any treatment-emergent AE related to study drug according to the investigator
●
Any severe treatment-emergent AE (Grade 3 and above according to NCI 
CTCAE version 5.0)
●
Any serious treatment-emergent AE (SAE)
●
Any treatment-emergent AE leading to discontinuation of study drug
●
Any treatment-emergent AE leading to death
●
AEs of Special Interest
●
Other Safety Topics of Interest
●
Any treatment-emergent SAE related to study drug according to the 
investigator
●
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 and > 84 days 
after last dose of dupilumab


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2. Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term
TEAEs will be summarized and presented using primary MedDRA version 22.1 or later 
by system organ class (SOC) and preferred terms (PT) 1) from Baseline to Week 16 visit 
and 2) the entire treatment period, respectively.  The SOCs will be presented in 
alphabetical order, and the PTs will be presented in alphabetical order within each SOC.  
Subjects reporting more than one adverse event for a given MedDRA preferred term will 
be counted only once for that term (most severe incident for the severity 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.
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
●
TEAE leading to death
3. Treatment-Emergent Adverse Events by Maximum Toxicity
The severity grading of AEs follows the NCI CTCAE version 5.0.
TEAEs will be summarized by maximum toxicity.  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 


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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.
4. Treatment-Emergent Adverse Events by Preferred Term in Decreasing 
Frequency
TEAEs occurring in either treatment groups will be summarized by MedDRA PT in 
decreasing frequency of upadacitinib, respectively.
5.  Overview of Adverse Events by 100 Patient Years 
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 1) 
from Baseline to Week 16 visit and 2) the entire treatment period, respectively.
●
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
●
Any TEAE leading to death
●
TEAEs of Special Interest
●
Other Safety Topics of Interest
Additional AEs may be considered for tabulation/summary based on recommendations 
from Clinical and Safety as deemed appropriate.
AEs per 100 patient-years of exposure is defined as the number of AEs divided by the 
total exposure in 100 patient-years.  Note that one event per preferred term per day per 
subject will be counted in the calculation of the number of AEs (i.e., a preferred term will 


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not be counted twice on the same day for the same subject).  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.
6. Treatment-Emergent Adverse Events Rates per 100 Patient-Years of 
Study Drug Exposure by SOC and PT
For each treatment group, the TEAE rate per 100 patient-years of exposure will be 
calculated overall, for each SOC and each PT, for each of the following events:
●
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
●
TEAE leading to death
7. Listing of Adverse Events
The following additional summaries will be provided for treatment-emergent adverse 
events, unless otherwise specified.
●
List of subject numbers associated with each PT for TEAEs.
●
List of subject numbers associated with each PT for -TEAEs related to study 
drug according to the investigator Listing of pretreatment AEs.
●
Listing of treatment-emergent SAEs.
●
Listing of TEAEs leading to discontinuation of study drug.
●
Listing of all deaths.
●
Listing of treatment-emergent AESIs.


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●
Listings of other safety topics of interest
●
Listings of pre-treatment AEs.
8. Acne Adverse Events
The investigator-identified acne AEs will be summarized by involvement, morphology, 
and acne risk factors.
9.2.2
Adverse Events of Special Interest for Upadacitinib
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 treatment period, respectively.
Detailed information about the search criteria are provided in Appendix B.
Tabular listings of selected adverse events of special interest will be provided.
9.2.3
Adverse Events of Other Safety Topics of Interest
Adverse Events of Other Safety Topics of Interest 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) 1) from Baseline to Week 16 visit and 2) the entire treatment 
period, respectively.
Detailed information about the search criteria are provided in Appendix J.
Tabular listings of Adverse Events of Other Safety Topics of Interest will be provided.
9.3
Analysis of Laboratory Data
Analyses of selected laboratory data will be performed in safety population.  Data 
collected from central and local laboratories, including additional laboratory testing due to 
an SAE, will be used in all analyses, except for Baseline derivation where SAE-triggered 
laboratory assessments on or before the first dose of study drug will be excluded.


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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.
All laboratory parameters to be collected in this study are listed below. Laboratory 
parameters will be reported using the standard international (SI) units.  The selected 
clinical laboratory tests defined in the protocol operations manual (e.g., hematology and 
clinical chemistry) will be summarized.


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Table 2.
List of Laboratory Values
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Other Tests
Hematocrit 
Hemoglobin 
RBC count 
WBC count 
Neutrophils 
Bands 
Lymphocytes 
Monocytes 
Basophils 
Eosinophils 
Platelet count
BUN 
Creatinine 
Total bilirubin
INR (reflex only)a
Albumin
ALT
AST
Alkaline phosphatase
CPK 
Sodium 
Potassium 
Bicarbonate/CO2
Chloride
Calcium
Inorganic phosphorus
Uric acid 
Total protein 
Glucose 
Cholesterol 
LDL-C
HDL-C
Triglycerides
Central Lab Tests:
Estimated glomerular filtration rate (eGFR) 
International normalized ratio (INR)  
Serum pregnancy (beta human chorionic 
gonadotropin [bHCG]) test
Hepatitis Screening:
Hepatitis B surface antigen (HBs Ag)
Hepatitis B surface antibody (HBs Ab)
Hepatitis B core antibody (HBc Ab)
Hepatitis B virus deoxyribonucleic acid 
polymerase chain reaction (HBV DNA PCR 
[rIeflex only])
Hepatitis C virus antibody (HCV Ab)
Hepatitis C virus ribonucleic acid (HCV RNA 
[reflex only])
Human immunodeficiency virus antibody (HIV 
Ab) 
QuantiFERON-TB Gold
High-sensitivity C-reactive protein (hsCRP)
Follicle stimulating hormone (FSH)b 
Drug and alcohol screen
Local Lab Tests:
Urine pregnancy test
Varicella antibody, if indicated
PPD test / T-SPOT TB
Urinalysis
Specific gravity
Ketones
pH 
Protein 
Blood Glucose
Urobilinogen 
Bilirubin 
Leukocytes 
Nitrites
Microscopic
examination, if needed
Ab = antibody; ALT = alanine aminotransferase; AST = aspartate aminotransferase; bHCG = beta human chorionic
gonadotropin; BUN = blood urea nitrogen; CO2 = carbon dioxide; CPK = creatine phosphokinase; DNA = 
deoxyribonucleic acid; FSH = follicle-stimulating hormone; HBc Ab = hepatitis B core antibody; HBs Ab = hepatitis B 
surface antibody; HBs Ag = hepatitis B surface antigen; HBV = hepatitis B virus; HCV Ab = hepatitis C virus
antibody; HDL-C = high-density lipoprotein cholesterol; HIV = human immunodeficiency virus; hsCRP = high
sensitivity C-reactive protein; INR = international normalized ratio; LDL-C = low-density lipoprotein cholesterol; PCR
= polymerase chain reaction; RBC = red blood cell; RNA = ribonucleic acid; TB = tuberculosis; WBC = white blood
cell
a.
INR will only be measured if ALT and/or AST > 3 × upper limit of normal (ULN).
b.
At screening only for female < 55 years old.


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Analysis of Quantitative Laboratory Parameters (Hematology and Chemistry)
Analyses of selected hematology, chemistry, and urinalysis variables which are measured 
longitudinally will be performed by visits and by treatment groups.  For analysis at each 
visit, the following summary statistics of visit values will be presented for each treatment 
group:  sample size, mean, standard deviation, minimum, median, and maximum.
An ANOVA with treatment as a fixed factor will be used to present mean difference vs. 
dupilumab and associated 95% CIs for selected laboratory variables.  Summaries for the 
Baseline and visit/final value means will be presented for subjects who have both Baseline 
and post-baseline values.  Categorical data will be summarized using frequencies and 
percentages.  If there are multiple post-baseline measurements on the same day, average 
value will be used.
Shift Table Analyses
Selected laboratory parameters will be tabulated using shift tables from Baseline to the 
worst value in each Period by NCI CTCAE.  Selected lipid parameters will be 
summarized using National Cholesterol Education Program (NCEP) Adult Treatment 
Panel III (ATPIII) guidelines and details can be find in Appendix D.  A similar shift table 
will be provided to summarize shifts from Baseline to the final post-baseline value.
Percent Change from Baseline in Immunoglobulin E
Immunoglobulin E percent change from baseline will be provided by visit. A summary 
including number of subjects, min, 25% quartile, median, 75% quartile, and max will be 
provided by visit. No statistical modeling will be applied.
Potentially Clinically Important Laboratory Values
Laboratory abnormalities will be evaluated based on Potentially Clinically Important 
(PCI) criteria (NCI CTCAE criteria of Grade 3 or above) with a grade worsening 
compared to Baseline.  For each laboratory PCI criterion, the number and percentage of 


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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
According to FDA's Guidance for Industry "Drug-Induced Liver Injury:  Premarketing 
clinical evaluation (July 2009), when aminotransferase (AT) abnormalities indicating 
hepatocellular injury are accompanied by evidence of impaired hepatic function (bilirubin 
elevation > 2 × ULN), in the absence of evidence of biliary obstruction (i.e., significant 
elevation of ALP) or some other explanation of the injury (e.g., viral hepatitis, alcohol 
hepatitis), the combined finding (i.e., Hy's Law cases) represents a signal of a potential for 
the drug to cause severe DILI.  For the purpose of assessing for potential Hy's law cases, 
the frequencies and percentages of subjects with post-baseline liver specific function test 
values that meet the following criteria of potential clinical interest should be presented:
●
ALT ≥ 3 × ULN
●
ALT ≥ 5 × ULN
●
ALT ≥ 10 × ULN
●
ALT ≥ 20 × ULN
●
AST ≥ 3 × ULN
●
AST ≥5 × ULN 
●
AST ≥ 10 × ULN
●
AST ≥ 20 × ULN
●
TBL ≥ 2 × ULN
●
Alkaline phosphatase ≥ 1.5 × ULN
●
ALT and/or AST ≥ 3 × ULN and concurrent TBL ≥ 1.5 × ULN
●
ALT and/or AST ≥ 3 × ULN and concurrent TBL ≥ 2 × ULN


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9.4
Analysis of Vital Signs
Analyses of selected vital signs variables will be performed in the safety population.  For 
each analysis, the following summary statistics will be presented by visit for each 
treatment group:  sample size, mean, standard deviation, minimum, median, and 
maximum.
For the analysis of vital signs 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.
An ANOVA model with only treatment as a factor will be used to present confidence 
intervals for the difference between upadacitinib group and dupilumab group.  Mean 
difference from dupilumab and associated 95% CIs will be presented.  Summaries of the 
Baseline and visit/final value means will be presented for subjects who have both Baseline 
and post-baseline values.
If there are multiple post-baseline measurements on the same day, the average value will 
be used.
The vital signs variables will be evaluated based on the PCI criteria.  For each vital signs 
PCI criterion, the number and percentage of subjects who have a vital sign value meeting 
the criteria at least once during the analysis period will be summarized.  Listings will be 
provided to summarize subject-level vital sign data for subjects meeting PCI criteria.  The 
PCI criteria are defined in Appendix C.
10.0
Interim Analyses
There will be no efficacy or futility interim analyses.
10.1
Data Monitoring Committee
An external data monitoring committee (DMC) composed of persons independent of 
AbbVie and with relevant expertise in their field will review unblinded safety data from 


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the ongoing study. The primary responsibility of the DMC will be to protect the safety of 
the subjects participating in this study.
A separate DMC charter describes the roles and responsibilities of the DMC members, 
frequency of data reviews, relevant data to be assessed, and general operations.
Since there are no efficacy analyses for early stopping, no alpha adjustment is needed.
11.0
Overall Type-I Error Control
A multiple testing procedure will be used to provide strong control of the type 1 error rate 
at alpha = 0.05 (2-sided) across analyses comparing upadacitinib vs dupilumab with 
respect to the primary endpoint and ranked secondary endpoints. Specifically, testing will 
utilize a sequence of hypothesis testing for the primary endpoints followed by the ranked 
secondary endpoints, and will begin with testing the primary endpoints using α of 0.05 
(2-sided) for upadacitinib vs dupilumab. If the primary endpoint achieves statistical 
significance, continued testing will follow a hierarchical order of the secondary endpoint. 
Only the significance of a higher ranked secondary endpoint implies the continuation of 
the next secondary endpoint.
Since there are no efficacy analyses for early stopping planned for the DMC review, no 
alpha spending is needed due to the DMC review.


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12.0
Version History
Table 3.
SAP Version History Summary
Version
Date
Summary
1.0
09 October 2018
Original version
2.0
02 November 2020
Added Section 5.0, Section 6.0, Section 7.0, Section 10.0 and 
Section 11.0 following the new SAP template.
Section 3.2: added some secondary endpoints and 'other 
endpoint' to be consistent with the protocol amendment.
Section 3.4, Section 9.2, Appendix J: added 'other safety 
topics of interest' to include information of dupilumab related 
safety topics of interest.
Section 4.0: changed the definition of PP Population to be 
aligned with classification plan.
Section 5.0, Section 6.0: added information of 'before Week 
16' to summarize the status before Week 16, which is the time 
for the primary endpoint.
Section 7.1: added IgE summary.
Section 7.3: Clarified that the concomitant medication will be 
summarized in Safety Population instead of ITT Population.
Section 8.2 through Section 8.5: Added details of efficacy 
analysis. Introduced NRI-C and NRI  to incorporate the 
COVID-19 pandemic's affection to the study.
Section 8.6: Changed 'Baseline vIGA-AD (moderate [vIGA-
AD 3], severe [vIGA-AD 4])' to 'Baseline vIGA-AD 
(moderate or milder [vIGA-AD ≤3] , severe [vIGA-AD 4])' to 
incorporate those who entered study with vIGA-AD<3.
Section 9.2: Clarified the definition of TEAE in order to more 
accurately reflect the safety profile of the active drugs
Section 9.2 through Section 9.4: added details of safety 
analysis
13.0
References


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Appendix A.
Protocol Deviations
The number and percentage of subjects who reported at least one of the following 
protocol deviation categories will be provided.
●
Subject entered into the study even though s/he did not satisfy entry criteria.
●
Subject developed withdrawal criteria during the study and was not withdrawn.
●
Subject received wrong treatment or incorrect dose of study.
●
Subject took prohibited concomitant medication.
●
Subject with deviation related to COVID-19 Pandemic 


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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:
AESI
Type of MedDRA 
Query
Broad or 
Narrow 
Search
SMQ/CMQ Search Criteria
Serious Infections
CMQ
"Infections" – Subset for SAEs
Opportunistic Infection
excluding tuberculosis and 
herpes zoster
CMQ
"Opportunistic Infection
excluding tuberculosis and herpes 
zoster"
Possible Malignancy
SMQ
Narrow
"Malignancies"
Malignancy
SMQ
"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
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"
Creatine Phosphokinase 
(CPK Elevation)
PT
Search only for the PT of "Blood 
creatine phosphokinase increased"


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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"
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
a.
Reviewed and adjudicated by an independent Cardiovascular Adjudication Committee in a blinded manner.
*
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).


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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, and the PCI criteria for vital sign findings are described in
Table C-3.
Table C-1.
Criteria for Potentially Clinically Important Hematology Values
Hematology Variables
Units
Definition of Potentially 
Clinically Important
Grade
Very Low
Hemoglobin
3
g/L
< 80.0
Platelets count
3
109/L
25.0 - < 50.0
4
109/L
< 25.0
Leukocytes
3
109/L
1.0 - < 2.0
4
109/L
< 1.0
Neutrophils
3
109/L
0.5 - < 1.0
4
109/L
< 0.5
Lymphocytes
3
109/L
0.2 - < 0.5
4
109/L
< 0.2
Note:
A post-baseline value must be more extreme than the Baseline value with at least one CTCAE grade of 
worsening to be considered a potentially clinically important finding.


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Table C-2.
Criteria for Potentially Clinically Important Chemistry Values
Chemistry 
Variables
Units
Definition of Potentially Clinically Important
Grade
Very Low
Very High
ALP
3
U/L
> 5.0 × ULN – 20.0 × ULN
4
U/L
> 20.0 × ULN
SGOT/AST
3
U/L
> 5.0 × ULN – 20.0 × ULN
4
U/L
> 20.0 × ULN
SGPT/ALT
3
U/L
> 5.0 × ULN – 20.0 × ULN
4
U/L
> 20.0 × ULN
Albumin
3
g/L
< 20
Glucose
3
mmol/L
1.7 - < 2.2
> 13.9 – 27.8 
4
mmol/L
< 1.7
> 27.8
Triglycerides
3
mmol/L
> 5.7 – 11.4
4
mmol/L
> 11.4
Creatinine
3
umol/L
> 3.0 × ULN – 6.0 × ULN or 
> 3.0 × Baseline 
4
mcmol/L
> 6.0 × ULN
Potassium
3
mmol/L
2.5 - < 3.0
> 6.0 – 7.0
4
mmol/L
< 2.5
> 7.0
Calcium
3
mmol/L
1.5 - < 1.75
> 3.1 – 3.4
4
mmol/L
< 1.5
> 3.4
Sodium
3
mmol/L
120 - < 130
155 - <160
4
mmol/L
< 120
    > 160
Phosphate
3
mmol/L
0.3 - < 0.6
4
mmol/L
< 0.3
CPK
3
U/L
> 5.0 × ULN – 10.0 × ULN
4
U/L
> 10.0 × ULN
Total Cholesterol
3
mmol/L
10.34 <- 12.92
4
mmol/L
> 12.92
Note:
A post-baseline value must be more extreme than the Baseline value with at least one CTCAE grade of 
worsening to be considered a potentially clinically important finding.


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Table C-3.
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
High
> 7% increase from Baseline
Low
> 7% decrease from Baseline


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Appendix D.
National Cholesterol Education Program (NCEP) Adult Treatment
●
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 E.
Random Seeds
In case of non-convergence, the random seed will be updated by adding 100000 at each 
attempt until convergence of model happens. (FSFV: 2019-03-06, 21614; LSFV: 2020-
05-05, 22040)
A. Random Seeds for NRI-C
Endpoints
Random Seed
MCMC Procedure
PROC MI
All EASI related endpoints
21614
22040
Worst Pruritus NRS improvement ≥ 4
21615
22041


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Appendix F.
Non-Responder Imputation Incorporating Multiple Imputation to 
Handle Missing Data Due to COVID-19 Pandemic 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 guidance1 in March 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 efficacy endpoints are not collected, the reasons for 
failing to obtain the efficacy assessment should be documented (e.g., 


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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 guidance1 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 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 under 
the general MAR framework. In particular, we explain using multiple imputation (MI) to 
handle missing data due to COVID-19 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-C)
2.1
Overall Description of the Method
For a dichotomized outcome variable with missing data, the NRI-C 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, 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, the information 
will be captured in the database and the subject's response status will be 
imputed using multiple imputation.
Of note, all assessments after the start of rescue medication will be set as missing before 
imputation.  As a result, these assessments will not contribute to the imputation and the
subjects will be counted as non-responders for the analysis. 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.
Non-responder imputation incorporating multiple imputation (NRI-C) for missing due to 
COVID-19 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 75 
(at least a 75% 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 75, 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), gender, 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), gender, 
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 (Graham, Olchowski, and Gilreath 2007).2 In the 
usual clinical settings expecting less than 30% missing information, K=30 repetitions are 
deemed sufficient. When missingness exceeds 30%, depending on the power falloff 
tolerance level, number of repetitions may need to be increased.  Recent research 


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suggested that the number of repetitions (K) should be at least equal to the percentage of 
missing (White et. al., 2011).4
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 75 at each visit) will be 
determined accordingly.
The imputed response status for missing due to reasons other than COVID-19 will be 
overridden by non-responder imputation (Section 2.1) to ensure that multiple imputation 
is only applied to missing due to COVID-19:
●
Using NRI approach, all missing due to reasons other than COVID-19 will be 
categorized as non-responders, including visits after a subject receives rescue 
medication. 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.
●
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.
2.5
Analysis
The statistical analysis will use the Cochran-Mantel-Haenszel (CMH) test adjusted by the 
stratification factors.
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 versus placebo and the corresponding standard error.


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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 (Rubin, 19873), 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  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), 	, is the 
average of the K individual estimators:
	 = 1
  .


The estimated variance of 	, is a combination of the between- and within-imputation 
variability as follows:
	 =  + (1 +

),
where  =

 ∑



is the within-imputation variability and  =

 ∑
( −	)


is the between-imputation variance. 
It has been shown1 that the statistic
 = 	 −
	


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has an approximate  distribution where  = ( −1)(1 +
!
").  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 SEX = "M" THEN SEXN = 1;
  ELSE IF SEX = "F" THEN SEXN = 0;   /*THIS IS TO TRANSFER SEX INTO 
NUMERICAL FORM FOR GETTING EASI MONO STEP BELOW*/
  IF BLVIGA = "Moderate" then VIGAN = 1;
  ELSE IF BLVIGA = "Severe" then VIGAN = 0;
RUN;
/*AUGMENTATION STEP -- TO HAVE 30 MONOTONE MISSING DATASETS*/
PROC MI DATA=EASI_2 OUT=EASI_MONO NIMPUTE=30 SEED= 21614 /*RANDOM SEED 
PRE-DEFINED*/
  ROUND=. . . 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1/*VALUE ROUND TO 1ST 
DECIMAL*/
  MIN=. . . 0 0 0 0 0 0 0 0 0           /*MINIMUM VALUE OF EASI IS 0*/
  MAX=. . . 72 72 72 72 72 72 72 72 72;   /*MAXIMUM VALUE OF EASI IS 
72*/
MCMC IMPUTE=MONOTONE ;
/*NOTE: CATEGORICAL VARIABLES 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 TRT01PN VIGAN SEXN BASE WK1 WK2 WK4 WK8 WK12 WK16 WK20 WK24;
/*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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/*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= 22040
/*RANDOM 
SEED PRE-DEFINED*/
  ROUND=. . . 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1   /*VALUE ROUND TO 1ST 
DECIMAL*/
  MIN=. . . 0 0 0 0 0 0 0 0 0              /*MINIMUM VALUE OF EASI IS 
0*/
  MAX=. . . 72 72 72 72 72 72 72 72 72        /*MAXIMUM VALUE OF EASI IS 
72*/
  MINMAXITER=1000;
  CLASS TRT01PN VIGAN SEXN;
  VAR TRT01PN VIGAN SEXN BASE WK1 WK2 WK4 WK8 WK12 WK16 WK20 WK24;
  MONOTONE REG (WK1 WK2 WK4 WK8 WK12 WK16 WK20 WK24);  /* IMPUTED 
SEQUENTIALLY, FROM WK 1 TO 24, 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 75*/
DATA ALL; SET EASI_FULL;
  IF 0<=WK1<=0.25*BASE THEN EASI75_1=1;
    ELSE EASI75 1=0;
  IF 0<=WK2<=0.25*BASE THEN EASI75_2=1;
    ELSE EASI75_2=0;
  IF 0<=WK4<=0.25*BASE THEN EASI75_4=1;
    ELSE EASI75_4=0;
  IF 0<=WK8<=0.25*BASE THEN EASI75_8=1;
    ELSE EASI75 8=0;
  IF 0<=WK12<=0.25*BASE THEN EASI75_12=1;
    ELSE EASI75_12=0;
  IF 0<=WK16<=0.25*BASE THEN EASI75_16=1;
ELSE EASI75_16=0;
  IF 0<=WK20<=0.25*BASE THEN EASI75_20=1;
    ELSE EASI75_20=0;
  IF 0<=WK24<=0.25*BASE THEN EASI75_24=1;
    ELSE EASI75_24=0;
RUN;
/***********************************************************************
*/
/*         DATA HANDLING STEPS TO MERGE COVID-19 STATUS OMITTED         
*/


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/*            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 WITH TRADITIONAL 
NRI*/
DATA ALLF; SET ALL;
  /*COVID19_XX='Y' IF MISSING AT WEEK XX IS DUE TO COVID-19; IF NOT, 
OVERRIDE WITH TRADITIONAL NRI*/
  IF COVID19_1 NE 'Y' THEN EASI75_1=EASI75NRI_1;
  IF COVID19_2 NE 'Y' THEN EASI75_2=EASI75NRI_2;
  IF COVID19_4 NE 'Y' THEN EASI75_4=EASI75NRI_4;
  /*VARIABLE EASI75NRI XX: TRADITIONAL NRI DATA AT WEEK XX, WHICH COVERS 
THE SPECIAL HANDLING SUCH AS THE BEFORE-AND-AFTER EXCEPTION*/
  IF COVID19_8 NE 'Y' THEN EASI75_8=EASI75NRI_8;
  IF COVID19_12 NE 'Y' THEN EASI75_12=EASI75NRI_12;
  IF COVID19_16 NE 'Y' THEN EASI75_16=EASI75NRI_16;
  IF COVID19_20 NE 'Y' THEN EASI75_20=EASI75NRI_20;
  IF COVID19_24 NE 'Y' THEN EASI75_24=EASI75NRI_24;
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) */
/*INDIVIDUAL-LEVEL DATA --> # OF RESPONDERS & # OF SUBJECTS, TO BE READ-
IN TO PROC STDRATE*/
PROC FREQ DATA=ALL;
  BY _IMPUTATION_;
  TABLES TRT01PN*STRATAN*EASI75_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 EASI75_16;
BY _IMPUTATION_ TRT01PN STRATAN;
VAR COUNT;
RUN;  
DATA FREQ_TABLE1; SET FREQ_TABLE;
  CASE=RESP1;


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  SIZE=SUM(RESP0, RESP1);
  KEEP _IMPUTATION_ TRT01PN STRATAN CASE SIZE;
RUN;
/*RE-ORDER TO SET 1 (PLACEBO) AS THE REFERENCE GROUP*/
DATA FREQ_TABLE2; SET FREQ_TABLE1;
  IF TRT01PN=3 THEN TRT01PN=0;
RUN;
/*CALCULATE THE COMMON RISK DIFF FOR EACH COMPLETE DATASET*/
PROC STDRATE DATA=FREQ_TABLE2
  METHOD=MH STAT=RISK EFFECT=DIFF;
  BY _IMPUTATION_;
  POPULATION GROUP=TRT01PN EVENT=CASE TOTAL=SIZE;
  STRATA STRATAN / 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;
4.0
Reference
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. 
1.
Points to consider on implications of Coronavirus disease (COVID-19) on 
methodological aspects of ongoing clinical trials.  EMA.  2020.
2.
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. 
3.
Rubin DB, Schenker N. Interval estimation from multiply-imputed data:  a case 
study using agriculture industry codes.  Journal of the American Statistical 
Association.  1987;81:366-74.


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4.
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 G.
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.
3.
Plain Topical Corticosteroids
4.
High Potency Topical Corticosteroids
5.
Medium Potency Topical Corticosteroids
6.
Low Potency Topical Corticosteroids
7.
Topical Calcineurin Inhibitor Therapy
8.
Other Topical therapy (not including moisturizers/emollients)
9.
Biologic Systemic Therapy
10.
Non-biologic systemic therapy
11.
Other Systemic Therapy
12.
Phototherapy
Concomitant medications (with the start date after the first date of study drug) that are 
categorized as "potential AD rescue" per medical review AND in categories 1 – 10 above 
are considered as rescue medications. 
The medical review process is documented in the Rescue Medication Medical Review 
Process – Upadacitinib AD.


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Appendix H.
EASI Scoring Algorithm
An EASI score is a tool used to measure the extent (area) and severity of atopic eczema 
(Eczema Area and Severity Index).  EASI score does not include a grade for dryness or 
scaling.
Assignments for the following body regions are as follows:
●
Head and Neck
●
Trunk:  include with the lower extremities
●
Upper limbs
●
Lower limbs
Area Score
Area score is recorded for each of the four regions of the body.  The area score is the 
percentage of skin affected by eczema.
Area score Percentage of skin affected by eczema in each region:
●
0 = no eczema in this region
●
1 = 1% – 9%
●
2 = 10% – 29%
●
4 = 30% – 49%
●
4 = 50% – 69%
●
5 = 70% – 89%
●
6 = 90% – 100%:  the entire region is affected by eczema
Severity Score
Severity score is recorded for each of the four regions of the body.  The severity score is 
the sum of the intensity scores for four signs.


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The four signs are:
1.
Redness (erythema, inflammation)
2.
Thickness (induration, papulation, swelling – acute eczema)
3.
Scratching (excoriation)
4.
Lichenification (lined skin, prurigo nodules – chronic eczema)
The average intensity of each sign in each body region is assessed as:  none (0), mild (1), 
moderate (2) and severe (3).
Score Intensity of redness, thickness/swelling, scratching, lichenification:
1.
0 = None, absent
2.
1 = Mild
3.
2 = Moderate
4.
3 = Severe
For each region, record the intensity for each of four signs and calculate the severity 
score.
Severity score = redness intensity + thickness intensity + scratching intensity + 
lichenification intensity
For each region, multiply the severity score by the area score and by a multiplier.
●
Head and neck:  severity score × area score × 0.1
●
Trunk:  severity score × area score × 0.3
●
Upper limbs:  severity score × area score × 0.2
●
Lower limbs:  severity score × area score × 0.4


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Add up the total scores for each region to determine the final EASI score.  The minimum 
EASI score is 0 and the maximum EASI score is 72.


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Appendix I.
Patient Report Outcome Scoring
1.0
Worst Pruritus Numerical Rating Scale (NRS)
1.1
Questionnaire
Worst Pruritus Numerical Rating Scale
On a scale 0 to 10, with 0 being "no itch" and 10 being "worst imaginable itch," how 
would you rate your itch at its worst during the past 24 hours?
0
1
2
3
4
5
6
7
8
9
10
No 
Itch
Worst 
Imaginable 
Itch
1.2
Scoring Algorithm
The Worst Pruritus NRS will be collected daily from patients electronically via a hand-
held device provided to the subject at Screening.  A rolling weekly average using hand-
held device data is calculated before Week 16.  Starting at the Week 16 visit, Worst 
Pruritus NRS is assessed at clinic visits. After Week 16, the Worst Pruritus NRS assessed 
at clinic visit will be used to represent the corresponding endpoint by visit and a rolling 
average will not be calculated.
1.3
Missing Value Handling
Missing values will not be imputed for the Worst Pruritus NRS.
1.4
Efficacy Variable
●
Proportion of subjects achieving an improvement (reduction) in Worst Pruritus 
Numeric Rating Scale (NRS) ≥ 4 from Baseline for subjects with Worst 
Pruritus NRS ≥ 4 at Baseline.


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●
Proportion of Subjects Achieving an Improvement (Reduction) in Daily Worst 
Pruritus NRS ≥ 4 from Baseline for Subjects with Daily Worst Pruritus NRS ≥ 
4 at Baseline by Day Up to Day 28
●
Percent change from Baseline in Worst Pruritus NRS.


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Appendix J.
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)
Acute allergic reactions 
Narrow SMQ "hypersensitivity" (20000214)
Injection site reactions
CMQ "Injection site reaction" (80000019)
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