Conditions: Non-Segmental Vitiligo
Keywords: Vitiligo Non-segmental vitiligo (NSV) Upadacitinib ABT-494 RINVOQ
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 185
Healthy volunteers: no

Brief summary:
Vitiligo is a common chronic autoimmune disease that causes the body's immune system to attack its own pigment producing skin cells. This study is to evaluate how safe and effective upadacitinib is in participants with non-segmental vitiligo. Adverse effects and change in disease activity will be assessed.

Upadacitinib is being evaluated for the treatment of non-segmental vitiligo. The study will enroll approximately 160 participants aged 18-65 with non-segmental vitiligo in 5 treatment arms across 35 sites worldwide.

Participants will either receive study drug vs placebo oral tablets once daily (QD) for 24 weeks (Period A). In Period B (up to 52 weeks), participants who received placebo during the first 24 weeks will switch to study drug. Participants who received study drug during the first 24 weeks, will continue to receive study drug.

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

Detailed description:

Arms:
arm 1: Participants received upadacitinib 22 mg administered orally once a day (QD) as tablets for 24 weeks during Period 1. Participants then received upadacitinib 22 mg administered orally once a day (QD) as tablets for 28 weeks during Period 2. arm 2: Participants received upadacitinib 11 mg administered orally once a day (QD) as tablets for 24 weeks during Period 1. Participants then received upadacitinib 11 mg administered orally once a day (QD) as tablets for 28 weeks during Period 2. arm 3: Participants received upadacitinib 6 mg administered orally once a day (QD) as tablets for 24 weeks during Period 1. Participants then received upadacitinib 6 mg administered orally once a day (QD) as tablets for 28 weeks during Period 2. arm 4: Participants received Placebo for upadacitinib administered orally once a day (QD) as tablets for 24 weeks during Period 1. Participants then received upadacitinib 22 mg administered orally once a day (QD) as tablets for 28 weeks during Period 2. arm 5: Participants received Placebo for upadacitinib administered orally once a day (QD) as tablets for 24 weeks during Period 1. Participants then received upadacitinib 11 mg administered orally once a day (QD) as tablets for 28 weeks during Period 2.

Interventions: intervention 1: Upadacitinib intervention 2: Placebo
Intervention descriptions: intervention 1: Oral tablets intervention 2: Oral tablets

Protocol document:
Prot_000.pdf: 


  
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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
OBJECTIVES AND ENDPOINTS
10
3.1
OBJECTIVES, HYPOTHESES, AND ESTIMANDS
10
3.2
PRIMARY ENDPOINT
10
3.3
SECONDARY ENDPOINTS
11
3.4
ADDITIONAL ENDPOINTS
11
3.5
SAFETY ENDPOINTS
12
3.6
PHARMACOKINETIC ENDPOINTS
12
3.7
BIOMARKER RESEARCH ENDPOINTS
12
3.8
EXPLORATORY AND/OR VALIDATION RESEARCH
12
4
INVESTIGATIONAL PLAN
13
4.1
OVERALL STUDY DESIGN AND PLAN
13
4.2
DISCUSSION OF STUDY DESIGN
15
5
STUDY ACTIVITIES
16
5.1
ELIGIBILITY CRITERIA
16
5.2
CONTRACEPTION RECOMMENDATIONS
20
5.3
PROHIBITED MEDICATIONS AND THERAPY
21
5.4
PRIOR AND CONCOMITANT THERAPY
25
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
26
5.6
FOLLOW-UP AFTER SUBJECT DISCONTINUATION
27
5.7
STUDY DRUG
27
5.8
RANDOMIZATION/DRUG ASSIGNMENT
28
5.9
PROTOCOL DEVIATIONS
29
6
SAFETY CONSIDERATIONS
30
6.1
COMPLAINTS AND ADVERSE EVENTS
30
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6.2
TOXICITY MANAGEMENT
34
6.3
INDEPENDENT DATA MONITORING COMMITTEE
37
7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
37
7.1
STATISTICAL AND ANALYTICAL PLANS
37
7.2
DEFINITION FOR ANALYSIS POPULATIONS
37
7.3
HANDLING POTENTIAL INTERCURRENT EVENTS FOR THE PRIMARY ENDPOINT
37
7.4
STATISTICAL ANALYSES FOR EFFICACY
38
7.5
STATISTICAL ANALYSES FOR SAFETY
39
7.6
INTERIM ANALYSIS
39
7.7
OVERALL TYPE I ERROR CONTROL
39
7.8
SAMPLE SIZE DETERMINATION
39
8
ETHICS
39
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD
39
8.2
ETHICAL CONDUCT OF THE STUDY
40
8.3
SUBJECT CONFIDENTIALITY
40
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
40
10 DATA QUALITY ASSURANCE
40
11 COMPLETION OF THE STUDY
41
12 REFERENCES
41
LIST OF TABLES
TABLE 1.
EXAMPLES OF COMMONLY USED STRONG CYP3A INHIBITORS AND INDUCERS
25
TABLE 2.
DESCRIPTION OF STUDY DRUG
28
TABLE 3.
SPECIFIC TOXICITY MANAGEMENT GUIDELINES FOR ABNORMAL LABORATORY VALUES
35
LIST OF FIGURES
FIGURE 1.
STUDY SCHEMATIC
14
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LIST OF APPENDICES
APPENDIX A.
STUDY-SPECIFIC ABBREVIATIONS AND TERMS
43
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
47
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
48
APPENDIX D.
ACTIVITY SCHEDULE
49
APPENDIX E.
PROTOCOL SUMMARY OF CHANGES
54
APPENDIX F.
OPERATIONS MANUAL
59
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2 INTRODUCTION
2.1 Background and Rationale
Why Is This Study Being Conducted?
Vitiligo is a common chronic autoimmune disorder of the skin characterized by depigmented skin lesions 
due to autoimmune-induced loss of melanocytes in the epidermis.1  The disease is associated with an 
impaired quality of life (QoL).2  There is no approved medical therapy for vitiligo re-pigmentation and 
current unapproved therapies have limited efficacy, emphasizing the need for improved treatment 
options.
The disease most commonly presents as white macules and patches of skin with equal impact on men 
and women.3  Vitiligo manifests as milky-white patches of pigment loss due to localized melanocyte 
destruction.  Early depigmentation typically occurs on the face and extremities.  In 2011, an 
international consensus classified vitiligo into segmental vitiligo and non-segmental vitiligo (NSV), with 
the majority of patients (> 90%) exhibiting the non-segmental variant.4  Segmental vitiligo refers to 
depigmented macules and patches distributed in a segmental or unilateral pattern, whereas NSV lesions 
are distributed bilaterally.4  In general, the term vitiligo is being used to describe all forms of NSV, which 
includes acrofacial, mucosal, generalized, universal, mixed, and rare variants.
The global prevalence of vitiligo is approximately 0.5% to 2%, and patients with vitiligo often have 
psychological and autoimmune comorbidities.2,5,6  Vitiligo has been associated with several 
auto-immune diseases such as thyroid disease (Hashimoto thyroiditis), psoriasis, rheumatoid arthritis 
(RA), alopecia areata, pernicious anemia, systemic lupus erythematosus, and diabetes mellitus.  It has 
also been associated with inflammatory bowel disease and sometimes ocular and audiological 
abnormalities.7,8  Although patients with vitiligo have a decreased risk of melanoma and non-melanoma 
skin cancer (NMSC),9,10 clinical practice recommends constant use of sunscreen due to the risks of 
sunburn from direct sunlight on depigmented skin.  Overall, the effect of vitiligo on QoL impairment 
seem to be associated with the distribution of vitiligo lesions (e.g., face, genital area) but also by the 
extent of the disease, highlighting the unmet need of effective systemic therapies.
There are few treatment options for vitiligo and these have limited efficacy.  Thus, there is a lack of 
options for patients with vitiligo, particularly those with severe manifestation of the disease, given the 
limited response to currently available topical and systemic therapies.
Impairment or death of melanocytes is believed to be the direct cause of vitiligo.  Melanocytes produce 
the pigment melanin, which colors the skin and provides protection from UV radiation.  While several 
theories describe vitiligo pathogenesis, the exact etiology is unknown. The autoimmune theory 
hypothesizes that interferon (IFN)-y is an important cytokine expressed in lesional skin and is required 
for the recruitment of melanocyte-specific, autoreactive CD8+ T cells to the skin via the chemokines 
CXCL9/10 and CXCR3.11,12  Cytotoxic CD8+ T cells are both necessary and sufficient for melanocyte 
destruction in the skin of vitiligo patients and therefore serve as the effector arm driving the 
autoimmunity of vitiligo.  The Janus kinase (JAK)/Signal Transducers and Activators of Transcription 
(STAT) pathway is therefore an attractive therapeutic target due to its direct effect on IFN-y and CXCL10 
levels.
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Evidence suggests that inhibition of JAK-mediated pathways may be a promising approach for the 
treatment of patients with vitiligo.13  Ruxolitinib (a JAK1/2 inhibitor), in a topical formulation, has 
demonstrated efficacy in treating patients with vitiligo in a Phase 2 study14 and is currently enrolling 
patients in two Phase 3 studies.15,16  AbbVie developed a JAK inhibitor, upadacitinib, which, when given 
systemically may address the current needs for patients with vitiligo.  Upadacitinib is a selective and 
reversible inhibitor of JAK1 that recently has received approval for the treatment of RA, psoriatic 
arthritis (PsA), and ankylosing spondylitis (AS) in some countries and is also being developed for the 
treatment of other immune-mediated inflammatory diseases, including dermatologic conditions such as 
atopic dermatitis (AD) and hidradenitis suppurativa.
Clinical Hypothesis
Vitiligo is a chronic autoimmune disorder of the skin characterized by an increase of proinflammatory 
cytokines involved in the JAK/STAT pathway.  Upadacitinib is predicted to provide better efficacy 
compared to placebo and to be well tolerated in vitiligo subjects.
2.2 Benefits and Risks to Subjects
Currently there are no approved medical therapies for skin re-pigmentation for patients with vitiligo and 
current unapproved therapies such as topical corticosteroids and calcineurin inhibitors have limited 
efficacy, indicating that there is a high unmet need.  Phototherapy is one of the most common therapies 
used for vitiligo; nonetheless, treatment can be burdensome to patients as it requires multiple and 
frequent visits to the office or home therapy and is associated with a high relapse rate within the first 
year upon discontinuation (average 40%), highlighting the need for long-lasting therapies.17
At this time, patients with significant vitiligo, including patients with rapidly progressive disease, are 
commonly treated with oral steroids which are not suitable for long-term use.
The efficacy of upadacitinib has shown promising results in various immune-mediated diseases including 
dermatologic conditions such as AD.18
Adverse events (AEs) such as infections, herpes zoster reactivation, malignancies, and hematologic AEs 
have been observed in patients receiving JAK inhibitors including upadacitinib.  The available long-term 
safety data from the Phase 3 RA studies with upadacitinib showed an increased risk of infection 
including opportunistic infections (e.g., mucosal candida infections) and herpes zoster, as well as 
abnormal laboratory changes have been observed (e.g., elevations of serum transaminases, lipids, 
creatine phosphokinase [CPK], and reductions in hemoglobin and white blood cells [WBCs]) with 
upadacitinib therapy.  The incidence rates of other clinically important AEs such as cardiovascular 
events, malignancies, and mortality reported during the RA studies were within the expected range for 
the general population or for a population of patients with moderately to severely active RA.19  Events of 
deep vein thrombosis (DVT) and pulmonary embolism have been reported in patients receiving JAK 
inhibitors including upadacitinib.  Similar findings of these important AEs were also observed in the 
clinical studies for other indications including PsA and AD.  AEs of acne have been observed more 
frequently with upadacitinib treatment versus placebo in Phase 3 PsA and AD studies.
The results of genetic toxicology testing indicate that upadacitinib is not genotoxic; however, 
upadacitinib is teratogenic based on animal studies, which necessitates avoidance of pregnancy in 
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females of childbearing potential.  Based on the calculated safety margins for human fetal exposure with 
seminal fluid transfer, there is judged to be no risk to the pregnancy of female partners of male subjects 
who are treated with upadacitinib.
A detailed discussion of the pre-clinical and clinical toxicology, metabolism, pharmacology, and safety 
experience with upadacitinib can be found in the current Investigator's Brochure.19
Taken together, the safety and efficacy data from upadacitinib studies to date show a favorable 
benefit:risk profile for upadacitinib and support the continued investigation of upadacitinib in patients 
with various immune-mediated inflammatory conditions including vitiligo.
In view of the coronavirus disease 2019 (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 OBJECTIVES AND ENDPOINTS
3.1 Objectives, Hypotheses, and Estimands
Primary
The primary objective of this study is to evaluate the safety and efficacy of upadacitinib for the 
treatment of adult subjects with NSV.
The primary efficacy objective is based on the percent change from Baseline in Facial Vitiligo Area 
Scoring Index (F-VASI) at Week 24 with upadacitinib treatment compared to placebo in the 
Intent-to-Treat (ITT) Population, which consists of all randomized subjects (Section 7.2).
The hypothesis corresponding to the primary endpoint (Section 3.2) is:

Percent change from Baseline in F-VASI with upadacitinib is greater than that with placebo at 
Week 24.
The estimand corresponding to the primary endpoint is defined as:

Difference in the percent change from Baseline in F-VASI at Week 24, regardless of treatment 
discontinuation, between each of the upadacitinib dose groups compared with placebo in the 
ITT Population.
3.2 Primary Endpoint
The primary endpoint is the percent change from Baseline in F-VASI at Week 24.
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3.3 Secondary Endpoints
Secondary Endpoints
1.
Achievement of F-VASI 75 (≥ 75% improvement in F-VASI from Baseline) at Week 24;
2.
Achievement of F-VASI 50 (≥ 50% improvement in F-VASI from Baseline) at Week 24;
3.
Achievement of total Vitiligo Area Scoring Index (T-VASI) 50 (≥ 50% improvement in T-VASI from
Baseline) at Week 24;
4.
Percent change from Baseline in T-VASI at Week 24;
5.
Change from Baseline in the vitiligo quality-of-life (VitiQoL) instrument total score at Week 24.
3.4 Additional Endpoints
Additional Efficacy Endpoints include the primary and all secondary endpoints assessed at visits as noted 
in the Activity Schedule (Appendix D), other than Week 24.  Additional Efficacy Endpoints also include 
the following measurements assessed at visits as specified in the Activity Schedule:

Achievement of F-VASI 90 (≥ 90% improvement in F-VASI from Baseline);

Achievement of T-VASI 75 (≥ 75% improvement in T-VASI from Baseline);

Achievement of T-VASI 90 (≥ 90% improvement in T-VASI from Baseline);

Mean and percent change from Baseline in the vitiligo extent score (VES);

Achievement of vitiligo noticeability scale (VNS) score of "A lot less noticeable (4)" or "No longer 
noticeable (5)";

Dermatology Life Quality Index (DLQI) total score of "0" or "1";

Change from Baseline in the Hospital Anxiety and Depression Scale (HADS) scores;

Proportion of subjects selecting each of the response categories of VitiQoL 16 questions;

Achievement of Physician's Global Impression of Change-Vitiligo (PhGIC-V) of "Much better (1)"
or "A little better (2)";

Achievement of Patient's Global Impression of Change-Vitiligo (PaGIC-V) of "Much better (1)" or 
"A little better (2)";

Achievement of Face – Physician Global Vitiligo Assessment (F-PhGVA) of "No depigmentation 
(0)" or "Limited extent of depigmentation (1)";

Achievement of Total – Physician Global Vitiligo Assessment (T-PhGVA) of "No depigmentation 
(0)" or "Limited extent of depigmentation (1)";

Achievement of Face – Patient Global Vitiligo Assessment (F-PaGVA) of "No depigmentation (0)"
or "Limited extent of depigmentation (1)";

Achievement of Total – Patient Global Vitiligo Assessment (T-PaGVA) of "No depigmentation (0)"
or "Limited extent of depigmentation (1)."
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Details on efficacy variables are provided in the operations manual (Appendix F).
3.5 Safety Endpoints
Safety evaluations include AEs, serious adverse events (SAEs), adverse events of special interest (AESIs), 
AEs leading to discontinuation, vital signs, laboratory tests (hematology, chemistry, liver function tests), 
and physical examination.
3.6 Pharmacokinetic Endpoints
Pharmacokinetic (PK) samples will be obtained at specified clinic visits as noted in Appendix D.  
Upadacitinib plasma concentrations will be determined and summarized in the clinical study report.  In 
addition, a nonlinear mixed-effects modeling approach may be used to estimate the population central 
values and the empirical Bayesian estimates of the individual values of upadacitinib PK parameters (e.g., 
oral clearance [CL/F] and apparent volume of distribution [V/F]).  Data from this study may be combined 
with data from other studies for the population PK analyses.
3.7 Biomarker Research Endpoints
Optional samples for biomarker research (e.g., whole blood, plasma, serum, and skin biopsies) will be 
collected at specified time points (Activity Schedule, Appendix D) throughout the study to evaluate 
known and/or novel disease-related or drug-related biomarkers in circulation or at tissue sites.  Types of 
biomarkers may include nucleic acids, proteins, cell populations, lipids, and/or metabolites, either free 
or in association with particular cell types.  The analyses may include but are not limited to soluble 
proteins, genomic transcripts, blood leukocyte populations, and genetic analysis to evaluate biomarker 
endpoints related to safety, disease state, and target pathway.  Results from this optional biomarker 
research may not be included in the clinical study report.  Further details regarding the biomarker 
research rationale and collection time points are located in the operations manual, Appendix F, 
Section 3.12.
3.8 Exploratory and/or Validation Research
Digital Imaging
Validation of a 3-D digital imaging tool will be explored at a subset of sites to objectively quantify the 
surface area of vitiligo lesions (depigmentation) on the face with precision. Approximately 5 sites will be 
selected to participate in the digital imaging research. Once the digital imaging platform is available for 
implementation at the selected sites, all subjects enrolled thereafter will be required to participate. The 
results from these analyses are exploratory in nature and may not be included with the clinical study 
report.
Individual Component Vitiligo Assessment (ICVA)
The ICVA will be used to collect exploratory information regarding vitiligo involvement on the genitals 
and individual components of the face using 2 assessments:  Physician Global Vitiligo Assessment 
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(PhGVA) and how much vitiligo lesions are bothersome to subjects.  The results from these analyses are 
exploratory in nature and may not be included with the clinical study report.
4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
This is a Phase 2, multicenter, randomized, double-blinded, parallel-group, placebo-controlled 
dose-ranging study that will evaluate the safety and efficacy of upadacitinib in adult subjects ≥ 18 to 
65 years of age with NSV.  The study is comprised of a 35-day Screening Period, a 24-week double-blind 
treatment period (Period 1), a 28-week blinded long-term extension (Period 2), and a 30-day Follow-up 
Period.
Subjects who meet eligibility criteria at Baseline will be randomized in a 2:2:2:1:1 ratio to one of five 
treatment groups:

Group 1:  upadacitinib 22 mg once daily (QD) (N = 40) (Period 1) → upadaciNnib 22 mg QD 
(Period 2)

Group 2:  upadacitinib 11 mg QD (N = 40) (Period 1) → upadaciNnib 11mg QD (Period 2)

Group 3:  upadacitinib 6 mg QD (N = 40) (Period 1) → upadaciNnib 6 mg QD (Period 2)

Group 4:  placebo (N = 20) (Period 1) → upadaciNnib 22 mg QD (Period 2)

Group 5:  placebo (N = 20) (Period 1) → upadaciNnib 11 mg QD (Period 2)
At Week 24, subjects who were randomized to placebo at Baseline will be switched to either 22 mg 
(Group 4) or 11 mg (Group 5) upadacitinib in a blinded fashion per pre-specified randomization 
assignments.
The AbbVie study team will be unblinded to perform the Week 24 primary analysis.  The unblinding will 
take place after all subjects have completed the Week 24 visit or have prematurely discontinued prior to 
Week 24.  Sites and subjects will remain blinded throughout the study.
Information on the Data Monitoring Committee (DMC) is described in Section 6.3.  Information on the 
Cardiovascular Adjudication Committee (CAC) and gastrointestinal (GI) perforation adjudication are 
described in Section 6.1.
See Section 5.1 for information regarding eligibility criteria and Section 5.8 for information on 
stratification.
The schematic of the study is shown in Figure 1.  Further details regarding study procedures are located 
in the operations manual (Appendix F).
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Figure 1.
Study Schematic
BL = Baseline; F-VASI = Facial Vitiligo Area Scoring Index; PBO = placebo; QD = once daily; UPA = upadacitinib
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4.2 Discussion of Study Design
Choice of Control Group
Placebo control will be used in this study.  Comparative studies utilizing a double-blind, 
placebo-controlled design provides an unbiased assessment of the efficacy and safety profile of 
upadacitinib.
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  All efficacy 
measurements in this study are for assessing disease activity and patient-reported outcomes in subjects 
with vitiligo.  All safety-related clinical and laboratory procedures in this study are standard and 
generally accepted.
Care should be taken to minimize the pain and discomfort of laboratory procedures.  Use of a butterfly 
needle for venipuncture and/or a needle gauge appropriate for vein size may optimize the comfort for 
some individuals.  Attempts at venipuncture should be limited to the subject's tolerance of the 
procedure; after more than 2 unsuccessful attempts for venipuncture, consider requesting the subject 
to return within the next 3 days if still within the visit window and after drinking plenty of fluids (1 L to 
2 L over a 24-hour period).
Suitability of Subject Population
The intended study population is adult subjects ≥ 18 to 65 years of age with NSV.  Subjects with 
documented clinical diagnosis of NSV and no segmental or localized vitiligo are eligible for this study.  At 
study entry, eligible subjects must have at least 0.5 F-VASI and at least 5 T-VASI.  Criteria relating to 
safety have been selected to allow subjects to be safely enrolled and treated with upadacitinib based on 
the current knowledge of this drug.
Selection of Doses in the Study
This study is designed as a dose-ranging study to evaluate upadacitinib doses of 6 mg, 11 mg, and 22 mg 
QD in adult subjects with vitiligo.  These doses were selected to provide comprehensive dose-ranging 
information in patients with vitiligo through evaluation of upadacitinib doses that have not been studied 
in other upadacitinib indications (e.g., RA, PsA, AS, and AD).
Patients with vitiligo generally present with a clinically (and biologically) different disease profile 
compared to previously studied indications for upadacitinib.  Although vitiligo significantly impairs QoL, 
it is generally considered an asymptomatic dermatosis (some patients may suffer from skin 
irritation/itching), and is usually associated with lower comorbidities, minimal background and 
concomitant therapies, and less heterogeneous signs and symptoms of the disease.  Hence, the 
upadacitinib dose(s) that may provide optimal benefit risk in patients with vitiligo are yet to be 
determined and may occur at dose levels that have not been previously explored for other indications.
Upadacitinib 15 mg QD and 30 mg QD doses showed significant clinical benefit for treatment of subjects 
with RA, PsA, AS, and AD in Phase 3 studies, with an added clinical benefit of 30 mg compared to 15 mg 
for some (e.g., AD) but not all (e.g., RA, PsA) indications.
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Two case studies have reported partial re-pigmentation of vitiligo white patches after administration of 
tofacitinib, a pan JAK-inhibitor, at a 5 mg twice a day dose together with narrowband UV-B therapy.20  
Although the observed response in these 2 case studies was achieved with a combination of tofacitinib 
and phototherapy, the findings suggest that JAK inhibition with dose levels comparable to efficacious 
doses in RA and PsA populations may provide clinical efficacy in patients with vitiligo.  Whether lower or 
higher doses could provide similar or higher efficacy, respectively, remains unclear and requires more 
data from adequate dose-ranging studies in patients with vitiligo.
Hence, upadacitinib doses of 11 mg and 22 mg have been selected to allow evaluation of upadacitinib 
exposure levels below and above the 15 mg dose, respectively, that have not been evaluated in other 
indications.  The proposed 11 mg and 22 mg doses are expected to provide upadacitinib exposures that 
partially overlap with those achieved with the 15 mg dose, but at the same time provide enough 
separation between the doses to enable adequate characterization of the dose/exposure-response 
relationship.  The 6 mg dose was selected to ensure characterization of the minimally efficacious dose in 
the vitiligo patient population.
5 STUDY ACTIVITIES
5.1 Eligibility Criteria
Subjects must meet all of the following criteria in order to be included in the study.  Anything other than 
a positive response to the questions below will result in exclusion from study participation.
Consent
1. Subject must be able to understand and willing to adhere to all protocol requirements and 
voluntarily sign and date an informed consent, approved by an Independent Ethics Committee 
(IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study-specific 
procedures.
Demographics
2. Adult (male or female) ≥18 to 65 years of age.
Disease/Condition Activity
3. Documented clinical diagnosis of NSV.
4. At Screening and Baseline visits, subjects must have ≥ 0.5 F-VASI AND ≥ 5 T-VASI.
5. No segmental or localized vitiligo.
Laboratory Assessments
6. Laboratory values meeting the following criteria within the Screening Period prior to the 
first dose of study drug:
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
Serum aspartate transaminase (AST) ≤ 2 × upper limit of normal (ULN); 

Serum alanine transaminase (ALT) ≤ 2 × ULN;

Estimated glomerular filtration rate ≥ 30 mL/min/1.73 m2 by simplified 4-variable 
Modification of Diet in Renal Disease (MDRD) formula;

Total WBC count ≥ 2,500/μL;

Absolute neutrophil count (ANC) ≥ 1,200/μL;

Platelet count ≥ 100,000/μL;

Absolute lymphocyte count (ALC) ≥ 750/μL;

Hemoglobin ≥ 9 g/dL.
Subject History
7. Subjects are judged to be in good health as determined by the Principal Investigator, based 
upon the results of medical history, laboratory profile, physical examination, chest x-ray (CXR), 
and a 12-lead electrocardiogram (ECG) performed during Screening.
8. Subjects must not have a history of clinically significant (per investigator judgment) drug or 
alcohol abuse within the last 6 months.  (Note:  Do not perform urine drug screen at Baseline 
Visit).
9. Subjects must have no current or past history of the following:

Two or more episodes of herpes zoster, or one or more episodes of disseminated herpes 
zoster;

One or more episodes of disseminated herpes simplex (including eczema herpeticum/Kaposi 
varicelliform eruption);

Human immunodeficiency virus (HIV) infection, defined as confirmed positive anti-HIV 
antibody (HIV Ab) test; 

Active tuberculosis (TB) or meet TB exclusionary parameters (specific requirements for TB 
testing are provided in the operations manual);

Positive result of beta-D-glucan (screening for pneumocystis jirovecii infection) or 
2 consecutive indeterminate results of beta-D-glucan during the Screening Period (for 
subjects in Japan only);

Active infection(s) requiring treatment with intravenous anti-infectives within 30 days, or 
oral/intramuscular (IM) anti-infectives within 14 days prior to the Baseline Visit;

Chronic recurring infection and/or active viral infection that, based on the investigator's 
clinical assessment, makes the subject an unsuitable candidate for the study;

Confirmed COVID-19:  The Baseline Visit must be at least 14 days from onset of 
signs/symptoms or positive SARS-CoV-2 test; symptomatic subjects must have recovered, 
defined as resolution of fever without use of antipyretics and improvement in symptoms;
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
Suspected COVID-19:  Subjects with signs/symptoms suggestive of COVID-19, known 
exposure, or high risk behavior should undergo molecular (e.g., polymerase chain reaction 
[PCR]) testing to rule out SARS-CoV-2 infection or must be asymptomatic for 14 days from a 
potential exposure.
10. Subjects must not have evidence of:

Hepatitis B virus (HBV):  hepatitis B surface antigen positive (+) test or detectable HBV DNA 
PCR qualitative test for subjects who are hepatitis B core antibody (HBc Ab) positive (+)(and 
for hepatitis B surface antibody [HBs Ab] positive [+] subjects where mandated by local 
requirements); 

Hepatitis C virus (HCV):  detectable HCV RNA in any subject with anti-HCV Ab.
11. Subjects must not have any of the following medical diseases or disorders:

Recent (within past 6 months) cerebrovascular accident, myocardial infarction, coronary 
stenting, and aorto-coronary bypass surgery;

History of an organ transplant which requires continued immunosuppression;

History of GI perforation (other than due to appendicitis or mechanical injury), diverticulitis, 
or significantly increased risk for GI perforation per investigator judgment;

Conditions that could interfere with drug absorption including but not limited to short 
bowel syndrome or gastric bypass surgery; subjects with a history of gastric 
banding/segmentation are not excluded;

History of malignancy except for successfully treated NMSC or localized carcinoma in situ of 
the cervix;

Uncontrolled thyroid disease;

Other skin conditions that would interfere with evaluation of vitiligo;

> 33% leukotrichia on the face or > 33% leukotrichia on the body (including face).
12. There must be no reason the investigator believes that the subject is an unsuitable 
candidate to participate in the study, receive study drug, or would be placed at risk by 
participating in the study.
Contraception
13. For all females of child-bearing potential:  must not have a positive serum pregnancy test at 
the Screening Visit and must have a negative urine pregnancy test at Baseline prior to the first 
dose of study drug (local practices may require serum pregnancy testing at Baseline).  Subjects 
with a borderline serum pregnancy test at Screening must have absence of clinical suspicion of 
pregnancy or other pathological causes of borderline results and a serum pregnancy 
test ≥3 days later to document continued lack of a positive result (unless prohibited by local 
requirements).
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14. Female subjects of childbearing potential must practice at least 1 protocol-specified method 
of birth control that is effective from Study Day 1 through at least 30 days after the last dose of 
study drug (local practices may require 2 methods of birth control) (refer to Section 5.2 for more 
details on contraception).  Female subjects of non-childbearing potential do not need to use 
birth control.
15. Female must not be pregnant, or breastfeeding, and is not considering becoming pregnant 
or donating eggs during the study and for 30 days after the last dose of study drug.
Prior and Concomitant Medications and Therapies
16. Subjects must not have previously been treated with any topical or systemic JAK inhibitor.
17. Subjects must not have previously been treated with any permanent skin bleaching agents
to treat vitiligo.
18. Subjects must not have been treated with any investigational drug of chemical or biologic 
nature within a minimum of 30 days or 5 half-lives (whichever is longer) prior to the first dose of 
study drug or is currently enrolled in another interventional clinical study or was previously 
enrolled in this study. 
19. Subjects who have had prior exposure to immunomodulatory biologic therapy, for any 
indications, must have discontinued the biologic therapy prior to the first dose of study drug.  
Recommended washout periods are specified below.  If not specified below, biologic therapies 
must be discontinued at least 5 times the mean terminal elimination half-life of a drug or 
3 months prior to Baseline, whichever is longer.

≥ 4 weeks for etanercept;

≥ 8 weeks for adalimumab, infliximab, certolizumab, golimumab, abatacept, tocilizumab, 
and ixekizumab;

≥ 16 weeks for secukinumab;

≥ 12 weeks for ustekinumab.
20. Subjects must not have been treated with any systemic vitiligo therapy (e.g., methotrexate 
[MTX], mycophenolate mofetil, corticosteroids) or supplemental vitiligo therapy 
(antioxidants/vitamins/herbal medicine/traditional Chinese medicine) within a minimum of 
30 days prior to the first dose of study drug.
21. Subjects must not have been treated with any topical vitiligo therapy including permanent 
and temporary tattoos within a minimum of 30 days prior to the first dose of study drug. (Note:  
Camouflage and makeup may be used).
22. Subjects must not have been treated with any phototherapy, including excimer (or other 
forms of laser therapy), within a minimum of 12 weeks prior to the first dose of study drug.
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23. Subjects must have no systemic use of known strong cytochrome P450 3A (CYP3A) inhibitors 
from Screening through the end of study drug administration or strong CYP3A inducers 30 days 
prior to study drug administration through the end of study drug administration (refer to Table 1
in Section 5.3 for examples of commonly used strong CYP3A inhibitors and inducers).  Subjects 
may not use herbal therapies or other traditional medicines with unknown effects on CYP3A 
from Screening through the end of study drug administration.
24. Subjects must not have received a live vaccine within 28 days (or longer if required locally) 
prior to the first dose of study drug, or have expected need of live vaccination during study 
participation including at least 30 days (or longer if required locally) after the last dose of study 
drug.
25. Subjects must not have a history of an allergic reaction or significant sensitivity to 
constituents of the study drug (and its excipients) and/or other products in the same class.
5.2 Contraception Recommendations
Contraception Requirements for Females
Subjects must follow the following contraceptive guidelines as specified:
Females, Non-Childbearing Potential
Females do not need to use birth control during or following study drug treatment if considered of 
non-childbearing potential due to meeting any of the following criteria:
1.
Premenopausal female with permanent sterility or permanent infertility due to one of the 
following:

Permanent sterility due to a hysterectomy, bilateral salpingectomy, bilateral oophorectomy.

Non-surgical permanent infertility due to Mullerian agenesis, androgen insensitivity, or 
gonadal dysgenesis; investigator discretion should be applied to determining study entry for 
these individuals.
2.
Postmenopausal female

Age > 55 years with no menses for 12 or more months without an alternative medical cause.

Age ≤ 55 years with no menses for 12 or more months without an alternative medical cause 
AND a follicle-stimulating hormone (FSH) level > 30 IU/L.
Females of Childbearing Potential
Review and document pregnancy avoidance recommendations with 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:
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
Combined (estrogen- and progestogen-containing) hormonal birth control (oral, intravaginal, 
transdermal, injectable) associated with inhibition of ovulation initiated at least 30 days prior to 
study Baseline Day 1.

Progestogen-only hormonal birth control (oral, injectable, implantable) associated with 
inhibition of ovulation initiated at least 30 days prior to study Baseline Day 1.

Bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a hysterosalpingogram 
confirms success of the procedure) (For Japan:  only bilateral tubal ligation).

Intrauterine device (IUD).

Intrauterine hormone-releasing system (IUS).

Vasectomized sexual partner (the partner has received medical confirmation of the surgical 
success of the vasectomy and is the sole sexual partner of the trial subject).

Practice true abstinence (unless not acceptable per local practices), defined as:  refraining from 
heterosexual intercourse when this is in line with the preferred and usual lifestyle of the subject 
(periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and 
withdrawal are not acceptable).
If required per local 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 Day 1.

Male or female condom with or without spermicide.

Cap, diaphragm, or sponge with spermicide.

A combination of male condom with a cap, diaphragm, or sponge with spermicide (double 
barrier method).
Contraception recommendations related to use of concomitant therapies prescribed per standard of 
care should be based on the local label.
5.3 Prohibited Medications and Therapy
Corticosteroids
Systemic corticosteroids for treatment of vitiligo including, but not limited to, oral, intravenous, IM, and 
intralesional are prohibited throughout the study.  For non-vitiligo reasons, use of systemic 
corticosteroids can be used but limited to prednisone or prednisolone for up to 1 mg/kg/day for no 
more than 2 consecutive weeks; any subject who receives systemic corticosteroids for more than 
2 consecutive weeks, regardless of the dosage of corticosteroid, should permanently discontinue study 
drug.
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Topical Therapy
Topical treatments for vitiligo (including, but not limited to topical calcineurin inhibitors, topical 
corticosteroids, topical prostaglandin analogs) are prohibited until after Week 24 Visit assessments.  
Subjects are not permitted to receive permanent or temporary tattoos within 30 days prior to the first 
dose of study drug through the end of the study.
Phototherapy, Tanning Booth, Extended Sun Exposure, and Surgical Grafting
Phototherapy (including, but not limited to, broadband UV-B, narrowband UV-B, psoralen and UV-A, 
excimer or other laser therapy, tanning booth use) is prohibited for at least 12 weeks prior to the 
Baseline Visit and prohibited during the study.  However, subjects are allowed to receive natural daily 
light following a normal routine, but, for a prolonged exposure to sunlight, sunscreen is recommended.  
Surgical grafting for vitiligo is not allowed during the study.
Supplemental Vitiligo Therapy Including Over the Counter (Antioxidants/Vitamins/Herbal 
Medicine/Traditional Chinese Medicine)
Supplemental therapy for vitiligo (including, but not limited to, antioxidants, vitamins, herbal 
supplements, traditional Chinese medicine) is not permitted until after Week 24 Visit assessments.  
However, for any drugs that are considered strong CYP3A inhibitors or inducers, or any herbal 
supplements or traditional medicines with unknown effects on CYP3A are prohibited throughout the 
entire the study.  Subjects must have discontinued supplemental therapies at least 30 days prior to the 
first dose of study drug.
JAK Inhibitors
Prior and concomitant oral and topical exposure to any other JAK inhibitors besides the investigational 
drug, upadacitinib, in this study (including but not limited to ruxolitinib [Jakafi®], tofacitinib [Xeljanz®], 
baricitinib [Olumiant®], abrocitinib [PF-04965842], and filgotinib) is not allowed.
Targeted Biologic Therapies
Subjects must have discontinued immunomodulatory biologic therapies prior to the first dose of study 
drug as specified in the washout procedures (Eligibility Criterion 19, Protocol Section 5.1).  No minimum 
washout prior to Baseline is required for a biologic therapy if an undetectable drug level measured by a 
commercially available assay is documented.
Current and concomitant biologic therapies and biosimilar versions of biologic drugs are prohibited 
during the study.  Examples of biologic therapies include, but are not limited to, the following:

Humira® (adalimumab)

Dupixent® (dupilumab)

Zolair® (omalizumab)

Enbrel® (etanercept)

Remicade® (infliximab)

Orencia® (abatacept)
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
Kineret® (anakinra)

Rituxan® (rituximab)

Cimzia® (certolizumab pegol)

Simponi® (golimumab)

Actemra® (tocilizumab)

Raptiva® (efalizumab)

Tysabri® (natalizumab)

Stelara® (ustekinumab)

Benlysta® (belimumab)

Taltz® (ixekizumab)

Cosentyx® (secukinumab)

Tremfya® (guselkumab)

SKYRIZI® (risankizumab) or SKYRIZI® (risankizumab-rzaa)
Other Non-Biologic Systemic Therapy
Other systemic therapy for the treatment of vitiligo is prohibited during the study including, but not 
limited to:

MTX

cyclosporine

azathioprine

phosphodiesterase type 4 -inhibitors (e.g., apremilast)

mycophenolate mofetil
Investigational Drugs
Subjects who have been treated with any investigational drug within 30 days or 5 half-lives of the drug 
(whichever is longer) prior to the first dose of study drug are excluded from participation in this study.  
Investigational drugs are also prohibited during the study.
Vaccines
Live vaccines are prohibited during study participation and including at least 30 days (or longer if 
required locally) after the last dose of study drug.  If the subject and investigator choose to 
receive/administer live vaccines, these vaccinations must be completed at least 28 days (or longer if 
required locally) before first dose of study drug with appropriate precautions.  Although not mandated 
by the protocol, vaccines recommended by local guidelines should be considered.  Examples of live 
vaccines include, but are not limited to, the following:
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
Monovalent live attenuated influenza A (H1N1) (intranasal)

Seasonal trivalent live attenuated 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

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.
COVID-19 Vaccine
Whenever possible, subjects should not have received a COVID-19 vaccination in the 7 days prior to 
randomization or plan to receive a COVID-19 vaccination within the first 7 days after initiation of study 
drug.
Strong CYP3A Inhibitors or Inducers
Systemic use of known strong CYP3A inhibitors (includes over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) is not permitted from Screening through the end of study drug 
administration and use of strong CYP3A inducers is not permitted from 30 days prior to study drug 
administration through the end of study drug administration.  Table 1 includes examples of commonly 
used strong CYP3A inhibitors and inducers.  In addition, herbal therapies and other traditional medicines 
with unknown effects on CYP3A are not permitted from Screening through the end of study drug 
administration.
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Table 1.
Examples of Commonly Used Strong CYP3A Inhibitors and Inducers
Strong CYP3A Inhibitors 
Strong CYP3A Inducers
Boceprevir
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 until the primary endpoint has been assessed 
(Week 24).  If the subject undergoes elective surgery, the study drug should be interrupted 1 week prior 
to the planned surgery.  Allow reintroduction of study drug once the physician has examined the surgical 
site and determined that it has healed and there is no sign of infection.
If the subject must undergo emergency surgery, the study drug should be interrupted at the time of the 
surgery.  After emergency surgery, allow reintroduction of study drug once the physician has examined 
the surgical site and determined that it has healed and there is no sign of infection.
5.4 Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and/or 
herbal supplements) that the subject is receiving at the time of Screening and/or receives during the 
study must be recorded along with the reason for use, date(s) of administration including start and end 
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dates, and dosage information including dose, route, and frequency on the appropriate electronic case 
report form (eCRF).  Also, medications taken for vitiligo since date of diagnosis (based on subject 
recollection and available medical records) should be entered into the appropriate eCRF inclusive of the 
dates of first and last dose, maximum dosage taken, and route of administration.
5.5 Withdrawal of Subjects and Discontinuation of Study
AbbVie may terminate this study prematurely, either in its entirety or at any site.  The study may be 
discontinued or terminated in case of an unacceptable risk, any relevant toxicity, or a negative change in 
the risk/benefit assessment.  This might include the occurrence of AEs with a character, severity, or 
frequency that is new in comparison to the existing risk profile.  In addition, data deriving from other 
clinical trials or toxicological studies which negatively influence the risk/benefit assessment might cause 
discontinuation or termination of the study.  The investigator may also stop the study at his/her site if 
he/she has safety concerns.  If AbbVie terminates the study for safety reasons, AbbVie will promptly 
notify the investigator.  Advance notice is not required by either party if the study is stopped due to 
safety concerns.
Subjects can request to be discontinued from participating in the study at any time for any reason.  The 
investigator may discontinue any subject's participation at any time for any reason.  The AbbVie 
Therapeutic Area Medical Director (TA MD)/Scientific Director may mandate individual subject 
discontinuation from study drug in case of safety concern.
Subjects must have study drug discontinued immediately if any of the following occur:

The subject requests withdrawal from study drug or the study.

The investigator believes it is in the best interest of the subject.

Abnormal laboratory results or AEs that either meet the criteria for discontinuation of study 
drug, as stated in Section 6.2, or rule out safe continuation of the study drug, as determined by 
the investigator or the AbbVie TA MD.

Serious infections (e.g., sepsis) which cannot be adequately controlled by anti-infective 
treatment or would put the subject at risk with continuation of the study drug.

Confirmed diagnosis of DVT, pulmonary embolus or non-cardiac, non-neurologic arterial 
thrombosis.

Subject is non-compliant with TB prophylaxis (if applicable) or develops active TB at any time 
during the study.

Subject develops a malignancy, except for localized NMSC or carcinoma in-situ of the cervix.

Subject develops a GI perforation (defined as acute, spontaneous perforation of the GI tract that 
requires inpatient medical care or urgent surgical intervention other than appendicitis or 
mechanical injury).  See also Section 6.2 Toxicity Management.

The subject becomes pregnant or plans to become pregnant while on study drug.

Eligibility criteria violation was noted after the subject started study drug, when continuation of 
the study drug would place the subject at risk.  Note:  intentional/prospective deviations from 
the protocol are NOT allowed, see Section 5.9 Protocol Deviations.
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
Introduction of prohibited medications or dosages when continuation of the study drug would 
place the subject at risk.

Subject is significantly non-compliant with study procedures.

Worsening vitiligo as defined by an increase of 25% or higher in T-VASI from Baseline beginning 
at Week 8.
Additional requirements related to abnormal laboratory values and selected AESIs are located in 
Section 6.2.
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.  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 all acceptable mitigation steps have been explored.
5.6 Follow-Up After Subject Discontinuation
If a subject prematurely discontinues study drug, the procedures outlined for the Premature 
Discontinuation (PD) Visit should be completed as soon as possible, preferably within 2 weeks of study 
drug discontinuation, and preferably prior to initiation of another therapy.  In addition, a 30-day 
Follow-up Visit or phone call should occur to determine the status of any ongoing AEs/SAEs or the 
occurrence of any new AEs/SAEs.
For subjects to be considered lost to follow-up, reasonable attempts must be made to obtain 
information on the subject's final status.  At a minimum, 2 telephone calls must be made and 1 certified 
letter must be sent and documented in the subject's source documentation.
If a subject withdraws from study follow up or withdraws permission for the collection of their personal 
data, the study staff may still use available public records to obtain information about survival status 
only, as appropriate per local regulations.
In the event a subject withdraws consent from the clinical study, biomarker research will continue 
unless the subject explicitly requests analysis to be stopped.  When AbbVie is informed the subject has 
withdrawn and no longer wishes biomarker research to continue, samples will not be analyzed, no new 
biomarker analysis data will be collected for the withdrawn subject or added to the existing data or 
database(s), and the samples will be destroyed.  A subject may withdraw consent for optional biomarker 
research at any time and remain in the clinical study.  Data generated from clinical study and/or optional 
biomarker research, before subject withdrawal of consent, will remain part of the study results.
5.7 Study Drug
Study drug will be taken orally QD, beginning on Day 1 (Baseline), and should be taken at approximately 
the same time each day, with or without food. Subjects will be instructed to return all drug containers 
(even if empty) to the study site personnel at each study visit; study site personnel will document 
compliance.
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
AbbVie will not supply any vitiligo disease-related concomitant medication therapy taken during the 
course of the study.  AbbVie will supply upadacitinib and matching upadacitinib placebo.
Study drug will be packaged in quantities sufficient to accommodate the study design.
Each kit will be labeled per local requirements and this label must remain affixed to the kit.  Upon 
receipt, study drug should be stored as specified on the label and kept in a secure location.  Each kit will 
contain a unique kit number.  This kit number is assigned to a subject via interactive response 
technology (IRT) and encodes the appropriate study drug to be dispensed at the subject's corresponding 
study visit.  All blank spaces on the label will be completed by the site staff prior to dispensing to 
subjects.  Study drug will only be used for the conduct of the study.
The individual study drug information is presented in Table 2.
Table 2.
Description of Study Drug
Investigational 
Product
Mode of 
Administration
Dosage Form
Strength
Blinded or 
Open Label
Frequency
Manufacturer
Upadacitinib 
(ABT-494)
Oral
Extended-release, 
film-coated 
tablets
6 mg, 
11 mg, or 
22 mg
Blinded
QD
AbbVie
Placebo for 
upadacitinib 
(ABT-494)
Oral
Film-coated 
tablets
Not 
applicable
Blinded
QD
AbbVie
During the COVID-19 pandemic, study drug shipment can be made from the study site to the subject if 
allowed by local regulations.  Refer to the operations manual for details on direct-to-patient shipment of 
study drug.
5.8 Randomization/Drug Assignment
All subjects will be assigned a unique identification number by the IRT at the Screening Visit.  For 
subjects who rescreen, the screening number assigned by the IRT at the initial screening visit should be 
used.  The IRT will assign a randomization number that will encode the subject's treatment group 
assignment according to the randomization schedule.  Subjects who meet eligibility criteria at Baseline 
will be randomized in a 2:2:2:1:1 ratio to one of the five treatment groups:

Group 1:  upadacitinib 22 mg QD (N = 40) (Period 1) → upadaciNnib 22 mg QD (Period 2)

Group 2:  upadacitinib 11 mg QD (N = 40) (Period 1) → upadaciNnib 11mg QD (Period 2)

Group 3:  upadacitinib 6 mg QD (N = 40) (Period 1) → upadacitinib 6 mg QD (Period 2)

Group 4:  placebo (N = 20) (Period 1) → upadaciNnib 22 mg QD (Period 2)

Group 5:  placebo (N = 20) (Period 1) → upadaciNnib 11 mg QD (Period 2)
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Randomization will be stratified by the age group (≤ 50 and > 50), Baseline disease severity (T-VASI < 15 
and ≥ 15), and status of active vitiligo (Yes/No) defined as follows:

Active:  Showing new lesions or progression (enlargement) of existing lesions within the last 
6 months and/or presenting clinical subtypes indicative of progressing vitiligo (i.e., confetti-like 
depigmentation, trichrome pattern, or Koebner phenomenon).
At Week 24, subjects who were randomized to placebo at Baseline will be switched to either 22 mg 
(Group 4) or 11 mg (Group 5) upadacitinib in a blinded fashion per pre-specified randomization 
assignments.
All AbbVie personnel with direct oversight of the conduct and management of the trial (with the 
exception of AbbVie Drug Supply Management Team) will remain blinded to each subject's treatment 
until the Week 24 primary analysis for the study, while the investigator, study site personnel, and the 
subject will remain blinded to each subject's treatment throughout the study.  To maintain the blind, the 
upadacitinib tablets and placebo tablets provided for the study will be identical in appearance.  The IRT 
will provide access to unblinded subject treatment information in the case of a medical emergency.
In the event of a medical emergency that requires unblinding of the study drug assignment, the 
investigator is requested to contact the AbbVie TA MD prior to breaking the blind.  However, if an 
urgent therapeutic intervention is necessary which warrants breaking the blind prior to contacting the 
AbbVie TA MD, the investigator can directly access the IRT system to break the blind without AbbVie 
notification or agreement.  Unblinding is available in the IRT system via the Unblind Subject transaction, 
which is available only to the investigator.  If the IRT system is unavailable, unblinding may occur by 
contacting the technical support of the IRT vendor via either phone (preferred) or email 
(support@endpointclinical.com).  For country-specific phone numbers, please see the following website:  
http://www.endpointclinical.com/helpdesk/.
In the event that the blind is broken before notification to the AbbVie TA MD, we request that the 
AbbVie TA MD be notified within 24 hours of the blind being broken.  The date and reason that the blind 
was broken must be conveyed to AbbVie and recorded on appropriate eCRF.
5.9 Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol except when necessary to 
eliminate an immediate hazard to study subjects.  The investigator is responsible for complying with all 
protocol requirements, written instructions, and applicable laws regarding protocol deviations.  If a 
protocol deviation occurs (or is identified, including those that may be due to the COVID-19 pandemic), 
the investigator is responsible for notifying IEC/IRB, regulatory authorities (as applicable), and AbbVie.
In Japan, the investigator will record all protocol deviations in the appropriate medical records at the 
site.
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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 drug component of the product.
For a product this may include, but is not limited to, damaged/broken product or packaging, product 
appearance whose color/markings do not match the labeling, labeling discrepancies/inadequacies in the 
labeling/instructions (e.g., printing illegible), missing components/product, device damage or not 
working properly, or packaging issues.
Product complaints concerning the investigational product and/or device must be reported to AbbVie 
within 24 hours of the study site's knowledge of the event.  Product complaints occurring during the 
study will be followed up to a satisfactory conclusion.
Medical Complaints/Adverse Events and Serious Adverse Events
An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not the event is considered causally related to the use of the 
product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as well as from 
"special situations" such as accidental or intentional overdose, medication error, occupational or 
accidental exposure, off-label use, drug abuse, drug misuse, or drug withdrawal, all which must be 
reported whether associated with an AE or not.  Any worsening of a pre-existing condition or illness is 
considered an AE.  Worsening in severity of a reported AE should be reported as a new AE.  Laboratory 
abnormalities and changes in vital signs are considered to be AEs only if they result in discontinuation 
from the study, necessitate therapeutic medical intervention, 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 on a routine basis 
throughout the study.  All AEs will be followed to a satisfactory conclusion.
An elective surgery/procedure scheduled to occur during a study will not be considered an AE if the 
surgery/procedure is being performed for a pre-existing condition and/or the surgery/procedure has 
been pre-planned prior to study entry.  However, if the pre-existing condition deteriorates unexpectedly 
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during the study (e.g., surgery performed earlier than planned), then the deterioration of the condition 
for which the elective surgery/procedure is being done will be considered an AE.
If an AE, whether associated with study drug or not, meets any of the following criteria, it is to be 
reported to AbbVie clinical pharmacovigilance or contract research organization (as appropriate) as an 
SAE within 24 hours of the site being made aware of the SAE (refer to Section 4.3 of the operations 
manual for reporting details and contact information):
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 (ADL) 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 until 30 days or 5 half-lives, whichever is 
longer, after discontinuation of study drug administration will be collected, whether solicited or 
spontaneously reported by the subject.  In addition, study procedure-related serious and nonserious AEs 
will be collected from the time the subject signs the study-specific informed consent.
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The following definitions will be used for Serious Adverse Reactions (SARs) and Suspected Unexpected 
Serious Adverse Reactions (SUSARs):
SAR
Defined as all noxious and unintended responses to an Investigational Medicinal 
Product (IMP) related to any dose administered that result in an SAE as defined 
above.
SUSAR
Refers to individual SAE case reports from clinical trials where a causal 
relationship between the SAE and the IMP was suspected by either the sponsor 
or the investigator, is unexpected (not listed in the applicable Reference Safety 
Information), and meets one of the above serious criteria.
AbbVie will be responsible for SUSAR reporting for the Investigational Medicinal Product (IMP) in 
accordance with global and local requirements.
AEs will be monitored throughout the study to identify any of special interest that may indicate a trend 
or risk to subjects.
Adverse Events of Special Interest
The following AESIs will be monitored during each study:

Serious infections

Opportunistic infections (excluding TB and herpes zoster)

Herpes Zoster

Active TB

Adjudicated GI perforations

Malignancy (all types)

Anemia

Neutropenia

Lymphopenia

Renal dysfunction

Hepatic disorders

Adjudicated cardiovascular events (e.g., major adverse cardiovascular event)

Adjudicated embolic and thrombotic events (non-cardiac, non-central nervous system)
Cardiovascular Adjudication Committee
An independent, external committee of physician experts in cardiovascular adjudication will be utilized 
to assess potential cardiovascular, cerebrovascular, embolic, and thrombotic AEs in a blinded manner as 
defined by the CAC charter.  The CAC charter will be prepared separate from the protocol and will 
describe the objective, scope, frequency, and triggers for data reviews.
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GI Perforation Adjudication
Two independent, blinded internal adjudicators along with a third potential tie-breaker adjudicator who 
are gastroenterologists or who have other highly relevant clinical experience will be utilized to assess 
potential AEs of acute spontaneous GI perforation.
Adverse Event Severity and Relationship to Study Drug
The investigator will rate the severity of each AE according to the NCI CTCAE version 5.0, which can be 
accessed at:  http://ctep.cancer.gov/protocolDevelopment/electronic_applications.
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 ADL (instrumental ADL refer to preparing 
meals, shopping for groceries or clothes, using the telephone, managing 
money, etc.)
Severe (Grade 3 – 5)
Grade 3
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self care ADL (self care ADL refers to bathing, dressing and 
undressing, feeding self, using the toilet, taking medications, and not 
bedridden)
Grade 4
Life-threatening consequences; urgent intervention indicated
Grade 5
Death related to AE
The Investigator will use the following definitions to assess the relationship of the AE to the use of study 
drug:
Reasonable 
Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is 
sufficient evidence (information) to suggest a causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is 
insufficient evidence (information) to suggest a causal relationship.
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Pregnancy
While not an AE, pregnancy in a study subject must be reported to AbbVie within 1 calendar day after 
the site becomes aware of the pregnancy.  If a pregnancy occurs in a study subject, information 
regarding the pregnancy and the outcome will be collected.
Female subjects should avoid pregnancy throughout the course of the study, starting with the 
Screening Visit through 30 days after the last study drug administration.  Results of a positive pregnancy 
test or confirmation of a pregnancy will be assessed starting with the Screening Visit through the final 
study visit.
Subjects who become pregnant during the study must be discontinued from study drug treatment 
(Protocol Section 5.5).
The pregnancy outcome of an elective or spontaneous abortion, stillbirth, or congenital anomaly is 
considered an SAE and must be reported to AbbVie within 24 hours of the site becoming aware of the 
event.
6.2 Toxicity Management
The toxicity management of the AEs, including AESIs, consists of safety monitoring (review of AEs on an 
ongoing basis, and periodic/ad hoc review of safety issues by an independent DMC), and, if applicable, 
interruption of study drug dosing with appropriate clinical management and/or discontinuation of the 
subjects from study drug.  The management of specific AEs and laboratory parameters is described 
below.
Serious Infections:  Study drug should be interrupted if a subject develops a serious infection.  Study 
drug may be restarted once the infection has been successfully treated.  Subjects who develop active TB 
must be permanently discontinued from study drug.
Herpes zoster:  If a subject develops herpes zoster, consider temporarily interrupting study drug until 
the episode resolves.
GI Perforation:  Subjects presenting with the onset of signs or symptoms of a GI perforation should be 
evaluated promptly for early diagnosis and treatment.  Subjects with acute, spontaneous perforation of 
the GI tract that requires inpatient medical care or urgent surgical intervention (except for appendicitis 
or mechanical injury) must be permanently discontinued from study drug.
Malignancy:  Subjects who develop malignancy other than NMSC or carcinoma in situ of the cervix must 
be permanently discontinued from study drug.  Information including histopathological results should be 
queried for confirmation of the diagnosis.  Periodic skin examination is recommended for subjects who 
are at increased risk for skin cancer.
Muscle-related symptoms:  If a subject experiences symptoms suggestive of myositis or 
rhabdomyolysis, consider checking CPK and aldolase with clinical management and/or study drug 
interruption as deemed appropriate by the treating physician.
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Thrombosis Events:  Subjects who develop symptoms of thrombosis should be promptly evaluated and 
treated appropriately.  If the diagnosis of DVT, pulmonary embolus, or non-neurologic arterial 
thrombosis is confirmed, the subject must be permanently discontinued from study drug.
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.
Management of Select Laboratory Abnormalities:  For any given laboratory abnormality, the 
investigator should assess the subject, apply the standard of care for medical evaluation and treatment 
following any local guidelines.  Specific toxicity management guidelines for abnormal laboratory values 
are described in Table 3 and may require a supplemental eCRF to be completed.  For subjects with 
ongoing laboratory abnormalities which require data entry into an eCRF, an additional eCRF related to 
subsequent laboratory abnormalities is only required if the subject has relevant changes in history (e.g., 
new onset signs or symptoms) or laboratory values which have returned to normal reference range or 
its Baseline value followed by subsequent laboratory abnormalities meeting toxicity guidelines 
(considered a new event).  All abnormal laboratory tests that are considered clinically significant by the 
investigator will be followed to a satisfactory resolution.  If a repeat test is required per Table 3, the 
repeat testing is to occur as soon as possible.  Further, repeat testing may be performed at a local 
laboratory if the subject is unable to use the central laboratory.
Table 3.
Specific Toxicity Management Guidelines for Abnormal Laboratory Values
Laboratory 
Parameter
Toxicity Management Guideline
Hemoglobin

If hemoglobin < 8 g/dL, interrupt study drug dosing and confirm by repeat testing 
with a new sample.

If 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.
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.
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 WBC count 

If confirmed < 2000/µL by repeat testing with new sample, interrupt study drug 
dosing until WBC count returns to normal reference range or its Baseline value.
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Laboratory 
Parameter
Toxicity Management Guideline
AST or ALT

Interrupt study drug if confirmed ALT or AST > 3 × ULN by repeat testing with new 
sample and either a total bilirubin > 2 × ULN or an international normalized ratio 
(INR) > 1.5.

A separate blood sample for INR testing will be needed to measure INR at the 
time of repeat testing for ALT or AST.  A repeat test of INR is not needed for 
determination if above toxicity management criteria are met.

Interrupt study drug if confirmed ALT or AST > 3 × ULN by repeat testing with new 
sample along with new appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5% increase from 
Baseline). 

Interrupt study drug if confirmed ALT or AST > 5 × ULN by repeat testing with new 
sample for more than 2 weeks.

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 
Screening who develop the following laboratory findings should have HBV DNA PCR testing 
performed within 1 week (based on initial elevated value): 

ALT > 5 × ULN OR 

ALT or AST > 3 × ULN if an alternative cause is not readily identified.

A separate blood sample for HBV DNA PCR testing will be needed at the time of 
repeat testing for ALT or AST.
A positive result for HBV DNA PCR testing will require immediate interruption of study drug 
(unless not acceptable by local practices) 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.  If applicable, the 
alternative etiology should be documented in the eCRF.  If ALT or AST values return to the 
normal reference range or the Baseline value, study drug may be restarted.  If restarting 
study drug, documentation should include reason that rechallenge is expected to be safe.  If 
after clinically appropriate evaluation no alternative etiology for ALT or AST elevation is 
found or the ALT or AST elevation has not resolved or is not trending down toward normal, 
the subject should be discontinued from study drug.
For any confirmed ALT or AST elevations > 3 ULN, complete the appropriate supplemental 
hepatic eCRF(s).
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 
restart study drug once serum creatinine returns to ≤ 1.5 × Baseline value 
and ≤ULN.
For the above serum creatinine elevation scenarios, complete the supplemental renal eCRF.
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6.3 Independent Data Monitoring Committee
To ensure subject safety, an external, independent DMC will review unblinded safety data on a cohort 
level, at approximately 4-month intervals throughout the course of the study, and alert AbbVie to 
possible safety concerns related to the conduct of the study.  The DMC will review safety data to 
determine if there are any significant safety concerns that would warrant any study action.  If necessary 
to assess benefit/risk, the DMC will also be given access to selected efficacy data.
The DMC charter will describe the roles and responsibilities of the DMC members, frequency of data 
reviews, and relevant data to be assessed.  Communications from the DMC to the Study Team will not 
contain information that could potentially unblind the team to subject treatment assignments.
7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
7.1 Statistical and Analytical Plans
The statistical methods provided in this protocol will be focused on primary and secondary analyses.  
Complete and specific details of the statistical analysis will be described in the Statistical Analysis Plan 
(SAP).
The primary analysis will be conducted after all subjects have completed Week 24, data pertaining to 
Period 1 have been cleaned, and a database lock has occurred for the purpose of efficacy and safety 
analysis in Period 1.  The efficacy analysis performed based on this database lock will be the only and 
final analysis for Period 1.
7.2 Definition for Analysis Populations
The ITT Population includes all randomized subjects.  Subjects will be included in the analysis based on 
treatment as randomized.  The ITT Population will be used for all efficacy analyses.
The following populations will be used for the safety analysis:

The Safety Population (Safety) is defined as all subjects who are randomized and received at 
least 1 dose of study drug in the study.

The all upadacitinib treated (ALL_UPA) Population is defined as all subjects who received at least 
1 dose of upadacitinib in the study.  This population will be used to provide a comprehensive 
summary of safety.
7.3 Handling Potential Intercurrent Events for the Primary Endpoint
The primary endpoint (Section 3.2) will be analyzed in the ITT Population and no intercurrent events will 
be considered.  All data collected, regardless of premature discontinuation of study drug, will be used in 
the analysis.
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7.4 Statistical Analyses for Efficacy
The efficacy analysis will be based on the ITT Population and all statistical tests will be performed at a 
2-sided significance level of 0.1.  The 95% confidence interval of the treatment effect will be provided.

For continuous variables, comparisons of change and/or percent change from Baseline will be 
made between upadacitinib and placebo based on the Mixed Model Repeated Measures 
(MMRM) adjusting for treatment, visit, treatment-by-visit interaction, and stratification factors 
derived by the actual value (age group [≤50 and > 50], Baseline disease severity [T-VASI < 15 
and ≥15], and status of active vitiligo [Yes/No]) as fixed factors, and Baseline value as a 
covariate.  The MMRM will be the primary approach to handle missing values for continuous 
endpoints.

For categorical variables, comparisons will be made between upadacitinib and placebo using the
Cochran-Mantel-Haenszel (CMH) test, adjusting for the stratification factors derived by the 
actual value:  age group (≤50 and > 50), Baseline disease severity (T-VASI < 15 and ≥ 15), and 
status of active vitiligo (Yes/No).  Non-Responder Imputation incorporating multiple imputation 
(MI) to handle missing data due to COVID-19 (NRI-MI) will be the primary approach to handle 
missing values for categorical endpoints.
Summary and Analysis of the Primary Endpoint
Analysis of the primary endpoint will be conducted on the ITT Population based on the treatment as 
randomized.  Comparison of the primary endpoint will be made between each upadacitinib dose and 
placebo using the MMRM adjusting for treatment, visit, treatment-by-visit interaction, stratification 
factors derived by the actual value, and Baseline value at a 2-sided significance level of 0.1.
MMRM will be the primary approach to handle missing values.  A sensitivity analysis will also be 
performed for the primary efficacy endpoint, using MI to handle missing values.  Analysis details for 
MMRM, MI, and other sensitivity analyses (if applicable) will be provided in the SAP.
Summary and Analysis of Secondary Endpoints
Analysis of secondary efficacy endpoints will be conducted on the ITT Population based on the 
treatment as randomized.  The continuous endpoints will be analyzed using the same method as for the 
primary endpoint.  The categorical endpoints will be analyzed using the CMH test.  The null hypotheses 
for all secondary endpoints will be tested at a 2-sided significance level of 0.1.
Summary and Analysis of Additional Efficacy Endpoints
Additional endpoints, as described in Section 3.4, will also be analyzed.  Analysis details will be provided 
in the SAP.
Subgroup Analysis for Efficacy
To evaluate the consistency of the efficacy across demographic and other Baseline characteristics, 
summaries and analyses will be performed for selected subgroups for the primary efficacy endpoint.  
The subgroups will be defined in SAP.
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7.5 Statistical Analyses for Safety
All safety analyses will be performed for the Safety Population and ALL_UPA Population.  Subjects will be 
analyzed based on the treatment actually received.  The number and percentage of subjects 
experiencing AEs will be tabulated using Medical Dictionary for Regulatory Activities system organ class 
and preferred term, as well as 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, and 
AEs leading to discontinuation will be provided as well.
For selected laboratory parameters, a listing of all subjects with any laboratory value above Grade 3 of 
Common Toxicity Criteria will be provided.  Mean change from Baseline in laboratory and vital sign 
variables will be summarized.  Additional details for the safety analysis will be provided in the SAP.
7.6 Interim Analysis
No formal interim analysis of efficacy is planned for this study.  Routine safety reviews will be performed 
by an external independent DMC (see details in Section 6.3).
7.7 Overall Type I Error Control
Multiplicity from multiple comparisons will not be adjusted in this Phase 2 study.
7.8 Sample Size Determination
Assuming a Week 24 percent change from Baseline in F-VASI of 0% in the placebo arm, a conservative 
estimate based on a prior study in vitiligo,14 the planned total sample size of 160 subjects (40 subjects in 
each upadacitinib group, 40 subjects total in the placebo groups) will provide more than 90% power to 
detect the treatment difference of 40% reduction (assuming a standard deviation of 54.8%) in at least 
1 upadacitinib group versus placebo using a 2-sided significance level of 0.1 based on the two-sample 
t-test.
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 IEC/IRB for review and approval.  Approval of both the protocol and the informed 
consent form(s) must be obtained before any subject is enrolled.  Any amendment to the protocol will 
require review and approval by the IEC/IRB before the changes are implemented to the study.  In 
addition, all changes to the consent form(s) will be IEC/IRB approved.
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8.2 Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, operations manual, International Council 
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (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 COVID-19 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., 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.
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.
9 SOURCE DOCUMENTS AND CASE REPORT FORM 
COMPLETION
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported.  All source documents should be attributable, legible, contemporaneous, original, 
accurate, and complete to ensure accurate interpretation of data.  Clinical site monitoring is conducted 
to ensure that the rights and well-being of human subjects are protected, that the reported trial data 
are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the 
currently approved protocol, ICH Good Clinical Practice (GCP), and applicable local regulatory 
requirement(s).  During the COVID-19 pandemic, remote data review/verification may be employed if 
allowed by the local regulatory authority, IRB/IEC, and the study site.
10
DATA QUALITY ASSURANCE
AbbVie will ensure that the clinical trial is conducted with a quality management system that will define 
quality tolerance limits in order to ensure human subject protection and reliability of study results.  Data 
will be generated, documented, and reported in compliance with the protocol, ICH GCP, and applicable 
regulatory requirements.
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11
COMPLETION OF THE STUDY
The end-of-study is defined as the date of the last subject's last visit or the actual date of follow-up 
contact, whichever is later.
12
REFERENCES
1.
Oiso N, Suzuki T, Fukai K, et al. Nonsegmental vitiligo and autoimmune mechanism. Dermatol Res 
Pract. 2011;2011:518090.
2.
Morrison B, Burden-Teh E, Batchelor JM, et al. Quality of life in people with vitiligo: a systematic 
review and meta-analysis. Br J Dermatol. 2017;177(6):e338-e9.
3.
Alikhan A, Felsten LM, Daly M, et al. Vitiligo: a comprehensive overview Part I. Introduction, 
epidemiology, quality of life, diagnosis, differential diagnosis, associations, histopathology, etiology, 
and work-up. J Am Acad Dermatol. 2011;65(3):473-91.
4.
Ezzedine K, Lim HW, Suzuki T, et al. Revised classification/nomenclature of vitiligo and related 
issues: the Vitiligo Global Issues Consensus Conference. Pigment Cell Melanoma Res. 2012;25(3):E1-
13.
5.
Patel KR, Singam V, Rastogi S, et al. Association of vitiligo with hospitalization for mental health 
disorders in US adults. J Eur Acad Dermatol Venereol. 2019;33(1):191-7.
6.
Sheth VM, Guo Y, Qureshi AA. Comorbidities associated with vitiligo: a ten-year retrospective study. 
Dermatology. 2013;227(4):311-5.
7.
Elbuluk N, Ezzedine K. Quality of Life, Burden of Disease, Co-morbidities, and Systemic Effects in 
Vitiligo Patients. Dermatol Clin. 2017;35(2):117-28.
8.
Dahir AM, Thomsen SF. Comorbidities in vitiligo: comprehensive review. Int J Dermatol. 
2018;57(10):1157-64.
9.
Teulings HE, Overkamp M, Ceylan E, et al. Decreased risk of melanoma and nonmelanoma skin 
cancer in patients with vitiligo: a survey among 1307 patients and their partners. Br J Dermatol. 
2013;168(1):162-71.
10. Rodrigues M. Skin Cancer Risk (Nonmelanoma Skin Cancers/Melanoma) in Vitiligo Patients. 
Dermatol Clin. 2017;35(2):129-34.
11. Rodrigues M, Ezzedine K, Hamzavi I, et al. New discoveries in the pathogenesis and classification of 
vitiligo. J Am Acad Dermatol. 2017;77(1):1-13.
12. Harris JE, Harris TH, Weninger W, et al. A mouse model of vitiligo with focused epidermal 
depigmentation requires IFN-γ for autoreactive CD8⁺ T-cell accumulation in the skin. J Invest 
Dermatol. 2012;132(7):1869-76.
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13. Relke N, Gooderham M. The Use of Janus Kinase Inhibitors in Vitiligo: A Review of the Literature. J 
Cutan Med Surg. 2019;23(3):298-306.
14. Rosmarin D, Pandya AG, Lebwohl M, et al. Ruxolitinib cream for treatment of vitiligo: a randomised, 
controlled, phase 2 trial. Lancet. 2020;396(10244):110-20.
15. Incyte. Topical Ruxolitinib Evaluation in Vitiligo Study 1 (TRuE-V1), CT.gov Identifier: NCT04052425. 
Bethesda, MD: US National Library of Medicine; Mar 2020 [cited 2020 Sep 08]. Available from: 
https://clinicaltrials.gov/ct2/show/NCT04052425.
16. Incyte. Topical Ruxolitinib Evaluation in Vitiligo Study 2 (TRuE-V2), CT.gov Identifier: NCT04057573. 
Bethesda, MD: US National Library of Medicine; Mar 2020 [cited 2020 Sep 08]. Available from: 
https://clinicaltrials.gov/ct2/show/NCT04057573.
17. Nicolaidou E, Antoniou C, Stratigos AJ, et al. Efficacy, predictors of response, and long-term follow-
up in patients with vitiligo treated with narrowband UVB phototherapy. J Am Acad Dermatol. 
2007;56(2):274-8.
18. Guttman-Yassky E, Thaçi D, Pangan AL, et al. Upadacitinib in adults with moderate to severe atopic 
dermatitis: 16-week results from a randomized, placebo-controlled trial. J Allergy Clin Immunol. 
2020;145(3):877-84.
19. AbbVie. Upadacitinib Investigator's Brochure Edition 11. 18 August 2020.
20. Kim SR, Heaton H, Liu LY, et al. Rapid Repigmentation of Vitiligo Using Tofacitinib Plus Low-Dose, 
Narrowband UV-B Phototherapy. JAMA Dermatol. 2018;154(3):370-1.
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APPENDIX A. STUDY-SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
Ab
antibody
AD
atopic dermatitis
ADL
activities of daily living
AE
adverse event
AESI
adverse event of special interest
ALC
absolute lymphocyte count
ALL_UPA
all upadacitinib treated
ALT
alanine transaminase
ANC
absolute neutrophil count
AS
ankylosing spondylitis
AST
aspartate transaminase
BSA
body surface area
CAC
Cardiovascular Adjudication Committee
CMH
Cochran-Mantel-Haenszel
COVID-19
coronavirus disease 2019
CPK
creatine phosphokinase
CRF
case report form
CRP
C-reactive protein
CXR
chest x-ray
CYP3A
cytochrome P450 3A
DLQI
Dermatology Life Quality Index
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DTP
direct-to-patient
DVT
deep vein thrombosis
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
F-PaGVA
Face – Patient Global Vitiligo Assessment
F-PhGVA
Face – Physician Global Vitiligo Assessment
FSH
follicle-stimulating hormone
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F-VASI
Facial Vitiligo Area Scoring Index
GCP
Good Clinical Practice
GI
gastrointestinal
HADS
Hospital Anxiety and Depression Scale
HBc Ab
hepatitis B core antibody
HBs Ab
hepatitis B surface antibody
HBs Ag
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HIV Ab
human immunodeficiency virus antibody
hsCRP
high-sensitivity C-reactive protein
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use
ICVA
Individual Component Vitiligo Assessment
IEC
Independent Ethics Committee
IFN
interferon
IM
intramuscular
IMP
Investigational Medicinal Product
INR
international normalized ratio
IRB
Institutional Review Board
IRT
interactive response technology
ITT
Intent-to-Treat
IU
International Unit
JAK
Janus kinase
MedDRA
Medical Dictionary for Regulatory Activities
MI
multiple imputation
MMRM
Mixed Model Repeated Measures
MTX
methotrexate
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NMSC
non-melanoma skin cancer
NSV
non-segmental vitiligo
PaGIC-V
Patient's Global Impression of Change-Vitiligo
PBMC
peripheral blood mononuclear cells
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PCR
polymerase chain reaction
PD
Premature Discontinuation
PhGIC-V
Physician's Global Impression of Change-Vitiligo
PhGVA
Physician Global Vitiligo Assessment
PK
pharmacokinetic
PPD
purified protein derivative (tuberculin)
PRO
patient-reported outcome
PsA
psoriatic arthritis
PT
preferred term
QD
once daily
QoL
quality of life
RA
rheumatoid arthritis
RNA
ribonucleic acid
RSI
Reference Safety Information
SAE
serious adverse event
SAP
Statistical Analysis Plan
SAR
Serious Adverse Reaction
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SOC
system organ class
STAT
Signal Transducers and Activators of Transcription
SUSAR
Suspected Unexpected Serious Adverse Reaction
TA MD
Therapeutic Area Medical Director
TB
tuberculosis
TEAE
treatment-emergent adverse event
T-PaGVA
Total – Patient Global Vitiligo Assessment
T-PhGVA
Total – Physician Global Vitiligo Assessment
TPO
thyroid peroxidase
TSH
thyroid-stimulating hormone
T-VASI
total Vitiligo Area Scoring Index
T4
thyroxine
ULN
upper limit of normal
UV
ultraviolet
VASI
Vitiligo Area Scoring Index
VES
vitiligo extent score
VitiQoL
vitiligo quality-of-life
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VNS
vitiligo noticeability scale
WBC
white blood cell
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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M19-051:  A Multicenter, Randomized, Double-Blind, Placebo-Controlled Dose-Ranging Study 
to Evaluate the Safety and Efficacy of Upadacitinib in Subjects with Non-Segmental Vitiligo
Protocol Date:  07 July 2021
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation 
of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practices (GCP) and 
local 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
Study Project Manager II
Clinical Program Development
Program Lead II
Clinical Program Development
Senior Medical Writer
Medical Writing
Senior Scientific Director
Immunology Clinical Development
Director
Data and Statistical Sciences
Senior Director & Statistics Therapeutic 
Area Head
Data and Statistical Sciences
Director
Clinical Pharmacology and 
Pharmacometrics
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APPENDIX D. ACTIVITY SCHEDULE
The following table shows the required activities across Screening and subsequent study visits.  The 
individual activities are described in detail in the operations manual (Appendix F).  Allowed 
modifications due to the COVID-19 pandemic are detailed within the operations manual.
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APPENDIX E. PROTOCOL SUMMARY OF CHANGES
Previous Protocol Versions
Protocol
Date
Version 1.0
15 March 2021
The purpose of this version is to address the following changes in addition to minor clerical corrections
for consistency throughout:
Protocol

Update Title Page to change sponsor/emergency medical contact from 
 MD, MS, 
DVM, FAAD to 
MD, PhD, and to update contact information accordingly.
Rationale:  To update due to personnel change.

Update Synopsis and Section 2.1 to add "in some countries" to clarify the approval status of 
upadacitinib for the treatment of RA, PsA, and AS.
Rationale:  To align with indication approvals outlined in the investigator brochure.  According to 
the current IB, upadacitinib is approved for RA and is being evaluated for other indications.

Update Synopsis and Section 5.1 eligibility criterion #17 to indicate that subjects must not have 
been previously treated with any permanent skin bleaching agents to treat vitiligo.  
Rationale:  To clarify that previous treatment with permanent skin bleaching agents to treat 
vitiligo is prohibited. 

Update Section 3.8 to add wording for site and subject participation in the Digital Imaging 
Research.
Rationale:  To clarify the approximate number of sites that will be selected and that subjects at 
participating sites will be required to participate after digital imaging platform is available for 
implementation at the site.

Update Section 5.3 to revise the dose for systemic corticosteroids from 1 mg/kg to 1 mg/kg/day.
Rationale:  To provide the correction needed regarding the maximum dose of systemic 
corticosteroids allowed.

Update Section 5.3 to change the wording regarding natural daily light exposure from 
"encouraged" to "allowed."
Rationale:  To provide clarification.  

Update Section 5.3 to add language prohibiting use throughout the study of any drugs 
considered to be strong CYP3A inhibitors or inducers, or herbal supplements or traditional 
medicines with unknown effects on CYP3A.
Rationale:  To provide additional language as topical and supplemental treatments may 
interfere with upadacitinib metabolism and exposure and may also impact efficacy and safety of 
upadacitinib treatment.
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
Update to Targeted Biologic Therapies in Section 5.3 to include the U.S. marketed product name
and to update to the registered trademark for EU SKYRIZI.
Rationale:  To provide clarification.

Update Section 5.5 to add the following language in the event that an eligibility criteria violation 
was noted after the subject started study drug and continuation of study drug would place the 
subject at risk:  "Note: indicate that intentional/prospective deviations from the protocol are not 
permitted."
Rationale:  To provide clarification in response to a request from Health Canada.  

Update Section 5.5 to condense the wording regarding subject non-compliance with study 
procedures.
Rationale:  To simplify the wording as significant non-compliance with study procedures would 
be sufficient cause to consider discontinuation for a clinical trial, regardless of the perceived risk 
to the subject.  Also, significant non-compliance has the potential to have a negative impact on 
the scientific integrity of the study.  

Update Section 5.5 to add "beginning at Week 8" to the discontinuation criterion regarding 
worsening vitiligo as defined by an increase of 25% or higher in T-VASI from Baseline.
Rationale:  To clarify that subjects with 25% increase in T-VASI will not be discontinued until 
Week 8 to allow sufficient time for upadacitinib to show some improvement, thus minimizing 
early premature discontinuation.

Update Section 7.4 to clarify that categorical stratification factors will be adjusted in the models.
Rationale: to clarify that categorical stratification factors are adjusted in the models instead of 
the continuous values of the variables.

Update Appendix A to add abbreviations.
Rationale:  To keep abbreviations list current.

Update Appendix C to revise List of Protocol Signatories.
Rationale:  To update protocol signatories to reflect current personnel.  

Update Appendix D to add respiratory rate and body temperature to vital signs.
Rationale:  To provide consistency for vital signs in Operations Manual Section 3.14 where vital 
signs are defined as "systolic and diastolic blood pressure in sitting position, heart rate, 
respiratory rate, and body temperature," and in Appendix D, Activity Schedule. 
Operations Manual

Update Section 1 and Section 4.3 to change sponsor/emergency medical contact from 
 
 MD, MS, DVM, FAAD to 
 MD, PhD, and to update contact 
information accordingly.
Rationale:  To update due to personnel change.

Update Section 2.1 Baseline/Day 1 to add a footnote indicating that study drug dispensed at 
Baseline contains 35 tablets; therefore, study drug will not be dispensed from IRT at Week 2.
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Rationale:  To provide clarification that no study drug dispensation from the IRT system will 
occur at the Week 2 visit.

Update Section 2.1 Week 2/Day 15 to add a footnote that study drug dispensation from IRT at 
Baseline will be reviewed for compliance and returned to subject at this visit. IRT dispensation 
at this visit is not available.
Rationale:  To clarify that no study drug dispensation from the IRT system will occur at the 
Week 2 visit.

Update Section 2.1 Week 12/Day 85, Week 24/Day 169, Week 36/Day 253, Week 44/Day 309, 
and Premature Discontinuation Visit to add the following footnote regarding HBV post-Baseline 
tests for subjects from Japan only: HBV DNA PCR testing approximately every 12 weeks is not 
necessary when the subject has a history of HBV vaccination and HBs Ab+ and HBc Ab–.  If 
necessary, HBV DNA PCR may be tested at unscheduled visits.
Rationale: To clarify when additional testing is required.

Update Section 3.3 to add language that additional temporary verbal consent may be obtained 
in accordance with local regulations, followed by an appropriately signed and dated informed 
consent form obtained from the subject afterwards, as soon as possible.
Rationale:  To provide updated guidance on informed consent from subjects due to protocol 
modifications that may become necessary during the COVID-19 pandemic.

Update Section 3.7 to clarify the description of the VNS and VitiQoL.
Rationale:  To provide clarification.

Update Section 3.7 to correct the response option ranges from 0 = no depigmentation to 
4 = very extensive pigmentation.
Rationale:  To provide correction for T-PaGVA and F-PaGVA scale response options.

Update Section 3.8 to add language regarding how the VES will initially be collected and how the 
final score will be calculated before upload into EDC by the site.
Rationale:  To clarify the steps necessary to collect the VES based on the way it was initially 
validated.

Update Section 3.9 to replace the level of bother response option of "not applicable" to "area 
not affected by vitiligo."
Rationale:  To clarify how some of the ICVA data is collected into EDC.

Update Section 3.11 to state that PK samples should be collected at 0.5 to 4 hours post-dosing
at Baseline and Week 4.  At Weeks 8, 12, and 24, subjects should take the study drug dose at the 
clinic within 30 minutes after collecting the PK blood sample.
Rationale:  To add PK collection timepoint for Baseline and a 30-minute window for taking study 
drug dose after PK sample collection at Weeks 8, 12, and 24.

Update Section 3.11 to indicate that data and accurate time of dose administration will be 
recorded in the eCRF for doses administered at the clinic during a study visit.
Rationale:  To provide additional clarification regarding data and accurate time capture of study 
drug dose administration.
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
Update Section 3.13 to indicate that body weight will be measured at scheduled visits as 
specified in Section 2.1 and in Appendix D, Activity Schedule.
Rationale:  To clarify weight collection timepoints.

Update Section 3.14 to change "pulse rate" to "heart rate."
Rationale:  To provide consistency with wording in Section 3.14 and Appendix D, Activity 
Schedule.

Update Section 3.18 to remove the following sentence:  "AbbVie will not receive results from 
the testing and will not be made aware of any positive result."
Rationale:  Although AbbVie does not require receiving HIV test results, AbbVie CRAs are 
required to verify all study eligibility criteria, including the lack of confirmed positive anti-HIV 
antibody test, therefore the statement was removed to accurately reflect the current AbbVie 
monitoring practice.

Update Section 3.19 to indicate that the first dose of study drug will be administered after all 
other Baseline (Day 1) procedures are completed, with the exception of the PK blood draw.
Rationale:  To clarify that Baseline PK draw should be performed post-dose.

Update Section 3.19 to indicate that subjects should be instructed to administer their dose at 
the site during the study visit and not at home prior to the visit; however, the subject should 
follow the regular dosing schedule if study drug administration is normally after the time of the 
scheduled study visit.
Rationale: To clarify that the dose on the study day visit should be administered at the site to 
allow appropriate collection of PK samples in relation to the dosing time.

Update Section 3.20 to add "unless performed at a local laboratory" to indicate when a lab re-
test will be considered an Unscheduled Visit.
Rationale:  To provide further clarification regarding on-study unscheduled visits.

Update Section 4.1 to add language regarding toxicity management for abnormal labs and that 
additional supplemental eCRFs (hepatic and renal) may need to be completed.
Rationale:  To provide clarification regarding additional supplemental eCRFs required for toxicity 
management for abnormal labs, as described in Protocol Section 6.2.

Update Section 7.1 to clarify the question in the PaGIC-V Example to "Since the start of the 
treatment you've received in this study, your vitiligo is…".
Rationale:  To clarify the question since this is a pill and therefore "your vitiligo in areas treated 
with the study" would not apply.

Update Section 7.1 to provide numerical score rate response options of 0 – 4 for the T-PaGVA 
and F-PaGVA scales.
Rationale:  To correct the T-PaGVA and F-PaGVA scales as score rate (0 – 4) was missing.

Update Section 7.2 to update the Vitiligo History Form Example wording from "any other family 
member" to "any other biological family member."
Rationale:  To provide a necessary correction on the paper version of the form.
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
Update Section 7.2 and Section 7.3 to provide more recent versions of the T-VASI, F-VASI, VES, 
ICVA and Individual Components of Face Examples, and to provide explanation that additional 
information containing instructions will be provided to the sites.
Rationale:  To keep this section current.
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SAP_001.pdf: 
Upadacitinib
M19-051 – Statistical Analysis Plan
Version 2.0 – 27 December 2022
1
Statistical Analysis Plan for Study M19-051
A Multicenter, Randomized, Double-Blind, Placebo-
Controlled Dose-Ranging Study to Evaluate the 
Safety and Efficacy of Upadacitinib in Subjects with 
Non-Segmental Vitiligo
Date:  27 December 2022
Version 2.0
 
NCT04927975


Upadacitinib
M19-051 – Statistical Analysis Plan
Version 2.0 – 27 December 2022
2
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.......................................................................... 6
2.3
Treatment Assignment and Blinding....................................................... 7
2.4
Sample Size Determination .................................................................... 8
3.0
Endpoints...............................................................................8
3.1
Primary Endpoint ................................................................................... 8
3.2
Secondary Endpoints.............................................................................. 9
3.3
Other Efficacy Endpoints ....................................................................... 9
3.4
Safety Endpoints .................................................................................. 10
4.0
Analysis Populations ...........................................................10
5.0
Subject Disposition..............................................................11
6.0
Study Drug Duration and Compliance ..............................12
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ...................14
7.1
Demographics and Baseline Characteristics.......................................... 14
7.2
Medical History.................................................................................... 14
7.3
Prior and Concomitant Medications...................................................... 15
8.0
Handling of Potential Intercurrent Events for the 
Primary Endpoint ...............................................................15
9.0
Efficacy Analyses.................................................................16
9.1
General Considerations......................................................................... 16
9.2
Handling of Missing Data..................................................................... 19
9.3
Primary Efficacy Endpoint and Analyses.............................................. 21
9.3.1
Primary Efficacy Endpoint ................................................................... 21
9.3.2
Main Analysis of Primary Efficacy Endpoint........................................ 21
9.3.3
Sensitivity Analyses of the Primary Efficacy Endpoint......................... 24
9.4
Secondary Efficacy Analyses ............................................................... 25
9.4.1
Main Analyses of Secondary Efficacy Endpoints.................................. 25
9.5
Additional Efficacy Analyses ............................................................... 25
 


Upadacitinib
M19-051 – Statistical Analysis Plan
Version 2.0 – 27 December 2022
3
9.6
Efficacy Subgroup Analyses................................................................. 26
10.0
Safety Analyses....................................................................27
10.1
General Considerations......................................................................... 27
10.2
Adverse Events..................................................................................... 27
10.2.1
Treatment-Emergent Adverse Events.................................................... 28
10.2.2
Adverse Event Overview...................................................................... 28
10.2.3
Treatment-Emergent Adverse Events by SOC and/or PT...................... 29
10.2.4
SAEs (Including Deaths) and TEAE Leading to Study Drug 
Discontinuation .................................................................................... 30
10.2.5
Adverse Events of Special Interest........................................................ 30
10.3
Analysis of Laboratory Data................................................................. 31
10.4
Analysis of Vital Signs......................................................................... 32
10.5
Safety Subgroup Analyses.................................................................... 33
10.6
Other Safety Analyses .......................................................................... 33
11.0
Other Analyses ....................................................................33
12.0
Interim Analyses..................................................................33
12.1
Data Monitoring Committee................................................................. 33
13.0
Overall Type-I Error Control.............................................33
14.0
Version History ...................................................................34
15.0
References............................................................................34
List of Tables
Table 1.
Analysis Models and Imputation Methods............................................ 17
Table 2.
Summary of the Estimand Attributes of the Primary Efficacy 
Endpoint............................................................................................... 22
Table 3.
Candidate Models................................................................................. 24
Table 4.
SAP Version History Summary ............................................................ 34
List of Figures
Figure 1.
Study Schematic..................................................................................... 7
 


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List of Appendices
Appendix A.
Protocol Deviations .............................................................................. 35
Appendix B.
Definition of Adverse Events of Special Interest................................... 36
Appendix C.
Potentially Clinically Important Criteria for Safety Endpoints .............. 38
Appendix D.
Random Seeds...................................................................................... 41
Appendix E.
Non-Responder Imputation Incorporating Multiple Imputation to 
Handle Missing Data Due to COVID-19 Pandemic or Any Other 
Missing Data that Can Be Reasonably Assumed to Be Missing at 
Random for Dichotomized Outcome Variables..................................... 42
 


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1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for upadacitinib 
Study M19-051 'A Multicenter, Randomized, Double-Blind, Placebo-Controlled Dose-
Ranging Study to Evaluate the Safety and Efficacy of Upadacitinib in Subjects with Non-
Segmental Vitiligo.'
Study M19-051 examines the efficacy and safety of upadacitinib for the treatment of adult 
subjects with non-segmental vitiligo (NSV).
The analyses of pharmacokinetic endpoints and biomarkers will not be covered in this 
SAP.
The SAP will not be updated in case of administrative changes or amendments to the 
protocol unless the changes impact the analysis.
Unless noted otherwise, all analyses will be performed using SAS Version 9.4 (SAS 
Institute Inc., Cary, NC  27513) or later under the UNIX operating system.
2.0
Study Design and Objectives
2.1
Objectives, Hypotheses and Estimands
The primary objective of this study is to evaluate the safety and efficacy of upadacitinib 
for the treatment of adult subjects with NSV.  The primary efficacy objective is based on 
the percent change from Baseline in Facial Vitiligo Area Scoring Index (F-VASI) at Week 
24 with upadacitinib treatment compared to placebo in the Intent-to-Treat (ITT) 
Population, which consists of all randomized subjects.
The hypothesis corresponding to the primary endpoint is:
Percent change from Baseline in F-VASI with upadacitinib is greater than that with 
placebo at Week 24.
The estimand corresponding to the primary endpoint is defined as:
 


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Difference in the percent change from Baseline in F-VASI at Week 24, regardless of 
treatment discontinuation, between each of the upadacitinib dose groups compared with 
placebo in the adult subjects with NSV.
2.2
Study Design Overview
This is a Phase 2, multicenter, randomized, double-blinded, parallel-group, placebo-
controlled dose-ranging study that will evaluate the safety and efficacy of upadacitinib in 
adult subjects ≥ 18 to 65 years of age with NSV.  The study is comprised of a 35-day 
Screening Period, a 24-week double-blind treatment period (Period 1), a 28-week blinded 
long-term extension (Period 2), and a 30-day Follow-up Period.
Subjects who meet eligibility criteria at Baseline will be randomized in a 2:2:2:1:1 ratio to 
one of five treatment groups:
●
Group 1: upadacitinib 22 mg once daily (QD) (N = 40) (Period 1) → 
upadacitinib 22 mg QD (Period 2)
●
Group 2: upadacitinib 11 mg QD (N = 40) (Period 1) → upadacitinib 11mg 
QD (Period 2)
●
Group 3: upadacitinib 6 mg QD (N = 40) (Period 1) → upadacitinib 6 mg QD 
(Period 2)
●
Group 4: placebo (N = 20) (Period 1) → upadacitinib 22 mg QD (Period 2)
●
Group 5: placebo (N = 20) (Period 1) → upadacitinib 11 mg QD (Period 2)
At Week 24, subjects who were randomized to placebo at Baseline will be switched to 
either upadacitinib 22 mg (Group 4) or upadacitinib 11 mg (Group 5) in a blinded fashion 
per pre-specified randomization assignments.
The AbbVie study team will be unblinded to perform the Week 24 primary analysis.  The 
unblinding will take place after all subjects have completed the Week 24 visit or have 
prematurely discontinued prior to Week 24.  Sites and subjects will remain blinded 
throughout the study.
 


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The schematic of the study is shown in Figure 1.
Figure 1.
Study Schematic
2.3
Treatment Assignment and Blinding
All subjects will be assigned a unique identification number by the IRT at the screening 
visit.  For subjects who rescreen, the screening number assigned by the IRT at the initial 
screening visit should be used.  The IRT will assign a randomization number that will 
encode the subject's treatment group assignment according to the randomization schedule.
Subjects who meet eligibility criteria at Baseline will be randomized in a 2:2:2:1:1 ratio to 
one of the five treatment groups:
●
Group 1: upadacitinib 22 mg QD (N = 40) (Period 1) →upadacitinib 22 mg 
QD (Period 2)
●
Group 2: upadacitinib 11 mg QD (N = 40) (Period 1) →upadacitinib 11mg 
QD (Period 2)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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●
Group 3: upadacitinib 6 mg QD (N = 40) (Period 1) →upadacitinib 6 mg QD 
(Period 2)
●
Group 4: placebo (N = 20) (Period 1) →upadacitinib 22 mg QD (Period 2)
●
Group 5: placebo (N = 20) (Period 1) →upadacitinib 11 mg QD (Period 2)
Randomization will be stratified by the age group (≤ 50 and > 50), Baseline disease 
severity (T-VASI < 15 and ≥ 15), and status of active vitiligo (Yes/No) defined as 
follows:
●
Active: Showing new lesions or progression (enlargement) of existing lesions 
within the last 6 months and/or presenting clinical subtypes indicative of 
progressing vitiligo (i.e., confetti-like depigmentation, trichrome pattern, or 
Koebner phenomenon).
At Week 24, subjects who were randomized to placebo at Baseline will be switched to 
either 22 mg (Group 4) or 11 mg (Group 5) upadacitinib in a blinded fashion per pre-
specified randomization assignments.
2.4
Sample Size Determination
Assuming a Week 24 percent change from Baseline in F-VASI of 0% in the placebo arm, 
a conservative estimate based on a prior study in vitiligo,1 the planned total sample size of 
160 subjects (40 subjects in each upadacitinib group, 40 subjects in total in the placebo 
groups) will provide more than 90% power to detect the treatment difference of 40% 
reduction (assuming a standard deviation of 54.8%) in at least 1 upadacitinib group versus 
placebo using a 2-sided significance level of 0.1 based on the two-sample t-test.
3.0
Endpoints
3.1
Primary Endpoint
The primary endpoint is the percent change from Baseline in F-VASI at Week 24.
 


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3.2
Secondary Endpoints
●
Achievement of F-VASI 75 (≥ 75% improvement in F-VASI from Baseline) at 
Week 24;
●
Achievement of F-VASI 50 (≥ 50% improvement in F-VASI from Baseline) at 
Week 24;
●
Achievement of total Vitiligo Area Scoring Index (T-VASI) 50 (≥ 50% 
improvement in T-VASI from Baseline) at Week 24;
●
Percent change from Baseline in T-VASI at Week 24;
●
Change from Baseline in the vitiligo quality-of-life (VitiQoL) total score at 
Week 24.
3.3
Other Efficacy Endpoints
Additional Efficacy Endpoints include the primary and all secondary endpoints assessed 
at visits as noted in the Study Activities table (Protocol Appendix D), other than Week 24.  
Additional Efficacy Endpoints also include the following measurements assessed at visits 
as specified in the Study Activities table (Protocol Appendix D):
●
Achievement of F-VASI 90 (≥ 90% improvement in F-VASI from Baseline);
●
Achievement of T-VASI 75 (≥ 75% improvement in T-VASI from Baseline);
●
Achievement of T-VASI 90 (≥ 90% improvement in T-VASI from Baseline);
●
Mean and percent change from Baseline in the vitiligo extent score (VES);
●
Achievement of vitiligo noticeability scale (VNS) score of "A lot less 
noticeable (4)" or "No longer noticeable (5)";
●
Achievement of Dermatology Life Quality Index (DLQI) total score of "0" or 
"1";
●
Change from Baseline in the Hospital Anxiety and Depression Scale (HADS) 
anxiety and depression scores;
●
Proportion of subjects selecting each of the response categories of VitiQoL 16 
questions;
 


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●
Achievement of Physician's Global Impression of Change-Vitiligo (PhGIC-V) 
of "Much better (1)" or "A little better (2)";
●
Achievement of Patient's Global Impression of Change-Vitiligo (PaGIC-V) of 
"Much better (1)" or "A little better (2)";
●
Achievement of Face – Physician Global Vitiligo Assessment (F-PhGVA) of 
"No depigmentation (0)" or "Limited extent of depigmentation (1)";
●
Achievement of Total – Physician Global Vitiligo Assessment (T-PhGVA) of 
"No depigmentation (0)" or "Limited extent of depigmentation (1)";
●
Achievement of Face – Patient Global Vitiligo Assessment (F-PaGVA) of "No 
depigmentation (0)" or "Limited extent of depigmentation (1)";
●
Achievement of Total – Patient Global Vitiligo Assessment (T-PaGVA) of 
"No depigmentation (0)" or "Limited extent of depigmentation (1)."
3.4
Safety Endpoints
Safety evaluations include AEs, serious adverse events (SAEs), adverse events of special 
interest (AESIs), AEs leading to discontinuation, vital signs, laboratory tests (hematology, 
chemistry, liver function tests), and physical examination.
4.0
Analysis Populations
The following Intent-to-Treat (ITT) populations will be used for the analyses.
●
The ITT Population in Period 1 (ITT_1) includes all randomized subjects in 
Period 1. Subjects will be included in the analysis according to the treatment 
groups that they are randomized to. Analyses will include the following 
4 groups: upadacitinib (UPA) 22 mg QD, UPA 11 mg QD, UPA 6 mg QD and 
placebo.
●
The ITT Population in Period 2 (ITT_2) includes all subjects entered Period 2. 
Subjects will be included in the analysis according to the 5 treatment groups 
that they are randomized to at baseline: UPA 22 mg QD-> UPA 22 mg QD, 
UPA 11 mg QD-> UPA 11 mg QD, UPA 6 mg QD-> UPA 6 mg QD, Placebo-
> UPA 22 mg QD and Placebo-> UPA 11 mg QD.
 


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●
The ITT_1/ITT_2 Populations will be used for all efficacy analyses across 
Period 1/Period 2.
The following three Safety Populations will be used for the safety analysis:
●
The Safety Population in Period 1 (Safety_1) is defined as all subjects who are 
randomized and received at least one dose of study drug in Period 1. Subjects 
will be summarized in the following 4 groups: UPA 22 mg QD, UPA 11 mg 
QD, UPA 6 mg QD and placebo, based on the treatment actually received 
(defined as the most frequent dose regimen received in Period 1).
●
The Safety Population in Period 2 (Safety_2) is defined as all subjects received 
at least one dose of study drug in Period 2. Subjects will be included in the 
5 groups same as which they were randomized to at baseline: UPA 22 mg QD-
> UPA 22 mg QD, UPA 11 mg QD-> UPA 11 mg QD, UPA 6 mg QD-> UPA 
6 mg QD, Placebo-> UPA 22 mg QD and Placebo-> UPA 11 mg QD. 
●
The all upadacitinib treated (ALL_UPA) Population is defined as subjects who 
received at least one dose of upadacitinib in the study. Subjects will be 
analyzed based on the treatment actually received: UPA 22 mg QD, 
UPA 11 mg QD and UPA 6 mg QD.
5.0
Subject Disposition
The number of subjects for each of the following categories will be summarized in 
Period 1, for overall and for each treatment group in ITT_1 Population:
●
Subjects randomized;
●
Subjects who took at least one dose of study drug in Period 1;
●
Subjects who completed Period 1;
●
Subjects who completed study drug in Period 1;
●
Subjects who prematurely discontinued from study in Period 1;
●
Subjects who prematurely discontinued study drug in Period 1;
 


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The summary will also be provided for Period 2 for each of the following categories and 
by treatment groups in the ITT_2 Population:
●
Subjects who entered Period 2;
●
Subjects who took at least one dose of study drug in Period 2;
●
Subjects who completed study;
●
Subjects who completed study drug in Period 2;
●
Subjects who prematurely discontinued from study in Period 2;
●
Subjects who prematurely discontinued study drug in Period 2.
Number and percentage of subjects who discontinue study drug or who discontinue from 
study will be summarized by primary reason for each treatment group and overall.
In addition, the above summaries (except for the reason for premature discontinuation) 
will also be summarized by center in the accountability table.
6.0
Study Drug Duration and Compliance
For Safety_1/Safety_2 Population, duration of treatment will be summarized for each
treatment group in Period 1 and Period 2.  For ALL_UPA Population, duration of 
treatment will be summarized overall and for each upadacitinib dose group.  Duration of 
treatment is defined as follows:
Period 1:
For subjects who did not continue into Period 2:
●
Date of last dose of study drug in Period 1 – Date of first dose of study drug in 
Period 1 + 1.
 


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For subjects who continued into Period 2:
●
Minimum of (Date of first dose of study drug in Period 2 – Date of first dose 
of study drug in Period 1, Date of last dose of study drug in Period 1 – Date of 
first dose of study drug in Period 1 + 1.)
Period 2:
For subjects who continued into Period 2:
●
Date of last dose of study drug in Period 2 – Date of first dose of study drug in 
Period 2 + 1.
ALL_UPA:
Study drug duration during the administration of study drug in ALL_UPA Population is 
defined as: 
●
Date of last dose of upadacitinib – Date of first dose of upadacitinib + 1.
Duration of treatment will be summarized using the number of subjects treated, mean, 
standard deviation, median, minimum and maximum.  In addition, the number and 
percentage of subjects in each treatment duration interval (≥ 4 weeks, ≥ 12 weeks, 
≥24 weeks, ≥ 36 weeks, ≥ 48 weeks) will be summarized for ALL_UPA Population.
Treatment compliance for Period 1 and 2 will be summarized by treatment groups for 
Safety Populations (Safety_1 and Safety_2).  For ALL_UPA Population, treatment 
compliance will be summarized overall and for each upadacitinib dose group.  Treatment 
compliance is defined as the number of tablets actually taken divided by the number of 
tablets that should have been taken.  For subjects who prematurely discontinued the study 
drug, the planned tablets will only be counted prior to that scheduled visit of 
discontinuation.  Percent compliance will be summarized.
 


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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 the ITT_1 Population overall and by treatment groups. Prior medications 
will be summarized for the Safety_1 Population overall and by treatment groups.  
Concomitant medications will be summarized for the Safety_1 and Safety_2 Populations 
overall and by treatment groups.  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).
7.1
Demographics and Baseline Characteristics
Continuous demographic variables include age, weight, height, and body mass index 
(BMI).  Categorical demographic variables include sex, ethnicity, race, country, age 
(≤50 and > 50), weight (< 60 or ≥ 60 kg), BMI (< 25, ≥ 25 - < 30 or ≥ 30 kg/m2), tobacco 
user (current, former, never, unknown), and alcohol user (current, former, never, 
unknown).
Disease characteristics include the following Baseline F-VASI, Baseline T-VASI, 
Baseline VitiQoL total score and each domain score, Baseline VES, Baseline HADS, 
vitiligo disease diagnosis duration in years as continuous variables and Baseline VNS, 
Baseline DLQI, Baseline F-PhGVA, Baseline T-PhGVA, Baseline F-PaGVA, Baseline T-
PaGVA, subject Fitzpatrick skin type, history of vitiligo-related symptoms (increased 
sensitivity, itch, and pain), status of active vitiligo, Baseline T-VASI (≤10 and > 10)as 
categorical variables.
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 
 


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statistical tables and clinical study report.  The number and percentage of subjects in each 
medical history category (by MedDRA system organ class and preferred term) will be 
summarized overall and by treatment groups in the Intent-to-Treat Population in Period 1 
(ITT_1).  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).
7.3
Prior and Concomitant Medications
Prior and concomitant medications will be summarized by generic name in the Safety 
population. A prior medication is defined as any medication taken prior to the date of the 
first dose of study drug and will be summarized in Period 1.  For Period 1 and 2, a 
concomitant medication in each period is defined as any medication that started prior to 
the date of the first dose of study drug in each period and continued to be taken after the 
first dose of study drug in each period or any medication that started on or after the date of 
the first dose of study drug in each period, but not after the date of the last dose +1 of 
study drug in each period.  The number and percentage of subjects taking medications will 
be summarized by generic drug name based on the World Health Organization (WHO) 
Drug Dictionary for both prior and concomitant medications.
In addition, subjects' prior exposure to topical treatment (topical corticosteroid [TCS], 
topical calcineurin inhibitor [TCI]), systemic corticosteroids, phototherapy, procedure, 
and other will be summarized for each treatment group.
8.0
Handling of Potential Intercurrent Events for the 
Primary Endpoint
The primary efficacy endpoint of percent change in F-VASI at Week 24 (defined in 
Section 3.1) will be analyzed based on the ITT_1 Populations.  For treatment policy 
strategy, the occurrence of the intercurrent event (treatment discontinuation) is considered 
as irrelevant in defining the treatment effect of interest.  Under this strategy, the value for 
the variable of interest is used regardless of whether or not the intercurrent event occurs.
 


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9.0
Efficacy Analyses
9.1
General Considerations
All efficacy analyses will be conducted in the ITT Population in each period (ITT_1 and 
ITT_2).  All tests will be 2-sided at an alpha level of 0.1.
The Primary Analysis will be performed after all ongoing subjects have completed 
Week 24 or have prematurely discontinued prior to Week 24, data pertaining to Period 1 
has been cleaned, and the database has been locked.  This will be the only and final 
analysis for the efficacy endpoints in Period 1.
For analysis in Period 1, continuous endpoints and categorical endpoints will be analyzed 
using Mixed-Effect Model Repeat Measurement (MMRM) and Cochran-Mantel-Haenszel 
(CMH), respectively.
The analysis models and imputation methods for categorical and continuous endpoints in 
Period 1 and Period 2 are summarized in the following table:
 


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Table 1.
Analysis Models and Imputation Methods
Period
Type of 
Variables
Imputation 
Method
Intercurrent Events 
Handling
Analysis Model
Period 1
Continuous
MMRMa
The treatment policy 
strategy is used in this study. 
Under this strategy, all 
values for the variable of 
interest are used regardless 
of the intercurrent event.
MMRM model includes 
treatment, visit and treatment 
by visit interaction, 
stratification factors (age group 
[≤ 50 and > 50]e, baseline 
disease severity [T-VASI < 15 
and ≥ 15]d, and status of active 
vitiligo [Yes/No]), and baseline 
measurement
Categorical 
NRI-MIb
The treatment policy 
strategy is used in this study. 
Under this strategy, all 
values for the variable of 
interest are used regardless 
of the intercurrent event.
CMH test adjusting for 
stratification factors (age group 
[≤ 50 and > 50], baseline 
disease severity [T-VASI < 15 
and ≥ 15], and status of active 
vitiligo [Yes/No])
Period 2
Continuous
AOc
The treatment policy 
strategy is used in this study. 
Under this strategy, all 
values for the variable of 
interest are used regardless 
of the intercurrent event.
ANCOVA includes treatment, 
stratification factors (age group 
[≤ 50 and > 50], baseline 
disease severity [T-VASI < 15 
and ≥ 15]d, and status of active 
vitiligo [Yes/No]), and baseline 
measurement
Categorical 
AOc
The treatment policy 
strategy is used in this study. 
Under this strategy, all 
values for the variable of 
interest are used regardless 
of the intercurrent event.
Descriptive summary 
CMH = Cochran-Mantel-Haenszel; ANCOVA = Analysis of Covariance
a.
Mixed-Effect Model Repeat Measurement.
b.
Non-Responder Imputation while incorporating Multiple Imputation (MI) to handle missing data due to COVID-19
or any other missing data that can be reasonably assumed to be Missing at Random.
c.
As observed (AO): The AO analysis will not impute values for missing evaluations, and thus a subject who does 
not have an evaluation at a scheduled visit will not be included in the AO analysis for that visit.
d.
The stratification factor of baseline disease severity (T-VASI <15 and ≥ 15) will not be included in model for 
percent change from Baseline in T-VASI. 
e.
If the MMRM model cannot converge, the stratification factor of age will not be included in the model.
 


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To evaluate long-term efficacy, all endpoints (categorical and continuous) will be 
summarized descriptively at each visit by treatment groups overall and by stratification 
factors.
Analysis of Continuous Variables
In Period 1, the Baseline means and visit means will be presented for each treatment 
group who have both Baseline and post-baseline visit values.  Change (and/or percent 
change) from Baseline in the treatment groups will be compared using MMRM as 
described in Table 1.  Point estimates, SE, and 95% confidence interval (CI) of LS mean 
change (and/or percent change) from Baseline within treatment groups, along with p-
values between each upadacitinib treatment group and placebo will be provided.  MMRM 
will be the primary approach to handle missing data for continuous endpoints 
(Section 9.2) in Period 1.  In addition, the primary efficacy endpoint will be analyzed 
using MI defined in Section 9.2 as the sensitivity analysis.
For long-term efficacy, the raw value at Baseline and each visit will be summarized using 
mean for each of the 5 treatment groups as observed.  For change (and/or percent change) 
from Baseline, LS mean, SE, and 95% CIs generated by ANCOVA by visit as described 
in Table 1.  Descriptive summary statistics including median, Q1, Q3, minimum and 
maximum of change (and/or percent change) from Baseline will also be provided.
Analysis of Categorical Variables
In Period 1, frequencies and percentages will be provided along with 95% CIs.  Point 
estimates, 95% CIs and p-values from the CMH test for the difference in proportions 
between each upadacitinib group and placebo will be provided.  Breslow-Day test will be 
performed to test the homogeneity between strata.
Non-Responder Imputation while incorporating Multiple Imputation (MI), NRI-MI, will 
be the primary approach to handle missing data for categorical endpoints in Period 1 
(Section 9.2 and Appendix E).
 


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●
If there are missing data due to COVID-19 or any other missing data that can 
be reasonably assumed to be Missing at Random, a total of 30 datasets will be 
generated by PROC MI, and subjects will be characterized as responders or 
non-responders based on MI imputed values.
○
If not all the imputed datasets are identical, analysis will be performed as 
described in Appendix E.
○
If all the 30 imputed datasets are identical, all statistical inferences will be 
calculated using the first imputed dataset: 1) The corresponding 95% CIs 
will be constructed based on normal approximation to the binomial 
distribution.  2) Adjusted differences, 95% CIs and p-values for the 
comparisons between each upadacitinib group and placebo will be 
calculated based on CMH test adjusting for stratification factors.
●
If there are no missing data due to COVID-19 or any other missing data that 
can be reasonably assumed to be Missing at Random, the NRI-MI method will 
be the same as traditional NRI method.  All statistical inferences will be 
calculated using the NRI imputed datasets.
For long-term efficacy, descriptive summary statistics including frequencies and 
percentages for categorical endpoints, along with 95% CIs based on normal 
approximation, will be provided based on as observed data.
Unless otherwise specified, any subject who is randomized based on a wrong stratum will 
be analyzed according to the actual stratum the subject belongs to.
"Baseline" refers to the last non-missing observation before the first administration of 
study drug or randomization if no study drug is given.
9.2
Handling of Missing Data
In Period 1, missing data will be imputed using the following methods for the efficacy 
analyses:
●
Mixed-Effect Model Repeat Measurement (MMRM):  The repeated measures 
analysis will be conducted using a mixed model including observed 
 


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measurements at all visits.  The mixed model includes treatment, visit and 
treatment-by-visit interaction, and stratification factors (age group [≤ 50 and 
> 50], Baseline disease severity [T-VASI < 15 and ≥ 15], and status of active 
vitiligo [Yes/No]) derived from actual values as fixed factors, and Baseline 
value as a covariate.  An unstructured variance covariance matrix will be used.  
If the model cannot converge, an appropriate covariance structure matrix 
(e.g., autoregressive (1) or compound symmetry) will be used, and/or the 
stratification factor of age will not be included in the model.  Parameter 
estimation is based on the assumption of data being missing at random and 
using the method of restrictive maximum likelihood (REML).  MMRM will be 
the primary approach in the analysis of continuous variables in Period 1.
●
Non-Responder Imputation while incorporating Multiple Imputation (MI) to 
handle missing data due to COVID-19 or any other missing data that can be 
reasonably assumed to be Missing at Random (NRI-MI): The NRI-MI will 
categorize any subject who does not have an evaluation during a pre-specified 
visit window (either due to missing assessment or due to early withdrawal 
from the study) as a non-responder for the visit.  The only exceptions are:  
1) when the subject is a responder both before and after the visit window in 
Period 1, the subject will be categorized as a responder for the visit.  
2) missing data due to COVID-19 infection or logistical restriction or any 
other missing data that can be reasonably assumed to be Missing at Random 
will be handled by MI.  The NRI-MI will be the primary approach in the 
analyses of categorical variables in Period 1.  Random seeds are provided in 
Appendix D and more details are provided in Appendix E.  NRI-MI is the 
primary approach to handle missing data for categorical endpoints in Period 1.
●
Multiple Imputation (MI):  The MI approach will be used as a sensitivity 
analysis for the primary efficacy endpoint.  Markov Chain Monte Carlo 
(MCMC) will be first applied to augment data into monotonic missing pattern 
and PROC MI will be used to generate 30 datasets using the regression 
method.  The variables to be included in the imputation model are:  treatment 
group, stratification factors (age group [≤ 50 and > 50], Baseline disease 
severity [T-VASI < 15 and ≥ 15], and status of active vitiligo [Yes/No]) 
derived from actual values, Baseline, and measurements at each visit up to the 
end of the Period 1.  The random seed for MCMC and the random seed for 
 


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PROC MI are specified in Appendix D.  The imputed post-baseline 
measurements will be rounded to the same precision as the observed data.  The 
imputed endpoint will be analyzed using each of the 30 datasets using 
ANCOVA for the primary endpoint.  SAS PROC MIANALYZE will be used 
to generate the final inferences of the difference between upadacitinib group 
and placebo.
In Period 2, all values collected in the study will be used to summarize the long-term
efficacy as observed (AO) in Period 2:
●
The AO analysis will not impute values for missing evaluations, and thus a 
subject who does not have an evaluation at a scheduled visit will not be 
included in the AO analysis for that visit.
9.3
Primary Efficacy Endpoint and Analyses
9.3.1
Primary Efficacy Endpoint
The primary endpoint is the percent change from Baseline in F-VASI at Week 24.
The corresponding statistical null hypothesis to the primary endpoint is that there is no 
difference between any upadacitinib treatment group and placebo, in the LS mean of 
percent change from Baseline in F-VASI at Week 24.
9.3.2
Main Analysis of Primary Efficacy Endpoint
The primary analysis of the primary efficacy endpoint will be conducted in the ITT_1 
Population based on treatment as randomized.  The primary analysis is the comparison 
between upadacitinib and placebo at Week 24 using MMRM, and the corresponding 
analyses are specified in Section 9.1.
The attributes of the estimands corresponding to the primary efficacy endpoint are 
summarized in Table 2.
 


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Table 2.
Summary of the Estimand Attributes of the Primary Efficacy 
Endpoint
Estimand 
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Intercurrent Events
Statistical 
Summary
Percent 
change from 
Baseline in 
F-VASI at 
Week 24
Upadacitinib 
22 mg QD/
Upadacitinib 
11 mg QD/
Upadacitinib 
6 mg QD/
Placebo
Percent 
change 
from 
Baseline 
in F-VASI 
at 
Week 24
adult 
subjects 
with NSV
For treatment policy 
strategy, the occurrence 
of the intercurrent event 
(treatment 
discontinuation) is 
considered irrelevant in 
defining the treatment 
effect of interest.  Under 
this strategy, all values 
for the variable of 
interest are used 
regardless of the 
intercurrent event.
Difference in 
the percent 
change from 
Baseline in 
F-VASI at 
Week 24 
between each 
upadacitinib 
dose and 
placebo
The second analysis of the primary efficacy endpoint is to test a pre-specified set of dose-
response models among upadacitinib dose groups and placebo group at Week 24 using 
Multiple Comparison Procedure – Modeling (MCP-Mod).
The dose-response relationship among upadacitinib dose groups and the placebo will be 
characterized for the primary endpoint using MCP-Mod2.  The percent change from 
Baseline and standard deviations in each upadacitinib dose groups and placebo based on 
the primary analysis will be used, and ADDPLAN DF software Version 4.0 will be used 
to perform the MCP-Mod analyses.
A set of 6 pre-specified standardized candidate dose-response models, as described in 
Table 3, will be utilized to examine the dose-response relationship.  For the primary 
endpoint, a statistically significant dose-response relationship will be declared if at least 
one model is identified by the MCP-Mod method to be statistically significant at 2-sided 
significance level of 0.1.  Instead of choosing an optimal dose-response relationship 
model, a weighted average of the minimum effective dose (MED) (i.e., the recommended 
MED) across all significant models will be calculated for the MED selection.
 


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1.
The MED of each statistically significant model will be determined based on the 
pre-specified clinical meaningful target of a 40% target difference from placebo.
2.
The weighted average of MED across all significant models will be calculated, 
with the weight  of model  calculated using Akaike information criterion (AIC) 
as: 
 =
	
(.(
))
∑
	
(.(
))


, 
 =

 ∑
!
 
!"
,  = 1, . . . , $,
J % &ℎ( )*+,(- ./ %0)/12)& +.3(4%.
The rationale for using a weighted average of MED is because selecting a single model as 
the 'best' representation of observed data and subsequently using it to estimate the MED 
does not account for uncertainty in model selection.  The uncertainty in model selection 
can be accounted for by averaging estimates of MED over all significant models.
 


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Table 3.
Candidate Models
Model
/(3, 5)
3 = 3.%(,
5 = 6.3(4 72-2+(&(-%
/(3, 5)
Standardized Model
Initial Value(s) for 
Parameter(s)
Linear
8 + :3
3
NA
Exponential
80 + 81 <(=> ?3
:@ −1B
(=> C3
:D −1
: =44
Logistic
80 +
8+2=
1 + (=> C8E50 −3
:
D
1
1 + (=> C8E50 −3
:
D
8E = 4.45, : = 5.96
Emax
80 +
8+2=3
8E50 + 3
3
8E50 + 3
8E = 2.41
SigEMax
80 +
8+2=3ℎ
8E50 + 3ℎ
3ℎ
8E50 + 3ℎ
8E = 7.28, ℎ= 2.66
Quadratic
8 + M3 + MN3N
3 + MN
|M| 3N
: =-0.02
Note:
For logistic, Emax, SigEMax, Quadratic models, the initial values for parameters are based on the 
assumptions that upadacitinib 11 mg will achieve 75% of the maximum efficacy effect, and upadacitinib 22 
mg will achieve 95% of the maximum efficacy effect.  For exponential model, the initial values for the 
parameter is solely based on the assumption that upadacitinib 22 mg will achieve 95% of the maximum 
efficacy effect.
The fitted dose-response curves will be presented graphically for all statistically 
significant models along with confidence bands. 
9.3.3
Sensitivity Analyses of the Primary Efficacy Endpoint
A sensitivity analysis using MI to handle missing data for the primary efficacy endpoint 
will be performed, as described in Section 9.2.
 


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9.4
Secondary Efficacy Analyses
9.4.1
Main Analyses of Secondary Efficacy Endpoints
Secondary efficacy endpoints in Period 1 will be analyzed by comparing each 
upadacitinib treatment group with placebo.
Comparisons of the categorical endpoints will be made between each upadacitinib 
treatment group and placebo using the CMH test, adjusting for the stratification factors 
derived from actual values under a two-sided significance level of 0.1 for each 
upadacitinib group, and the corresponding analyses are specified in Section 9.1.
The continuous endpoints will be analyzed using MMRM at a two-sided significance 
level of 0.1 for each upadacitinib group, and the corresponding analyses are specified in 
Section 9.1 and Section 9.2.
9.5
Additional Efficacy Analyses
In Period 1, unless otherwise specified, additional efficacy endpoints will be compared 
between the each upadacitinib treatment group and placebo.  The categorical endpoints 
and continuous endpoints will be analyzed by CMH and MMRM, respectively, and the 
analyses are specified in Section 9.1 and Section 9.2.  Proportion of subjects selecting 
each of the 16 VitiQoL questions will be summarized for each of the 16 questions by 
response categories at each visit as observed.
In Period 2, the categorical endpoints will be summarized by treatment groups as 
observed, and the continuous endpoints will be analyzed as observed using ANCOVA as 
described in Table 1.  The analyses are specified in Section 9.1 and Section 9.2.
In Addition, at the time of the Primary Analysis, additional long-term analysis up to 
Week 52 will be provided for the below variables among all subjects who may potentially 
reach to Week 52 by the data cutoff using NRI-MI (categorical variables) or MMRM 
(continuous variables):
 


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●
F-VASI 50, F-VASI 75,
●
T-VASI 50,
●
Percent change from Baseline in F-VASI,
●
Percent change from Baseline in T-VASI
At the time of the final analysis, the above variables will be evaluated up to Week 52 
using NRI-MI (categorical variables) or MMRM for the continuous variables.
In addition, for VitiQoL, VNS, DLQI and HADS, analyses will be performed, for up to
Week 52, for the following:
●
Change from Baseline in VitiQoL question 16 regarding the severity of skin 
condition.
●
Proportion of subjects selecting each of the response categories of VNS 
●
Change from Baseline in Dermatology Life Quality Index (DLQI) total score
●
Achievement of a clinically meaningful improvement in DLQI total score 
defined as Δ DLQI ≥ 4 (for subjects with DLQI ≥ 4 at baseline)
●
Achievement of a clinically meaningful improvement in HADS anxiety and 
depression scores defined as Δ HADS ≥ 1.5 (for subjects with HADS ≥ 1.5 at 
baseline)
9.6
Efficacy Subgroup Analyses
To evaluate the consistency of the efficacy over demographic and other Baseline 
characteristics, the primary efficacy endpoint will be analyzed in the following subgroups:
●
Age group (≤ 50 and > 50)
●
Age group ((≥ 18 – < 28, ≥ 28 – < 40 and ≥ 40) 
●
Sex (male, female)
●
BMI (normal: < 25, overweight: ≥ 25 – < 30, obese: ≥ 30)
●
Race (White, Asian, Black, and Other)
●
Weight (< median, ≥ median)
 


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●
Baseline disease severity (T-VASI < 15 and ≥ 15)
●
Baseline disease severity (T-VASI ≤10 and > 10), 
●
Status of active vitiligo (Yes/No)
●
Baseline F-VASI (< median, ≥ median)
●
Fitzpatrick skin types (≤ II, III, > III)
●
Duration of vitiligo since diagnosis (< median, ≥ median)
●
Prior topical therapy (with and without)
●
Prior phototherapy (with and without)
'BMI ≥ 30' or 'BMI ≥ 25 – < 30' subgroups will be combined when either of the subgroups 
have fewer than 10% subjects.  Any Race subgroups with fewer than 10% subjects will be 
combined with 'Other' subgroup for analyses.
10.0
Safety Analyses
10.1
General Considerations
Safety data will be summarized for each safety population.
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.
 


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10.2.1
Treatment-Emergent Adverse Events
For Period 1, treatment-emergent adverse events (TEAEs) are defined as any adverse 
events that begin or worsen in severity after initiation of study drug through 30 days 
following the last dose of study drug in Period 1 or prior to first dose in Period 2, 
whichever is earlier.  For Period 2, TEAEs are defined as any adverse events that begin or 
worsen in severity after initiation of study drug in Period 2 through 30 days following the 
last dose of study drug in Period 2.  A TEAE during the administration of upadacitinib 
(i.e., among the ALL_UPA Population) is defined as any AE with an onset date on or 
after the first dose of upadacitinib and within 30 days after the last dose of upadacitinib.  
Events where the onset date is the same as the study drug start date are assumed to be 
treatment emergent.
All TEAEs will be summarized overall, as well as by primary MedDRA SOC and PT.  
The SOCs will be presented in alphabetical order, and the PTs will be presented in 
alphabetical order within each SOC. For the Safety_1 and ALL_UPA Populations, the 
number and percentage of subjects experiencing TEAEs and the number of events per 
100 patient-years of exposure will be summarized. 
10.2.2
Adverse Event Overview
An overview of AEs will be presented consisting of the number and percentage of 
subjects experiencing at least one event for each of the following AE categories for the 
Safety_1 and ALL_UPA Populations:
●
Any TEAE
●
Any TEAE related to study drug according to the investigator
●
Any severe TEAE (Grade 3 and above according to National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5)
●
Any serious TEAE (SAE)
●
Any TEAE leading to discontinuation of study drug
●
Any TEAE leading to death
●
TEAEs of special interest
 


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●
All deaths
●
Deaths occurring ≤ 30 days after last dose of study drug
●
Deaths occurring > 30 days after last dose of study drug.
The overview of number of TEAEs/deaths per 100 patient-years of exposure will also be 
provided for the above categories for the Safety_1 and ALL_UPA Populations.
TEAEs per 100 patient-years of exposure are defined as the number of TEAEs divided by 
the total exposure in 100 patient-years. The exposure-adjusted TEAE rate per 100 patient-
years is calculated as:
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 day (not to exceed the start of subsequent period) of all subjects 
normalized by 365.25, and rounded to 1 decimal place.
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 maximum toxicity and SOC and PT; by 
relationship to COVID-19 and SOC and PT; by ≥5% subjects in any treatment group by 
SOC and PT.  The number and percentage of subjects experiencing TEAEs will be 
provided for these summaries in the Safety_1 and ALL_UPA Populations.  Number of 
TEAEs per 100 patient-years of exposure will be summarized by SOC and PT for the 
Safety 1 and All_UPA Populations.  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.
 


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In addition, treatment-emergent adverse events will be summarized by PT and sorted by 
decreasing frequency for the total active treatment group.
10.2.4
SAEs (Including Deaths) and TEAE Leading to Study Drug 
Discontinuation
SAEs (including deaths) and TEAEs leading to study drug discontinuation will be 
summarized by SOC and PT and in listing format. The number and percentage of subjects 
experiencing SAEs and TEAE leading to study drug discontinuation as well as the 
number of events per 100 patient-years of exposure will be summarized for the Safety_1 
and ALL_UPA Populations.
10.2.5
Adverse Events of Special Interest
Treatment emergent Adverse events of special interest (AESI) will be summarized by 
SOC and PT and will be based on standardized or company MedDRA queries (SMQs or 
CMQs) or based on adjudication results.  The number and percentage of subjects 
experiencing treatment emergent AESIs and the number of events per 100 patient-years of 
exposure of the AESI overview table will be summarized for the Safety_1 and ALL_UPA 
Populations. For ALL_UPA, number of events per 100 patient-years of exposure of the 
AESI by SOC and PT will be summarized.
Adverse events of special interest are categorized as follows:
●
Serious infections
●
Opportunistic infection excluding tuberculosis and herpes zoster
●
Possible malignancy 
●
Malignancy
●
Non-melanoma skin cancer (NMSC)
●
Malignancy excluding NMSC
●
Lymphoma
●
Hepatic disorder
●
Adjudicated gastrointestinal perforation
 


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●
Anemia
●
Neutropenia
●
Lymphopenia
●
Herpes zoster
●
Renal dysfunction
●
Active tuberculosis
●
Adjudicated MACE
●
Adjudicated VTE
Detailed information about the search criteria is provided in Appendix B.
Tabular listings of adverse events of special interest will be provided.
10.3
Analysis of Laboratory Data
Data collected from central and local laboratories, including additional laboratory testing 
due to an SAE, will be used in all analyses, except for Baseline where SAE-related 
laboratory assessments on or before the first dose of study drug will be excluded.  The 
clinical laboratory tests defined in the protocol operations manual (e.g., hematology and 
clinical chemistry) will be summarized.
Raw values and change from Baseline (percent change if applicable) to each applicable 
post-baseline visit will be summarized for selected laboratory variables in the Safety_1 
and Safety_2 Populations. The following descriptive statistics will be presented by 
treatment groups: number of observations, Baseline mean (Standard deviation, SD), visit 
mean (SD), medium, change from Baseline mean (SD), standard error, and the 95% 
confidence interval of the mean change from Baseline.
Percent change from Baseline in LDL-C, HDL-C, total cholesterol and ratio of LDL-C to 
HDL-C will also be summarized similarly in the Safety_1 and Safety_2 Populations.
 


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For the Safety_1 and ALL_UPA Populations:
A shift table from baseline to the worse post-baseline value (based on NCI CTC criteria) 
during treatment will be created. A similar shift table will be provided to summarized 
shifts from baseline to the final post-baseline value. The number and percentage of 
subjects will be summarized.
Laboratory abnormalities will be evaluated based on Potentially Clinically Important 
(PCI) criteria (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.
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 PCI criteria 
(Appendix C) of potential clinical interest should be presented.
10.4
Analysis of Vital Signs
Vital sign measurements of systolic and diastolic blood pressure, heart rate, respiratory 
rate, and body temperature will be summarized.
Each vital sign variable will be summarized for all time points (starting with Baseline) 
with the number of non-missing observations, mean and standard deviation, median, 
minimum and maximum.  Change from Baseline to each applicable post-baseline visit 
will be summarized for each vital sign variable, with the number of observations, Baseline 
mean, and visit mean.  Mean, standard error, and 95% confidence interval will be 
presented for the change from Baseline within each treatment group in Safety_1 and 
Safety_2 Populations.
Vital sign variables will be evaluated based on PCI criteria (Appendix C) for the Safety_1 
and ALL_UPA Populations.  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
 


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will be provided to summarize subject-level vital sign data for subjects meeting PCI 
criteria.
10.5
Safety Subgroup Analyses
Not applicable.
10.6
Other Safety Analyses
A post-Baseline treatment ECG listing will be provided.
11.0
Other Analyses
Not applicable.
12.0
Interim Analyses
No formal interim analysis of efficacy is planned for this study.  Routine safety reviews 
will be performed by an external DMC.
12.1
Data Monitoring Committee
An external data monitoring committee (DMC) composed of persons independent of 
AbbVie and with relevant expertise in their field will periodically review unblinded safety 
data from the ongoing study.  The primary responsibility of the DMC will be to protect 
the safety of the subjects participating in this study.
A separate DMC charter describes the roles and responsibilities of the DMC members, 
frequency of data reviews, relevant data to be assessed, and general operations.
Since there are no efficacy analyses for early stopping, no alpha adjustment is needed.
13.0
Overall Type-I Error Control
Due to the Phase 2 nature of the phase 2 study, all the endpoints will be tested at a two-
sided significance level of 0.1 and overall type-1 error control is not considered necessary.
 


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14.0
Version History
Table 4.
SAP Version History Summary
Version
Date
Summary
1.0
30 July 2021
Original version
2.0
27 December 2022

Modify the ITT and Safety Population to ITT_1/ITT_2, 
Safety_1/Safety_2 Population.

Removed Baseline PhGIC-V and T-PaGVA from the 
disease characteristic table in Section 7.1

Added NRI-MI approach for subject who have 
opportunity to reach Week 52 for F-VASI 50, F-VASI 
75, T-VASI 50. In additional, percent change from 
Baseline in F-VASI, T-VSI and change from Baseline in 
VitiQoL question 16 are added in Section 9.5

Added additional efficacy subgroup analyses in 
Section 9.6

Update severity to toxicity in Treatment Emergent 
Adverse Events by SOC and/or PT in Section 10.2.3

Added a post-Baseline treatment ECT listing in 
Section 10.6

Clarify the efficacy and safety analyses for each analysis 
population 
15.0
References
1.
Rosmarin D, Pandya AG, Lebwohl M, et al.  Ruxolitinib cream for treatment of 
vitiligo:  a randomised, controlled, phase 2 trial.  Lancet.  2020;396(10244):110-20.
2.
Pinheiro J, Bornkamp B, Bretz F. Design and analysis of dose-finding studies 
combining multiple comparisons and modeling procedures.  J Biopharm Stat.  
2006;16(5):639-56.
 


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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.
 


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


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


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Appendix C.
Potentially Clinically Important Criteria for Safety Endpoints 
The criteria for Potentially Clinically Important (PCI) laboratory findings are described in 
Table C-1 and Table C-2, and the PCI criteria for vital sign findings are described in 
Table C-3.
Table C-1.
Criteria for Potentially Clinically Important Hematology Values
Hematology Variables
Units
Definition of Potentially Clinically Important 
(NCI CTCAE Grade 3 or higher)
Very Low
Hemoglobin
g/dL
< 8.0
Platelets count
109/L
< 50.0
WBC count
109/L
< 2.0
Neutrophils
109/L
< 1.0
Lymphocytes
109/L
< 0.5
Note:
A post-baseline value must be more extreme than the Baseline value with at least one CTCAE grade of 
worsening to be considered a potentially clinically important finding.
 


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


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


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Appendix D.
Random Seeds
In case of non-convergence, the random seed will be updated by adding 10000 at each 
attempt until convergence of model happens.
A. Random Seeds for NRI-MI
Endpoints
Random Seed
MCMC procedure
PROC MI
F-VASI 50
1001
9001
F-VASI 75
1002
9002
F-VASI 90 
1003
9003
T-VASI 50
1004
9004
T-VASI 75
1005
9005
T-VASI 90
1006
9006
VNS 4/5
1007
9007
DLQI 0/1
1008
9008
PhGIC-V 1/2
1009
9009
PaGIC-V 1/2
1010
9010
F-PhGVA 0/1
1011
9011
T-PhGVA 0/1
1012
9012
F-PaGVA 0/1
1013
9013
T-PaGVA 0/1
1014
9014
DLQI 4
1015
9015
B. Random Seeds for MI
Endpoints
Random Seed
MCMC procedure
PROC MI
Percent change from Baseline in F-VASI
1015
9015
 


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Appendix E.
Non-Responder Imputation Incorporating Multiple Imputation to 
Handle Missing Data Due to COVID-19 Pandemic or Any Other 
Missing Data that Can Be Reasonably Assumed to Be Missing at 
Random for Dichotomized Outcome Variables
1.0
Overview
1.1
Background and Justification for Missing at Random (MAR) 
Assumption
The COVID-19 pandemic is interfering with the conduct of many ongoing trials, with 
potential impacts on treatment duration and the collection, analysis and the interpretation 
of clinical trial data.  Some protocol-specified visits in the clinical trials may be impacted 
due to COVID-19 infection or logistical restrictions during the pandemic.  For example, 
some scheduled visits may be missed due to self-quarantine or local government 
restrictions on travel; some visits may also be delayed or canceled due to healthcare 
resource constraints during the pandemic.  Impacted visits due to COVID-19 will be 
recorded in the database.  The probability of having missed visits and missing data due to 
COVID-19 infection or logistical restrictions related to the COVID-19 pandemic can be 
reasonably assumed to be unrelated to the unobserved values.  Therefore, for the purpose 
of statistical analysis, it is reasonable to assume that these missing data are missing at 
random (MAR) and the statistical models that require MAR assumption are appropriate.  
In some cases, sensitivity analyses may be performed to assess the impact of missing data 
and the robustness of the conclusion.
1.2
FDA Guidance
FDA provided two guidance documents1,2 in March 2020 and June 2020 on the efficacy 
collection and possible changes in the statistical analysis plan:
●
"With respect to efficacy assessments, FDA recommends consultation with the 
appropriate review division regarding protocol modifications for the collection 
of efficacy endpoints, such as use of virtual assessments, delays in 
assessments, and alternative collection of research-specific specimens, if 
feasible.  For individual instances where efficacy endpoints are not collected, 
 


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


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2.0
Non-responder Imputation Incorporating Multiple 
Imputation (NRI-MI)
2.1
Overall Description of the Method
For a dichotomized outcome variable with missing data, the NRI-MI will categorize any 
subject who does not have evaluation during a pre-specified visit window as a non-
responder for the visit, with two exceptions:
●
If the subject is a responder both before and after the pre-specified visit 
window in Period 1, the subject will be categorized as a responder for the visit.
●
If the reason for missing (e.g., missed visits, incomplete visit, out-of-schedule 
visits, or discontinuations of study drug) is due to COVID-19 or any other 
missing data that can be reasonably assumed to be Missing at Random, the 
information will be captured in the database and the subject's response status 
will be imputed using multiple imputation.
In addition, subjects whose change/percent change from Baseline cannot be calculated 
because of a missing Baseline will be considered as a non-responder at all post-baseline 
visits unless the post-baseline value is zero.
Non-responder imputation incorporating multiple imputation (NRI-MI) for missing due to 
COVID-19 or any other missing data that can be reasonably assumed to be Missing at 
Random will be implemented as follows.
2.2
Multiple Imputation (MI) and MAR Assumption
When a dichotomized variable is derived from a continuous scale, for example, F-VASI 
75 (at least a 75% reduction in F-VASI relative to Baseline), the multiple imputation will 
be applied to the original scale, F-VASI (ranges from 0 – 100) assuming multivariate 
normal distribution.  Then the dichotomized variable will be derived from the imputed 
value.
 


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The MI procedure assumes that the data are missing at random (MAR).  That is, for an 
outcome variable Y, the probability that an observation is missing depends only on the 
observed values of other variables, not on the unobserved values of the outcome variable 
Y.  Statistical inference from the MI procedure is valid under the MAR assumption.
2.3
Imputation Algorithm 
It is reasonable to assume the missing values of the longitudinal data for an outcome 
variable (e.g., F-VASI, the original scale of F-VASI 75, at each post-baseline visit) 
follows a monotone missing pattern.  In practice, the missing data of the outcome variable 
might have an arbitrary (non-monotone) missing data pattern.  An extra step may be 
added accordingly, to augment data into a monotone missing pattern.
For the outcome variable (e.g., F-VASI at each visit), K 'complete' datasets can be 
generated in two steps:  augmentation step and imputation step.  K, the number of 
repetitions, is determined below.
Augmentation Step
For datasets with non-monotone missing data pattern, the augmentation step will 
first impute enough values to augment the data into a monotonic missing pattern:
Markov Chain Monte Carlo (MCMC) will be applied to augment the data using PROC MI 
with the MCMC IMPUTE=monotone statement, assuming a multivariate normal 
distribution.  The augmented data will be used in the subsequent imputation step to 
generate 'complete' datasets.  Covariates included in the model are treatment, stratification 
factors (the age group [≤ 50 and > 50], Baseline disease severity [T-VASI < 15 and ≥ 15], 
and status of active vitiligo [Yes/No]), Baseline, and all post-baseline visits of the 
outcome variable according to the pre-specified order.  For T-VASI related endpoints, 
Baseline disease severity (T-VASI < 15 and ≥ 15) will not be included in the model.  Of 
note, categorical variables are included using the form of dummy variables.
 


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Repeat the imputation process K=30 times using the procedure described above to form 
K=30 monotone missing datasets, where K is determined as described in "Repetition of 
Imputations (K)."
Imputation Step
For missing data with monotone missing patterns, the choice of multiple imputation using 
a parametric regression model that assumes multivariate normality is appropriate.
The imputation step is described below:
●
The imputation model for the missing data is a regression model, which 
controls for treatment, stratification factors (the age group [≤ 50 and > 50], 
Baseline disease severity [T-VASI < 15 and ≥ 15], and status of active vitiligo 
[Yes/No]), Baseline, and all post-baseline visits of the outcome variable.  For 
T-VASI related endpoints, Baseline disease severity (T-VASI < 15 and ≥ 15) 
will not be included in the model.  The covariates included in the model and 
the order of these variables are consistent with the augmentation step.
●
For each monotone missing dataset, using SAS PROC MI with MONOTONE 
REG model statement, the outcome variable at each post-baseline visit with 
missing values will be imputed sequentially with covariates constructed from 
their corresponding sets of preceding variables.
A 'complete' dataset with imputed values for the missing data is generated after the 
augmentation and imputation steps are completed.
Repetition of Imputations (K)
Repetition of imputations, K, must be determined in advance.  When estimating the 
overall variance of multiple imputation, the additional sampling variance is the between-
imputation variance divided by K.  This value represents the sampling error associated 
with the overall or average coefficient estimates.  It is used as a correction factor for using 
a specific number of imputations.  The more imputations (K) are conducted, the more 
precise the parameter estimates will be.  For example, with a 1% power falloff tolerance 
 


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in multiple imputation, as compared to an infinite number of imputations, multiple 
imputation requires 20 repetitions of imputation for 30% missing information and 
40 repetitions for 50% missing information.4  In the usual clinical settings expecting less 
than 30% missing information, K = 30 repetitions are deemed sufficient.  When 
missingness exceeds 30%, depending on the power falloff tolerance level, number of 
repetitions may need to be increased.  Recent research4 suggested that the number of 
repetitions (K) should be at least equal to the percentage of missing.6
2.4
Derivation of Response Status and Non-Responder 
Imputation
For each 'complete' dataset, the imputed post-baseline values will be rounded to the same 
precision as the observed data.  Response status (e.g., F-VASI 75 at each visit) will be 
determined accordingly.
The imputed response status for missing due to reasons other than COVID-19 or any other 
missing data that can be reasonably assumed to be Missing at Random will be overridden 
by non-responder imputation (Section 2.1) to ensure that multiple imputation is only 
applied to missing due to COVID-19 or any other missing data that can be reasonably 
assumed to be Missing at Random:
●
Using NRI approach, all missing due to reasons other than COVID-19 or any 
other missing data that can be reasonably assumed to be Missing at Random 
will be categorized as non-responders.  In addition, subjects whose 
change/percent change from Baseline cannot be calculated because of a 
missing Baseline will be considered as a non-responder at all post-baseline 
visits unless the post-baseline value is zero.
●
The only exception is that a subject will be categorized as a responder for the 
visit if the subject is a responder both before and after an SAP-specified visit 
window in Period 1.
 


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2.5
Analysis
The statistical analysis will use the Cochran-Mantel-Haenszel (CMH) test adjusted by the 
stratification factors derived from actual values.
2.5.1
Analysis of Each Dataset
For each of the K 'complete' datasets, the CMH test will be used to estimate the treatment 
difference versus placebo and the corresponding standard error.
2.5.2
Synthesis of Results for Statistical Inference
The results from the K 'complete' datasets will be synthesized using the SAS procedure 
PROC MIANALYZE, following Rubin's formula (Rubin, 19875), to derive the MI 
estimator of the treatment difference for the final inferences.
Rubin's formula
We fit the analysis model to the kth 'complete' dataset, denoting the estimate of the 
treatment difference q by 5de from the kth 'complete' dataset, and denoting the 
corresponding estimate of the variance as Vk.
The MI estimator of q (point estimator obtained from PROC MIANALIZE), 5df, is the 
average of the K individual estimators:
5df = 1
g h 5de.
i
e"
The estimated variance of 5df, is a combination of the between- and within-imputation 
variability as follows:
jf =  + (1 +

i)k,
where  =

i ∑
je
i
e"
is the within-imputation variability and k =

i ∑
(5de −5df)N
i
e"
is the between-imputation variance. 
 


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It has been shown1 that the statistic
l = 5df −5
mjf
has an approximate &n distribution where o = (g −1)(1 +
p
q)N.  Statistical inference, 
including hypothesis testing and confidence intervals for the treatment effect, will be 
based on this T-statistic.
3.0
Sample SAS Code
/**********************/
/*IMPUTATION ALGORITHM*/
/**********************/
/*NOTE: THIS APPROACH REQUIRES NO MISSING IN CATEGORICAL COVARIATES AND 
REQUIRES AT LEAST ONE OBSERVATION IN BASELIBE OR ONE OF THE POST-
BASELINE VISIT*/
/*PRE-AUGMENTATION – CREATE DUMMY FOR CATEGORICAL VARIABLES*/
/********************************************/
DATA VASI_2; SET VASI;
  /*THE MCMC STATMENT BELOW ASSUMES MULTI-VARIATE NORMAL*/
  /*IF TREATMENT OR ANY COVARIATES ARE CATEGORICAL WITH L>2 LEVELS*/
  /*NEED TO CREATE L-1 DUMMY VARIABLES*/
  /*HERE, TREATMENT (TRT01PN) HAS 4 LEVELS, SO WE NEED 3 DUMMY 
VARIABLES*/
  IF TRT01PN=1 THEN TRT1=1;
  ELSE TRT1=0;
  IF TRT01PN=2 THEN TRT2=1;
  ELSE TRT2=0;
  IF TRT01PN=3 THEN TRT3=1;
  ELSE TRT3=0;
RUN;
/*AUGMENTATION STEP -- TO HAVE 30 MONOTONE MISSING DATASETS*/
PROC MI DATA=VASI_2 OUT=VASI_MONO NIMPUTE=30 SEED= 1001 /*RANDOM SEED 
PRE-DEFINED*/
  ROUND=. . . . . . 0.1 0.1 0.1 0.1 0.1 0.1 0.1 /*VALUE ROUND TO 1ST 
DECIMAL*/
  MIN=. . . . . . 0 0 0 0 0 0 0            /*MINIMUM VALUE OF F-VASI IS 
0*/
  MAX=. . . . . . 100 100 100 100 100 100 100;   /*MAXIMUM VALUE OF F-
VASI IS 100*/
  MCMC IMPUTE=MONOTONE ;
 


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/*NOTE: CATEGORICAL VARIABLES SUCH AS TRT1 TRT2 TRT3 ARE DUMMY, CREATED 
ABOVE*/
/*NOTE: ALL OTHER NON-DUMMIED COVARIATES MUST BE CONTINUOUS*/
/*SUPPOSE STRATAN (NUMERIC VARIABLE FOR STRATA) HAS ONLY 2 LEVELS, NO 
NEED TO CREATE DUMMY*/
  VAR TRT1 TRT2 TRT3 AGEGR1N TVAGR1N ACTVGR1N BASE WK2 WK4 WK8 WK12 WK18 
WK24;
/*CAUTION TO USE THE "BY" STATEMENT IN MCMC: */
/*MVN MODEL IS FITTED WITHIN EACH 'BY' GROUP, INSTEAD OF ACROSS ALL 
GROUPS*/
RUN;
/*IMPUTATION STEP – DETERMINE IMPUTATION DISTRIBUTION AND RANDOMLY 
IMPUTE MISSING VALUE TO GENERATE 'COMPLETE' DATASETS*/
/***************************************************/
PROC MI DATA=VASI_MONO OUT=VASI_FULL NIMPUTE=1 SEED= 9001  /*RANDOM SEED 
PRE-DEFINED*/
  ROUND=. . . . . . 0.1 0.1 0.1 0.1 0.1 0.1 0.1 /*VALUE ROUND TO 1ST 
DECIMAL*/
  MIN=. . . . . . 0 0 0 0 0 0 0            /*MINIMUM VALUE OF F-VASI IS 
0*/
  MAX=. . . . . . 100 100 100 100 100 100 100;   /*MAXIMUM VALUE OF F-
VASI IS 100*/
  MINMAXITER=1000;
  CLASS TRT01PN AGEGR1N TVAGR1N ACTVGR1N;
  VAR TRT01PN AGEGR1N TVAGR1N ACTVGR1N BASE WK2 WK4 WK8 WK12 WK18 WK24;
  MONOTONE REG (WK2 WK4 WK8 WK12 WK18 WK24);  /* IMPUTED SEQUENTIALLY, 
FROM WK 2 TO 24, WITH COVARIATES CONSTRUCTED FROM THE CORRESPONDING 
PRECEDING VARIABLES*/
  BY _IMPUTATION_;                   /*FOR EACH OF THE 30 MONOTONE 
MISSING DATASETS, IMPUTE A 'COMPLETE' DATASET*/
RUN;
/*DETERMINE DICHOTOMOUS RESPONSE STATUS, VASI 50*/
DATA ALL; SET VASI _FULL;
  IF 0<=WK2<=0.5*BASE THEN VASI50_2=1;
    ELSE VASI50 2=0;
  IF 0<=WK4<=0.5*BASE THEN VASI50_4=1;
    ELSE VASI50 4=0;
  IF 0<=WK8<=0.5*BASE THEN VASI50_8=1;
    ELSE VASI50_8=0;
  IF 0<=WK12<=0.5*BASE THEN VASI50_12=1;
    ELSE VASI50 12=0;
  IF 0<=WK18<=0.5*BASE THEN VASI50_18=1;
    ELSE VASI50 18=0;
  IF 0<=WK24<=0.5*BASE THEN VASI50_24=1;
    ELSE VASI50_24=0;
RUN;
 


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/***********************************************************************
*/
/*    DATA HANDLING STEPS TO MERGE COVID-19 or Other MAR STATUS OMITTED         
*/
/*            PLACE TO ADD DATA HANDLING AND MERGING STEPS              
*/
/***********************************************************************
*/
/*FOR MI, SKIP THE FOLLOWING CODE, PROCEED TO THE CODE AFTER ANALYSIS 
MODEL *//*OVERRIDE MISSING VALUES NOT DUE TO COVID-19 or Other MAR WITH 
TRADITIONAL NRI*/
DATA ALLF; SET ALL;
  /*COVID19 XX='Y' IF MISSING AT WEEK XX IS DUE TO COVID-19 or Other 
MAR; IF NOT, OVERRIDE WITH TRADITIONAL NRI*/
  IF COVID19_2 NE 'Y' THEN VASI50_2=VASI50NRI_2;
  IF COVID19 4 NE 'Y' THEN VASI50 4=VASI50NRI 4;
  IF COVID19 8 NE 'Y' THEN VASI50 8=VASI50NRI 8;
  /*VARIABLE VASI50NRI_XX: TRADITIONAL NRI DATA AT WEEK XX, WHICH COVERS 
THE SPECIAL HANDLING SUCH AS THE BEFORE-AND-AFTER EXCEPTION*/
  IF COVID19 12 NE 'Y' THEN VASI50 12=VASI50NRI 12;
  IF COVID19_18 NE 'Y' THEN VASI50_18=VASI50NRI_18;
  IF COVID19_24 NE 'Y' THEN VASI50_24=VASI50NRI_24;
RUN;
PROC SORT DATA=ALLF; BY _IMPUTATION_ SUBJID; RUN;
/****************/
/*ANALYSIS MODEL*/
/****************/
/*KEY CODE: ANALYZING EACH 'COMPLETE' DATASET*/
/***********************************/
/*COMPARE TREATMENT GROUPS 1 (PLACEBO) AND 2 (HIGH-DOSE) ONLY*/
DATA ALL; SET ALL;
  WHERE TRT01PN IN (1,2);
RUN;
/*INDIVIDUAL-LEVEL DATA --> # OF RESPONDERS & # OF SUBJECTS, TO BE READ-
IN TO PROC STDRATE*/
PROC FREQ DATA=ALL;
  BY _IMPUTATION_;
  TABLES TRT01PN*AGEGR1N*TVAGR1N*ACTVGR1N*VASI50_24/LIST NOCUM NOPRINT
OUT=COUNT_TABLE;
  /*WEEK 24 RESULTS AS AN EXAMPLE*/
RUN;
DATA COUNT TABLE; SET COUNT_TABLE;
  DROP PERCENT;
 


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RUN;
PROC TRANSPOSE DATA=COUNT_TABLE OUT=FREQ_TABLE PREFIX=RESP;
ID VASI50_24;
BY
IMPUTATION_ TRT01PN AGEGR1N TVAGR1N ACTVGR1N;
VAR COUNT;
RUN;  
DATA FREQ TABLE1; SET FREQ_TABLE;
  CASE=RESP1;
  SIZE=SUM(RESP0, RESP1);
  KEEP _IMPUTATION_ TRT01PN AGEGR1N TVAGR1N ACTVGR1N CASE SIZE;
RUN;
/*RE-ORDER TO SET 1 (PLACEBO) AS THE REFERENCE GROUP*/
DATA FREQ_TABLE2; SET FREQ_TABLE1;
  IF TRT01PN=2 THEN TRT01PN=0;
RUN;
/*CALCULATE THE COMMON RISK DIFF FOR EACH COMPLETE DATASET*/
PROC STDRATE DATA=FREQ TABLE2
  METHOD=MH STAT=RISK EFFECT=DIFF;
  BY _IMPUTATION_;
  POPULATION GROUP=TRT01PN EVENT=CASE TOTAL=SIZE;
  STRATA AGEGR1N TVAGR1N ACTVGR1N / ORDER=DATA STATS(CL=NONE) EFFECT;
  ODS OUTPUT EFFECT=EFFECT;
RUN;
/*COMBINING RESULTS USING PROC MIANALYZE*/
/****************************************/
PROC MIANALYZE DATA=EFFECT;
  ODS OUTPUT PARAMETERESTIMATES=RISK_DIFF_MH;  
  MODELEFFECTS RISKDIFF;
  STDERR STDERR;
RUN;
4.0
References
1.
FDA Guidance on Conduct of Clinical Trials of Medical Products during 
COVID-19 Pandemic - Guidance for Industry, Investigators, and Institutional 
Review Boards.  FDA.  2020.
2.
Statistical Considerations for Clinical Trials During the COVID-19 Public Health 
Emergency - Guidance for Industry.  FDA.  2020. 
3.
Points to consider on implications of Coronavirus disease (COVID-19) on 
methodological aspects of ongoing clinical trials.  EMA.  2020.
 


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4.
Graham JW, Olchowski AE, Gilreath TD.  How many imputations are really 
needed?  Some practical clarifications of multiple imputation theory.  Prev Sci.  
2007;8(3):206-13.
5.
Rubin DB, Schenker N.  Interval estimation from multiply-imputed data:  a case 
study using agriculture industry codes.  J Am Stat Assoc.  1987;81:366-74.
6.
White IR, Royston P, Wood AM.  Multiple imputation using chained equations:  
Issues and guidance for practice.  Stat Med.  2011;30(4):377-99.