Clinical trial NCT04195698
Conditions: Atopic Dermatitis
Keywords: Atopic Dermatitis Upadacitinib ABT-494 RINVOQ
Sponsor: AbbVie
Start date: 2020-01-15; Completion date: 2023-09-11
Enrollment: 475 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a study for adults (18-75 years) who have successfully completed treatment either with Dupilumab or with Upadacitinib in the study M16-046. At the end of M16-046, they have the option to receive Upadacitinib with a duration of 52 weeks beyond the timeframe of Study M16-046. There will be a 30 day follow-up visit after the treatment period is completed.

Main objective of this study is to assess long-term safety, tolerability and efficacy of upadacitinib in participants with moderate to severe atopic dermatitis who successfully completed treatment in the study M16-046.

Detailed description:

Arms: arm 1: Participants will be administered with upadacitinib once daily (QD)
Interventions: intervention 1: Upadacitinib
Intervention descriptions: intervention 1: Upadacitinib will be administered oral as tablet

Protocol documents:
Prot_000.pdf: 


STUDY M19-850  |  Version 5.0  |  EudraCT 2019-001227-12
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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 SAFETY ENDPOINTS
11
3.3
OTHER EXPLORATORY ENDPOINTS
11
3.4
BIOMARKER SAMPLES
12
3.5
SAFETY EVALUATIONS
12
4
INVESTIGATIONAL PLAN
13
4.1
OVERALL STUDY DESIGN AND PLAN
13
4.2
DISCUSSION OF STUDY DESIGN
14
5
STUDY ACTIVITIES
14
5.1
ELIGIBILITY CRITERIA
14
5.2
CONTRACEPTION RECOMMENDATIONS
16
5.3
PROHIBITED MEDICATIONS AND THERAPY
17
5.4
PRIOR AND CONCOMITANT THERAPY
21
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
21
5.6
FOLLOW-UP FOR SUBJECT WITHDRAWAL FROM STUDY
23
5.7
TREATMENT AFTER END OF STUDY
24
5.8
STUDY DRUG
24
5.9
PROTOCOL DEVIATIONS
26
5.10 OTHER STUDY PROCEDURES
27
6
SAFETY CONSIDERATIONS
35
6.1
COMPLAINTS AND ADVERSE EVENTS
35
6.2
TOXICITY MANAGEMENT
42
6.3
CARDIOVASCULAR ADJUDICATION COMMITTEE
46
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6.4
OTHER SAFETY DATA COLLECTION
46
6.5
SUSAR REPORTING
46
7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
46
7.1
STATISTICAL AND ANALYTICAL PLANS
46
7.2
DEFINITION FOR ANALYSIS POPULATIONS
46
7.3
STATISTICAL ANALYSES FOR EFFICACY
47
7.4
STATISTICAL ANALYSES FOR SAFETY
47
7.5
STATISTICAL ANALYSIS OF OPTIONAL PROTEOMIC BIOMARKER DATA
47
8
ETHICS
48
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD
48
8.2
ETHICAL CONDUCT OF THE STUDY
48
8.3
SUBJECT CONFIDENTIALITY
48
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
48
10 DATA QUALITY ASSURANCE
49
11 COMPLETION OF THE STUDY
49
12 REFERENCES
50
LIST OF TABLES
TABLE 1.
EXAMPLES OF COMMONLY USED STRONG CYP3A INHIBITORS AND INDUCERS
20
TABLE 2.
DESCRIPTION OF STUDY DRUG
24
TABLE 3.
CLINICAL LABORATORY TESTS
34
TABLE 4.
SUPPLEMENTAL ELECTRONIC CASE REPORT FORMS
37
TABLE 5.
SPECIFIC TOXICITY MANAGEMENT GUIDELINES FOR ABNORMAL LABORATORY VALUES
44
LIST OF FIGURES
FIGURE 1.
STUDY SCHEMATIC
13
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FIGURE 2.
ADVERSE EVENT COLLECTION
39
LIST OF APPENDICES
APPENDIX A.
STUDY SPECIFIC ABBREVIATIONS AND TERMS
52
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
55
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
56
APPENDIX D.
ACTIVITY SCHEDULE
57
APPENDIX E.
PROTOCOL SUMMARY OF CHANGES
59
APPENDIX F.
OPERATIONS MANUAL
61
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2 INTRODUCTION
2.1 Background and Rationale
Why Is This Study 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 2018 Consensus-based European guidelines for 
treatment of AD 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, 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 efficacious treatment of inflammatory and autoimmune disorders 
such as AD, rheumatoid arthritis (RA), psoriatic arthritis, Crohn's disease, ulcerative colitis, axial 
spondyloarthritis, 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 versus [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.
Upadacitinib is also being investigated in clinical programs for various indications including RA and 
inflammatory bowel disease.  The results from the RA studies have been submitted for marketing 
authorization application.  Upadacitinib is generally safe and well tolerated as demonstrated in the RA 
patient population.  No new safety concerns have been identified in the ongoing studies for other 
indications.  Upadacitinib is expected to be well tolerated in adult subjects with moderate to severe AD.
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Clinical Hypothesis
Based on the differentiated selectivity profile for JAK1 inhibition, upadacitinib could demonstrate a 
sustained, favorable benefit-risk profile in AD.  
Additional information regarding indications under study can be found in the current edition of the 
upadacitinib Investigator's Brochure.10
2.2 Benefits and Risks to Subjects
Treatment of AD in 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, dyspigmentation, and striae.  Common AEs associated with use of topical calcineurin 
inhibitors are transient warmth, burning, itching, or stinging at the application site.  When topical 
therapies are insufficient for treating the signs and symptoms of AD, systemic therapy or phototherapy 
are generally added to topical agents.4,11
Treatment guidelines developed by the American Academy of Dermatology recommend the use of 
systemic immunomodulatory agents for subjects in whom optimized topical regimens and/or
phototherapy do not adequately control the signs and symptoms of disease.  These guidelines recognize 
that insufficient data exist to firmly recommend optimal dosing, duration of therapy, and precise 
monitoring protocols for any systemic immunomodulating medication.5,12  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.5,12
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)13 and United States 
(US)14 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), 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 52.13  Dupilumab is generally well-tolerated, and the most 
common AEs are injection site reaction, conjunctivitis, and blepharitis.5,12
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.5,12  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, or 
azathioprine.5,12
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.5,12  The most 
common AEs associated with use of methotrexate are gastrointestinal disorders (e.g., stomatitis, oral 
ulcers, dyspepsia, abdominal pain, nausea, diarrhea) and abnormal liver function tests (e.g., increased 
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aspartate transaminase [AST] or increased alanine transaminase [ALT]).5,12  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.5,12
Taken together, these agents may generally increase the risk of infections and cytopenias, 
gastrointestinal disorders, and may impact renal and/or liver function.5,12  Rarely, lymphoproliferative 
disorders, lymphoma, and other malignancies are associated with these agents.5,12
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.15,16
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 also 
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 (CPK); both increased and reduced hemoglobin, 
depending on baseline inflammatory burden; and reductions in white blood cell (WBC) counts, including 
natural killer (NK) cells.
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 an embryo fetal development study in rats, there is judged 
to be no risk associated with administration of upadacitinib to male partners of females of childbearing 
potential.
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 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.
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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.10
In view of the COVID-19 pandemic, the benefit:risk profile of various immunomodulatory therapies on 
COVID-19 is being evaluated.  At this time, the effects of upadacitinib on the course of COVID-19 are not 
well defined.
3 STUDY OBJECTIVES AND ENDPOINTS
3.1 Objectives
The objective of this study is to assess the long-term safety, tolerability and efficacy of upadacitinib in 
adult subjects with moderate to severe AD who successfully completed treatment in Study M16-046.
3.2 Primary Safety Endpoints

Treatment emergent adverse events (TEAEs);

Serious adverse events (SAEs);

Adverse events of special interest (AESI);

AEs leading to discontinuation of study drug;

Vital signs, laboratory tests, and physical examination findings.
3.3 Other Exploratory Endpoints
The following efficacy endpoints will be assessed at all visits through Week 52.  Baseline refers to the 
Baseline value in Study M16-046.  All endpoints are defined relative to the Baseline values in 
Study M16-046.

Change and percent Change from Baseline in EASI;

Change and percent change from Baseline in Worst Pruritus Numerical Rating Scale (NRS);

Proportion of subjects achieving EASI 75/90/100;

Change from Baseline in body surface area (BSA);

Proportion of subjects achieving an improvement (reduction) in Worst Pruritus NRS ≥ 4 from 
Baseline among subjects who had Worst Pruritus NRS ≥ 4 at Baseline;

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;
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
Proportion of subjects achieving 75% reduction in EASI in the head and neck body region among 
subjects who received dupilumab in Study M16-046 and did not achieve 75% reduction in EASI 
in the head and neck body region at Week 24 of Study M16-046;

Proportion of subjects achieving 75%/90%/100% reduction in EASI (EASI 75/90/100) among 
subjects who received dupilumab in Study M16-046 and did not achieve EASI 75 at Week 24 of 
Study M16-046;

Proportion of subjects achieving EASI 90/100 among subjects who received dupilumab in 
Study M16-046 and did not achieve EASI 90 at Week 24 of Study M16-046;

Proportion of subjects achieving EASI 100 among subjects who received dupilumab in 
Study M16-046 and did not achieve EASI 100 at Week 24 of Study M16-046;

Proportion of subjects achieving an improvement (reduction) in Worst Pruritus NRS reduction 
≥4 among subjects who had Worst Pruritus NRS ≥ 4 at Baseline, received dupilumab in 
Study M16-046 and did not achieve Worst Pruritus NRS reduction ≥ 4 at Week 24 of 
Study M16-046.
3.4 Biomarker Samples
Optional biospecimens (e.g., blood, serum, plasma, and skin biopsies) will be collected at specified time 
points through Week 52 to evaluate known and/or novel disease-related or drug-related biomarkers.  
Optional lesional and non-lesional skin biopsies will be collected at Baseline and Week 16.  Further, 
optional deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and serum/plasma samples will be 
collected at Week 4, Week 16, and Week 52.
Of note, 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, tyrosine kinase 2 [Tyk2], tumor necrosis factor [TNF]), or other 
genes believed to be related to AD and other inflammatory diseases (Filaggrin [FLG], Claudin 1, Human 
Leukocyte Antigen [HLA], Immunoglobulin E [IgE]).  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.
This research may be exploratory in nature and the results may not be included with the clinical study 
report.
3.5 Safety Evaluations
The following safety evaluations will be performed during the study:  treatment-emergent adverse 
events (TEAEs), SAEs, AEs of special interest (AESIs), AEs leading to discontinuation, vital signs, and 
laboratory tests.
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4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
This is a Phase 3b, single arm, open-label extension (OLE) study for adults (18 – 75 years of age at entry 
into Study M16-046) with moderate to severe AD who have successfully completed treatment in 
Study M16-046.  These subjects should be determined to be eligible to continue treatment with 
upadacitinib by the Principal Investigator during the Baseline visit of this OLE study.  The Baseline visit 
for this study will be the Week 24 visit of Study M16-046.
The study is comprised of a Baseline visit (Week 24 visit of Study M16-046), a 52-week open-label 
treatment period, and an End-of-Study Follow-Up Visit (or phone call if a visit is not possible) 30 days 
after the last dose of upadacitinib.  The 30-day follow-up visit is done to determine the status of any 
ongoing AEs/SAEs or the occurrence of any new AEs/SAEs is required.  These subjects will be considered 
as having completed the study.
Subjects, who are eligible to enroll in the OLE study, will receive daily oral doses of upadacitinib 30 mg 
from the Baseline visit up to the Week 52 visit.
The schematic of the study is shown in Figure 1.  Further details regarding study procedures are in the 
Operations Manual (Appendix F).
See Section 5 for information regarding eligibility criteria.
An interim analysis will occur after all ongoing subjects have completed the Week 16 visit.
Figure 1.
Study Schematic
QD = once daily
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4.2 Discussion of Study Design
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  All efficacy 
measurements in this study are standard for assessing disease activity in subjects with AD.  All clinical 
and laboratory procedures in this study are standard and generally accepted.
Suitability of Subject Population
Subjects who have completed Study M16-046 without permanent discontinuation of study drug are 
eligible for Study M19-850.  Results in 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 this OLE study.
Selection of Doses in the Study
This study will evaluate upadacitinib (30 mg QD) as the same dose selected in Study M16-046.  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 Phase 2 AD Study M16-048, which evaluated 3 doses of upadacitinib 
(7.5 mg, 15 mg, or 30 mg QD) versus placebo.  In addition, all the currently available PK, 
pharmacodynamic, safety, and efficacy data from upadacitinib studies were used to support the 
selection of these doses.
The Phase 2 study results demonstrated superior efficacy of upadacitinib with an acceptable safety 
profile at the selected dose (30 mg QD) compared to placebo in subjects with moderate to severe AD.  
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 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.
5 STUDY ACTIVITIES
5.1 Eligibility Criteria
Subjects must meet all 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. Subjects should have successfully completed treatment in Study M16-046, without 
developing any permanent discontinuation criteria.
2. Subject 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 study-
specific procedures and comply with the requirements of this study protocol.
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3. Subject remains eligible to continue treatment in the long-term extension study by not 
meeting any of the criteria during Study M16-046 that would have warranted study drug 
discontinuation:

a) Rescue treatment was administered outside of the protocol-specified parameters in 
Study M16-046;

b) Initiation of any systemic rescue therapy for AD as defined in Study M16-046;

c) Any subject with an EASI score worsening of 25% or more compared with their 
Study M16-046 Baseline EASI score at any 2 consecutive scheduled study visits (after a trial 
of rescue treatment, if appropriate);

d) Anaphylactic reaction or other severe systemic or local reaction to study drug injection;

e) Clinically significant abnormal laboratory results or AEs, which rule out continuation of 
the study drug;

f) The investigator believes it is in the best interest of the subject;

g) The subject requests withdrawal from the study;

h) Eligibility criteria violation was noted after the subject started study drug, when 
continuation of the study drug would place the subject at risk;

i) Introduction of prohibited medications or dosages when continuation of the study drug 
would place the subject at risk;

j) Subject is non-compliant with TB prophylaxis (if applicable) or develops active TB at any 
time during the study;

k) The subject becomes pregnant or plans to become pregnant while on study drug;

l) Malignancy, except for localized non-melanoma skin cancer (NMSC) or carcinoma in-situ 
of the cervix;

m)Subject develops a GI perforation;

n) 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;

o) 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.
Contraception
4. Females of childbearing potential must not have a positive urine pregnancy test at the 
Baseline Visit prior to study drug dosing.
5. If female, subject must be postmenopausal OR permanently surgically sterile OR for females 
of childbearing potential practicing at least one protocol-specified method of birth control (refer 
to Section 5.2), that is effective from the Baseline Visit through at least 30 days after the last 
dose of study drug.
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6. Female subject must not be pregnant, breastfeeding, or considering becoming pregnant 
during the study or for approximately 30 days after the last dose of the study drug.
7. Additional local requirements may apply (see Section 5.2).
Prior and Concomitant Therapy
8. Subjects should not be taking excluded concomitant medication at the end of treatment in 
Study M16-046, according to the M16-046 protocol.
Medical History
9. Any ongoing adverse event from Study M16-046 or medical condition prior to continuing in 
the long-term extension study which would put the subject at risk by participating in the open 
label treatment extension study.
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 
30 days after the last dose of study drug.  Females must commit to one of the following 
methods of highly effective birth control:

Combined (estrogen- and progestogen-containing) hormonal birth control (oral, 
intravaginal, transdermal, injectable) associated with inhibition of ovulation.

Progestogen-only hormonal birth control (oral, injectable, implantable) associated with 
inhibition of ovulation.

Bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a hysterosalpingogram 
confirms success of the procedure).
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
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 childbearing 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 Baseline.

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
Concomitant oral and topical exposure to any other JAK inhibitors (including but not limited to 
ruxolitinib [Jakafi®], tofacitinib [Xeljanz®], baricitinib, abrocitinib [PF-04965842], and filgotinib) is not 
allowed.
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
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

certolizumab

dupilumab

efalizumab

etanercept

golimumab

guselkumab

infliximab

ixekizumab

natalizumab

omalizumab

risankizumab

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:

methotrexate

cyclosporine

azathioprine

PDE4-Inhibitors (e.g., apremilast)

mycophenolate mofetil
See also Section 5.4 Rescue Therapy for further details on allowed rescue.
Corticosteroids
Concomitant treatment with systemic corticosteroids (oral, intravenous, intramuscular) and intralesional 
corticosteroids for the treatment of AD is prohibited during treatment with study drug.
Inhaled, ophthalmic drops, and nasal corticosteroid formulations are allowed throughout the study.
See also Section 5.4 Rescue Therapy for further details on allowed rescue.
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Investigational Drugs
Investigational drugs are prohibited during treatment with study drug.
Phototherapy, Tanning Booth, and Extended Sun Exposure
Ultra-violet (UV) B or UVA phototherapy including psoralen and ultraviolet A (PUVA) or laser therapy are 
not allowed during the study.  Tanning booth use or extended sun exposure that could affect disease 
severity or interfere with disease assessments are not allowed during treatment with study drug.
Topical Therapy
No topical treatments for AD should be started for the duration of the treatment with study drug except 
for rescue treatment (see Section 5.4 Rescue Therapy).  This includes but is not limited to calcineurin 
inhibitors, corticosteroids, prescription moisturizers or moisturizers containing additives such as 
ceramide, hyaluronic acid, urea, or filaggrin.  Topical emollient treatments are allowed.
Topical anti-infectives, topical antihistamines, and bleach baths are allowed per investigator discretion 
for the remainder of the study.
If there is any question regarding whether a concomitant medication may be used during the study, the 
study site should contact the AbbVie Therapeutic Area Medical Director (TA MD).
Vaccines
Live vaccinations are prohibited during study participation including at least 30 days (or longer if 
required locally) after the last dose of study drug.
Examples of live vaccines 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 (Bacilli Calmette-Guérin);

Typhoid (oral).
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.
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Cannabis
Use of medicinal and recreational marijuana is prohibited during the study.
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.
Strong CYP3A Inhibitors or Inducers
Systemic use of known strong cytochrome P450 3A isoform subfamily (CYP3A) inhibitors or strong 
CYP3A inducers is not allowed through the end of the study.  The most common strong CYP3A inhibitors 
and inducers are listed in Table 1.
Table 1.
Examples of Commonly Used Strong CYP3A Inhibitors and Inducers
Strong CYP3A Inhibitors 
Strong CYP3A Inducers
Boceprevir
Avasimibe
Clarithromycin
Carbamazepine
Cobicistat
Phenytoin
Conivaptan
Rifampin (Rifampicin)
Grapefruit (fruit or juice)
Rifapentine
Indinavir
St. John's Wort
Itraconazole
Ketoconazole
Lopinavir/Ritonavir
Mibefradil
Nefazodone
Nelfinavir
Posaconazole
Ritonavir
Saquinavir
Telaprevir
Telithromycin
Troleandomycin
Voriconazole
Elective and Emergency Surgeries
Elective surgery will not be allowed during the study.
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
If the subject must undergo emergency surgery, the study drug should be interrupted at the time of the 
surgery.  See Section 5.8 Study Drug Administration 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 the Baseline visit and/or receives during the 
study, must be recorded along with the reason for use, date(s) of administration including start and end 
dates, and dosage information including dose, route and frequency on the appropriate electronic case 
report form (eCRF).  Also, medications taken for AD since date of diagnosis (based on subject 
recollection and available medical records) should be reviewed.
If there are any questions regarding concomitant or prior therapies, the AbbVie TA MD should be 
contacted.
Required Concomitant Medications
Twice daily use of an additive-free, bland emollient that was used during Study M16-046 should be 
continued for the duration of Study M19-850.
Note:  Subject may use prescription moisturizers or moisturizers containing ceramide, urea, filaggrin 
degradation products or hyaluronic acid if such moisturizers were initiated before Study M16-046 
Baseline 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.
If a subject needs rescue treatment with a systemic agent (including but not limited to corticosteroids, 
cyclosporine, methotrexate, mycophenolate mofetil, azathioprine) or phototherapy, study drug should 
be permanently discontinued prior to the initiation of rescue systemic agent or phototherapy and 
subject should be discontinued from the study.
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 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, lack of 
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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, electrocardiogram 
(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 Study M19-850 baseline for 
any subject with an EASI score worsening of 25% or more compared with their Study M16-046 
Baseline EASI score at any 2 consecutive scheduled study visits in this study (after a trial of 
rescue treatment, if appropriate; see Section 5.4 Rescue Therapy).  For example, permanent 
study drug discontinuation would apply at Week 4 if EASI score worsening criteria are met at
Study M19-850 Baseline and Week 4 without rescue therapy given at Study M19-850 Baseline.  
Permanent study drug discontinuation would apply at Week 8 if EASI score worsening criteria 
are met at Week 4 and Week 8 with rescue therapy given at Study M19-850 Baseline.  This rule 
applies similarly to later timepoints.

Clinically significant abnormal laboratory results or AEs, which rule out continuation of the study 
drug, as determined by the investigator and the AbbVie Therapeutic Area Medical/Scientific 
Director.

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 enrollment of the subject in the study, when 
continuation of the study drug would place the subject at risk as determined by the AbbVie 
Therapeutic Area Medical/Scientific Director.

Introduction of prohibited medications or dosages when continuation of the study drug would 
place the subject at risk, as determined by the AbbVie Therapeutic Area Medical/Scientific 
Director.

Subject is non-compliant with tuberculosis (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 non-melanoma skin cancer (NMSC) or carcinoma in-situ of the 
cervix.

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 Therapeutic Area 
Medical/Scientific Director.

Subject develops a GI perforation (defined as acute, spontaneous perforation of the 
gastrointestinal tract that requires inpatient medical care or urgent surgical intervention other 
than appendicitis or mechanical injury).  See also Section 6.2 Toxicity Management.
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
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 final status of the subject.  At a minimum, 2 telephone calls must be made and one 
certified letter must be sent and documented in the subject's source documentation.
COVID-19 Pandemic-Related Acceptable Protocol Modification
During the COVID 19 pandemic, it has been necessary to employ mitigation strategies to enable the 
investigator to ensure subject safety and continuity of care.  Acceptable mitigation strategies are 
identified and included in the Operations Manual in Appendix F.
The investigator should contact the sponsor medical contact before discontinuing a subject from the 
study for a reason other than "planned per protocol," to ensure that all acceptable mitigation steps have 
been explored.
Refer to the Operations Manual in Appendix F for details on how to handle study activities/procedures.
Interruption/Discontinuation of Study Drug Due to COVID-19 Infection
Delays in study drug dosing due to the COVID-19 pandemic must be discussed with the AbbVie medical 
contact, along with the possibility of premature discontinuation from the study drug dosing period.  
Follow subsequent protocol Section 5.6 for subjects who discontinue study drug.
5.6 Follow-Up for Subject Withdrawal from Study
Discontinuation of Study Drug and Study Participation
Subjects who prematurely discontinue study drug treatment will be discontinued from study 
participation entirely.  If the subject is prematurely discontinued from the study, a Premature 
Discontinuation (PD visit) should be completed as soon as possible, preferably within 2 weeks or 
12 weeks after last injection from Study M16-046, whichever is sooner.  Following discontinuation of 
study drug, the subject will be treated in accordance with the investigator's best clinical judgment.
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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 or 12 weeks after last injection from Study M16-046, whichever is 
sooner.  In addition, if subject is willing, a 30-day follow-up phone call after the last dose of study drug 
may be completed to ensure all treatment-emergent AEs/SAEs have been resolved.
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 Treatment After End of Study
At the subject's last visit, the investigator will discuss the appropriate subsequent treatment with the 
subject.  AbbVie will not provide drug or any other therapy once the subject's participation is concluded.
5.8 Study Drug
The study drug information is presented in Table 2.
Table 2.
Description of Study Drug
Investigational Product
Mode of 
Administration
Formulation
Strength
Manufacturer
Upadacitinib (ABT-494) tablet
oral
Film-coated tablet
30 mg
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.
In cases of state of emergency or pandemic situations, study drug shipment can be made from the study 
site to the subject if allowed by local regulations.  Refer to the Operations Manual Appendix F for details 
on direct-to-patient (DTP) shipment of study drug.
There are no time limits for study drug interruption if no permanent study discontinuation criteria have 
been met.
Storage and Disposition of Study Drug
Upadacitinib tablets must be stored at controlled room temperature (15° to 25°C/59° to 77°F).
The investigational product is for investigational use only and are to be used only within the context of 
this OLE study.  The investigational product 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.  
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Upon receipt, study drug should be stored as specified on the label and kept in a secure location.  Each 
kit will contain a unique kit number.  This kit number is assigned to a subject via 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 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.
Dispense Study Drug 
The type and amount of kits dispensed will be managed by the IRT.  Upadacitinib tablets will be 
dispensed through IRT beginning at Baseline (Day 1) according to dispensation schedule 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 dispensed by the site.  Accountability will also need to be recorded in 
the IRT system at each visit.
State of Emergency or Pandemic-Related Acceptable Protocol Modifications
Study drug may be shipped from the study site directly to the study subject's home if all the following 
criteria are met:

DTP shipment of study drug is allowed by local regulations and the relevant ethics committee

Study drug can be administered by the subject (or subject's caregiver) at home

Subject agrees to have the study drug shipped directly to their home

Shipments may also include other study supplies (e.g., drug dosing diaries, paper copies of 
PROs).  Instructions will be provided by AbbVie as to how a study site can initiate a DTP 
shipment using Marken, a global vendor selected by AbbVie to provide this service when 
necessary.  Shipments of study drugs from the study site to a subject's home will be 
appropriately temperature controlled (qualified shipper or temperature monitoring) within the 
labeled storage conditions.  Signature is required upon delivery; this may be provided by the 
courier after delivery if social distancing measures are in place.  Documentation of the shipment 
is to be retained by the clinical site.

AbbVie will not receive subject identifying information related to these shipments, as the site 
will work directly with the courier.
The study site is responsible for meeting IRB/IEC reporting requirements related to DTP shipments of 
study drug, and for obtaining consent to provide delivery information to the courier and documenting 
this consent in source documents.
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
State of Emergency or Pandemic-Related Acceptable Protocol Modifications for Home 
Healthcare Services 
Subjects may be offered the option of home healthcare visits provided by a study nurse or third-party 
vendor.  Study procedures conducted in the home setting may include those detailed in Section 2.1 of 
the Operations Manual and the collection of blood samples for central or local laboratory testing.  This 
option can only be offered in countries and sites that comply with local regulatory and IRB/IEC 
requirements for homecare.  Any pre-requisite submissions or notifications to the site IRB/IEC and local 
competent health authority should be made, and approvals must be obtained prior to implementation 
of home blood sample collection.
The investigator should be available via phone call if a consultation is necessary.
It is recommended that medical personnel entering a subject's home adhere to local health regulations 
during the COVID-19 pandemic, such as the use of Personal Protective Equipment (PPE), as required.
If the home visits will not be performed by site personnel, the site may be responsible for selecting a 
vendor, contracting with a vendor, and for ensuring continued compliance with the terms of the Clinical 
Study Agreement.  Vendors may not perform efficacy assessments.
Individuals performing home visits need to be added to the delegation log.
Study Drug Administration
Upadacitinib 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 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 tablets should be swallowed whole and should not be split, crushed, or dissolved.
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.
5.9 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, including those that may be due to the COVID-19 pandemic), the investigator is responsible 
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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 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.
In cases of state of emergency or pandemic situations, it is possible that additional protocol 
modifications not outlined in this protocol may become necessary.  If this situation arises, in addition to 
the study informed consent, additional verbal consent may be obtained prior to these adaptations or 
substantial changes in study conduct in accordance with local regulations.
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.  AEs or SAEs ongoing at Week 24 of Study M16-046 will be followed in Study M19-850.  
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.
Subjects will complete the following questionnaires (described below) as specified in the Operations 
Manual (Appendix F):  Worst Pruritus NRS; and Head and Neck - Patient Global Impression of Severity 
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(HN-PGIS).  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.
The PRO instrument should be completed prior to drug administration on Day 1 and prior to any 
discussion of AEs or any review of laboratory findings.
State of Emergency or Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, subject visits may be conducted via phone or video conference.  The 
primary site monitor will inform the site which PROs are eligible for completion by interview.  In this 
situation, sites will read the PRO questions and response options to the subject and record the subject's 
responses.  The subject's ability to view the PRO to understand the questions and response options 
should be preserved.  Sites may share the questionnaire by videoconference or send the questionnaires 
(email or hard copy) to the subjects to allow them to read/understand the questions and responses 
when the subject is providing responses over the phone.  The date and time of PRO data collection 
should be recorded along with who collected the information.
Subjects will complete the following questionnaires as specified in the schedule of assessments:
Worst Pruritus NRS
The Worst Pruritus Numerical Rating Scale (NRS) is an assessment tool that subjects used to report the 
intensity of their pruritus during a daily recall period.  Subjects are asked the question:  "On a scale of 0 
to 10, with 0 being no itch and 10 being the worst imaginable itch, how would you rate your itch at its 
worst during the past 24 hours?"  The NRS will be administered on the tablet at specified site visits in 
Appendix D.
Head and Neck Patient Global Impression of Severity
The Head and Neck - Patient Global Impression of Severity (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 PGIS will be administered on the tablet at specified 
site visits in Appendix D.
Investigator Assessment
The investigator assessments will be recorded on paper worksheets and entered into the eCRF and 
conducted at the study visits specified in Appendix D.  In order to minimize variability, the same assessor 
should evaluate the subject at each visit for the duration of the trial.  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 principal investigator to 
ensure that all assessors are qualified and trained to perform assessments and that all training is 
documented.
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Eczema Area and Severity Index
The EASI is a validated measure used in clinical practice and clinical trials to assess the severity and 
extent of AD.  The EASI is a composite index with scores ranging from 0 to 72.  Four AD disease 
characteristics (erythema, thickness [induration, papulation, edema], scratching [excoriation], and 
lichenification) will each be assessed for severity by the investigator or designee on a scale of "0" 
(absent) through "3" (severe).  In addition, the area of AD involvement will be assessed as a percentage 
by body area of head, trunk, 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 physician 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.
None of the investigator assessments described above (EASI, BSA) can be performed remotely, as they 
require in person evaluation of the skin.
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.
Subjects with a negative TB test result during Study M16-046 will require an annual TB follow-up test to 
be performed.  At Week 28 (approximately 1 year after the TB screening in Study M16-046), all subjects 
will be assessed for evidence of increased risk for TB by a risk questionnaire (see Operations Manual, 
Appendix F) and tested for TB infection by QuantiFERON-TB Gold test.  The site staff will complete the 
TB risk questionnaire in its entirety and enter the data into the appropriate eCRF.  One or more "yes" 
response on the TB risk questionnaire indicates increased risk of TB.
The annual TB-test can be completed at the earliest feasible opportunity if not able to be completed per 
protocol schedule due to COVID-19 restrictions.  If an annual TB test (at Week 28) is newly positive 
(seroconversion), a chest x-ray needs to be performed as soon as possible to aid in distinguishing active 
versus latent TB.  Any positive TB test during 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 at Week 28 visit, the case (including the TB test results) should be discussed with the AbbVie TA 
MD.
Subjects with evidence of active TB must not continue in the OLE study.
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TB Testing:

The QuantiFERON-TB Gold test (or equivalent) should be performed for all subjects.  The 
purified protein derivative (tuberculin) (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 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.

If only a PPD is placed at Study M16-046, then the TB test to be used for the open label study for 
that subject is the PPD test.  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 
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 (i.e., no risk factors identified in the TB 
questionnaire) 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 (such as T-SPOT TB test) may be substituted for 
the QuantiFERON-TB Gold.
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Tuberculosis Prophylaxis
Note:  Rifampicin and Rifapentine are not allowed for TB prophylaxis.
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.
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.
Chest X-Ray
Chest x-ray (posterior-anterior and lateral views) is required for all subjects to rule out the presence of 
TB or other clinically relevant findings following a newly positive result of a TB test.
Subjects can have a repeat chest x-ray 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 chest x-ray.  The 
Principal Investigator will indicate the clinical significance of any findings and will sign and date the 
report.  In the assessment of the chest x-ray, 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 chest x-ray 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.
State of Emergency or Pandemic-Related Acceptable Protocol Modifications
In the event that CXR may not be performed at the planned timepoint due to a state of emergency or 
pandemic situation, perform the CXR at the next feasible visit.
12-Lead Electrocardiogram
A 12-lead ECG will be performed at Week 28 (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
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State of Emergency or Pandemic-Related Acceptable Protocol Modifications
In the event that ECG may not be performed at the planned timepoint due to a state of emergency or 
pandemic situation, perform the 12-lead ECG at the next feasible visit.
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 
AD 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.
State of Emergency or Pandemic-Related Acceptable Protocol Modifications
Due to a state of emergency or pandemic situation, subject visits may be conducted via phone or video 
conference.  In these situations, height and weight measurements may be performed by the subject or 
caregiver as needed.
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.17
State of Emergency or Pandemic-Related Acceptable Protocol Modifications
Due to a state of emergency or pandemic situation, subject visits may be conducted via phone or video 
conference.  In these situations, vital signs may be obtained by the subject or caregiver as needed.
Physical Examination
A complete physical examination including whole surface and adjacent mucosal surfaces for potential 
NMSC will be performed at visits specified in Appendix D.  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.
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State of Emergency or Pandemic-Related Acceptable Protocol Modifications
Due to a state of emergency or pandemic situation, subject visits may be conducted via phone or video 
conference.  In these situations, if a visit by phone or video conference occurs at one of the designated 
study visits specified for complete physical examination, the complete physical examination will be 
performed at the next feasible visit.
Clinical Laboratory Tests
Samples will be obtained for the clinical laboratory tests listed in Table 3.  Blood and urine samples will 
be collected following a minimum 8-hour fast.  If a subject is not able to fast when necessary, 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 Baseline laboratory test results for clinical 
assessment for a particular test will be defined as the Week 24 values from Study M16-046 prior to the 
initial dose of study drug in Study M19-850.
State of Emergency or Pandemic-Related Acceptable Protocol Modifications
During a state of emergency or pandemic situation, if travel restrictions or other changes in local 
regulations prevent the subject from having blood drawn for laboratory testing at the study site, if 
possible, arrange for subjects to have laboratory work done at a local lab, hospital, or other facility.  
Local lab results should be obtained along with reference ranges and kept within the subjects' source 
documentation.  Local laboratory results should be reviewed by the investigator as soon as possible.
If laboratory samples cannot be obtained, study drug administration may be continued provided the 
subject has at least 1 post-baseline visit and investigator has reviewed all prior laboratory results and 
confirms and discusses with the subject that there is no safety concern for the subject to continue use of 
the study drug in the absence of current laboratory values.  Laboratory draws should be obtained as 
close as possible to the scheduled visit.
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Table 3.
Clinical Laboratory Tests
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:
Serum pregnancy (beta human chorionic 
gonadotropin [bHCG]) test
Hepatitis B virus deoxyribonucleic acid 
polymerase chain reaction (HBV 
DNA PCR [Per Toxicity Management 
Guidelines only])
QuantiFERON-TB Gold
High-sensitivity C-reactive protein 
(hsCRP)
Local Lab Tests:
Urine pregnancy test
PPD test / T-SPOT TB
Urinalysis
Specific gravity
Ketones
pH Protein Blood Glucose
Urobilinogen Bilirubin Leukocytes
Nitrites
Microscopic examination, if
needed
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CO2 = carbon dioxide; 
CPK =creatine phosphokinase; DNA = deoxyribonucleic acid; HBV = hepatitis B virus; HDL-C = high-density lipoprotein 
cholesterol; INR = international normalized ratio; LDL-C = low-density lipoprotein cholesterol; PCR = polymerase chain 
reaction; PPD = purified protein derivative (tuberculin); RBC = red blood cell; TB = tuberculosis; WBC = white blood cell
a.
INR will only be measured if ALT and/or AST > 3 × upper limit of normal (ULN).
Pregnancy Tests (Serum and Urine)
A urine pregnancy test will be performed for female of childbearing potential at the Baseline Visit 
(Week 24 visit of Study M16-046) and at minimum at monthly intervals if not already done at study 
visits.  More frequent pregnancy tests will be performed throughout the study if required per local 
requirements.  If the interval between the study visits is more 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 urine pregnancy test performed at the site or at home is negative, then dosing with study 
drug may continue.

In case of positive urine pregnancy test, a serum pregnancy test will be sent to and performed 
by the central laboratory.  If the serum pregnancy test is negative, study drug may continue.  If 
the positive urine pregnancy test is confirmed with the serum pregnancy test the subject is not 
considered eligible to continue in the OLE study and study drug must be permanently 
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discontinued.  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 not eligible;

Negative, the subject can be enrolled into the study;

Still borderline ≥ 3 days later, the subject is considered not eligible.
If during the course of the study a female becomes surgically sterile or post-menopausal and complete 
documentation as described in Section 5.2 for female is available, pregnancy testing is no longer 
required.
A pregnant, planning to become pregnant, or breastfeeding female will not be eligible to enter the study 
or be allowed to continue study drug.
6 SAFETY CONSIDERATIONS
6.1 Complaints and Adverse Events
Complaints
A complaint is any written, electronic, or oral communication that alleges deficiencies related to the 
physical characteristics, identity, quality, purity, potency, durability, reliability, safety, effectiveness, or 
performance of a product/device.  Complaints associated with any component of this investigational 
product must be reported to AbbVie.
Product Complaint
A product complaint is any complaint related to the biologic or drug component of the product or to the 
medical device component(s).
For a product this may include, but is not limited to, damaged/broken product or packaging, product 
appearance whose color/markings do not match the labeling, labeling discrepancies/inadequacies in the 
labeling/instructions (e.g., printing illegible), missing components/product, device not working properly, 
or packaging issues.
Product complaints concerning the investigational product and/or device must be reported to AbbVie 
within 1 business day of the study site's knowledge of the event.  Product complaints occurring during 
the study will be followed up to a satisfactory conclusion.
Medical Complaints/Adverse Events and Serious Adverse Events
An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not the event is considered causally related to the use of the 
product.  In contrast, an adverse reaction (AR) refers to all untoward and unintended responses to an 
investigational medicinal product at least possibly related to any dose administered.
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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 AEs at each visit 
throughout the study.  All AEs will be followed to a satisfactory conclusion.
If any of the following events are reported, then the following supplemental report must be completed 
(Table 4).
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Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not been 
taken.  This does not include an event that would have been fatal if it 
had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any length 
of time or prolongs the subject's hospital stay.  This does not include 
an emergency room visit or admission to an outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that results in 
fetal loss.
Persistent or Significant 
Disability/Incapacity
An event that results in a condition that substantially interferes with 
the activities of daily living of a study subject.  Disability is not 
intended to include experiences of relatively minor medical 
significance such as headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle).
Important Medical Event 
Requiring Medical or Surgical 
Intervention to Prevent 
Serious Outcome
An important medical event that may not be immediately life-
threatening or result in death or hospitalization, but based on 
medical judgment may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the outcomes 
listed above (i.e., death of subject, life threatening, hospitalization, 
prolongation of hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity).  Additionally, any elective or 
spontaneous abortion or stillbirth is considered an important 
medical event.  Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or 
drug abuse.
All AEs reported from the time of study drug administration through 30 days after the last dose of study 
drug administration will be collected, whether solicited or spontaneously reported by the subject.
Additionally, in order to assist the adjudication process, additional information on any potential major 
adverse cardiovascular events will be collected, if applicable.
Adverse event information will be collected as shown in Figure 2.
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Figure 2.
Adverse Event Collection
*
Any AEs occurring prior to the first dose of Study M19-850 should be considered as AEs for Study M16-046, regardless of 
when the consent form is signed.
**
Any AEs occurring on or after the first dose of Study M19-850 should be considered as AEs for Study M19-850.
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.  A SUSAR 
is an adverse reaction of which the nature or severity is not consistent with the applicable product 
information such as investigator's brochure.
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 AESI 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

Renal dysfunction

Hepatic disorders

Elevated CPK
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
Adjudicated embolic and thrombotic events (non-cardiac, non-central nervous system).

COVID-19 (consider while pandemic is ongoing).
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 5.0.
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)
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.
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appropriate clinical management if applicable, and discontinuation of the subjects from the study drug).  
The management of specific AEs and laboratory parameters is described below.
Management of Serious Infections
Subjects should be closely monitored for the development of signs and symptoms of infection during 
and after treatment with study drug.  Study drug should be interrupted if a subject develops a serious 
infection.  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.  If a subject develops zoster, or shows infection with or 
reactivation of any other herpes virus (e.g., HSV, VZV, EBV, CMV), any study drug should at least be 
temporarily interrupted until the episode resolves, or discontinued as patient safety requires.
Management of Herpes Zoster
If a subject develops herpes zoster, consider temporarily interrupting study drug until the episode 
resolves.  Serious AEs of herpes zoster should be reported as serious infections.
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.  Subjects with acute, spontaneous perforation of 
the gastrointestinal tract that requires inpatient medical care or urgent surgical intervention (except for 
appendicitis or mechanical injury) must be permanently 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 subjects who are at
increased risk of 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.
COVID-19
Interrupt study drug in subjects with a confirmed diagnosis of COVID-19.  Consider interrupting study 
drug in subjects with signs and/or symptoms and suspicion of COVID-19.  The COVID-19 eCRF must be 
completed.
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Management of Select Laboratory Abnormalities
For any given laboratory abnormality, the investigator should assess the subject, apply the standard of 
care for medical evaluation and treatment following any local guidelines.  Specific toxicity management 
guidelines for abnormal laboratory values are described in Table 5, and may require a supplemental 
eCRF to be completed (see Protocol Section 6.1 [Complaints and AEs]).  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 5, the repeat testing must occur as soon as possible.
Table 5.
Specific Toxicity Management Guidelines for Abnormal Laboratory Values
Laboratory 
Parameter
Toxicity Management Guideline
Hemoglobin

If hemoglobin < 8 g/dL interrupt study drug dosing and confirm by repeat testing 
with a new sample

If hemoglobin decreases ≥ 3.0 g/dL from Baseline, without an alternative etiology, 
interrupt study drug dosing and confirm by repeat testing with new sample.

If hemoglobin decreases ≥ 3.0 g/dL from Baseline and an alternative etiology is 
known or the hemoglobin value remains in the normal reference range, the subject 
may remain on study drug at the investigator's discretion.

If confirmed, continue to withhold study drug until hemoglobin value returns to 
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.

Interrupt study drug if confirmed < 500/μL by repeat testing with new sample.  If 
value returns to normal reference range or its Baseline value, restarting study drug is 
allowed if there is an alternative etiology identified; documentation should include 
reason that rechallenge is expected to be safe for the subject.
Study drug should be discontinued if no alternative etiology can be found. 
Absolute 
lymphocyte counts 
(ALC)

If confirmed < 500/µL by repeat testing with new sample, interrupt study drug dosing 
until ALC returns to 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.
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 
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Laboratory 
Parameter
Toxicity Management Guideline
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.

If ALT or AST > 8 × ULN, interrupt study drug immediately, confirm by repeat testing 
with a new sample, and contact the TA MD.

Subjects with HBc Ab+ (irrespective of HBs Ab status) and negative HBV DNA PCR 
testing at Study M16-046 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.
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).
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
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6.3 Cardiovascular Adjudication Committee
An independent committee of physician experts in cardiovascular adjudication will be utilized to assess 
potential cardiovascular and thromboembolic AEs in a blinded manner.  Briefly, CAC consists of 
11 voting members including 5 cardiologists, 3 neurologists and 3 thrombotics/vascular specialists.  The 
events that are adjudicated are defined in the CAC charter.  The Sponsor/CRO will provide the list of 
events based on the pre-specified search criteria and all relevant information as a case package for CAC 
adjudication on a monthly basis.  Each randomly assigned CAC member will conduct independent review 
and submit an assessment of the adjudication outcome.  Events may be re-adjudicated if clinically 
relevant data changes or updates occur.  If a decision is not reached via independent review for events, 
a panel meeting may be held for the purpose of adjudication.  A CRO is responsible for coordinating all 
adjudication activities.  The details of the composition and process for the CAC are provided in the CAC 
Charter.
6.4 Other Safety Data Collection
Specific manifestations of AD (i.e., itching, excoriations, oozing, crusting, erythema, etc.) should not be 
reported as individual AEs if they are considered to be a worsening of the underlying disease; instead, 
worsening of AD should be reported as 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 statistical methods provided in this protocol will be focused on efficacy and safety summaries.  
Complete and specific details of the statistical analysis will be described in the Statistical Analysis Plan 
(SAP), which will be signed off within 30 business days after the first subject is dosed.  Furthermore, a 
Week 16 Interim Analysis will be conducted after all ongoing subjects have completed Week 16 and all 
data pertaining to Week 16 are cleaned.  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 subjects who receive at least one dose of study drug 
in the study and will be used for the efficacy analyses.
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The Safety Population is the same as the ITT Population for this study.  This population will be used to 
provide a comprehensive summary of safety.
7.3 Statistical Analyses for Efficacy
All efficacy endpoints will be summarized in the ITT population.
The ITT Population will be summarized by treatment group as randomized at the Baseline of 
Study M16-046.
Continuous variables will be summarized by the number of observations, mean, standard deviation, 
median, minimum, maximum, as well as the 95% confidence intervals (CIs) of the mean values.  
Categorical variables will be summarized by counts and percentages, as well as the 95% CIs of the 
percentages.
There will be no statistical testing for all of the efficacy and safety endpoints.
Efficacy assessments will be summarized by Observed Cases (OC) approach.  No data imputation will be 
applied.  Observed Cases will not include values after a subject prematurely discontinue from study 
drug.
Sample Size Estimation
Approximately 600 subjects that complete treatment in Study M16-046 will roll over in this open label 
treatment extension study.  The sample size is determined by the completion of Study M16-046 and the 
consenting for the extension.
7.4 Statistical Analyses for Safety
Safety will be assessed by AEs, physical examination, laboratory assessments, and vital signs.  Note that 
missing safety data will not be imputed.  Analysis details will be specified in the SAP.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  
Treatment-emergent adverse events are defined as those that began or worsened in severity after the 
first dose of study drug and no more than 30 days after the last dose of the study drug.  The number and 
percentage of subjects experiencing TEAEs will be tabulated using the MedDRA SOC and PT, by severity, 
and by relationship to the study drug as assessed by the investigator.  Summaries (including percentages 
and events per 100 patient-years) of SAEs, deaths, AEs leading to discontinuation, and AESI will be 
provided as well. 
For laboratory and vital signs, mean change from Study M16-046 Baseline and percentage of subject 
with evaluations meeting criteria for pre-defined Potentially Clinically Significant values will be 
summarized.
7.5 Statistical Analysis of Optional Proteomic Biomarker Data
Analysis may be conducted on optional biomarker data for the purpose of identification of prognostic, 
predictive, surrogate, and pharmacodynamic biomarkers associated with efficacy or safety.  The 
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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
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the Independent Ethics Committee/Institutional Review Board (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.
In cases of state of emergency or pandemic situations leading to difficulties in performing protocol-
specified procedures, AbbVie will engage with study site personnel in efforts to ensure the safety of 
subjects, maintain protocol compliance, and minimize risks to the integrity of the study while trying to 
best manage subject continuity of care.  This may include alternative methods for assessments (e.g., 
phone contacts or virtual site visits), alternative locations for data collection (e.g., use of a local lab 
instead of a central lab), and shipping investigational product and/or supplies direct to subjects to 
ensure continuity of treatment where allowed.  Refer to the Operations Manual for additional details.  In 
all cases, these alternative measures must be allowed by local regulations and permitted by IRB/IEC.  
Investigators should notify AbbVie if any urgent safety measures are taken to protect the subjects 
against any immediate hazard.
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.
In cases of state of emergency or pandemic situations, remote monitoring of data may be employed if 
allowed by the local regulatory authority, IRB/IEC, and the study site.
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, 
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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).  During the COVID-19 pandemic, remote monitoring of data may be employed if allowed 
by the local regulatory authority, IRB/IEC, and the study site.
Electronic Patient Reported Data
Patient reported data must be completed for each subject enrolled in this study.  Some of these data are 
being collected with an Electronic Patient Reported Outcome (ePRO) system called Trialmax, provided 
by the technology vendor CRF Health of Plymouth Meeting, PA, USA.  The ePRO system is in compliance 
with Title 21 CFR Part 11.  The documentation related to the system validation of the ePRO system is 
available through the vendor, CRF Health, while the user acceptance testing of the study-specific PRO 
design will be conducted and maintained at AbbVie.
The subject will be entering the data on an electronic device; these data will be uploaded to a server.  
The data on the server will be considered source, and maintained and managed by CRF Health.  Worst 
Pruritus NRS will be completed electronically via an onsite tablet device.  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 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.
Ring J, Alomar A, Bieber T, et al. Guidelines for treatment of atopic eczema (atopic dermatitis) Part I. 
J Eur Acad Dermatol Venereol. 2012;26(8):1045-60.
3.
Krakowski AC, Eichenfield LF, Dohil MA. Management of atopic dermatitis in the pediatric 
population. Pediatrics. 2008;122(4):812-24.
4.
Wollenberg A, Barbarot S, Bieber T, et al. Consensus-based European Guideliines for Treatment of 
Atopic Eczema (Atopic Dermatitis) in Adults and Children:  Part I. J Eur Acad Dermatol Venereol. 
2018;32(5):657-82.
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-Yassky E, et al. Two phase 3 trials of dupilumab versus placebo in 
atopic dermatitis. N Engl J Med. 2016;375(24):2335-48.
8.
Chu CC, 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. AbbVie. Upadacitinib Investigator's Brochure Edition 11. 18 August 2020.
11. 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.
12. 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.
13. European Medicines Agency. Dupixent (dupilumab) SmPC London, England2018 [Available from: 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/004390/huma
n_med_002158.jsp&mid=WC0b01ac058001d124.
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14. Dupixent (dupilumab) injection, for subcutaneous use [prescribing information]. Bridgewater, NJ; 
Sanofi-Aventis, 2017.
15. 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.
16. Norman P. Selective JAK1 inhibitor and selective Tyk2 inhibitor patents. Expert Opin Ther Pat. 
2012;22(10):1233-49.
17. 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.
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APPENDIX A. STUDY SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
AD
atopic dermatitis
AE
adverse event
AESI
adverse events of special interest
BCG
bacilli Calmette-Guérin
BSA
body surface area
CAC
Cardiovascular Adjudication Committee
CI
confidence interval
CLDN1
Claudin 1
CNS
central nervous system
COVID-19
Coronavirus Disease – 2019
CPK
creatine phosphokinase
CRF
case report form
CTCAE
Common Terminology Criteria for Adverse Events
CYP3A
cytochrome P450 3A isoform subfamily
DNA
deoxyribonucleic acid
DTP
Direct-to-patient
EASI
Eczema Area and Severity Index
ECG
Electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
ePRO
Electronic Patient Reported Outcome
EU
European Union
EudraCT
European Clinical Trials Database
FLG
Filaggrin
FSH
follicle-stimulating hormone
GCP
Good clinical practice
GI
gastrointestinal
HLA
Human Leukocyte Antigen
HN-PGIS
Head and Neck - Patient Global Impression of Severity
hs-CRP
High-sensitivity C reactive protein
ICH
International Council for Harmonisation
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IEC
Independent ethics committee
IEC/IRB
Independent Ethics Committee/Institutional Review Board
IGA
Investigator's Global Assessment
IgE
Immunoglobulin E
IGRA
Interferon Gamma Release Assay
IL
interleukin
IMP
Investigational Medicinal Product
IRB
Institutional review board
IRT
Interactive response technology
ITT
intent-to-treat
IU
International Unit
IUD
intrauterine device
IUS
Intrauterine hormone-releasing system
JAK
Janus kinase
JAK1
Janus kinase 1
JAK2
Janus kinase 2
MACE
major adverse cardiac event
MedDRA
Medical Dictionary for Regulatory Activities
NCI
National Cancer Institute
NK
natural killer
NMSC
non-melanoma skin cancer
NRS
numerical rating scale
OC
Observed Cases
OLE
open-label extension
PD visit
Premature Discontinuation visit
PK
Pharmacokinetic(s)
PPD
purified protein derivative (tuberculin)
PRO
patient-reported outcome
Ps
psoriasis
PT
preferred term
PUVA
psoralen and ultraviolet A radiation
QD
once a day
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate using Fridericia's formula
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RA
rheumatoid arthritis
RNA
ribonucleic acid
RSI
Reference Safety Information
SAE
Serious adverse event
SAP
Statistical analysis plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SOC
system organ class
SUSAR
Suspected unexpected serious adverse reactions
TA MD
Therapeutic Area Medical Director
TB
tuberculosis
TEAE
treatment-emergent adverse event
TNF
tumor necrosis factor
Tyk2
tyrosine kinase 2
US
United States
UV
ultraviolet
WBC
white blood cell
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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M19-850:  Evaluation of Upadacitinib in Adult Subjects with Moderate to Severe Atopic 
Dermatitis
Protocol Date:  07 January 2021
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
Data and Statistical Sciences
Pharmacovigilance & Patient Safety
Immunology Translational Science 
Medical Writing
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APPENDIX E. PROTOCOL SUMMARY OF CHANGES
Previous Protocol Versions
Protocol
Date
Version 1.0
28 May 2019
Version 1.1 (VHP countries only)
26 July 2019
Version 2.0
26 August 2019
Version 3.0
28 January 2020
Version 3.1 (Germany and Czech Republic only)
02 April 2020
Version 4.0
06 March 2020
Version 4.1 (Germany and Czech Republic only)
10 June 2020
Version 4.1.1 (Germany only)
31 July 2020
The purpose of this Amendment is to incorporate the following changes:
Summary of Protocol Changes:
The purpose of this version is to incorporate necessary protocol modifications due to the COVID-19 
pandemic, add an interim analysis, incorporate additional description about management of 
gastrointestinal performation and serious herpes zoster, and provide clarification about the timing of 
efficacy assessments.
Protocol modifications due to the COVID-19 pandemic are as follows:

Section 2.2 – included information on the re-evaluation of the benefit and risk to subjects 
participating in the study.  There is no additional risk to subjects or state what the additional 
risks are that may change the benefit-risk balance to participating subjects.

Section 5.5 – added instructions to refer to Operations Manual for necessary changes to 
activities or procedures in the event of temporary study [drug] interruption/halt.

Section 5.7 – included instructions that in the event the subject cannot pick up study drug 
onsite, refer to the Operations Manual for DTP shipment as needed and permitted by local 
regulations.

Section 5.9 – clarified that protocol deviations may include modifications due to COVID-19.

Section 8.2 – noted that AbbVie will modify the study protocol as necessary due to the 
pandemic, referring to the Operations Manual in Appendix F for additional details.  Investigators 
must also notify AbbVie if any urgent safety measures are taken.

Section 9 – noted that remote monitoring may be employed as needed

Appendix D – added reference to Operations Manual for allowed modification
Page 59 of 79
 


STUDY M19-850  |  Version 5.0  |  EudraCT 2019-001227-12
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

Appendix F – Operations Manual updated to include details on how to perform specific 
activities/procedures that may be impacted by changes in global/local regulations due to the 
pandemic.
Statements about the interim analysis were added to the following subsections to incorporate this 
change:

Section 4.1 – Sentence added that an interim analysis will be performed after all subjects have 
completed the Week 16 visit.

Section 7.1 – Sentence added that an interim analysis will be performed after all subjects have 
completed the Week 16 visit and all data pertaining to Week 16 are cleaned.
Rationale:  To assess efficacy and safety after switching from dupilumab to upadacitinib at a 
similar timeframe as the upadacitinib atopic dermatitis pivotal Phase 3 studies.
Updates to the description and management of gastrointestinal perforation (added text underlined) 
were made to:

Section 5.5 – "Subject develops a gastrointestinal perforation (defined as acute, spontaneous 
perforation of the gastrointestinal tract that requires inpatient medical care or urgent surgical 
intervention other than appendicitis or mechanical injury).  See also Section 6.2 Toxicity 
Management."

Section 6.2 – 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.  Subjects with acute, spontaneous perforation of the 
gastrointestinal tract that requires inpatient medical care or urgent surgical intervention (except 
for appendicitis or mechanical injury) must be permanently discontinued from study drug.
Rationale:  To provide further clarity on the characteristics of GI perforations for investigators 
and requirement for permanent discontinuation of study drug.
Other changes:

Synopsis and Section 3.3 – Wording was updated to state that efficacy endpoints will be 
assessed at all visits through Week 52 only. 
Rationale:  To provide clarification about the timing of efficacy assessments.

Section 6.2 – Wording about management of herpes zoster was added:  "Serious AEs of herpes 
zoster should be reported as serious infections."
Rationale:  To incorporate wording from protocol version 4.1.1.

Section 6.2 – Management of Hypersensitivity was removed.  Management of hypersensitivity 
was included in Study M16-046 for subjects who received dupilumab and is not used in studies 
in which upadacitinib is the only treatment drug.  No subjects receive dupulimab in this 
extension study.
Rationale:  Management of hypersensitivity is not needed in studies when upadacitinib is the 
only treatment drug.
Page 60 of 79
 

SAP_001.pdf: 
Upadacitinib
M19-850 – Statistical Analysis Plan
Version 5.0 – 01 August 2023
1
Statistical Analysis Plan for Study M19-850
An Open-Label Treatment Extension Study for the 
Treatment of Adult Subjects with Moderate to 
Severe Atopic Dermatitis Who Completed Treatment 
in Study M16-046
Date: 01 August 2023
Version 5.0
 
NCT04195698


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Table of Contents
1.0
Introduction...........................................................................5
2.0
Study Design and Objectives ................................................5
2.1
Objectives, Hypotheses and Estimands................................................... 5
2.2
Study Design Overview.......................................................................... 5
2.3
Treatment Assignment and Blinding....................................................... 7
2.4
Sample Size Determination .................................................................... 7
3.0
Endpoints...............................................................................8
3.1
Primary Endpoints.................................................................................. 8
3.2
Secondary Endpoints.............................................................................. 8
3.3
Other Efficacy Endpoints ....................................................................... 8
3.4
Safety Endpoints .................................................................................... 9
4.0
Analysis Populations .............................................................9
5.0
Subject Disposition..............................................................10
6.0
Study Drug Duration and Compliance ..............................10
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ...................12
7.1
Demographics and Baseline Characteristics.......................................... 12
7.2
Medical History.................................................................................... 13
7.3
Prior and Concomitant Medications...................................................... 13
8.0
Handling of Potential Intercurrent Events for the 
Primary and Key Secondary Endpoints ............................14
9.0
Efficacy Analyses.................................................................14
9.1
General Considerations......................................................................... 14
9.2
Handling of Missing Data..................................................................... 15
9.3
Primary Efficacy Endpoints and Analyses ............................................ 16
9.3.1
Primary Efficacy Endpoints.................................................................. 16
9.3.2
Main Analysis of Primary Efficacy Endpoints ...................................... 16
9.3.3
Sensitivity and Supplementary Analyses of the Primary Efficacy 
Endpoints ............................................................................................. 16
9.4
Secondary Efficacy Endpoints and Analyses ........................................ 16
9.4.1
Key Secondary Efficacy Endpoints....................................................... 16
 


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9.4.2
Main Analyses of Key Secondary Efficacy Endpoints .......................... 16
9.4.3
Sensitivity and Supplementary Analyses for Key Secondary 
Efficacy Endpoints ............................................................................... 16
9.4.4
Supportive Secondary Efficacy Endpoints and Analyses....................... 16
9.5
Additional Efficacy Analyses ............................................................... 17
9.6
Efficacy Subgroup Analyses................................................................. 17
10.0
Safety Analyses....................................................................18
10.1
General Considerations......................................................................... 18
10.2
Adverse Events..................................................................................... 18
10.2.1
Treatment-Emergent Adverse Events.................................................... 18
10.2.2
Adverse Event Overview...................................................................... 19
10.2.3
Treatment-Emergent Adverse Events by SOC and/or PT...................... 20
10.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure .............................................................................................. 20
10.2.5
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation ........................................................................... 21
10.2.6
Adverse Events of Special Interest........................................................ 21
10.2.7
Listing of Adverse Events..................................................................... 22
10.2.8
Acne Adverse Events ........................................................................... 22
10.3
Analysis of Laboratory Data................................................................. 22
10.4
Analysis of Vital Signs......................................................................... 25
10.5
Safety Subgroup Analyses.................................................................... 26
10.6
Other Safety Analyses .......................................................................... 26
11.0
Other Analyses ....................................................................26
12.0
Interim Analyses..................................................................26
12.1
Data Monitoring Committee................................................................. 26
13.0
Overall Type-I Error Control.............................................27
14.0
Version History ...................................................................27
15.0
References............................................................................28
List of Tables
Table 1.
List of Laboratory Variables................................................................. 23
 


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Table 2.
SAP Version History Summary ............................................................ 27
List of Figures
Figure 1.
Study Schematic..................................................................................... 7
List of Appendices
Appendix A.
Protocol Deviations .............................................................................. 29
Appendix B.
Definition of Adverse Events of Special Interest................................... 30
Appendix C.
Potentially Clinically Important Criteria for Safety Endpoints .............. 32
Appendix D.
EASI Scoring Algorithm ...................................................................... 35
Appendix E.
Patient Report Outcome Scoring........................................................... 38
Appendix F.
Activity Schedule ................................................................................. 39
 


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1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for upadacitinib 
Study Protocol M19-850, A Phase 3b, open-label treatment extension study of 
upadacitinib for the treatment of adult subjects with moderate to severe atopic dermatitis 
who completed treatment in Study M16-046.
Study M19-850 examines the long-term safety, tolerability and efficacy of upadacitinib in 
adult subjects with moderate to severe atopic dermatitis who successfully completed 
treatment in Study M16-046.
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 14.0.
2.0
Study Design and Objectives
2.1
Objectives, Hypotheses and Estimands
The objective of this study is to assess the long-term safety, tolerability and efficacy of 
upadacitinib in adult subjects with moderate to severe AD who successfully completed 
treatment in Study M16-046.
2.2
Study Design Overview
This is a Phase 3b, single arm, open-label extension (OLE) study for adults (18 – 75 years 
of age at entry into Study M16-046) with moderate to severe AD who have successfully 
completed treatment in Study M16-046. These subjects should be determined to be 
eligible to continue treatment with upadacitinib by the Principal Investigator during the 
 


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Baseline visit of this OLE study. The Baseline visit for this study will be the Week 24 
visit of Study M16-046.
The study is comprised of a Baseline visit (Week 24 visit of Study M16-046), a 52-week 
open-label treatment period, and an 84-Week End-of-Study Follow-Up Visit (or phone 
call if a visit is not possible 30 days after the last dose of upadacitinib). End-of-Study 
Follow-Up visits are only applicable for the following countries and regions: Germany, 
France, Finland, Netherlands, Norway, Taiwan, Croatia, Poland, Czech Republic, and 
Hungary. The 30-day follow-up visit is done to determine the status of any ongoing 
AEs/SAEs or the occurrence of any new AEs/SAEs is required. These subjects will be 
considered as having completed the study. Subjects, who are eligible to enroll in the OLE 
study, will receive daily oral doses of upadacitinib 30 mg from the Baseline visit up to the 
Week 52 visit. The schematic of the study is shown in Figure 1.
Safety and efficacy assessments will be performed through Week 52 for all sites, and 
additional safety assessments will be performed every 12 weeks after Week 52 up to 
Week 136 for sites in the following countries and regions: Germany, France, Finland, 
Netherlands, Norway, Taiwan, Croatia, Poland, Czech Republic, and Hungary. 
See Section 5.0 of the protocol for information regarding eligibility criteria.
An interim analysis will occur after all ongoing subjects have completed the Week 16 
visit. The schematic of the study is shown in Figure 1.
The Final database lock will take place after all subjects complete the study.
 


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Figure 1.
Study Schematic
QD=once daily
a.
Efficacy evaluations will not be performed after Week 52.
2.3
Treatment Assignment and Blinding
All subject enrolled to M19-850 will receive open label upadacitinib 30 mg QD 
throughout the study.
The type and amount of kits dispensed will be managed by the Interactive Response 
Technology (IRT).
2.4
Sample Size Determination
Approximately 600 subjects who complete treatment in Study M16-046 will roll over in 
this open label treatment extension study. The sample size is determined by the expected 
rate of completion of Study M16-046 and subject consent for the extension.
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.0
Endpoints
3.1
Primary Endpoints
There is no primary efficacy endpoint for this study.
The primary safety endpoints are:
●
Treatment emergent adverse events (TEAEs);
●
Serious adverse events (SAEs);
●
Adverse events of special interest (AESI);
●
AEs leading to discontinuation of study drug;
●
Vital signs, laboratory tests, and physical examination findings
3.2
Secondary Endpoints
There is no secondary efficacy endpoint for this study.
3.3
Other Efficacy Endpoints
The following efficacy endpoints will be assessed at all visits through Week 52. Baseline 
refers to the Baseline value in Study M16-046. All endpoints are defined relative to the 
Baseline values in Study M16-046.
●
Change and percent Change from Baseline in EASI;
●
Change and percent change from Baseline in Worst Pruritus Numerical Rating 
Scale (NRS);
●
Proportion of subjects achieving EASI 75/90/100;
●
Change from Baseline in body surface area (BSA);
●
Proportion of subjects achieving an improvement (reduction) in Worst Pruritus 
NRS ≥ 4 from Baseline among subjects who had Worst Pruritus NRS ≥ 4 at 
Baseline;
●
Proportion of subjects achieving 75% reduction in EASI in the head and neck 
body region from Baseline;
 


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●
Proportion of subjects achieving 75% reduction in EASI in each body region 
(other than head and neck) from Baseline;
●
Proportion of subjects achieving 75% reduction in EASI in the head and neck 
body region among subjects who received dupilumab in Study M16-046 and 
did not achieve 75% reduction in EASI in the head and neck body region at 
Week 24 of Study M16-046;
●
Proportion of subjects achieving 75%/90%/100% reduction in EASI (EASI 
75/90/100) among subjects who received dupilumab in Study M16-046 and 
did not achieve EASI 75 at Week 24 of Study M16-046;
●
Proportion of subjects achieving EASI 90/100 among subjects who received 
dupilumab in Study M16-046 and did not achieve EASI 90 at Week 24 of 
Study M16-046;
●
Proportion of subjects achieving EASI 100 among subjects who received 
dupilumab in Study M16-046 and did not achieve EASI 100 at Week 24 of 
Study M16-046;
●
Proportion of subjects achieving an improvement (reduction) in Worst Pruritus 
NRS reduction ≥ 4 among subjects who had Worst Pruritus NRS ≥ 4 at 
Baseline, received dupilumab in Study M16-046 and did not achieve Worst 
Pruritus NRS reduction ≥ 4 at Week 24 of Study M16-046.
3.4
Safety Endpoints
The safety endpoints are described in Section 3.1.
4.0
Analysis Populations
Significant non-compliance was identified at a site. As a result of this finding, subjects 
enrolled in this site will not be included in any analysis population and data collected from 
this site will not be included in any analysis.
The following populations will be used for the analyses.
The Intent-to-Treat (ITT) Population consists of all enrolled subjects who receive at least 
one dose of study drug in the study and will be used for the efficacy analyses.
 


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The Safety Population is the same as the ITT Population for this study. This population 
will be used to provide a comprehensive summary of safety.
5.0
Subject Disposition
The total number of subjects who were treated will be summarized.
The number of subjects for each of the following categories will be summarized by 
treatment group randomized in M16-046 in the ITT Population:
●
Subjects who completed protocol-specified treatment;
●
Subjects who prematurely discontinued study drug (all reasons and primary 
reason);
●
Subjects who completed the study;
Number and percentage of subjects who discontinued study drug will be summarized by 
reason (primary reason and all reasons). Subjects with multiple reasons for premature 
discontinuation will be counted once in the calculation of the number and percentage of 
total discontinuations.
6.0
Study Drug Duration and Compliance
Study Drug Duration (in Days):
Summary of study drug duration and study drug compliance will be provided in M19-850
for the Safety Population during the entire treatment period. Study drug duration (days) 
will be summarized using the number of subjects, mean, standard deviation, minimum, 
median and maximum for each treatment group.
●
Duration of upadacitinib is defined for each subject as last dose date of 
upadacitinib minus first dose date of upadacitinib +1, 
 


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In addition, the number and percentage of subjects exposed to upadacitinib will be 
summarized for the following categories of exposure duration for the Safety Population 
starting from the first dose of upadacitinib in M16-046 or M19-850:
●
≥ 4 weeks
●
≥ 12 weeks
●
≥ 24 weeks
●
≥ 36 weeks
●
≥ 48 weeks
●
≥ 52 weeks
●
≥ 64 weeks
●
≥ 76 weeks
●
≥ 88 weeks
●
≥ 100 weeks
●
≥ 112 weeks
●
≥ 124 weeks
●
≥ 136 weeks
●
≥ 148 weeks
●
≥ 160 weeks
Compliance:
Treatment compliance will be summarized in the Safety Population for the entire 
treatment period.
Upadacitinib compliance for an individual subject is defined as the number of 
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.
 


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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 M16-046 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 M16-046 treatment group.
7.1
Demographics and Baseline Characteristics
Subject Demographics
The following demographic and Baseline parameters will be summarized.
Unless otherwise specified, the baseline below refers to the baseline of Study M16-046.
Subject Demographics
●
Sex (male, female)
●
Age (years), defined as the number of years from date of birth to date of 
first drug
●
Age categories (< 40, ≥ 40 to < 65, ≥ 65 years).
●
Race (White, Black or African American, Asian, American Indian or Alaska 
Native, Native Hawaiian or Other Pacific Islander, Other, Multi Race)
●
Ethnicity (Hispanic or Latino, Not Hispanic or Latino)
●
Body weight (kg)
General Baseline Characteristics at the Entry of Study M16-046 and Study M19-850
●
EASI (Eczema Area and Severity Index)
●
BSA (Body Surface Area) with Atopic Dermatitis
 


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●
Worst Pruritus NRS
●
Daily Worst Pruritus NRS (Entry of Study M16-046 only)
●
IGA categories (< 3 or missing, 3, 4) (Entry of Study M16-046 only)
Atopic Dermatitis History
●
Duration of Atopic Dermatitis since diagnosis (years)
●
Duration of Atopic Dermatitis between symptoms and diagnosis (years)
Nicotine and Alcohol Use
●
Smoking history (Unknown, Never, Current, Former)
●
Alcohol History (Unknown, Never, Current, Former)
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. 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 of Study M16-046. A concomitant medication is defined as any medication that 
started prior to the date of the first dose of study drug of Study M19-850 and continued to 
 


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be taken after the first dose of study drug of Study M19-850 or any medication that started 
on or after the date of the first dose of study drug of Study M19-850, but not after the date 
of the last dose of study drug of Study M19-850. 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
Handling of Potential Intercurrent Events for the 
Primary and Key Secondary Endpoints
Since M19-850 does not have primary or secondary efficacy endpoints, so there is no 
handling of potential intercurrent events for them.
9.0
Efficacy Analyses
9.1
General Considerations
An Interim Analysis will be performed after all ongoing subjects have completed the 
Week 16 visit. The Final database lock will be performed at the end of study.
Efficacy variables will be summarized in the Study M19-850 ITT Population at each visit 
of Study M16-046 and Study M19-850, unless otherwise specified. No statistical testing 
will be performed. 
A subject's M16-046 Baseline is defined as the last non-missing observation on or before 
their first dose of study drug in M16-046. For randomized but not treated subjects, the 
Baseline value will be the last non-missing measurement recorded prior to randomization. 
All efficacy endpoints defined below are relative to the M16-046 Baseline unless 
otherwise specified.
Efficacy assessments for ITT Population will be presented for the following three groups 
at each visit:
●
subjects originally randomized to dupilumab in Study M16-046
 


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●
subjects originally randomized to upadacitinib in Study M16-046
●
ITT Population (only applicable at visits of Study M19-850)
Continuous variables will be summarized by the number of observations, mean, standard 
deviation, median, minimum, maximum, 25th and 75th percentiles, as well as the 95% 
confidence intervals (CIs) of the mean values. Categorical variables will be summarized 
by counts and percentages, as well as the 95% CIs of the percentages.
The Observed Cases (OC) approach as defined in Section 9.2 will be used for all efficacy 
variables.
Analysis of Categorical Variables
For ITT Population, frequencies and percentages will be summarized along with 95% 
confidence interval (CI) based on normal approximation.
OC will be the only approach for categorical endpoints (Section 9.2).
Analysis of Continuous Variables
For ITT Population, the raw values at each visit and Baseline, change from 
Baseline/percent change from Baseline will be presented for the three treatment groups
mentioned in this Section who have both Baseline and post-baseline visit values. The 
mean, 95% confidence interval, standard error, Min, Q1, median, Q3 and Max will be 
summarized.
9.2
Handling of Missing Data
Missing data will be handled using the following methods for the efficacy analyses:
●
Observed Cases (OC): The OC analysis will not impute values for missing 
evaluations, and thus a subject who does not have an evaluation on a scheduled 
visit will be excluded from the OC analysis for that visit. OC will exclude 
values after a subject prematurely discontinue from study drug + 1 days.
 


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OC will be the only imputation method for all the efficacy endpoints.
9.3
Primary Efficacy Endpoints and Analyses
9.3.1
Primary Efficacy Endpoints
There is no primary efficacy endpoint for this study.
9.3.2
Main Analysis of Primary Efficacy Endpoints
This section is not applicable since there is no primary endpoint in this study.
9.3.3
Sensitivity and Supplementary Analyses of the Primary 
Efficacy Endpoints
This section is not applicable since there is no primary endpoint in this study.
9.4
Secondary Efficacy Endpoints and Analyses
9.4.1
Key Secondary Efficacy Endpoints
There is no secondary efficacy endpoint for this study.
9.4.2
Main Analyses of Key Secondary Efficacy Endpoints
This section is not applicable since there is no secondary endpoint in this study. 
9.4.3
Sensitivity and Supplementary Analyses for Key Secondary 
Efficacy Endpoints
This section is not applicable since there is no secondary endpoint in this study.
9.4.4
Supportive Secondary Efficacy Endpoints and Analyses
This section is not applicable since there is no secondary endpoint in this study.
 


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9.5
Additional Efficacy Analyses
Other efficacy endpoints are listed in Section 3.3. The analysis detail is specified in 
Section 9.1.
The following endpoints will be summarized only at the visits of Study M18-850.
●
Proportion of subjects achieving 75% reduction in EASI in the head and neck 
body region among subjects who received dupilumab in Study M16-046 and 
did not achieve 75% reduction in EASI in the head and neck body region at 
Week 24 of Study M16-046;
●
Proportion of subjects achieving 75%/90%/100% reduction in EASI 
(EASI 75/90/100) among subjects who received dupilumab in Study M16-046 
and did not achieve EASI 75 at Week 24 of Study M16-046;
●
Proportion of subjects achieving EASI 90/100 among subjects who received 
dupilumab in Study M16-046 and did not achieve EASI 90 at Week 24 of 
Study M16-046;
●
Proportion of subjects achieving EASI 100 among subjects who received 
dupilumab in Study M16-046 and did not achieve EASI 100 at Week 24 of 
Study M16-046;
●
Proportion of subjects achieving an improvement (reduction) in Worst Pruritus 
NRS reduction ≥ 4 among subjects who had Worst Pruritus NRS ≥ 4 at 
Baseline, received dupilumab in Study M16-046 and did not achieve Worst 
Pruritus NRS reduction ≥ 4 at Week 24 of Study M16-046.
Missing data will be imputed as specified in Section 9.2.
9.6
Efficacy Subgroup Analyses
There will be no efficacy subgroup analyses in this study.
 


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10.0
Safety Analyses
10.1
General Considerations
Safety data will be summarized for the Safety Population. Safety summaries will include 
data collected from the first dose of updacitinib in Study M16-046 or Study M19-850, 
whichever is earlier.
All the safety related endpoints will be summarized for the following three groups, unless 
otherwise specified:
●
Subjects originally randomized to dupilumab in Study M16-046 and continued 
in Study M19-850
●
Subjects originally randomized to upadacitinib in Study M16-046 and 
continued in Study M19-850
●
All the subjects dosed in Study M19-850
For laboratory and vital sign tables, only the first two groups will be included.
10.2
Adverse Events
Adverse events (AEs) will be summarized and presented using primary MedDRA System 
Organ Classes (SOCs) and preferred terms (PTs) according to the version of the MedDRA 
coding dictionary used for the study at the time of database lock. The actual version of the 
MedDRA coding dictionary used will be noted in the AE tables and in the clinical study 
report. Specific adverse events will be counted once for each subject for calculating 
percentages, unless stated otherwise. In addition, if the same adverse event occurs 
multiple times within a subject, the highest severity and level of relationship to 
investigational product will be reported.
10.2.1
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 during Study M16-046 or 
 


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Study M19-850 through 30 days following the last dose of upadacitinib. If an incomplete 
onset date is collected for an adverse event, the event will be assumed to be treatment-
emergent unless there is other evidence that confirms that the event is not treatment-
emergent (e.g., the event end date is prior to the study drug start date). Events where the 
onset date is the same as the study drug start date are assumed to be treatment-emergent. 
All treatment-emergent AEs in the Safety Population will be summarized during the 
administration of upadacitinib in Study M16-046 and/or Study M19-850, as well as by 
primary MedDRA SOC and Preferred Term. The SOCs will be presented in alphabetical 
order, and the PTs will be presented in alphabetical order within each SOC.
The number and percentage of subjects experiencing treatment-emergent AEs as well as 
exposure-adjusted number of events will be summarized.
10.2.2
Adverse Event Overview
An overview of TEAEs will be presented consisting of the number and percentage of 
subjects experiencing at least one event for each of the following TEAE categories:
●
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)
●
Any serious treatment-emergent AE
●
Any treatment-emergent AE leading to discontinuation of study drug
●
Any treatment-emergent AE leading to death
○
All deaths will be summarized:
●
Deaths occurring ≤ 30 days after last dose of study drug
●
Deaths occurring > 30 days after last dose of study drug.
 


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10.2.3
Treatment-Emergent Adverse Events by SOC and/or PT
Treatment-emergent adverse events will be summarized by SOC and PT; by maximum 
relationship to study drug as assessed by the investigator (e.g., reasonable possibility or no 
reasonable possibility) and SOC and PT; by SOC and PT and maximum toxicity; and by 
subject number and SOC and PT. Specific adverse events will be counted once for each 
subject for calculating percentages, unless stated otherwise. In addition, if the same 
adverse event occurs multiple times within a subject, the highest toxicity and level of 
relationship to investigational product will be reported.
In addition, treatment-emergent adverse events will be summarized by PT and sorted by 
decreasing frequency for the study treatment group.
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
10.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure
Exposure-adjusted number of TEAEs per 100 patient-years will be provided, where 
number of TEAEs per 100 patient-years of exposure are defined as the number of TEAEs 
divided by the total exposure in 100 patient-years. These will be presented for the 
following TEAE categories. 
●
Any TEAE 
●
Any treatment-emergent SAE 
●
Any TEAE leading to discontinuations of study drug
 


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●
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
Note that one event per preferred term per day per subject will be counted in the 
calculation of the number of TEAEs (i.e., a preferred term will 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) + 1 days of all subjects normalized by 365.25, and rounded to 1 decimal 
place.
10.2.5
SAEs (Including Deaths) and Adverse Events Leading to 
Study Drug Discontinuation
SAEs (including deaths) and AEs leading to study drug discontinuation will be 
summarized by SOC and PT and in listing format.
10.2.6
Adverse Events of Special Interest
The AESI categories will be identified by the following search criteria per Standard 
MedDRA Queries (SMQs)/Company MedDRA Queries (CMQs) specified in 
Appendix B.
Overview and exposure-adjusted event rates per 100 patient-years of Treatment-emergent 
Adverse events of special interest will be provided.
Treatment-emergent Adverse events of special interest will be summarized by SOC and 
PT and listing format. Additionally, AESI rates per 100 patient years of study drug 
exposure using SOC by PT will be provided for each treatment group.
 


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Information on the extent of herpes zoster infection and acne will be summarized as 
collected in the respective AE form.
10.2.7
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 treatment-emergent SAEs.
●
Listing of TEAEs leading to discontinuation of study drug.
●
Listing of all deaths.
●
Listing of treatment-emergent AESIs.
10.2.8
Acne Adverse Events
The investigator-identified acne AEs will be summarized by involvement, morphology, 
and predisposing factors.
10.3
Analysis of Laboratory Data
Data collected from central and local laboratories, including additional laboratory testing 
due to an SAE, will be used in all analyses, except for Baseline where SAE-related 
laboratory assessments on or before the first dose of study drug will be excluded. For the 
assessments of laboratory data, values collected more than 30 days after the last dose of 
study drug will be excluded. The clinical laboratory tests defined in the protocol 
operations manual (e.g., hematology and clinical chemistry) will be summarized.
 


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Table 1.
List of Laboratory Variables
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:
Serum pregnancy (beta human chorionic 
gonadotropin [bHCG]) test
Hepatitis B virus deoxyribonucleic acid 
polymerase chain reaction (HBV DNA PCR 
[Per Toxicity Management Guidelines 
only])
QuantiFERON-TB Gold
High-sensitivity C-reactive protein (hsCRP)
Local Lab Tests:
Urine pregnancy test
PPD test/T-SPOT TB
Urinalysis
Specific gravity
Ketones
pH Protein Blood
Glucose
Urobilinogen Bilirubin
Leukocytes
Nitrites
Microscopic examination, 
if needed
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CO2 = carbon dioxide; 
CPK = creatine phosphokinase; DNA = deoxyribonucleic acid; HBV = hepatitis B virus; HDL-C = high-density 
lipoprotein cholesterol; INR = international normalized ratio; LDL-C = low-density lipoprotein cholesterol; PCR = 
polymerase chain reaction; PPD = purified protein derivative (tuberculin); RBC = red blood cell; TB = tuberculosis; 
WBC = white blood cell
a.
INR will only be measured if ALT and/or AST > 3 × upper limit of normal (ULN).
Each laboratory variable will be summarized for the following time points:
●
Subjects originally randomized to dupilumab in Study M16-046 and continued 
in Study M19-850: All post-baseline visits in M19-850. The Baseline for this 
group is defined as the last non-missing observation on or before their first 
dose of study drug in M19-850.
 


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●
Subjects originally randomized to upadacitinib in Study M16-046 and 
continued in Study M19-850: All post-baseline visits in M16-046 and 
M19-850. The Baseline for this group is defined as the last non-missing 
observation on or before their first dose of study drug in M16-046. 
The summary includes the number of non-missing observations, mean and standard 
deviation, median, minimum and maximum. Mean change from baseline to each 
applicable post-baseline visit mentioned above will be summarized for selected laboratory 
variables, with the number of observations, baseline mean, and visit mean. The change 
from baseline mean, standard error, and 95% confidence interval will be presented for the 
mean change from baseline.
Changes in laboratory parameters will be tabulated using shift tables by NCI CTC criteria 
version 4.03. A shift table from baseline either to the worse value (based on NCI CTC 
criteria) during treatment or to minimum and maximum value (based on normal range), 
will be created. A similar shift table will be provided to summarize shifts from baseline to 
the final post-baseline value.
Laboratory abnormalities meeting CTC criteria grade 3 and 4 will be summarized.
Laboratory abnormalities will be evaluated based on Potentially Clinically Important 
(PCI) criteria during the administration of upadacitinib in Study M16-046 and 
Study M19-850 (Appendix C). For each laboratory PCI criterion, the number and 
percentage of subjects who have a laboratory value meeting the criteria will be 
summarized. Listings will be provided to summarize subject-level laboratory data for 
subjects meeting PCI criteria.
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 
 


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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
10.4
Analysis of Vital Signs
Each vital sign variable will be summarized for the following time points:
●
Subjects originally randomized to dupilumab in Study M16-046 and continued 
in Study M19-850: All post-baseline visits in M19-850. The Baseline for this 
group is defined as the last non-missing observation on or before their first 
dose of study drug in M19-850.
●
Subjects originally randomized to upadacitinib in Study M16-046 and 
continued in Study M19-850: All post-baseline visits in M16-046 and 
M19-850. The Baseline for this group is defined as the last non-missing 
observation on or before their first dose of study drug in M16-046. 
 


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The summary includes non-missing observations, mean and standard deviation, median, 
minimum and maximum. Mean change from baseline to each applicable post-baseline 
visit mentioned above will be summarized for each vital sign variable, with the number of 
observations, baseline mean, and visit mean. The change from baseline mean, standard 
error, and 95% confidence interval will be presented for the mean change from baseline.
Vital sign variables will be evaluated based on potentially clinically important (PCI) 
criteria during the administration of upadacitinib in Study M16-046 and Study M19-850 
(Appendix C). For each vital sign PCI criterion, the number and percentage of subjects 
who have a vital sign value meeting the criteria will be summarized. Listings will be 
provided to summarize subject-level vital sign data for subjects meeting PCI criteria.
10.5
Safety Subgroup Analyses
There are no planned subgroup analyses for safety.
10.6
Other Safety Analyses
There are no other safety analyses planned.
11.0
Other Analyses
There are no other analyses.
12.0
Interim Analyses
One interim analysis is planned for this study, which will take place after all ongoing 
subjects finish the Week 16 Visit with cutoff date as 09MAR2021.
12.1
Data Monitoring Committee
There is no Data Monitoring Committee for this open-label study.
 


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13.0
Overall Type-I Error Control
14.0
Version History
Table 2.
SAP Version History Summary
Version
Date
Summary
1.0
26 February 2020
Original version
2.0
09 April 2021
Added Section 8.0 following new SAP template.
Section 2.2: Updated Figure of study design to incorporate the 
protocol amendment. Also added description about extending 
the study duration of certain countries and regions.
Section 5.0: Removed the statement of summarizing screen 
failures since there will be no screening for this study. Also 
removed the statement of summarizing subjects with at least 
one dose of study drug. Because 'having at least one dose of 
study drug' is already the definition of ITT Population.
Section 6.0: Added more categories of exposure duration 
following the protocol amendment of extending the dosing 
duration. 
Section 7.1. Removed baseline summary of Daily worst 
pruritus Numerical Rating Scale (NRS) as this is not 
applicable for M19-850 Baseline.
Section 7.2: Clarified that Medical History will be 
summarized based on ITT Population.
Section 7.3: Clarified that Prior and Concomitant Medication 
will be summarized based on Safety Population.
Section 9.1 and Section 12.0: State that we would conduct an 
Interim Week 16 Lock.
Section 9.2: Clarified that OC will exclude values after a 
subject prematurely discontinue from study +1 days.
Section 10.3: Clarified the Baseline definition of lab analysis, 
as well as the visits for analysis.
Section 10.4: Clarified the Baseline definition of vital sign 
analysis, as well as the visits for analysis.
Appendix A: Added 'Subject with Deviation Related to 
COVID-19 Pandemic' to be consistent with M16-046.
Appendix F: Added this section to include the activity 
schedule. 
 


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Table 2.
SAP Version History Summary (Continued)
Version
Date
Summary
3.0
14 April 2021
Section 10.2.7: Deleted 'listings of pre-treatment AE' as they 
are not needed for this open label extension study.
4.0
21 June 2021
Section 5.0: Clarified that subjects who were rescued in the 
study will not be summarized.
Section 6.0: Clarified that study drug duration and 
compliance will be summarized based on Safety Population.
Section 7.1: Modified the demographics section to be 
consistent with eCRF design.
Section 7.1: Added the Worst Pruritus NRS summary for both 
M16-046 and M19-850 Baseline, as well as Daily NRS for 
M16-046 Baseline.
Section 10.2.3: Clarified that the TEAE will be summarized 
by SOC and PT and maximum toxicity instead of by 
maximum toxicity and SOC and PT.
Appendix C: Updated the PCI criteria to be consistent with 
M16-046. 
5.0
01 August 2023
Section 4.0: Added statement about excluding a site from all 
analyses due to non-compliance.
15.0
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"
Malignancy
SMQ
"Malignant Tumours"
Non-Melanoma Skin Cancer 
(NMSC)
SMQ/CMQ
SMQ Broad
Skin Malignant tumours (Broad 
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
Adjudicated 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"
Renal Dysfunction
SMQ
Narrow
"Acute Renal Failure"
Active Tuberculosis
CMQ
"Active Tuberculosis"
 


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


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Appendix C.
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
Grade
Units
Definition of Potentially 
Clinically Important
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 in CTC grade to be considered a 
potentially clinically important finding.
 


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Table C-2.
Criteria for Potentially Clinically Important Chemistry Values
Chemistry 
Variables
Grade
Units
Definition of Potentially Clinically Important
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 CTC 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 Signs
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 (bpm)
Low
Value ≤ 50 bpm and decrease ≥ 15 bpm from Baseline
High
Value ≥ 120 bpm and increase ≥ 15 bpm from Baseline
Weight
Low
> 7% increase from baseline
High
> 7% decrease from baseline
 


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Appendix D.
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 E.
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 completed electronically via an onsite tablet device.
1.3
Missing Value Handling
Missing values will not be imputed for the Worst Pruritus NRS.