Conditions: Hidradenitis Suppurativa (HS)
Keywords: Hidradenitis suppurativa (HS) Upadacitinib
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 68
Healthy volunteers: no

Brief summary:
Hidradenitis suppurativa (HS) is an inflammatory skin disease that causes painful lesions in the axilla (underarm), inguinal (groin) and anogenital (anal and genital) regions. This study will evaluate how well upadacitinib compared to placebo (no medicine) works to treat hidradenitis suppurativa in adult participants with moderate to severe disease. The study will assess change in disease signs and symptoms.

Detailed description:
Upadacitinib is an investigational drug being developed for the treatment of HS. This study is "double-blinded," which means that neither the trial participants nor the study doctors will know who will be given study drug and who will receive placebo (no medicine). Participants are randomly (by chance) put into 1 of 2 groups, called treatment arms. They are randomized in a 2 to 1 ratio meaning more participants have a chance to receive upadacitinib compared to placebo.

Participants will undergo approximately 35-days of screening followed by a 48-week treatment period and a 30-day follow-up visit after the last dose of study drug for a total study duration of up to 57 weeks. The treatment period will consist of a 12-week placebo-controlled, double-blind period (Period 1) and a 36-week blinded extension period (Period 2).

There may be a higher burden for participants in this trial compared to their standard of care. Participants will attend visits every other week, once a month, or once every 2 months during the course of 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.

Arms:
arm 1: Participants will receive 30 mg upadacitinib orally once a day for 12 weeks (Period 1) followed by 30 mg upadacitinib orally once a day for 36 weeks (Period 2). arm 2: Participants will receive matching placebo orally once a day for 12 weeks (Period 1) followed by 15 mg upadacitinib orally once a day for 36 weeks (Period 2).

Interventions: intervention 1: Upadacitinib intervention 2: Placebo
Intervention descriptions: intervention 1: Tablet; Oral intervention 2: Tablet; Oral

Protocol document:
Prot_000.pdf: 


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TABLE OF CONTENTS
1
SYNOPSIS
5
2
INTRODUCTION
7
2.1
BACKGROUND AND RATIONALE
7
2.2
BENEFITS AND RISKS TO SUBJECTS
8
3
OBJECTIVES AND ENDPOINTS
9
3.1
PRIMARY ENDPOINT
9
3.2
SECONDARY ENDPOINT
9
3.3
ADDITIONAL ENDPOINTS
9
3.4
SAFETY ENDPOINTS
10
3.5
PHARMACOKINETIC ENDPOINTS
10
3.6
BIOMARKER RESEARCH OBJECTIVES
10
4
INVESTIGATIONAL PLAN
10
4.1
OVERALL STUDY DESIGN AND PLAN
10
4.2
DISCUSSION OF STUDY DESIGN
11
5
STUDY ACTIVITIES
12
5.1
ELIGIBILITY CRITERIA
12
5.2
CONTRACEPTION RECOMMENDATIONS
16
5.3
PROHIBITED MEDICATIONS AND THERAPY
18
5.4
PRIOR AND CONCOMITANT THERAPY
21
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
22
5.6
FOLLOW-UP AFTER SUBJECT DISCONTINUATION OF STUDY DRUG OR FROM STUDY
24
5.7
STUDY DRUG
24
5.8
RANDOMIZATION/DRUG ASSIGNMENT
25
5.9
PROTOCOL DEVIATIONS
26
5.10 DATA MONITORING COMMITTEE
26
6
SAFETY CONSIDERATIONS
27
6.1
COMPLAINTS AND ADVERSE EVENTS
27
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6.2
TOXICITY MANAGEMENT
31
7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
34
7.1
STATISTICAL AND ANALYTICAL PLANS
34
7.2
DEFINITION FOR ANALYSIS POPULATIONS
34
7.3
STATISTICAL ANALYSES FOR EFFICACY
35
7.4
STATISTICAL ANALYSES FOR SAFETY
36
7.5
INTERIM ANALYSIS
36
7.6
OVERALL TYPE I ERROR CONTROL
36
7.7
SAMPLE SIZE DETERMINATION
36
8
ETHICS
37
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD (IEC/IRB)
37
8.2
ETHICAL CONDUCT OF THE STUDY
37
8.3
SUBJECT CONFIDENTIALITY
37
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
37
10 DATA QUALITY ASSURANCE
38
11 COMPLETION OF THE STUDY
38
12 REFERENCES
38
LIST OF TABLES
TABLE 1.
EXAMPLES OF COMMONLY USED STRONG CYP3A INHIBITORS AND INDUCERS
20
TABLE 2.
DESCRIPTION OF STUDY DRUG
25
TABLE 3.
SPECIFIC TOXICITY MANAGEMENT GUIDELINES FOR ABNORMAL LABORATORY VALUES
32
LIST OF FIGURES
FIGURE 1.
STUDY SCHEMATIC
11
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LIST OF APPENDICES
APPENDIX A.
STUDY-SPECIFIC ABBREVIATIONS AND TERMS
41
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
44
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
45
APPENDIX D.
ACTIVITY SCHEDULE
46
APPENDIX E.
PROTOCOL SUMMARY OF CHANGES
50
APPENDIX F.
OPERATIONS MANUAL
56
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2 INTRODUCTION
2.1 Background and Rationale
This study will compare upadacitinib versus placebo for the treatment of adult subjects with moderate 
to severe hidradenitis suppurativa (HS).
HS is an inflammatory, debilitating skin disease with a characteristic clinical presentation of recurrent or 
chronic painful or suppurating lesions that most commonly present in the axilla, inguinal, and anogenital 
regions.1,2  The estimated prevalence of HS varies between < 1% and 4%.3-7  It is a difficult to diagnose 
condition, and therefore, there is a significant delay (7.2 years on average) in establishing the diagnosis 
of HS after its initial presentation.8
HS lesions (i.e., nodules, abscesses, and sinuses) are painful, typically located in the intertriginous areas, 
and can be malodorous with purulent discharge.  This constellation of signs and symptoms results in 
substantial disability and social stigma of the patients and a profound impact on the quality of life.9  
Depression, anxiety, and an increased suicide risk may be seen in patients with HS, as well as a negative 
impact on a patient's sexual health.10-14  Patients may have several comorbidities, such as obesity, 
metabolic syndrome, diabetes, arthritis, Crohn's disease, and polycystic ovary disease.2,15  Patients with 
HS have an increased risk of adverse cardiovascular outcomes and all-cause mortality, and their risk of 
CV-associated death was shown to be higher than in psoriasis patients.16
Available treatment options for patients with HS include medical treatments such as topical non-
antibiotics (e.g., exfoliants and peels), topical antibiotics (e.g., clindamycin), systemic antibiotics (e.g., 
clindamycin, tetracycline, rifampicin), anti-inflammatory therapies (e.g., corticosteroids, dapsone, 
ciclosporin A), hormones (e.g., antiandrogens and estrogens), retinoids (e.g., isotretinoin, acitretin), 
biologics (e.g., adalimumab, infliximab), analgesics (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs], 
opioids), and surgical treatments (e.g., deroofing, excision, laser).17  However, with the exception of 
adalimumab, most of those treatments have not been adequately studied in patients with HS or do not 
appear to be very effective through the course of the disease.  The only approved treatment option for 
patients with moderate to severe HS is adalimumab (Humira®), a tumor necrosis factor (TNF)-α 
inhibitor.18  The results from Phase 3 studies with adalimumab, PIONEER I and II, showed approximately 
42% and 59% of subjects achieved Hidradenitis Suppurative Clinical Response (HiSCR) at Week 12, 
respectively, versus 26% and 28% in placebo.19  HiSCR is defined as a reduction of at least 50% of total 
abscess and inflammatory nodule (AN) count, without an increase in abscesses or draining fistula count 
relative to Baseline.19  Additional treatment options are needed for those patients who fail to achieve 
adequate efficacy.
The Janus kinases (JAKs) are a family of intracellular tyrosine kinases that function as dimers in the 
signaling process of many cytokine receptors.20  The JAK family is composed of 4 members:  JAK1, 2, 3, 
and tyrosine kinase 2 (Tyk2).  These cytoplasmic tyrosine kinases act in tandem to activate the signal 
transducer and activator of transcription (STAT) that transduce cytokine-mediated signals, and are 
associated with multiple membrane cytokine receptors such as common gamma-chain receptors and 
the glycoprotein 130 trans-membrane proteins.20  The JAKs play a critical role in both innate and 
adaptive immunity, making them attractive targets for the treatment of inflammatory diseases.21-24  
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The exact pathogenesis of HS has not been fully defined and cytokine studies in HS have had variable 
methodologies and results.25  However, cytokines and receptors that signal via the JAK1 pathway are 
elevated in HS, such as interleukin (IL)-2, IL-7, Type 1 interferons (IFNs), IFNγ, the IL-10 family, as well as 
IL-6.26,27  This suggests that JAK1 inhibition may be an effective target in the treatment of HS. 
Upadacitinib (Rinvoq®) is an oral, selective and reversible JAK inhibitor that recently has received 
approval for the treatment of rheumatoid arthritis (RA) in the United States (US), European Union (EU), 
Japan, and several other countries28,29 and is also being developed for the treatment of other 
immune-mediated inflammatory diseases, including dermatologic conditions such as atopic dermatitis 
(AD).  Positive results from a Phase 2b dosing ranging study with upadacitinib in adult patients with 
moderate to severe AD enabled advancement into Phase 3 AD registration trials that are currently 
ongoing with 2 doses of upadacitinib, 15 mg and 30 mg.
Clinical Hypothesis
Proinflammatory cytokines identified in the lesional skin of HS patients signal via the JAK/STAT pathway.  
Inhibition of the JAK/STAT pathway with upadacitinib may decrease the high inflammatory burden in HS 
patients and improve clinical outcomes.  Upadacitinib should provide superior efficacy compared to 
placebo with an acceptable safety profile in subjects with HS.
2.2 Benefits and Risks to Subjects
Increased expression of various proinflammatory cytokines (i.e., IL-6, IL-7, and IL-15, IFNγ) has been 
described in affected HS skin; many of these cytokines signal through the JAK-STAT pathway.  This 
provides a strong rationale for evaluating upadacitinib in HS, a disease with a high unmet need due to 
very limited approved treatment options.  The efficacy of various JAK inhibitors, including upadacitinib 
has shown promising results in various immune-mediated diseases including AD.  Common adverse 
events (AEs) reported to be associated with the class of JAK inhibitors, including upadacitinib, are 
infections, herpes zoster reactivation, and hematologic AEs.  Based on class labeling, serious infection, 
malignancy, and thrombosis were highlighted as a black box warning in the US package inserts.28  
Potential differences in the safety profile of upadacitinib in dermatologic versus non-dermatologic 
conditions will be closely monitored during the course of the clinical study and a robust safety 
monitoring plan, including a Data Monitoring Committee (DMC), Cardiovascular Adjudication committee 
and Gastrointestinal Perforation Adjudication committee, is in place to ensure patient safety.
The results of genetic toxicology testing indicate that upadacitinib is not genotoxic; however, 
upadacitinib may be teratogenic, which necessitates avoidance of pregnancy in females of childbearing 
potential.  Based on an embryo fetal development study in rats, there is judged to be no risk associated 
with administration of upadacitinib to male partners of females of childbearing potential.
A detailed discussion of the pre-clinical and clinical toxicology, metabolism, pharmacology, and safety 
experience with upadacitinib can be found in the current Investigator's Brochure.
Taken together, the efficacy and safety data from upadacitinib studies to date show a favorable 
benefit:risk profile for upadacitinib and support the continued investigation of upadacitinib in patients 
with various autoimmune/inflammatory conditions including HS.  Upadacitinib as a new oral therapeutic 
drug could expand treatment options for patients with HS.
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In view of the COVID-19 pandemic, the benefit:risk profile of various immunomodulatory therapies on 
COVID-19 is being evaluated.  At this time, the effects of upadacitinib on the course of COVID-19 are not 
well defined.
3 OBJECTIVES AND ENDPOINTS
Objective and Hypothesis
The objective of this study is to assess the efficacy and safety of upadacitinib 30 mg versus placebo for 
the treatment of signs and symptoms of moderate to severe HS in adult subjects.
The hypothesis is that upadacitinib 30 mg group should achieve a higher clinical response rate compared 
with the placebo group after 12 weeks of treatment.
3.1 Primary Endpoint
The primary endpoint is the achievement of HiSCR at Week 12.  HiSCR is defined as at least a 50% 
reduction in the total AN count with no increase in abscess count and no increase in draining fistula 
count relative to Baseline.
3.2 Secondary Endpoint
The secondary endpoint is the achievement of at least 30% reduction and at least 1 unit reduction from 
Baseline in Patient's Global Assessment (PGA) of Skin Pain (numeric rating scale [NRS30]) – at worst at 
Week 12 among subjects with baseline NRS ≥ 3.
3.3 Additional Endpoints
The primary and secondary endpoints will also be analyzed at all visits other than Week 12.  In addition, 
the following endpoints will be analyzed at visits as noted in the Study Activities Table (Appendix D).

Increase in AN count of at least a 25% with a minimum increase of 2 relative to Baseline;

Change from Baseline in Dermatology Life Quality Index (DLQI);

Change from baseline in Hidradenitis Suppurativa Symptom Assessment (HSSA);

Change from baseline in HS-related swelling, assessed based on the HSSA;

Change from baseline in HS-related odor, assessed based on the HSSA;

Change from baseline in HS-related worst drainage, assessed based on the HSSA;

Change from baseline in Hidradenitis Suppurativa Impact Assessment (HSIA).
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3.4 Safety Endpoints
Safety will be assessed by AE monitoring, physical examination, vital signs, electrocardiogram (ECG), 
imaging, and clinical laboratory testing during the study.  Laboratory assessments will include 
hematologic parameters, chemistry, liver function tests, and lipid parameters.
3.5 Pharmacokinetic Endpoints
Pharmacokinetic (PK) samples will be collected from subjects at the visits indicated in Appendix D.  Using 
the data available from these subjects, a nonlinear mixed-effects modeling approach will be used to 
estimate the population central values and the empirical Bayesian estimates of the individual values of 
upadacitinib oral clearance (CL/F) and volume of distribution (V/F).  Additional parameters may be 
estimated if useful in the interpretation of the data.  Data from this study may be combined with data 
from other studies for the population PK analyses.
3.6 Biomarker Research Objectives
Optional blood samples (whole blood, serum, plasma, peripheral blood mononuclear cells [PBMC]) will 
be collected as described in the Activity Schedule (Appendix D) to evaluate known and or novel disease 
related or drug related biomarkers.  Types of biomarkers may include nucleic acids, proteins, lipids, 
cellular populations, and/or metabolites.  The objective of research is to analyze samples for biomarkers 
that will help to understand HS, related conditions, response to treatment with upadacitinib or similar 
compounds.  Research may also include changes in epigenetics, gene expression, and proteomics that 
may associate with HS, related conditions, or the subject's response to treatment.  This research is 
exploratory in nature and the results 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 study to 
evaluate the efficacy and safety of upadacitinib in adult subjects with moderate to severe HS.
The duration of the study will be up to 57 weeks and will include an approximately 35-day screening 
period followed by a 48-week double-blinded treatment period and a 30-day follow up visit after the last 
dose of study drug.
Subjects who meet eligibility criteria will be randomized in a 2:1 ratio to 1 of the 2 arms as shown below:

Upadacitinib 30 mg once daily (QD) (N = 40):  Daily oral doses of upadacitinib 30 mg from the 
Baseline visit through Period 1 and Period 2.

Placebo (N = 20):  Placebo for upadacitinib from the Baseline visit up to the Week 12 visit 
(Period 1).  At Week 12, subjects will be switched to blinded upadacitinib 15 mg QD through 
Period 2.
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The schematic of the study is shown in Figure 1.  Further details regarding study procedures are included 
in the Operations Manual (Appendix F).
See Section 5 for information regarding eligibility criteria.
The primary efficacy analysis will be conducted when all ongoing subjects have completed their Week 12 
visit.
Figure 1.
Study Schematic
PBO = placebo; UPA = upadacitinib
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 standard for assessing disease activity or quality of life in subjects with 
HS.  All clinical and laboratory procedures in this study are standard and generally accepted.
Suitability of Subject Population
Adult subjects with moderate to severe HS (defined as a total AN count of ≥ 5 at Baseline, presence of 
HS lesions in at least 2 distinct anatomic areas and draining fistula count of ≤ 20 at Baseline) are eligible 
for this study.  Subjects are to have a diagnosis of HS for at least 1 year prior to Baseline.  The criteria 
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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.  The study population selected reflects a 
population typical of new treatment intervention studies in moderate to severe HS.
Selection of Doses in the Study
This study will evaluate upadacitinib 30 mg QD.  The selection of this dose was informed by the safety 
and efficacy of the upadacitinib dosing in different indications including RA, AD, psoriatic arthritis, and 
Crohn's disease.  Due to a high inflammatory burden in the HS population, in general, higher dosing may 
be required to achieve optimal clinical response compared to other autoimmune disease indications 
such as RA.  Hence, upadacitinib 30 mg QD has been selected to establish proof-of-concept for 
upadacitinib in the treatment of HS in this Phase 2 study.  The adalimumab PIONEER I and II studies 
demonstrated that 40 mg every week resulted in better efficacy than 40 mg every other week (initial 
prescribed dose for most indications such as RA, plaque psoriasis, etc.).19  The results from Phase 2 dose-
ranging studies with upadacitinib in AD and Crohn's disease showed upadacitinib 30 mg QD resulted in 
greater efficacy compared to upadacitinib 15 mg QD, which is the approved dose for RA.30
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. Subjects must voluntarily sign and date an informed consent, approved by an independent 
ethics committee (IEC)/institutional review board (IRB), prior to the initiation of any screening or 
study-specific procedures.
Demographics
2. Adult male or female, at least 18 years old and functionally able to read and understand 
study questionnaires.
3. Are willing and able to comply with procedures required in this protocol.
4. Subject is not an employee or a family member of the sponsor and/or study site.
Disease Criteria
5. Diagnosis of HS for at least 1 year prior to Baseline, as determined by the investigator (i.e., 
through medical history and interview of subject).
6. Subject must have a total AN count of ≥ 5 at Baseline.
7. HS lesions must be present in at least 2 distinct anatomic areas.
8. Draining fistula count of ≤ 20 at Baseline.
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9. Inadequate response (lack of efficacy after a course of therapy) or an intolerance to oral 
antibiotics for treatment of HS.
Laboratory Assessments
10. Laboratory values meeting the following criteria within the screening period prior to the 
first dose of study drug:

Serum aspartate transaminase (AST) ≤ 2 × upper limit of normal (ULN);

Serum alanine transaminase (ALT) ≤ 2 × ULN;

Estimated glomerular filtration rate by simplified 4-variable Modification of Diet in Renal 
Disease formula ≥ 30 mL/min/1.73 m2;

Total white blood cell (WBC) count ≥ 2,500/µL;

Absolute neutrophil count (ANC) ≥ 1,200/µL;

Platelet count ≥ 100,000/µL;

Absolute lymphocyte count (ALC) ≥ 750/µL;

Hemoglobin ≥ 9 g/dL.
Subject History
11. No history of active skin disease (other than HS) that could interfere with the assessment of 
HS, including skin infections (bacterial, fungal, or viral) requiring systemic treatment within 
4 weeks of the Baseline visit.
12. Subject is 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 ECG performed during Screening.
13. Subject must not have a history of clinically significant (per investigator's judgment) drug or 
alcohol abuse within the last 6 months.
14. Subject must have no current or past history of any of the following infections:

Two or more episodes of herpes zoster, or one or more episodes of disseminated herpes 
zoster;

One or more episodes of disseminated herpes simplex (including eczema herpeticum);

Human immunodeficiency virus (HIV) infection defined as confirmed positive anti-HIV 
antibody (HIV Ab) test;

Active tuberculosis (TB) or meet TB exclusionary parameters (specific requirements for TB 
testing are provided in the operations manual [Appendix F]);

Positive result of beta-D-glucan (screening for pneumocystis jirovecii infection) or two 
consecutive indeterminate results of beta-D-glucan during the Screening Period (for subjects 
in Japan only)
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
Active infection(s) requiring treatment with intravenous anti-infectives within 30 days, or 
oral/intramuscular anti-infectives within 14 days prior to the Baseline Visit;

Chronic recurring infection and/or active viral infection that, based on the investigator's 
clinical assessment, makes the subject an unsuitable candidate for the study;

Confirmed COVID-19:  the Baseline visit must be at least 14 days from onset of 
signs/symptoms or positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
test; symptomatic subjects must have recovered, defined as resolution of fever without use 
of antipyretics and improvement of symptoms;

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;

Subjects must not have evidence of:

Hepatitis B virus (HBV):  hepatitis B surface antigen positive (+) test or detected 
sensitivity on the HBV deoxyribonucleic acid (DNA) PCR qualitative test for subjects who 
are hepatitis B core antibody (HBc Ab) positive (+) (and for Hepatitis B surface antibody 
positive [+] subjects where mandated by local requirements);

Hepatitis C virus (HCV):  HCV ribonucleic acid (RNA) detectable in any subject with anti-
HCV antibody.
15. Subject must not have any of the following medical diseases or disorders:

Recent (within past 6 months) cerebrovascular accident, myocardial infarction, coronary 
stenting;

History of an organ transplant which requires continued immunosuppression;

History of gastrointestinal perforation (other than due to appendicitis or mechanical injury), 
diverticulitis, or significantly increased risk for gastrointestinal 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 nonmelanoma skin cancer (NMSC) or 
localized carcinoma in situ of the cervix.
16. 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.
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Contraception
17. 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).
18. Female subjects of childbearing potential must practice at least 1 protocol-specified method 
of birth control that is effective from Study Day 1 through at least 30 days after the last dose of 
study drug (local practices may require 2 methods of birth control).  Female subjects of non-
childbearing potential do not need to use birth control.
19. Females must not be pregnant, breastfeeding, or considering becoming pregnant during the 
study and for approximately 30 days after the last dose of study drug.
Prior and Concomitant Medications
20. Subject 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.
21. Subject must have no systemic use of known strong cytochrome P450 3A (CYP3A) inhibitors 
from Screening through the end of study drug administration or strong CYP3A inducers 30 days 
prior to study drug administration through the end of study drug administration (refer to Table 1
for examples of commonly used strong CYP3A inhibitors and inducers).  Subjects may not use 
herbal therapies or other traditional medicines with unknown effects on CYP3A from Screening 
through the end of study drug administration.
22. Subject 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.
23. Subject must not have a history of an allergic reaction or significant sensitivity to 
constituents of the study drug (and its excipients) and/or other products in the same class.
24. Subjects who have had prior exposure to immunomodulatory biologic therapies for any 
indication, including but not limited to anti-TNF therapy and anti-IL-1 (e.g., anakinra, 
canakinumab) therapy must have discontinued the biologic therapies prior to the first dose of 
study drug.  Subjects who need to discontinue other biologic therapies prior to the Baseline Visit 
to comply with this inclusion criterion must follow the washout periods 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;
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
≥ 16 weeks for secukinumab;

≥ 12 weeks for ustekinumab.
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.
25. Subject must not have had prior exposure for 14 days or more or any prior intolerance to a 
JAK inhibitor for any indication.  The washout period for JAK inhibitors prior to the first dose of 
study drug is ≥ 30 days or 5 times the half-life, whichever is longer.
26. No previous treatment with any cell-depleting therapies including but not limited to anti-
CD20 (e.g., rituximab) within 12 months prior to Baseline or until B cell count returns to normal 
level or pre-treatment level.
27. Subjects must not have received prescription topical therapies (including topical antibiotics) 
that can also be used to treat HS within 14 days prior to the Baseline visit.
28. Subjects must not have received systemic non-biologic therapies that can also be used to 
treat HS within 4 weeks prior to the Baseline visit.
29. Subjects must not have received any systemic (including oral) antibiotic treatment for HS or 
any other chronic inflammatory disorder within 4 weeks prior to the Baseline visit.
30. Subjects must be willing to and are required to use a daily antiseptic wash on their HS lesions 
starting at least 14 days prior to Baseline.  Allowable antiseptic washes are limited to one of the 
following: chlorhexidine gluconate, benzoyl peroxide, benzalkonium chloride, benzethonium 
chloride, or dilute bleach in bath water.
31. Subjects who are on non-opioid analgesics for HS or non-HS related pain, must be on a 
stable dose and dosing regimen for at least 14 days preceding the Baseline visit and are 
expected to remain on a stable dose and dosing regimen at least until the Week 16 visit.  
Otherwise, subjects must not have received oral analgesics including but not limited to opioids, 
antiepileptics (e.g., gabapentin), tricyclics (e.g., nortriptyline), or selective serotonin 
norepinephrine reuptake inhibitors (e.g., duloxetine, venlafaxine) within 14 days prior to the 
Baseline visit.
Note: For HS-related pain, analgesic therapy is limited to ibuprofen (as per local labeling, but 
not exceeding a dose of 800 mg orally every 6 hours and 3.2 g orally every 24 hours) AND/OR 
acetaminophen (paracetamol) as per local labeling.
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:
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
Postmenopausal, age > 55 years with no menses for 12 or more months without an 
alternative medical cause.

Postmenopausal, age ≤ 55 years with no menses for 12 or more months without an 
alternative medical cause AND a follicle stimulating hormone (FSH) level > 40 IU/L.

Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy, or 
hysterectomy).

Females, of Childbearing Potential

Females of childbearing potential must avoid pregnancy while taking study drug and for at 
least 30 days after the last dose of study drug.  Females must commit to one of the following 
methods of highly effective birth control:

Combined (estrogen- and progestogen-containing) hormonal birth control (oral, 
intravaginal, transdermal, injectable) associated with inhibition of ovulation 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.

Intrauterine hormone-releasing system.

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 Study Day 1.

Male or female condom with or without spermicide.

Cap, diaphragm, or sponge with spermicide.

A combination of male condom with a cap, diaphragm, or sponge with spermicide 
(double barrier method).
Contraception recommendations related to use of concomitant therapies prescribed per standard of 
care should be based on the local label.
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
5.3 Prohibited Medications and Therapy
Background Therapies
The following therapies are prohibited until after Week 16 assessments unless otherwise specified:
1.
Throughout the study, any other systemic therapy that can also be used to treat HS, including 
but not limited to intramuscular or intravenous corticosteroids, oral corticosteroids equivalent 
to > 10 mg/day of prednisone, methotrexate (> 25 mg/week), cyclosporine, mycophenolate 
mofetil, azathioprine, intramuscular gamma-globulin.
2.
Apremilast, hormonal therapy (except for contraception), metformin (except for continuous 
treatment of preexisting diabetes), zinc gluconate, colchicine, retinoids, acitretin/etretinate, and 
fumaric acid esters, methotrexate, and oral corticosteroids are prohibited until after Week 16 
assessments.
3.
New topical therapies used to treat HS (other than protocol-allowed antiseptic) or changes in 
the concentration/frequency of current topical therapies used to treat HS (including but not 
limited to exfoliants, e.g., resorcinol).
4.
Deroofing or skin-tissue-saving excision with electrosurgical peeling (STEEP), laser therapy, 
intense pulse light, local/wide/radical excision, incision and/or draining of lesions, or 
intralesional corticosteroid injections. 
5.
Concomitant use of antibiotics (topical or systemic) is not permitted for the treatment of HS or 
other chronic inflammatory disorders.
6.
Use of any treatments for HS-related pain, other than ibuprofen or acetaminophen 
(paracetamol), including but not limited to opioids, antiepileptics (e.g., gabapentin), tricyclics 
(e.g., nortriptyline), or selective serotonin norepinephrine reuptake inhibitors (e.g., duloxetine, 
venlafaxine).  For non-HS-related pain, all other non-opioid analgesics are allowed at the 
recommended or prescribed dose per local label.  Use of opioid analgesics for HS-related or non-
HS related pain is prohibited until after Week 16 assessments.

Subjects who are on a documented stable dose and dosing regimen of non-opioid analgesic 
treatment for at least 14 days prior to the Baseline visit are not permitted to adjust their 
regimen at least until after the Week 16 assessment.  Note:  For HS-related pain, analgesic 
therapy is limited to ibuprofen (as per local labeling, but not exceeding a dose of 800 mg 
orally every 6 hours and 3.2 g orally every 24 hours) AND/OR acetaminophen (paracetamol) 
as per local labeling.
7.
Over-the-counter topical antiseptic washes (other than those allowed as per the concomitant 
therapy section), creams, ointments, gels, and liquids containing antibacterial agents to treat HS, 
other than those allowed as per concomitant therapy section.
8.
Phototherapy treatment (ultraviolet B or ultraviolet A phototherapy, including psoralen and 
ultraviolet A), tanning booth, or extended sun exposure.
9.
Medicinal and recreational cannabis.
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STUDY M20-040  |  Version 2.0 
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Biologic Therapies 
Subjects must have discontinued biologic therapies at least 3 months or 5 half-lives (whichever is longer) 
prior to Baseline or with specified washout periods as detailed in 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.
Therapies including but not limited to the following biologic therapies are prohibited medications during 
the study (throughout Period 1 and Period 2):

Abatacept

Adalimumab

Anakinra

Belimumab

Certolizumab

Dupilumab

Etanercept

Golimumab

Infliximab

Ixekizumab

Natalizumab

Rituximab

Secukinumab

Tocilizumab

Ustekinumab

Vedolizumab

Guselkumab

Risankizumab
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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CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Table 1.
Examples of Commonly Used Strong CYP3A Inhibitors and Inducers
Strong CYP3A Inhibitors 
Strong CYP3A Inducers  
Boceprevir
Cobicistat
Clarithromycin
Conivaptan
Grapefruit (fruit or juice)
Indinavir
Itraconazole
Ketoconazole
Lopinavir/Ritonavir
Mibefradi
Nefazodone
Nelfinavir
Posaconazole
Ritonavir
Saquinavir
Telaprevir
Telithromycin
Troleandomycin
Voriconazole
Avasimibe
Carbamazepine
Phenytoin
Rifampin (rifampicin)
Rifapentine
St. John's Wort
Investigational Drugs or Therapies
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
If the subject and investigator choose to receive/administer live vaccines, these vaccinations must be 
completed (per local label) at least 28 days (or longer if required locally) before first dose of study drug.  
Live vaccinations are prohibited during study participation including at least 30 days (or longer if 
required locally) after the last dose of study drug.
If the live herpes zoster vaccine is to be administered and there is no known history of primary varicella 
(chicken pox), preexisting immunity to varicella should be confirmed with antibody testing at or prior to 
Screening and prior to administration of the herpes zoster vaccine.  If screening varicella antibody 
testing is negative, the live herpes zoster vaccine should not be administered.
Examples of live vaccines include, but are not limited to, the following:

Monovalent live influenza A (H1N1) (intranasal);

Seasonal trivalent live influenza (intranasal);

Zostavax (herpes zoster, live attenuated);

Rotavirus;
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STUDY M20-040  |  Version 2.0 
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

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.
Other Medications Prohibited During the Study
JAK inhibitors (e.g., upadacitinib [Rinvoq®], tofacitinib [Xeljanz®], ruxolitinib [Jakafi®], baricitinib 
[Olumiant®], peficitinib [Smyraf®], abrocitinib [PF-04965842], and filgotinib).
5.4 Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins and/or herbal 
supplements) that the subject is receiving at the time of screening, and/or receives during the study, 
must be recorded along with the reason for use, date(s) of administration including start and end dates, 
and dosage information including dose, route and frequency on the appropriate electronic case report 
form (eCRF).  Also, medications taken for HS since date of diagnosis (based on subject recollection and 
available medical records) should be entered into the appropriate eCRF inclusive of the dates of first and 
last dose, maximum dosage taken, route of administration.
Any questions regarding concomitant or prior therapy should be raised to the AbbVie Therapeutic Area 
Medical Director (TA MD)/AbbVie emergency contact.  Information regarding potential drug interactions 
with upadacitinib can be located in the upadacitinib Investigator's Brochure.
Allowed Therapies
Antibiotics
Concomitant use of antibiotics is allowed for the treatment of acute infections during the study.  Use of 
topical or systemic antibiotics to treat HS or other chronic inflammatory disorders is prohibited up to 
Week 16.  After Week 16, concomitant use of any antibiotics for any indication, including HS, is 
permitted.
Dosing and/or frequency need to be reported in the eCRF documentation; "as needed" (PRN) use is not 
permitted.
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STUDY M20-040  |  Version 2.0 
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Antiseptic Wash
Subjects are required to use a daily antiseptic wash on their HS lesions for the duration of the study.
Allowable antiseptic washes are limited to:  chlorhexidine gluconate, benzoyl peroxide, benzalkonium 
chloride, benzethonium chloride, or dilute bleach in bathwater.
Wound Care
Use of wound care dressings on HS wounds is allowed.  Recommended options include alginates, 
hydrocolloids, and hydrogels.
Lesion Intervention
Deroofing or STEEP, laser therapy, intense pulse light, local/wide/radical excision, incision and/or 
draining of lesions, and intralesional injections are allowed after Week 16 assessments.  Refer to 
Section 6.2 for study drug interruption guidelines for elective and emergency surgeries.
Analgesic therapy
If a subject experiences pain (HS- related or non-HS-related) after Baseline, they may initiate analgesic 
treatment.  For HS-related pain, analgesic therapy is limited to the following until after the Week 16 
assessments:

ibuprofen as per local labeling, but not exceeding a dose of 800 mg orally every 6 hours and 
3.2 grams orally every 24 hours, AND/OR

acetaminophen (paracetamol) as per local labeling
For non-HS-related pain, all other non-opioid analgesics are allowed at the recommended or prescribed 
dose.
Use of opioid analgesics for HS-related or non-HS related pain is prohibited until after Week 16 
assessments.
Subjects will complete a daily diary of their analgesic use.  Subjects will be required to record their 
analgesic use daily through Week 16.  Any changes in dosing and/or frequency need to be reported in 
the daily dairy; documentation of only PRN use is not permitted.
Subjects who are on a documented stable dose and dosing regimen of non-opioid analgesic treatment 
for at least 14 days prior to the Baseline visit may not adjust their regimen until after Week 16 
assessments.
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 will be 
discontinued or terminated in case of an unacceptable risk, any relevant toxicity, or a negative change in 
the risk/benefit assessment.  This might include the occurrence of AEs with a character, severity or 
frequency that is new in comparison to the existing risk profile.  In addition, data deriving from other 
clinical trials or toxicological studies which negatively influence the risk/benefit assessment might cause 
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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.  
Subjects who discontinue the study prematurely after randomization will not be replaced. The 
investigator may discontinue any subject's participation at any time for any reason.  The AbbVie TA MD 
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 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 deep vein thrombosis, pulmonary embolus, or non-cardiac, non-
neurologic arterial thrombosis.

Malignancy, except for localized NMSC or carcinoma in-situ of the cervix.

Subject develops a gastrointestinal perforation (other than due to appendicitis or mechanical 
injury).

The subject becomes pregnant or plans to become pregnant while on study drug.

Subject is non-compliant with TB prophylaxis (if applicable) or develops active TB at any time 
during the study.

Eligibility criteria violation was noted after the subject started study drug, when continuation of 
the study drug would place the subject at risk.

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, which would put the subject at risk 
for continued participation in the trial
Additional requirements related to abnormal laboratory values and selected AEs of special interest are 
located in Section 6.2 (Toxicity Management).
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5.6 Follow-Up After Subject Discontinuation of Study Drug or from 
Study
Discontinuation of Study Drug and Continuation of Study Participation
To minimize missing data for efficacy and safety assessments, subjects who prematurely discontinue 
study drug treatment should continue to be followed for all regularly scheduled visits as outlined in the 
Activity Schedule (Appendix D), unless subjects have decided to discontinue study participation entirely 
(withdrawal of informed consent).  Subjects should be advised on the continued scientific importance of 
their data even if they discontinue treatment with study drug early.  Following discontinuation of study 
drug, the subject should be treated in accordance with the investigator's best clinical judgment 
irrespective of whether the subject decides to continue participation in the study.
Premature Discontinuation of Study (Withdrawal of Informed Consent)
If a subject prematurely discontinues study participation (withdrawal of informed consent), the 
procedures outlined for the Premature Discontinuation visit should be completed as soon as possible, 
preferably within 2 weeks.  In addition, if subject is willing, a 30-day follow-up visit (or phone call if a 
visit is not possible) after the last dose of study drug may be completed to determine the status of any 
ongoing AEs/serious adverse events (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.
In the event a subject withdraws consent from the clinical study, biomarker research will continue 
unless the subject explicitly requests analysis to be stopped.  When AbbVie is informed that samples are 
withdrawn from research, samples will not be analyzed, no new biomarker analysis data will be 
collected, 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.
Subjects will continue their disease-related concomitant medications therapy as allowed per protocol.  
AbbVie will not supply any disease-related concomitant medication therapy taken during the course of 
the study.
AbbVie will supply upadacitinib and matching upadacitinib placebo.
All study drug must be stored at controlled room temperature (15° to 25°C/59° to 77°F).  Study drug will 
be packaged in quantities sufficient to accommodate study design.
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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
Oral
Film-coated 
tablets
15 mg or 
30 mg
Blinded
QD
AbbVie
Placebo for 
upadacitinib
Oral
Film-coated 
tablets
Not 
applicable
Blinded
QD
AbbVie
In cases of state of emergency or pandemic situations, study drug shipment can be made from the study 
site to the subject if allowed by local regulations.  Refer to the Operations Manual for details on 
direct-to-patient (DTP) 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 generated by the statistics department at AbbVie.
Subjects will be randomized in a 2:1 ratio to 1 of 2 treatment groups:

Upadacitinib 30 mg QD (N = 40)

Placebo (N = 20)
Randomization will be stratified by anti-TNF use prior to baseline and Hurley stage (< III or III).
Subjects in the placebo group will be switched to upadacitinib 15 mg QD at Week 12.
All AbbVie personnel with direct oversight of the conduct and management of the trial (with the 
exception of AbbVie Drug Supply Management Team), the investigator, study site personnel, and the 
subject will remain blinded to each subject's treatment through Week 12.  Sites and subjects will remain 
blinded for the duration of the study.  In order 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 medical emergency.
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CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
In the event of a medical situation that requires unblinding of the study drug assignment, the 
investigator is requested to contact the AbbVie TA MD prior to breaking the blind.  However, if an 
urgent therapeutic intervention is necessary which warrants breaking the blind prior to contacting the 
AbbVie TA MD, the investigator can directly access the IRT system to break the blind without AbbVie 
notification or agreement.  Unblinding is available in the IRT system via the 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), 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.
5.10 Data Monitoring Committee
An external DMC composed of clinicians and statisticians independent of AbbVie and with relevant 
expertise in their field will review unblinded data from the ongoing study.  The DMC is responsible for 
safeguarding the interests of trial subjects, assessing the safety as well as for monitoring the integrity 
and interpretability of the trial.  The DMC will provide recommendations to the sponsor regarding 
ongoing trial conduct, or modifications to the trial as described in a separate DMC charter.
In order to maintain sponsor blinding, an external Statistical Data Analysis Center is responsible for 
performing the analyses described in the DMC charter as well as additional analyses requested by the 
DMC and facilitating interpretation and answering questions that arise before, during or after DMC 
review.  
The DMC will regularly review unblinded safety data from the ongoing study according to the schedule 
provided in the DMC Charter, including AEs, laboratory values and vitals sign values.
A separate DMC charter will be prepared outside of the protocol and will further describe the roles and 
responsibilities of the DMC members, frequency and scope of the data reviews, and expectations for 
blinded communications.
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
6 SAFETY CONSIDERATIONS
6.1 Complaints and Adverse Events
Complaints
A complaint is any written, electronic, or oral communication that alleges deficiencies related to the 
physical characteristics, identity, quality, purity, potency, durability, reliability, safety, effectiveness, or 
performance of a product/device.  Complaints associated with any component of this investigational 
product must be reported to AbbVie.
Product Complaint
A product complaint is any complaint related to the biologic or drug component of the product or to the 
medical device component(s).
For a product this may include, but is not limited to, damaged/broken product or packaging, product 
appearance whose color/markings do not match the labeling, labeling discrepancies/inadequacies in the 
labeling/instructions (e.g., printing illegible), missing components/product, device not working properly, 
or packaging issues.
Product complaints concerning the investigational product and/or device must be reported to AbbVie 
within 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" 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 
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been pre planned prior to study entry.  However, if the pre-existing condition deteriorates unexpectedly 
during the study (e.g., surgery performed earlier than planned), then the deterioration of the condition 
for which the elective surgery/procedure is being done will be considered an 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 serious AE (refer to Section 4.3 of the 
Operations Manual [Appendix F] 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 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 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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AbbVie will be responsible for Suspected Unexpected Serious Adverse Reactions reporting for the 
Investigational Medicinal Product in accordance with global and local requirements.
Adverse events will be monitored throughout the study to identify any of special interest that may 
indicate a trend or risk to subjects.
Adverse Events of Special Interest
The following AEs of special interest will be monitored during the study:

Serious infections

Opportunistic infections

Herpes zoster

Active TB

Malignancy (all types)

Adjudicated gastrointestinal perforations

Anemia

Neutropenia

Lymphopenia

Renal dysfunction

Hepatic disorder

Adjudicated cardiovascular events (e.g., major adverse cardiovascular event [MACE])

Adjudicated embolic and thrombotic events (non-cardiac, non-central nervous system)
Adverse Event Severity and Relationship to Study Drug
The Investigators will rate the severity of each AE according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events version 4.03 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:
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Mild (Grade 1)
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated
Moderate (Grade 2)
Minimal, local, or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living (ADL; instrumental ADL 
refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc.)
Severe (Grade 3 - 5)
Grade 3
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self care ADL (self care ADL refer 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.
Cardiovascular Adjudication Committee
An independent, external committee of physician experts in cardiovascular adjudication will be utilized 
to assess potential cardiovascular, embolic, and thrombotic AEs in a blinded manner as defined by the
Cardiovascular Adjudication Committee charter.
Gastrointestinal Perforation Adjudication
Two independent, 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 gastroinestinal perforation in a blinded manner as defined by the 
Gastrointestinal Perforation Adjudication Charter.
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Pregnancy
While not an AE, pregnancy in a study subject must be reported to AbbVie within 24 hours after the site 
becomes aware of the pregnancy.  If a pregnancy occurs in a study subject, information regarding the 
pregnancy and the 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 a SAE and must be reported to AbbVie within 24 hours of the site becoming aware of the 
event.
6.2 Toxicity Management
The toxicity management of the AEs including AEs of special interest consists of safety monitoring 
(review of AEs on an ongoing basis, and periodic/ad hoc review of safety issues by an independent Data 
Monitoring Committee), 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.
For subjects who discontinue study drug but continue study participation and are on standard of care 
therapies, these toxicity management requirements do not apply (including alerts from the central 
laboratory) and any intolerability to standard of care therapies should be managed by the prescribing 
physician.
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.
Gastrointestinal Perforation:  If a diagnosis of gastrointestinal perforation is confirmed (other than due 
to appendicitis or mechanical injury), the subject 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.
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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.
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.
Thrombosis Events:  Subjects who develop symptoms of thrombosis should be promptly evaluated and 
treated appropriately.  If the diagnosis of deep vein thrombosis, pulmonary embolus or non-cardiac, 
non-neurologic arterial thrombosis is confirmed, the subject must be discontinued from study drug.
Management of 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.
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.
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Laboratory 
Parameter
Toxicity Management Guideline
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.
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 > 1.5.

A separate blood sample for international normalized ratio (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 hepatitis B surface antibody 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 its Baseline value, study drug may be 
restarted.  If restarting study drug, documentation should include reason that 
rechallenge is expected to be safe.  If after clinically appropriate evaluation, no 
alternative etiology for ALT or AST elevation is found or the ALT or AST elevation has not 
resolved or is not trending down toward normal, the subject should be discontinued 
from study drug.
For any confirmed ALT or AST elevations > 3 ULN, complete the appropriate 
supplemental hepatic eCRF(s).
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Laboratory 
Parameter
Toxicity Management Guideline
Serum Creatinine
•
If serum creatinine is > 1.5 × the Baseline value and > ULN, repeat the test for 
serum creatinine (with subject in an euvolemic state) to confirm the results.  If 
the results of the repeat testing still meet this criterion, 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.
Elective and Emergency Surgeries
For elective and emergency surgeries the following rules will apply:

If the subject must undergo emergency surgery, the study drug should be interrupted at the 
time of the surgery.  After emergency surgery, allow reintroduction of study drug once the 
physician has examined the surgical site and determined that study drug may be safely 
restarted.

Elective surgery, and interruption of study drug for such a surgery, will not be allowed until after 
the Week 16 visit has been completed.  If the subject undergoes elective surgery, the study drug 
should be interrupted at least 1 week prior to the planned surgery.  Allow reintroduction of 
study drug once the physician has examined the surgical site and determined that study drug 
may be safely restarted.
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 ongoing subjects have completed Week 12, data 
pertaining to Period 1 has 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 is the only 
and final analysis for Period 1.  Study sites and subjects will remain blinded for the duration of the study.
7.2 Definition for Analysis Populations
The Intent to Treat (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.
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The following 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.

The All Upadacitinib Treated (ALL_UPA) Population is defined as subjects who received at least 
one dose of upadacitinib in the study.  This population will be used to provide a comprehensive 
summary of safety.
For safety analyses, subjects will be analyzed based on the treatment actually received.
7.3 Statistical Analyses for Efficacy
Primary Efficacy Analysis
Analysis of the primary endpoint will be conducted in the ITT Population based on treatment as 
randomized.  Comparison of the primary endpoint will be made between upadacitinib 30 mg QD and 
historical placebo rate using a one sample Chi-square test.  For the primary analysis, Non-Responder 
Imputation while incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C) will 
be used to handle missing data.  A supplementary analysis will be performed to compare upadacitinib 
30 mg QD versus in-trial placebo group combined with unblinded placebo data from existing trials.
Secondary Efficacy Analysis
The secondary endpoint will be analyzed using the same method as for the primary endpoint.  In 
addition, analgesic use will be handled as follows:

Prohibited analgesic (including opioids):  A subject will be counted as a non-responder from the 
day that the subject initiates prohibited analgesic to 5 days after the end of such analgesic use.

Protocol-allowed analgesic use:

A subject who enters the study without concomitant analgesic will be counted as a non-
responder from the day that the subject initiates a protocol-allowed analgesic to 2 days 
after the end of such analgesic use.

A subject who entered the study on a stable dose of a protocol-allowed concomitant 
analgesic will be counted as a non-responder from the first day of an analgesic dose increase 
to 2 days after the end of the dose increase.
Additional Efficacy Analyses
Details on additional efficacy analyses are provided in the SAP.
Subgroup Analysis for Efficacy
To evaluate the consistency of the efficacy over demographic and other baseline characteristics, 
summaries will be provided for the following subgroups for the primary efficacy endpoint.

Age group (< 40 years, ≥ 40 – < 65 years, ≥ 65 years)
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
Sex (male, female)

Race (white, non-white)

Smoking (current, ex or never)

Body mass index (normal:  < 25, overweight:  ≥ 25 – < 30, obese:  ≥ 30)

Duration of HS (by median)

Prior exposure to TNF antagonists (yes, no)

Baseline Hurley stage (II, III)
7.4 Statistical Analyses for Safety
All safety analyses will be performed on the safety populations.  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 lab parameters, a listing of all subjects with any laboratory value 
above Grade 3 of Common Toxicity Criteria will be provided.  Mean change in laboratory and vital signs 
variables will be summarized. Additional details for the safety analysis will be provided in the SAP.
7.5 Interim Analysis
No formal interim analysis of efficacy is planned for this study.  Routine safety reviews will be performed 
by an external DMC (see details given in Section 5.10).
7.6 Overall Type I Error Control
Not applicable for this study.
7.7 Sample Size Determination
The primary endpoint is the achievement of HiSCR at Week 12.  The primary analysis compares the 
proportion of subjects achieving HiSCR response to that of historical placebo (25% HiSCR response).  
Assuming the Week 12 HiSCR response is 57% for the upadacitinib 30 mg arm, 40 subjects on 
upadacitinib will provide more than 95% power with a one-sample Chi-square test and one-sided alpha
= 0.05 significance level.
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8 ETHICS
8.1 Independent Ethics Committee/Institutional Review Board 
(IEC/IRB)
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the IEC/IRB for review and approval.  Approval of both the protocol and the informed 
consent form(s) must be obtained before any subject is enrolled.  Any amendment to the protocol will 
require review and approval by the IEC/IRB before the changes are implemented to the study.  In 
addition, all changes to the consent form(s) will be IEC/IRB approved.
8.2 Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, Operations Manual, International Council 
for Harmonisation (ICH) guidelines, applicable regulations, and guidelines governing clinical study 
conduct and the ethical principles that have their origin in the Declaration of Helsinki.  Responsibilities of 
the investigator are specified in Appendix B.
In cases of state of emergency or pandemic situations leading to difficulties in performing protocol-
specified procedures, AbbVie will engage with study site personnel in efforts to ensure the safety of 
subjects, maintain protocol compliance, and minimize risks to the integrity of the study while trying to 
best manage subject continuity of care.  This may include alternative methods for assessments (e.g., 
phone contacts or virtual site visits), alternative locations for data collection (e.g., use of a local lab 
instead of a central lab), and shipping investigational product and/or supplies direct to subjects to 
ensure continuity of treatment where allowed.  Refer to the Operations Manual for additional details.  In 
all cases, these alternative measures must be allowed by local regulations and permitted by IRB/IEC.  
Investigators should notify AbbVie of 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.
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 
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currently approved protocol, ICH Good Clinical Practice (GCP), and applicable local regulatory 
requirement(s).  
In cases of state emergency or pandemic situations, remote monitoring of data 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.
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.
Zouboulis CC, Del Marmol V, Mrowietz U, et al. Hidradenitis suppurativa/acne inversa: criteria for 
diagnosis, severity assessment, classification and disease evaluation. Dermatology. 2015;231(2):184-
90.
2.
Fimmel S, Zouboulis CC. Comorbidities of hidradenitis suppurativa (acne inversa). 
Dermatoendocrinol. 2010;2(1):9-16.
3.
Fitzsimmons JS, Guilbert PR, Fitzsimmons EM. Evidence of genetic factors in hidradenitis 
suppurativa. Br J Dermatol. 1985;113(1):1-8.
4.
Jemec GB. The symptomatology of hidradenitis suppurativa in women. Br J Dermatol. 
1988;119(3):345-50.
5.
Lookingbill DP. Yield from a complete skin examination: findings in 1157 new dermatology patients. 
J Am Acad Dermatol. 1988;18(1 Pt 1):31-7.
6.
Jemec GB, Heidenheim M, Nielsen NH. The prevalence of hidradenitis suppurativa and its potential 
precursor lesions. J Am Acad Dermatol. 1996;35(2 Pt 1):191-4.
7.
Revuz JE, Canoui-Poitrine F, Wolkenstein P, et al. Prevalence and factors associated with hidradenitis 
suppurativa: results from two case-control studies. J Am Acad Dermatol. 2008;59(4):596-601.
8.
Saunte DM, Boer J, Stratigos A, et al. Diagnostic delay in hidradenitis suppurativa is a global 
problem. Br J Dermatol. 2015;173(6):1546-9.
Page 38 of 105
 


STUDY M20-040  |  Version 2.0 
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
9.
von der Werth JM, Jemec GB. Morbidity in patients with hidradenitis suppurativa. Br J Dermatol. 
2001;144(4):809-13.
10. Sampogna F, Abeni D, Gieler U, et al. Impairment of sexual life in 3,485 dermatological outpatients 
from a multicentre study in 13 European countries. Acta Derm Venereol. 2017;97(4):478-82.
11. Janse IC, Deckers IE, van der Maten AD, et al. Sexual health and quality of life are impaired in 
hidradenitis suppurativa: a multicentre cross-sectional study. Br J Dermatol. 2017;176(4):1042-7.
12. Thorlacius L, Cohen AD, Gislason GH, et al. Increased suicide risk in patients with hidradenitis 
suppurativa. J Invest Dermatol. 2018;138(1):52-7.
13. Vangipuram R, Vaidya T, Jandarov R, et al. Factors contributing to depression and chronic pain in 
patients with hidradenitis suppurativa: results from a single-center retrospective review. 
Dermatology. 2016;232(6):692-5.
14. Shavit E, Dreiher J, Freud T, et al. Psychiatric comorbidities in 3207 patients with hidradenitis 
suppurativa. J Eur Acad Dermatol Venereol. 2015;29(2):371-6.
15. Miller IM, McAndrew RJ, Hamzavi I. Prevalence, risk factors, and comorbidities of hidradenitis 
suppurativa. Dermatol Clin. 2016;34(1):7-16.
16. Egeberg A, Gislason GH, Hansen PR. Risk of major adverse cardiovascular events and all-cause 
mortality in patients with hidradenitis suppurativa. Jama dermatol. 2016;152(4):429-34.
17. Zouboulis CC, Desai N, Emtestam L, et al. European S1 guideline for the treatment of hidradenitis 
suppurativa/acne inversa. J Eur Acad Dermatol Venereol. 2015;29(4):619-44.
18. HUMIRA [package insert]. North Chicago, IL, United States; AbbVie, Inc., 2019.
19. Kimball AB, Okun MM, Williams DA, et al. Two phase 3 trials of adalimumab for hidradenitis 
suppurativa. N Engl J Med. 2016;375(5):422-34.
20. Murray PJ. The JAK-STAT signaling pathway: input and output integration. J Immunol. 
2007;178(5):2623-9.
21. Vaddi K, Luchi M. JAK inhibition for the treatment of rheumatoid arthritis: a new era in oral DMARD 
therapy. Expert Opin Investig Drugs. 2012;21(7):961-73.
22. Cheung TT, McInnes IB. Future therapeutic targets in rheumatoid arthritis? Semin Immunopathol. 
2017;39(4):487-500.
23. Iwata S, Tanaka Y. Progress in understanding the safety and efficacy of Janus kinase inhibitors for 
treatment of rheumatoid arthritis. Expert Rev Clin Immunol. 2016;12(10):1047-57.
24. Banerjee S, Biehl A, Gadina M, et al. JAK-STAT signaling as a target for inflammatory and 
autoimmune diseases: current and future prospects. Drugs. 2017;77(5):521-46.
Page 39 of 105
 


STUDY M20-040  |  Version 2.0 
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
25. Frew JW, Hawkes JE, Krueger JG. A systematic review and critical evaluation of 
immunohistochemical associations in hidradenitis suppurativa. F1000Res. 2018;7:1923.
26. Clark JD, Flanagan ME, Telliez JB. Discovery and development of Janus kinase (JAK) inhibitors for 
inflammatory diseases. J Med Chem. 2014;57(12):5023-38.
27. Lowe MM, Naik HB, Clancy S, et al. Immunopathogenesis of hidradenitis suppurativa and response 
to anti-TNFalpha therapy. JCI Insight. 2020.
28. RINVOQ [package insert]. North Chicago, IL, United States; AbbVie Inc., 2019.
29. RINVOQ [SmPC]. Ludwigshafen, Germany; AbbVie Deutschland GmbH & Co. KG. Available from: 
https://www.ema.europa.eu/en/documents/product-information/rinvoq-epar-product-
information_en.pdf, 2019.
30. AbbVie. RINVOQ Investigator's Brochure Edition 10. 19 August 2019.
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STUDY M20-040  |  Version 2.0 
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX A. STUDY-SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
AD
Atopic dermatitis
ADL
Activities of daily living
AE
Adverse event
ALC
Absolute lymphocyte count
ALT
Alanine transaminase
AN
Abscess and inflammatory nodule
ANC
Absolute neutrophil count
AST
Aspartate transaminase
CL/F
Oral clearance
COVID-19
Coronavirus disease - 2019
CXR
Chest x-ray
CYP3A
Cytochrome P450 3A
DLQI
Dermatology Life Quality Index
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
DTP
Direct-to-patient
ECG
Electrocardiogram
eCRF
electronic case report form
EU
European Union
FSH
Follicle stimulating hormone
HBc Ab
Hepatitis B core antibody
HBV
Hepatitis B virus
HCV
Hepatitis V virus
HDL-C
High-density lipoprotein cholesterol
HiSCR
Hidradenitis Suppurative Clinical Response
HIV
Human immunodeficiency virus
HIV Ab
HIV antibody
hsCRP
High sensitivity C-reactive protein
HS
Hidradenitis suppurativa
HSSA
Hidradenitis Suppurativa Symptom Assessment
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STUDY M20-040  |  Version 2.0 
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
HSIA
Hidradenitis Suppurativa Impact Assessment
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use
IEC
Independent Ethics Committee
IFN
Interferon
IgG
Immunoglobulin G
IL
Interleukin
IRB
Institutional Review Board
IRT
interactive response technology
ITT
Intent-to-treat
JAK
Janus kinase
LDL-C
Low-density lipoprotein cholesterol
MACE
Major adverse cardiovascular event
NMSC
Nonmelanoma skin cancer
NRI
non-responder imputation
NRS
Numeric rating scale
NSAID
Nonsteroidal anti-inflammatory drug
PBMC
Peripheral blood mononuclear cells
PCR
Polymerase chain reaction
PGA
Patient's Global Assessment
PK
Pharmacokinetic
PPD
Purified protein derivative
PRN
As needed
PRO
Patient reported outcome
QD
Once daily
RA
Rheumatoid arthritis
RNA
Ribonucleic acid
SAE
Serious adverse event
SAP
Statistical analysis plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
STAT
Signal transducer and activator of transcription
STEEP
Skin-tissue-saving excision with electrosurgical peeling
TA MD
Therapeutic Area Medical Director
TB
Tuberculosis
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TNF
Tumor necrosis factor
Tyk2
Tyrosine kinase 2
ULN
Upper limit of normal
US
United States
V/F
Volume of distribution
WBC
White blood cell
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STUDY M20-040  |  Version 2.0 
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M20-040:  A Phase 2, Multicenter, Randomized, Placebo-Controlled, Double-Blind Study to 
Evaluate Upadacitinib in Adult Subjects with Moderate to Severe Hidradenitis Suppurativa
Protocol Date:  25 October 2020
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation 
(ICH) Good Clinical Practices (GCP) and local regulations and guidelines governing the study at the site 
location.  In signing the Investigator Agreement, the investigator is agreeing to the following:
1.
Conducting the study in accordance with ICH GCP, the applicable regulatory requirements, 
current protocol and operations manual, and making changes to a protocol only after notifying 
AbbVie and the appropriate Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC), except when necessary to protect the subject from immediate harm.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed consent and 
ethics committees (e.g., IEC or IRB) review and approval of the protocol and its amendments.
4.
Reporting complaints that occur in the course of the investigation(s) to AbbVie.
5.
Reading the information in the Investigator's Brochure/safety material provided, including the 
instructions for use and the potential risks and side effects of the investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the study about 
their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making those records 
available for inspection by representatives of AbbVie and/or the appropriate regulatory agency, 
and retaining all study-related documents until notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and approved the initial 
clinical protocol and all of its amendments.
9.
Reporting promptly, all changes in the research activity and all unanticipated problems involving 
risks to human subjects or others, to the appropriate individuals (e.g., coordinating investigator, 
institution director) and/or directly to the ethics committees and AbbVie.
10. Providing direct access to source data documents for study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s).
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
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STUDY M20-040  |  Version 2.0 
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APPENDIX C. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
Study Project Manager II
Clinical Program Development
Senior Medical Writer
Medical Writing
Executive Medical Director
Immunology Development
Therapeutic Area Medical Director
Immunology Development
Senior Scientific Director
Immunology Development
Senior Manager
Statistics
Senior Director and Therapeutic Area Head 
(Immunology)
Statistics
Director and Therapeutic Area Lead (Dermatology)
Statistics
Director
Clinical Pharmacology and 
Pharmacometrics
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STUDY M20-040  |  Version 2.0 
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APPENDIX E. PROTOCOL SUMMARY OF CHANGES
Previous Protocol Versions
Protocol
Date
Version 1.0
09 March 2020
The purpose of this version is to update safety information, correct minor clerical errors for consistency 
throughout the protocol, and incorporate necessary protocol modifications due to the COVID-19 
pandemic as follows:
Modifications to the Protocol and Operations Manual due to State-of Emergency or Pandemic 
Situations 
One of the purposes of this version is to provide flexibility during state-of emergency or pandemic 
situations so subjects may safely enroll and continue study participation as follows:

Included information in Section 2.2 on the re-evaluation of the benefit and risk to subjects 
participating in the study.  The benefit:risk profile of various immunomodulatory therapies is 
being evaluated.
Rationale: To clarify the benefit:risk balance to participating subjects in this study in light of the 
COVID-19 pandemic.

In Section 5.1, updated eligibility criterion #14 with details regarding subject eligibility with 
regards to COVID-19 infection.
Rationale: Modified eligibility criteria to exclude subjects with suspected or confirmed active 
COVID-19 infection to maintain subject safety.

Modify the following sections to account for state-emergency or pandemic situations:  

Update Section 5.7 and Operations Manual Section 3.18 to permit direct-to-patient (DTP)
shipment of study drug in the event the subject cannot pick up study drug onsite.

Update Section 8.2 with a reference to the Operations Manual to permit modifications to 
the study protocol as necessary due to state-of emergency or pandemic situations and note 
investigators should also notify AbbVie if any urgent safety measures are taken.

Update Section 9 to note that remote monitoring may be employed as needed.

Update Appendix D to add reference to Operations Manual for allowed modifications.
Rationale:  To provide flexibility during state-of emergency or pandemic situations to ensure the 
safety of subjects, maintain protocol compliance, and minimize risk to the integrity of the study 
while trying to best manage continued care of study subjects.

Update Section 6.2 with toxicity management guidelines related to COVID-19.
Rationale: To clarify guidelines for interruption of study drug in event of confirmed diagnosis of 
COVID-19.
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STUDY M20-040  |  Version 2.0 
CONFIDENTIAL INFORMATION
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
The following modifications were made in the Operations Manual to account for state-of 
emergency or pandemic situations:  

Update Section 2 and Section 2.1 with specifics regarding activities that may be affected by 
state-of emergency or pandemic situations, including a table in Section 2.1 specifying 
alternate locations at which certain activities may be performed.

Update Section 3.3 to clarify subject information and informed consent in case of state-of 
emergency or pandemic situations.

Update Section 3.7 to clarify that all PROs (except at Baseline and Week 12 visits) may be 
conducted via phone or video conference in the case of state-of emergency or pandemic 
situations.  Details instructions regarding PROs conducted over the phone or video 
conference are also provided.

Update Section 3.19 with instructions on performing laboratory work in the case of a 
state-of emergency or pandemic situation.

Update Section 4.1 to add COVID-19 as an event necessitating a supplemental eCRF.
Rationale:  To provide flexibility for subject activities while ensuring subject safety during 
state-of emergency or pandemic situations.
Protocol

Added a reference in Section 2.1 and Section 12 and deleted 3 references to support text 
regarding cytokines and receptors that signal via the JAK1 pathway and are elevated in HS.
Rationale: To update text with the most recent data available.

In Section 3.3, updated primary and secondary endpoints will be analyzed 'at' instead of 'for' all 
visits other than Week 12.
Rationale:  Corrected typographical error.

In Section 3.3, updated additional endpoints to be analyzed at visits noted in the Study Activities 
Table.
Rationale: To clarify additional endpoints are not measured/analyzed at all visits.

In Section 5.1, eligibility criterion #5, added clarification of HS diagnosis by the investigator.
Rationale: To clarify diagnosis of HS is determined by the investigator through medical history 
and subject interview.

In Section 5.1, eligibility criterion #27, clarified that subjects must not have received prescription 
topical therapies (including topical antibiotics) that can also be used to treat HS within 14 days 
prior to the Baseline visit.
Rationale: To clarify potential prescribed treatments for HS.

In Section 5.1, eligibility criterion #29, clarified that subjects must not have received any 
systemic (including oral) antibiotic treatment for HS or any other chronic inflammatory disorder 
within 4 weeks prior to the Baseline visit.
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STUDY M20-040  |  Version 2.0 
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Rationale: To clarify the eligibility of subjects with prior systemic antibiotic treatment for 
chronic inflammatory disorder other than HS.

In Section 5.1, eligibility criterion #31, added clarification that subjects who are on non-opioid 
analgesics for HS or non-HS related pain, are expected to remain on a stable dose and dosing 
regimen at least until the Week 16 visit.
Rationale: To clarify the dose and dose regimen for subjects on non-opioid analgesics for HS or 
non-HS related pain.

In Section 5.3, added that the use of methotrexate at >25 mg/week is prohibited.
Rationale: To clarify the maximum dose of methotrexate as a background therapy during the 
study.

In Section 5.3, clarified that the use of methotrexate and oral corticosteroids (regardless of 
dose) is prohibited until after Week 16 assessments.
Rationale: To prohibit the use of any methotrexate or oral corticosteroids until after Week 16 
assessments.

In Section 5.3, restricted the use of new topical therapies used to treat HS (other than 
protocol-allowed antiseptic) or changes in the concentration/frequency of current topical 
therapies used to treat HS.
Rationale: To clarify the restriction regarding new topical therapies and changes in the 
concentration/frequency of current topical therapies.

In Section 5.3, clarified that the use of concomitant antibiotics is not permitted for the 
treatment of chronic inflammatory disorders.
Rationale: To clarify the use of antibiotics to treat other chronic inflammatory disorders besides 
HS.

In Section 5.5, updated that subjects must have study discontinued immediately if abnormal 
laboratory results or AEs that either meet the criteria for discontinuation of study drug as stated 
in Protocol Section 6.2 or rule out safe continuation of the study drug, and serious infections 
which cannot be adequately controlled by anti-infective treatment or would put the subject at 
risk with continuation of study drug.
Rationale: To clarify the circumstances warranting study drug discontinuation.

In Section 5.9, corrected that if a protocol deviation occurs (or is identified), the investigator is 
responsible for notifying listed committee, regulatory authorities, and sponsors.
Rationale: Corrected typographical error.

In Section 6.2, removed wording '(for Study 1 and Study 2)' from Table 3 (Specific Toxicity 
Management Guidelines for Abnormal Laboratory Values) title.
Rationale:  Updated for clarity.

In Section 6.2, updated toxicity management guidelines from Table 3 to clarify that if ALT or AST 
> 8 × ULN, interrupt study drug immediately, confirm by repeat testing with a new sample, and 
contact the TA MD.
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STUDY M20-040  |  Version 2.0 
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Rationale:  To update toxicity management guidelines according to revised upadacitinib safety 
standard language.

In Section 7.3, added clarification that for the primary analysis, Non-Responder Imputation while 
incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C) will be used 
to handle missing data.
Rationale:  Updated primary efficacy analysis to handle missing data due to COVID-19 infection 
or logistical reasons.

In Section 7.3, updated that 'supplementary' analysis instead of 'sensitivity' analysis will be 
performed for the primary endpoint.
Rationale:  Updated analysis description based on the finalization of the ICF-E9R1 guidelines.

In Section 7.4, deleted the following text:  'Pre-treatment AEs will be summarized separately."
Rationale:  Removed unnecessary detail.

In Section 7.7, corrected sample size determination to be analyzed by a one-sample Chi-square 
test instead of a one-sample t-test.
Rationale:  Corrected typographical error.

In Appendix C, updated the protocol signatories.
Rationale:  to align protocol text with relevant standard operating procedures and update due to 
personnel changes for this study.

In Appendix D, updated the Activity Schedule table as follows:  

Added visit windows.

Added that assessments for analgesic use (for HS-related pain), PGA Skin Pain, and HSSA will 
be collected at the Screening visit.

Added clarification that analgesic use (for HS-related pain) will be collected daily from at 
least 7 consecutive days prior to Baseline and up to Week 16, and that PGA Skin Pain will be 
collected daily from at least 7 consecutive days prior to Baseline and up to Week 16 and 
afterwards for 7 consecutive days leading up to each visit.

Added clarification that the HSSA assessment will be collected 7 consecutive days prior to 
the Baseline visit and the visits at Weeks 2, 4, 8, 12, 16, 24, and 48/PD.

Added "paper diary (for Analgesic Use for HS-related Pain" as an additional method of PRO 
assessment collection.

Added footnote 'a' to clarify the timing of study activities if subjects are out of the visit 
window.
Rationale: To clarify study conduct and activities at different visits and for consistency with 
Section 2 of the Operations Manual.
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STUDY M20-040  |  Version 2.0 
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Operations Manual

Appendix F – Operations Manual was updated to include details on how to perform specific 
activities/procedures that may be impacted by changes in global/local regulations due to the 
pandemic.
Rationale:  To reflect necessary changes in study activities and procedures due to the COVID-19 
pandemic.

In Appendix F – Operations Manual, Section 2.1 was updated in the following ways: 

Added text describing the visit windows for study visits.

Added text to specify that all visits with the exception of Screening, Baseline, and Week 12 
may be conducted remotely or in the subject's home residence.

Added text and footnotes to clarify that laboratory draws (except for blood samples for PK 
assay) should be obtained as soon as feasible and preferably within the protocol-defined 
visit window for the scheduled visit.  Blood samples for PK assay that cannot be performed 
on-site for a specific will be considered missing.

Added text to specify paper diary (for Analgesic Use for HS-related Pain) as an additional 
method of PRO assessment collection.

Added PGA Skin Pain, Analgesic Use, and HSSA as PRO assessments at the Screening visit.  
Updated the footnotes that Analgesic use (for HS-related pain) will be collected daily from at 
least 7 consecutive days prior to Baseline and up to Week 16, PGA Skin Pain will be collected 
daily from at least 7 consecutive days prior to Baseline and up to Week 16 and afterwards 
for 7 consecutive days leading up to each visit Baseline, and HSSA will be collected 
7 consecutive days prior to the Baseline visit and the visits at Weeks 2, 4, 8, 12, 16, 24, and 
48/PD.

Reordered some footnotes that were not in alphabetical order.

Corrected footnote 'f' to 'HBs Ab+ and HBcAb-' for Weeks 12, 24, and 48 study visit tables.

Added a footnote to clarity the timing of study activities if subjects are out of the visit 
window.

Added the footnote that if urine pregnancy tests cannot be performed on-site or at home 
due to COVID-19, urine pregnancy tests may be performed by a local lab.

Removed footnote 'e' for pre-dose sample collection at the Week 48 visit table since there is 
no dosing at Week 48.
Rationale:  For clarify regarding study conduct and consistency with Appendix D of the protocol.

In Section 3.12, removed wording 'annually if required by country regulatory authorities.'
Rationale:  To clarify there is no annual requirement for the 12-lead ECG assessment.

In Section 3.19, the figure for the interpretation and management of HBV serologic test results 
was updated to reflect the correct placement of footnotes, and a related figure footnote was 
update to include the HBV DNA PCR test may be tested at unscheduled visits.
Rationale:  To update hepatitis screening guidelines for interpretation and management of HBV 
serologic test results according to revised upadacitinib safety standard language.
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STUDY M20-040  |  Version 2.0 
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
In Section 3.20, removed wording 'except for annual TB testing.'
Rationale:  To add clarification that annual TB testing is not required.
In addition to these modifications, minor typographical edits and corrections were throughout the 
protocol and operations manual for consistency, and other revisions were made for clarity and 
readability (e.g., addition of abbreviations, rearrangement of text).
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STUDY M20-040  |  Version 2.0 
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX F. OPERATIONS MANUAL
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p. 2 of 47
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M20-040 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
1 CONTACTS
Sponsor/
Emergency 
Medical 
Contact
 MD
AbbVie Inc.
1 North Waukegan Road 
North Chicago, IL 60064, USA
EMERGENCY 24 hour Number:  
Office:
Mobile:
Fax:
Email:
Safety 
Concerns
Immunology Safety Team
Bldg. AP51-3
1 North Waukegan Road
North Chicago, IL 60064, USA
Phone:
+1 (847) 938-8737
Email:
GPRD_SafetyManagement_Immunology@abbvie.com
SAE Reporting 
outside of 
RAVE
Email:
PPDINDPharmacovigilance@abbvie.com
Fax:
+1 (847) 938-0660
Protocol 
Deviations and 
Product 
complaints
AbbVie Deutschland
Knollstrasse
67061 Ludwigshafen
Germany
Phone:
Fax:
Email:
Certified 
Clinical Lab
Covance Central Laboratory Services 
SA
8211 Scicor Drive
Indianapolis, IN 46214, USA
Phone:
1 (866) 762-6209 (Toll free)
+1 (317) 271-1200 (Local calls) 
Fax:
+1 (317) 616-2362
For country specific toll free numbers please refer to 
Covance Lab Manual.
Pharmacokinetic 
Laboratory
AbbVie Inc.
Sample Receiving
Dept. R46W, Bldg. AP13A, Rm. 2310
1 North Waukegan Rd.
North Chicago, IL 60064, USA
Phone: +1 (847) 937-0889
Fax:
+1 (847) 938-9898
Exploratory 
Sample 
Laboratory
BioStorage Technologies, Inc.
BioStorage Receiving Department
2910 Fortune Circle West, Suite E
Indianapolis, IN 46241, USA
Phone: +1 (317) 452-4287
Fax:
+1 (317)-241-5202
Genomic 
Sample 
Laboratory
Pharmacogenetics and 
Pharmacogenomics
Dept. R4AE, Bldg. AP32, Room 1 - 224
AbbVie
1 North Waukegan Rd.
North Chicago, IL  60064, USA
Phone: +1 (847) 938-8525
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M20-040 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
TABLE OF CONTENTS
1
CONTACTS
2
2
PROTOCOL ACTIVITIES BY VISIT
5
2.1
INDIVIDUAL TREATMENT PERIOD VISIT ACTIVITIES
5
2.2
INDIVIDUAL POST-TREATMENT PERIOD VISIT ACTIVITIES
16
3
STUDY PROCEDURES
17
3.1
SCREENING PERIOD
17
3.2
RESCREENING
17
3.3
STUDY SUBJECT INFORMATION AND INFORMED CONSENT
18
3.4
ELIGIBILITY CRITERIA
18
3.5
MEDICAL HISTORY
19
3.6
ADVERSE EVENT ASSESSMENT
19
3.7
PATIENT-REPORTED OUTCOMES
19
3.8
INFLAMMATORY LESION COUNTS
21
3.9
HURLEY STAGE
21
3.10 PHARMACOKINETIC SAMPLING
21
3.11 BIOMARKER RESEARCH SAMPLING
22
3.12 12-LEAD ELECTROCARDIOGRAM
22
3.13 CHEST X-RAY
22
3.14 HEIGHT AND WEIGHT
23
3.15 VITAL SIGNS
23
3.16 PHYSICAL EXAMINATION
23
3.17 HANDHELD EPRO DEVICE
23
3.18 DISPENSE STUDY DRUG
24
3.19 CLINICAL LABORATORY TESTS
24
3.20 SUBJECT WITHDRAWAL FROM STUDY
32
4
SAFETY MANUAL
32
4.1
METHODS AND TIMING OF SAFETY ASSESSMENT
32
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M20-040 Version 2.0
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4.2
RECORDING DATA AND ANALYSES OF SAFETY FINDINGS
33
4.3
REPORTING ADVERSE EVENTS AND INTERCURRENT ILLNESSES
34
5
COUNTRY-SPECIFIC REQUIREMENTS
35
5.1
SUSAR REPORTING
35
6
STUDY DRUG
35
6.1
TREATMENTS ADMINISTERED
35
6.2
PACKAGING AND LABELING
35
6.3
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS
36
6.4
SELECTION AND TIMING OF DOSE FOR EACH SUBJECT
36
7
APPENDICES
37
7.1
PATIENT'S GLOBAL ASSESSMENT OF SKIN PAIN
37
7.2
HIDRADENITIS SUPPURATIVA SYMPTOM ASSESSMENT QUESTIONNAIRE
38
7.3
HIDRADENITIS SUPPURATIVA IMPACT ASSESSMENT QUESTIONNAIRE
41
7.4
DERMATOLOGY LIFE QUALITY INDEX
46
7.5
SCREENING TB RISK ASSESSMENT QUESTIONNAIRE
47
LIST OF TABLES
TABLE 1.
CLINICAL LABORATORY TESTS
25
LIST OF FIGURES
FIGURE 1.
INTERPRETATION AND MANAGEMENT OF HBV SEROLOGIC TEST RESULTS
28
FIGURE 2.
ADVERSE EVENT COLLECTION
33
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M20-040 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
2 PROTOCOL ACTIVITIES BY VISIT
Study visits may be impacted due to cases of state of emergency or pandemic situations.  This may 
include changes such as phone or virtual visits, visits at alternative locations, or changes in the visit 
frequency and timing of study procedures, among others.  Additional details are provided in the 
subsequent sections.  Every effort should be made to ensure the safety of subjects and site staff, while 
maintaining the integrity of the study.  If visits cannot be conducted on-site due to travel restrictions or 
other state of emergency or pandemic-related reasons, follow the updates below on how to proceed.  
Supplemental study case report forms should be completed in the event of missed/virtual visits, or 
study drug interruptions or discontinuations related to coronavirus disease 2019 (COVID-19).
2.1 Individual Treatment Period Visit Activities
This section presents a list of activities performed during each visit, organized by visit.  The dot pattern 
on the upper right indicates the place of the visit in the overall Treatment Period Activity Schedule.
Subjects will be allowed a visit window of ± 3 days for all study visits (with the exception of the Baseline 
Visit, as the screening window is a maximum of 35 days) up to the Week 16 visit.  Visits after the 
Week 16 visit will have a visit window of ± 7 days.
Activities are grouped by category (Interview, Exam, etc.).  Further information about each activity is 
provided in Section 3.
State of Emergency or Pandemic-Related Acceptable Protocol Modifications
During a state of emergency or pandemic situation, if it is not possible for all study procedures to be 
performed as specified due to travel restrictions or other reasons, the following modifications are 
allowed:

If permitted by local regulations, the Institutional Review Board (IRB)/ Independent Ethics 
Committee (IEC), and the subject, some study visits and/or activities may be performed by 
phone/virtually.  These are indicated by a hashtag (#) in the appropriate visit table(s) below.

Some study visits and/or activities may be performed by a local clinic/hospital/laboratory.  
These are indicated by a plus sign (+) in the appropriate visit table(s) below.  All procedures 
performed at local facilities must be performed by appropriately qualified personnel.

Study visits and/or activities should be performed as scheduled whenever possible.  If it is not 
possible to do so due to the pandemic, the following modifications should be followed:

The Screening, Baseline, and Week 12 visits should be performed on-site only.

If an activity is missed during a virtual visit, perform the activity at the earliest feasible 
opportunity.  Laboratory draws for safety assessments should be obtained as soon as 
feasible and preferably within the protocol-defined visit window for the scheduled visit.  
Blood samples for PK assay that cannot be performed on-site for a specific visit will be 
considered missed.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M20-040 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

QuantiFERON TB Gold Plus or equivalent and/or a PPD test (or both if required per local 
guidelines)

CXR

ECG

Beta-D-glucan (Japan only)
If a subject is being re-screened within 14 days (≤ 14 days have passed) from the collection date of the 
previous screening testing, it is not required to repeat Screening testing for chemistry, hematology, 
urinalysis, and serum pregnancy provided that the subject's health status has not changed to warrant a 
repeat test.
3.3 Study Subject Information and Informed Consent
The investigator or his/her representative will explain the nature of the study to the subject and answer 
all questions regarding this study.  Prior to any study-related screening procedures being performed on 
the subject or any medications being discontinued by the subject in order to participate in this study, 
the informed consent statement will be reviewed, signed, and dated by the subject or their legally 
authorized representative, the person who administered the informed consent, and any other 
signatories according to local requirements.  A copy of the signed informed consent will be given to the 
subject and the original will be placed in the subject's medical record.  An entry must also be made in 
the subject's dated source documents to confirm that informed consent was obtained prior to any 
study-related procedures and that the subject received a signed copy.
Information regarding benefits for subjects and information regarding provisions for treating and/or 
compensating subjects who are harmed as a consequence of participation in the study can be found in 
the informed consent form.
Optional biomarker research samples will only be collected if the subject has voluntarily signed and 
dated a written consent form describing the exploratory research. The written consent may be part of 
the main consent form.  If the subject does not consent to providing optional samples, the subject will 
still be allowed to participate in the study.
In cases of state of emergency or pandemic situations, it is possible that additional protocol 
modifications not outlined in this protocol may become necessary.  If this situation arises, in addition to 
the study informed consent, additional verbal consent may be obtained prior to these adaptations or 
substantial changes in study conduct in accordance with local regulations.  
3.4 Eligibility Criteria
Subjects will be evaluated to ensure they meet all eligibility criteria at both Screening and Baseline 
Visits.
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p. 19 of 47
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M20-040 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
3.5 Medical History
A complete non-study disease-related medical and surgical history, including demographics and history 
of alcohol and nicotine use, will be taken from each subject during the Screening Visit.  Additionally, a 
list of each subject's specific disease-related medical and surgical history will be recorded at Screening.  
History of herpes zoster, herpes zoster vaccination, and hepatitis B vaccination status will be recorded as 
part of the medical history.  The subject's medical history will be updated at the Study Day 1 visit.  This 
updated medical history will serve as the baseline for clinical assessment.
3.6 Adverse Event Assessment
Please refer to Section 4.2.
3.7 Patient-Reported Outcomes
Data Collection
Subjects will complete self-administered patient-reported outcome (PRO) instruments.  Subjects should 
be instructed to follow the instructions provided with the instrument(s) and to provide the best possible 
response to each item.  Site personnel shall not provide interpretation or assistance to subjects other 
than encouragement to complete the tasks.  Site personnel will encourage completion of the instrument 
at all specified time points and will ensure that a response is entered for all items.
PRO instruments that are administered at the site should be completed prior to drug administration and 
prior to any discussion of AEs or any review of laboratory findings.  The subject should complete the 
questionnaire(s) before site personnel perform any clinical assessments and before any other 
interaction with site personnel has occurred to avoid biasing the subject's response.
From at least 7 consecutive days prior to the Baseline visit and up to the Week 16 visit, PGA Skin Pain 
will be collected from subjects using an electronic daily diary and analgesic use using a paper diary.  
After the Week 16 visit, PGA Skin Pain will be collected for 7 consecutive days leading up to the next 
scheduled visits as specified in Section 2.1.  HSSA will be collected for 7 consecutive days prior to visits 
specified in Section 2.1.  PGA Skin Pain will be collected from subjects electronically every evening using 
a handheld device provided to the subject at Screening.  All data entered on the device will be 
immediately stored to the device itself, as well as automatically uploaded to a central server.  Analgesic 
use for HS-related pain will be collected from subjects during the same timeframe by completing a paper 
diary.  Data from the pain medication diary will be transcribed into the electronic data capture (EDC) 
system by study site staff.
Data from the DLQI and HSIA will be collected electronically at the visits specified in Section 2.1.  
Subjects will use a tablet device at the site to enter the required pieces of information.  The electronic 
tablet device will be programmed to allow data entry for only the visits specified in the protocol and will 
not allow subjects to complete more than one of the same assessment at any one visit.  All data entered 
on the tablet device will be immediately stored to the devise itself and automatically uploaded to a 
central server.
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p. 20 of 47
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M20-040 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
State of Emergency or Pandemic-Related Acceptable Protocol Modifications
During a state emergency or pandemic situation, subject visits may be conducted via phone or video 
conference.  Patient-reported outcomes (DLQI and HSIA) are eligible for completion at these virtual 
visits, except Baseline and Week 12.  If conducted by phone or video conference, sites will read the PRO 
questions and response options to the subject and record the subject's responses.  The subject's ability 
to view the PRO to understand the questions and response options should be preserved.  Sites may send 
the questionnaires (email or hard copy) to the subjects to allow them to read/understand the questions 
and responses when the subject is providing responses over the phone.  The date and time of PRO data 
collection should be recorded along with who collected the information.
Patient's Global Assessment of Skin Pain
The PGA Skin Pain (Appendix 7.1) will be used to assess the worst skin pain due to HS.  The scoring for 
PGA Skin Pain is based on an 11-point numerical rating scale (NRS), with ratings for the item ranging 
from 0 (i.e., no skin pain) to 10 (i.e., skin pain as bad as you can imagine).  Patients are asked to respond 
to the items based on a recall period of "the last 24 hours."  The weekly average score is calculated 
based on the 7 available daily scores from the days within each visit window that were closest to the 
nominal day.
Hidradenitis Suppurativa Symptom Assessment Questionnaire
The HSSA (24-hour recall) is a 9-item PRO questionnaire (Appendix 7.2) developed to assess the primary 
symptoms of HS in the 7 consecutive days prior to assessments.  Each item of the HSSA is scored on an 
11-point (0 to 10) NRS, where 0 represents no symptoms and 10 represents extreme symptom 
experience.  In this way, item scores can be generated to characterize the subject's experience at a 
symptom level.  Additionally, Items 1 – 9 can be scored together to create a Total Symptom Score to 
characterize an overall symptom experience by averaging the scores collected from the non-missing 
items collected at the same assessment.  The weekly average score is calculated based on the 7 available 
daily scores from the days within each visit window that were closest to the nominal day.
Hidradenitis Suppurativa Impact Assessment Questionnaire
The HSIA is an 18-item PRO questionnaire (Section 7.3) developed to assess the impact of HS on the 
daily lives of subjects in the 7 days prior to the assessment.  Items 1 – 16 of the HSIA are scored on a 0 to 
10 NRS, where 0 represents no impact and 10 represents extreme impact.  In this way, item scores can 
be generated to characterize the subject's experience at an individual impact level.  Additionally, Items 1 
– 16 characterize the overall impact of HS and can be scored together to create a weekly Overall HSIA 
score.  The Overall HSIA score is generated by summing the completed individual impact, item-level 
scores collected on the same day, and dividing that sum by the total number of completed responses 
(i.e., the Overall HSIA score is an average).  The Overall HSIA score will only be derived if eight or more 
(i.e., at least 50%) of responses are available (and adjusting the denominator to match the number of 
completed items).  Items 17 and 18 utilize an open field where patients are asked to fill in a number, and 
are not included in the Overall HSIA score.  Instead, a separate mean score for the hours worked (Item 
17) or hours missed at school or work (Item 18) will be calculated.  If the response is "Not Applicable" for 
any of the Items 13 – 14 or 16 – 18 then the subject will be deemed as "not applicable" for calculating 
scores.
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p. 21 of 47
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M20-040 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Dermatology Life Quality Index
The DLQI is a 10-item validated questionnaire (Section 7.4) used to assess the impact of HS disease 
symptoms and treatment on quality of life (QoL).  It consists of 10 questions evaluating impact of skin 
diseases on different aspects of a subject's QoL over the prior week, including symptoms and feelings, 
daily activities, leisure, work or school, personal relationships, and the side effects of treatment.  Each 
item is scored on a 4-point scale (0 = not at all/not relevant; 1 = a little; 2 = a lot; and 3 = very much).  
Item scores are added to provide a total score, ranging from 0 to 30, with higher scores indicating 
greater impairment of QoL.  For general inflammatory skin conditions, a change in DLQI score of at least 
4 points is considered the minimum clinically important difference (MCID).
3.8 Inflammatory Lesion Counts
The number of inflammatory nodules, abscesses, and draining fistulas, as well as the respective physical 
location (right/left axilla, right/left inframammary, intermammary, right/left buttock, right/left inguino-
crural fold, perianal, perineal, other) will be recorded at designated study visits outlined in Section 2.1.
3.9 Hurley Stage
The investigator will determine the Hurley Stage in each affected anatomical region at designated study 
visits outlined in Section 2.1.  Hurley stages are described as follows:

Stage I - Abscess formation, single or multiple, without sinus tracts and cicatrization

Stage II - Single or multiple, widely separated, recurrent abscesses with tract formation and 
cicatrization

Stage III - Diffuse or near-diffuse involvement, or multiple interconnected tracts and abscesses 
across the entire area
If more than one stage is present in a region, the worst stage in each region should be entered.  The site 
should make every attempt to have the same investigator conduct these assessments throughout the 
study for each subject.
3.10 Pharmacokinetic Sampling
Blood samples for the analysis of upadacitinib plasma concentrations will be collected from subjects 
throughout the treatment period on the study days specified in Section 2.1.
At Week 2 and Week 8 visits, pharmacokinetic (PK) samples should be collected prior to dosing and the 
subjects should take the study drug dose at the clinic after collecting the PK blood sample.  However, if 
the subject normally takes the study drug dose at a time that is after the time of the scheduled study 
visit, the subject should follow the regular dosing schedule and the PK sample will be collected at any 
time during the visit.
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p. 22 of 47
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M20-040 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
For all PK samples, the date and accurate time of the PK sample collection will be recorded on the lab 
requisition form.  The date and accurate time of the last 2 study drug doses will be recorded on the 
electronic case report form (eCRF) to the nearest minute.
Refer to the study specific laboratory manual for detailed instructions on sample collection, processing, 
and shipment.
Measurement Method
Plasma concentrations of upadacitinib will be determined by the Bioanalysis Department at AbbVie 
using a validated liquid chromatography/mass spectrometry method.
3.11 Biomarker Research Sampling
Optional blood samples will be collected for biomarker research.  Refer to Section 2.1 for the schedule 
of biomarker research sample collections.  All biomarker samples should be collected pre-dose.  All 
biomarker samples should be labeled and shipped as outlined in the study-specific laboratory manual.  
AbbVie (or people or companies working with AbbVie) will store the samples and data in a secure 
storage space with adequate measures to protect confidentiality.  The samples may be retained while 
research on upadacitinib (or drugs of this class) or HS and related conditions continues, but for no longer 
than 20 years after study completion, or per local requirement.
3.12 12-Lead Electrocardiogram
For all subjects, a resting 12-lead ECG will be performed at Screening, and if clinically indicated at any 
time during the study at the investigator's discretion.  A qualified physician will interpret the clinical 
significance of any abnormal finding, sign, and date each ECG.  If there are findings that are considered 
to be clinically significant by the investigator, the investigator must contact the AbbVie TA MD before 
enrolling the subject.  In addition, any clinically significant findings will be documented in the source 
documents and later transcribed on to the appropriate eCRF.
For subjects with a normal ECG taken within 90 days of Screening, a repeat ECG at Screening will not be 
required, provided all protocol-required source documentation is available and provided nothing has 
changed in the subject's health status or medical history to warrant a repeat ECG.
3.13 Chest X-ray
CXR (posterior-anterior and lateral views) is required for all subjects at Screening to rule out the 
presence of TB or other clinically relevant findings.  The CXR will not be required if the subject had a 
previous normal CXR (posterior-anterior and lateral views) within 90 days of Screening, provided all 
source documentation is available at the site, as outlined below, and provided nothing has changed in 
the subject's medical history to warrant a repeat test.
Subjects can have a repeat CXR at any time during a study as warranted based on the opinion of the 
Investigator or as required per local guidelines.
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p. 23 of 47
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M20-040 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
A radiologist or pulmonologist must perform and document an assessment of the CXR.  The Principal 
Investigator will indicate the clinical significance of any findings and will sign and date the report.  In the 
assessment of the CXR, the Principal Investigator or their delegate must indicate the presence or 
absence of (1) calcified granulomas, (2) pleural scarring/thickening, and (3) signs of active TB.  If the CXR 
demonstrates changes suggestive of previous TB (e.g., calcified nodule, fibrotic scar, apical or basilar 
pleural thickening) or other findings that are clinically significant, the Principal Investigator should 
contact the AbbVie TA MD before enrolling the subject.
The AbbVie TA MD may approve substitution of computed tomography or MRI of the chest for the CXR 
in individual subjects.
3.14 Height and Weight
Height will be measured at the Screening Visit only (with shoes off).  Body weight will be measured at all 
scheduled visits, as specified in Section 2.1.  All measurements will be recorded in metric units where 
applicable.
3.15 Vital Signs
Vital sign determinations of systolic and diastolic blood pressure in sitting position, pulse rate, 
respiratory rate, and body temperature will be obtained at visits specified in Section 2.1.  Blood 
pressure, pulse rate, body temperature, and respiratory rate should be performed before blood draws 
are performed.
3.16 Physical Examination
A complete physical examination will be performed at the designated study visits as specified in 
Section 2.1.  The physical examination at the Baseline Visit will serve as the Baseline physical 
examination for the entire study.  Physical examination abnormalities noted by the investigator at 
Baseline prior to the first dose of study drug will be recorded in the subject's medical history; 
abnormalities noted after the first dose of study drug will be evaluated and documented by the 
investigator as to whether or not the abnormality is an AE.  All findings, whether related to an AE or part 
of each subject's medical history, will be captured on the appropriate eCRF page.
At any time, a symptom-directed physical examination can be performed as deemed necessary by the 
investigator.
3.17 Handheld ePRO Device
During the Screening Visit, subjects will be dispensed a handheld ePRO device to collect information 
about PGA Skin Pain and HSSA.  PGA Skin Pain information will be collected daily from at least 
7 consecutive days before the Baseline visit through the Week 16 visit.  Post-Week 16 visit, PGA Skin 
Pain will be collected for 7 consecutive days prior to the scheduled visits outlined in Section 2.1.  HSSA 
will be collected daily for 7 consecutive days prior to the scheduled visits outlined in Section 2.1.  At 
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p. 24 of 47
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M20-040 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
each visit, site representatives should check to see that subjects have performed the required 
assessments between study visits.
3.18 Dispense Study Drug
Study drug will be dispensed to subjects beginning at Baseline (Day 1) and as specified in Section 2.1.  
The first dose of study drug will be administered after all other baseline (Day 1) procedures are 
completed.  At the visits specified in Section 2.1, the site personnel will review and retain a copy of the 
dosing diary, review returned study drug kits, and empty study drug packaging to verify compliance.
Study drug will be taken orally once daily, beginning on Day 1 (Baseline), and should be taken at 
approximately the same time each day, with or without food.
State of Emergency or Pandemic-Related Acceptable Protocol Modifications
Study drug may be shipped from the study site directly to the study subject's home if all of the following 
criteria are met:

Direct-to-patient (DTP) shipment of study drug is allowed by local regulations and the relevant 
ethics committee

Study drug can be administered by the subject (or subject's caregiver) at home

Subject agrees to have the study drug shipped directly to their home

Shipments may also include other study supplies (e.g., drug dosing diaries, paper copies of 
PROs).  Instructions will be provided by AbbVie as to how a study site can initiate a DTP 
shipment using Marken, a global vendor selected by AbbVie to provide this service when 
necessary.  Shipments of study drugs from the study site to a subject's home will be 
appropriately temperature controlled (qualified shipper or temperature monitoring) within 
the labeled storage conditions.  Signature is required upon delivery; this may be provided by 
the courier after delivery if social distancing measures are in place.  Documentation of the 
shipment is to be retained by the clinical site.

AbbVie will not receive subject identifying information related to these shipments, as the 
site will work directly with the courier.
The study site is responsible for meeting IRB/IEC reporting requirements related to DTP shipments of 
study drug, and for obtaining consent to provide delivery information to the courier and documenting 
this consent in source documents.
3.19 Clinical Laboratory Tests
Samples will be obtained for the clinical laboratory tests listed in Table 1.  Unscheduled clinical labs may 
be obtained at any time during the study if deemed appropriate per investigator's discretion.  A certified 
central laboratory will be utilized to process and provide results for the clinical laboratory tests.
The central laboratory chosen for this study will provide instructions regarding the collection, 
processing, and shipping of these samples.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M20-040 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Blood samples will be obtained for the laboratory tests at visits specified in Section 2.1.  Blood draws 
should be performed after all questionnaires, clinical assessments, and vital sign determinations are 
obtained.
For blood sampling, subjects should be fasting (a minimum 8-hour fast).  If a subject is not able to fast 
the non-fasting status will be recorded in study source documentation.
For any laboratory test value outside the reference range that the investigator considers to be clinically 
significant, the investigator should apply the standard of care for medical evaluation and treatment per 
local guidelines:

The investigator will repeat the test to verify the out-of-range value.

The investigator will follow the out-of-range value to a satisfactory clinical resolution.
A laboratory test value that requires a subject to be discontinued from study drug or requires a subject 
to receive treatment will be recorded as an AE.
Table 1.
Clinical Laboratory Tests
Hematology 
(Central Lab)
Clinical Chemistry
(Central Lab)
Urinalysis
(Central Lab)
Other Laboratory Tests
Hematocrit
Hemoglobin
Red blood cell (RBC) 
count
White blood cell (WBC) 
count
Neutrophils
Bands
Lymphocytes
Monocytes
Basophils
Eosinophils
Reticulocyte count
Platelet count
Blood urea nitrogen 
(BUN)
Creatinine
Total bilirubin
Alanine transaminase 
(ALT)
Aspartate transaminase 
(AST)
Alkaline phosphatase
Sodium
Potassium
Chloride
Bicarbonate
Calcium
Inorganic phosphate
Total protein
Albumin
Glucose
Uric acid
Total cholesterol
Low density lipoprotein 
cholesterol (LDL-C)
High density lipoprotein 
cholesterol (HDL-C)
Triglycerides
Specific gravity
Ketones
pH
Protein
Blood
Glucose
Urobilinogen
Bilirubin
Leukocytes
Nitrites
Microscopic 
examination, if 
needed
Central Lab Tests:
Estimated glomerular 
filtration rate
International normalized 
ratio (INR)
Serum pregnancy (beta 
human chorionic 
gonadotropin 
[bHCG]) test
Beta-D-glucan (Japan 
only) (if the result from 
the central lab is 
indeterminate or 
otherwise not 
interpretable, a 
local lab may be used)
hsCRP
Follicle stimulating 
hormone (FSH)
Human immunodeficiency 
virus antibody
(HIV Ab)  
QuantiFERON-TB Gold Plus
Hepatitis Screening:
Hepatitis B surface antigen 
(HBs Ag)
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M20-040 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Hematology 
(Central Lab)
Clinical Chemistry
(Central Lab)
Urinalysis
(Central Lab)
Other Laboratory Tests
Hepatitis B surface antibody 
(HBs Ab)
Hepatitis B core antibody 
(HBc Ab)
Hepatitis B virus 
deoxyribonucleic 
acid 
polymerase chain 
reaction (HBV DNA 
PCR)
Hepatitis C virus antibody 
(HCV Ab)
Hepatitis C virus ribonucleic 
acid (HCV RNA 
[reflex only])
Local Lab Tests:
Urine pregnancy test
Varicella antibody, if 
indicated
QuantiFERON-TB Gold Plus
Beta-D-glucan (Japan only)
Purified protein derivative 
(PPD)
Pregnancy Tests (Serum and Urine)
A pregnant or breastfeeding female will not be eligible to enter the study or be allowed to continue 
study drug.
As described in the Contraception Recommendations section of the Protocol, females considered to be 
of non-childbearing potential should not have pregnancy testing performed.
A quantitative serum pregnancy test will be performed at the Screening Visit and if any urine pregnancy 
test is positive.
The serum pregnancy test will be sent to and performed by the central laboratory.  If the serum 
pregnancy test is positive the subject is considered a screen failure.  If the serum pregnancy test is 
borderline, it should be repeated ≥ 3 days later to determine eligibility.  If the repeat serum pregnancy 
test is:

Positive, the subject is considered a screen failure;

Negative, the subject can be enrolled into the trial;

Still borderline ≥ 3 days later, this will be considered documentation of continued lack of a positive 
result and the subject can be enrolled into the study (unless prohibited per local requirements) in 
the absence of clinical suspicion of pregnancy and other pathological causes of borderline results.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M20-040 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
A urine pregnancy test will be performed for all females of childbearing potential at the Baseline Visit 
prior to the first dose of study drug (local practices may require serum pregnancy testing at Baseline).  
Additional urine pregnancy tests will be performed (as indicated in the Activities Schedule) at a 
minimum of monthly intervals (either at study visits or at home or at unscheduled visits between 
scheduled study visits).  The results of at home tests must be communicated to the site and recorded in 
source documentation.  More frequent pregnancy tests can be performed throughout the study at the 
investigator's discretion or if required per local/country requirements.

If the Baseline urine pregnancy test is negative, then dosing with study drug may begin.

If the Baseline or post-Baseline urine pregnancy test is positive, dosing with study drug must be 
withheld and a serum pregnancy test is required (as stated above).
At each visit, the study staff should review the pregnancy avoidance recommendations with each female 
of childbearing potential and document this discussion in the subject's source records.
Follicle Stimulating Hormone (FSH)
FSH should be tested at the Screening Visit for female subjects who are ≤55 years of age AND have had 
no menses for 12 months AND have no history of permanent surgical sterilization (bilateral 
oophorectomy, bilateral salpingectomy, or hysterectomy).
Urinalysis
Urine samples will be obtained for urinalysis testing at visits specified in Section 2.1.  The central 
laboratory will be responsible for performing a macroscopic urinalysis (urine dipstick) on the collected 
urine specimens.  A microscopic analysis will be performed in the event the dipstick results show 
leukocytes, nitrite, protein, ketones, or blood greater than negative or glucose greater than normal.
International Normalized Ratio
International normalized ratio (INR) will only be measured if ALT and/or AST > 3 × ULN.  A separate 
blood sample for INR testing will be needed to measure INR at the time of repeat testing for ALT or AST.
Hepatitis Screening
All subjects will be tested for the presence of HBV and HCV at Screening.
HBV:
Subjects will be tested for the presence of HBV at Screening using the following tests:

HBs Ag

HBc Ab/anti-HBc

HBs Ab/anti-HBs
A positive result for HBs Ag will be exclusionary.
A negative result for HBs Ag will trigger automatic reflex testing for HBc Ab and HBs Ab.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M20-040 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

A negative test result for HBc Ab does not require HBV DNA PCR qualitative testing and the 
subject may be enrolled (Figure 1, Scenarios A and B).

For a subject who has had a HBV vaccination (should document in the medical history), a 
positive test result for HBs Ab is expected, the HBV DNA PCR qualitative testing is not required 
and the subject may be enrolled (Figure 1, Scenario B).*

For subjects without a history of HBV vaccination (and where mandated by local requirements) a 
positive result for HBs Ab requires HBV DNA PCR testing (automatic reflex testing; Figure 1, 
Scenario B).
A positive test result for HBc Ab requires HBV DNA PCR testing (automatic reflex testing) (Figure 1, 
Scenarios C and D).  A result for HBV DNA that exceeds detection sensitivity will be considered positive 
and will be exclusionary.  A subject with a negative result for HBV DNA may be enrolled.
Figure 1.
Interpretation and Management of HBV Serologic Test Results
*
Subjects who have had an HBV vaccination are expected to have a positive test result for HBs Ab and do not require HBV 
DNA PCR testing.  For subjects without a history of HBV vaccination (and where mandated by local requirements), a 
positive result for HBs Ab requires HBV DNA PCR testing.
**
Where mandated by local requirements, subjects with HBs Ab+ and/or HBc Ab+ and negative HBV DNA at Screening 
should have HBV DNA PCR testing performed approximately every 12 weeks.  HBV DNA PCR testing every 12 weeks is not 
necessary when the subject has a history of HBV vaccination and is HBs Ab+ and HBc Ab–.  If necessary, HBV DNA PCR may 
be tested at unscheduled visits.
HCV:
Blood samples for HCV serology will be obtained at the Screening Visit.  A positive HCV Ab will trigger a 
HCV RNA test.  A subject will not be eligible for study participation if test results indicate active Hepatitis 
C (HCV RNA detectable in any subject with anti HCV Ab).
Human Immunodeficiency Virus (HIV) Screening  
Subjects with HIV infection (positive HIV test) are excluded from study participation.  An anti-HIV 
antibody (Ab) test will be performed at Screening, unless prohibited by local regulations.  The 
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M20-040 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
investigator must discuss any local reporting requirements to local health agencies with the subject.  The 
site will report confirmed positive results to their health agency per local regulations, if necessary.  If a 
subject has a confirmed positive result, the investigator must discuss with the subject the potential 
implications to the subject's health and subject should receive or be referred for clinical care promptly.  
AbbVie will not receive results from the testing and will not be made aware of any positive result.
High-Sensitivity C-Reactive Protein (hsCRP)
During the study the hsCRP results starting after Baseline (Day 1) will not be reported to the Sponsor, 
investigator, study site personnel, and/or to the subject.  Results of hsCRP may unblind the treatment 
assignment or introduce bias, and the results may be blunted in subjects taking a JAK inhibitor, thereby 
limiting clinical utility in the setting of a safety assessment or AE management.  Any local testing of 
hsCRP or CRP during the study is therefore strongly discouraged and any local hsCRP or CRP tests
reported to the investigator during the study will be recorded as protocol deviations.
Tuberculosis (TB) Testing/TB Prophylaxis
All subjects must be evaluated for TB at Screening.  The results of the TB screening must be interpreted 
in the context of the subject's epidemiology, history, exam findings, etc., and it is the responsibility of 
the investigator to determine if a subject has previous, active, or latent TB.
At Screening, all subjects will be assessed for evidence of increased risk for TB by a risk assessment 
questionnaire (Section 7.5) and tested for TB infection as described below.  The site staff will complete 
the TB risk assessment questionnaire in its entirety (Part I and Part II) and enter the data into the 
appropriate eCRF.
Subjects with a negative TB test and CXR not suggestive of active TB may be enrolled.  Subjects with 
history of active TB may be enrolled if it has been adequately treated with no evidence of current active 
TB; subjects with inadequate documentation of treatment should be cleared by a TB specialist prior to 
enrollment.
Subjects with a positive TB test must be assessed for evidence of active TB versus latent TB, including 
signs and symptoms and CXR.  Subjects with latent TB (positive TB test with no signs or symptoms and a 
CXR not suggestive of active TB) may be enrolled after initiation of TB prophylaxis (see below).
Subjects with evidence of active TB must not be enrolled.
TB Testing:

The QuantiFERON-TB Gold Plus test should be performed at Screening on all subjects unless the 
subject is considered to be TB test positive prior to Screening.  The PPD skin test (also known as 
TB Skin Test or Mantoux test) should be utilized when the QuantiFERON-TB Gold Plus test is not 
possible or if both tests are required per local guidelines.

If a subject had a QuantiFERON-TB Gold Plus test within 90 days prior to Screening and source 
documentation is available TB testing does not need to be performed by the central laboratory 
at Screening provided nothing has changed in the subject's medical history to warrant a repeat 
test.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M20-040 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

For subjects with only a negative PPD Skin Test available within 90 days prior to Screening a 
QuantiFERON-TB Gold Plus test is required at Screening.  If the QuantiFERON-TB Gold Plus test is 
not possible and source documentation is available, the PPD Skin Test does not need to be 
repeated provided nothing has changed in the subject's medical history to warrant a repeat test.

For regions that require both PPD and QuantiFERON-TB Gold Plus testing, both will be 
performed.  If either PPD or QuantiFERON-TB Gold Plus is positive, the TB test is considered 
positive.

Subjects with documentation of prior positive result of QuantiFERON-TB Gold Plus Test, PPD skin 
test, and/or history of latent or active TB are not required to repeat a TB test at Screening or 
during the study and should be considered TB test positive.

If TB testing is done at Screening for subjects with a prior positive TB test and a positive 
result is reported the subject is considered TB test positive.

If TB testing is done at Screening in subjects considered at low risk for TB as described below 
and a positive or indeterminate result is reported the procedure for "Interpretation of a 
positive TB test in low risk subjects" should be followed OR either prior or concomitant 
treatment for latent TB is required.

If performed, the PPD should be read by a licensed healthcare professional between 48 and 
72 hours after administration.  A subject who does not return within 72 hours will need to be 
rescheduled for another skin test.  The reaction will be measured in millimeters (mm) of 
induration and induration ≥ 5 mm is considered a positive reaction.  The absence of induration 
will be recorded as "0 mm" not "negative."

Subjects who have had an ulcerating reaction to PPD in the past should not be re-exposed and 
the PPD should be considered positive and do not require subsequent testing with either PPD or 
QuantiFERON-TB Gold Plus.

If the QuantiFERON-TB Gold Plus test is indeterminate, then the investigator should perform a 
local QuantiFERON-TB Gold Plus test (or through the central laboratory if not locally available) to 
rule out a positive test result.  If testing remains indeterminate or is positive, then the subject is 
considered to be positive for the purpose of this study.  If the testing result is negative, then the 
patient is considered to be negative.

Interpretation of a positive TB test in low risk subjects:  In cases where the QuantiFERON-TB 
Gold Plus test by the central laboratory is positive and the investigator considers the subject at 
low risk for TB (i.e., no risk factors identified using the Part I and Part II questions of the TB risk 
assessment questionnaire at Screening) and has no clinical suspicion of TB, the investigator may 
perform a local QuantiFERON-TB Gold Plus test (or repeat testing through the central laboratory 
if not locally available) to confirm the positive test result.  If the repeat testing result is negative, 
the investigator may consider the test to be negative based on his/her clinical judgment; if the 
repeat testing result is positive or indeterminate, the test is considered positive.

An equivalent Interferon Gamma Release Assay (IGRA) (such as T-SPOT TB test) may be 
substituted for the QuantiFERON-TB Gold Plus.

TB test(s) results will be retained at the site as the original source documentation.
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p. 31 of 47
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M20-040 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
If the subject is experiencing signs or symptoms suspicious for TB or something has changed in the 
subject's medical history to warrant investigation and a repeat test during the study, the case (including 
the TB test results) should be discussed with the AbbVie TA MD.
TB Prophylaxis:
Note:  Rifampicin and Rifapentine are not allowed for TB prophylaxis while on study drug.
At Screening, if the subject has evidence of latent TB infection, prophylactic treatment with isoniazid 
must be initiated at least 2 weeks prior to administration of study drug (or per local guidelines, 
whichever is longer).  If receiving isoniazid prophylaxis during the study at least 6 months must be 
completed; however, the full course of prophylaxis does not need to be completed prior to the first dose 
of study drug.
Subjects with a prior history of active or latent TB that have documented completion of a full course of 
anti-TB therapy will be allowed to enter the study provided nothing has changed in the subject's medical 
history to warrant repeat treatment.  Prior to the study, a full course of latent TB prophylaxis may be 
achieved with at least 4 months of rifampin, at least 6 months of isoniazid, or at least 3 months of 
combination rifapentine and isoniazid.  Rifampin and rifapentine must be completed at least 30 days 
prior to baseline.  For subjects with completion of a full course of anti-TB therapy, but insufficient 
documentation, the investigator should consult with the AbbVie TA MD.
During the study, subjects with new evidence of latent TB must initiate prophylactic treatment with 
isoniazid immediately and complete at least 6 months of prophylaxis.  Study drug should not be 
withheld.  Two to four weeks later, the subject should be re-evaluated (unscheduled visit) for signs and 
symptoms as well as laboratory assessment of toxicity to TB prophylaxis.
At Screening newly diagnosed latent TB should be entered in the TB Screening eCRF; prior history of 
latent or active TB should be entered into the medical history eCRF.  Any positive TB test after the 
patient has started the study should be reported as an AE of latent TB or active TB (as applicable).  
Newly initiated prophylactic treatment and prior therapy should be captured in the concomitant/prior 
medications eCRF as appropriate.
State of Emergency or Pandemic-Related Acceptable Protocol Modifications
During a state of emergency or pandemic situation, if travel restrictions or other changes in local 
regulations prevent the subject from having blood drawn for laboratory testing at the study site, if 
possible, arrange for subjects to have laboratory work done at a local lab, hospital, or other facility.  
Local lab results should be obtained along with reference ranges and kept within the subjects' source 
documentation.  Local lab results should be reviewed by the investigator as soon as possible.
If laboratory samples cannot be obtained, study drug administration may be continued provided the 
subject has at least 1 post Baseline visit and the investigator has reviewed all prior laboratory results and 
confirms and discusses with the subject that there is no safety concern for the subject to continue use of 
the study drug in the absence of current labs.  Laboratory draws should be obtained as close as possible 
to the scheduled visit.
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p. 32 of 47
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M20-040 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
3.20 Subject Withdrawal from Study
All attempts must be made to determine the date of the last study drug dose and the primary reason for 
discontinuation of study drug or study participation.  The information will be recorded on the 
appropriate eCRF page.  However, these procedures should not interfere with the initiation of any new 
treatments or therapeutic modalities that the investigator feels are necessary to treat the subject's 
condition.  Following discontinuation of study drug, the subject should be treated in accordance with 
the investigator's best clinical judgment irrespective of whether the subject decides to continue 
participation in the study.
Premature Discontinuation of Study (Withdrawal of Informed Consent)
Subjects may withdraw from the study completely (discontinuation of study drug treatment and study 
participation; withdrawal of informed consent) for any reason at any time.  If a subject prematurely 
discontinues study participation, the procedures outlined for the Premature Discontinuation visit (PD 
visit) should be completed as soon as possible, preferably within 2 weeks of study drug discontinuation.  
In addition, a 30-day follow-up visit (or phone call if a visit is not possible) should occur to determine the 
status of any ongoing AEs/SAEs or the occurrence of any new AEs/SAEs.  Subjects who discontinue the 
study prematurely after randomization will not be replaced.
Discontinuation of Study Drug and Continuation of Study Participation
Subjects may discontinue study drug treatment but may choose to continue to participate in the study.
Subjects who prematurely discontinue study drug should complete a Premature Discontinuation visit 
(PD visit) as soon as possible, preferably within 2 weeks.  Afterwards, subjects should follow the regular 
visit schedule as outlined in the Protocol Study Activities Table and adhere to all study procedures 
except for dispensing study drug, PK sample collection, and blood sample collection for optional 
exploratory research and validation studies.  Female subjects who discontinue study drug due to
pregnancy will not undergo additional imaging tests.  Once the subject has discontinued study drug, 
subjects should be treated per standard of care.  If at any point a subject no longer wants to provide 
assessments (withdrawal of informed consent) following discontinuation of study drug, a second PD visit 
is not required.
4
SAFETY MANUAL
4.1 Methods and Timing of Safety Assessment
All AEs reported from the time of study drug administration until 30 days following discontinuation of 
study drug administration have elapsed will be collected, whether solicited or spontaneously reported 
by the subject.  Subjects who discontinue study drug treatment but continue to participate in the study 
will have AEs collected for the remainder of study participation.  In addition, SAEs and protocol-related 
nonserious AEs (AEs due to study procedures) will be collected from the time the subject signed the 
study-specific informed consent.
AE information will be collected as shown in Figure 2.
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p. 33 of 47
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M20-040 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Figure 2.
Adverse Event Collection
Note:
Subjects who discontinue study drug but continue to participate in the study will have SAEs and non serious AEs 
collected for the remainder of study participation.
In the case of any of the following reported events, a supplemental eCRF should be completed:

Cardiac events;

Myocardial infarction or unstable angina;

Heart failure;

Cerebral vascular accident and transient ischemic attack;

Cardiovascular procedures (SAE Supplemental Procedure eCRF);

Embolic and/or thrombotic event (non-cardiac, non-central nervous system);

Herpes zoster infection;

COVID-19.
4.2 Recording Data and Analyses of Safety Findings
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  The 
number and percentage of subjects with treatment-emergent adverse events (i.e., any event that begins 
or worsens in severity after initiation of study drug through 30 days post-study drug dosing) will be 
tabulated by primary MedDRA System Organ Class (SOC) and preferred term (PT) and compared 
between arms using Fisher's exact test.  The tabulation of the number of subjects with 
treatment-emergent adverse events by severity grade and relationship to study drug also will be 
provided.  Subjects reporting more than 1 AE for a given MedDRA preferred term will be counted only 
once for that term using the most severe grade according to the severity grade table and the most 
related according to the relationship to study drug tables.  Subjects reporting more than 1 type of event 
within an SOC will be counted only once for that SOC.
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p. 35 of 47
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M20-040 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
The sponsor will be responsible for Suspected Unexpected Serious Adverse Reactions (SUSAR) reporting 
for the Investigational Medicinal Product (IMP) in accordance with Directive 2001/20/EC.
In Japan, the principal investigator will provide documentation of all SAEs to the Director of the 
investigative site and the Sponsor.
5 COUNTRY-SPECIFIC REQUIREMENTS
5.1 SUSAR Reporting
AbbVie will be responsible for SUSAR reporting for the IMP in accordance with global and local 
guidelines and Appendix A of the Investigator Brochure will serve as the Reference Safety Information 
(RSI).  The RSI in effect at the start of a DSUR reporting period serves as the RSI during the reporting 
period.  For follow-up reports, the RSI in place at the time of occurrence of the 'suspected' Serious 
Adverse Reaction will be used to assess expectedness.
6 STUDY DRUG
6.1 Treatments Administered
Study drug will be taken orally once daily, beginning on Day 1 (Baseline), and should be taken at 
approximately the same time each day, with or without food.
Study drug includes the investigational product of upadacitinib and matching upadacitinib placebo.  
Details regarding study drug dosing and administration are provided in the Study Drug section of the 
Protocol.  The study drug will be dispensed at the visits listed in Section 2.1.
Study drug must not be dispensed without contacting the IRT system.  Study drug may only be 
dispensed to subjects enrolled in the study through the IRT system.  At the end of the Treatment Period 
or at the Premature D/C visit, the site will contact the IRT system to provide visit date information and 
study drug return information for each kit.
AbbVie will not supply any disease-related concomitant medication (indication) therapy taken during the 
course of the study.
6.2 Packaging and Labeling
All study drugs will be supplied in bottles.  Each bottle will be labeled per local requirements.  The labels 
must remain affixed to the bottles.  All blank spaces should be completed by site staff prior to 
dispensing to subject.
Storage and Disposition of Study Drug
Study drug must be stored at controlled room temperature (15° to 25°C/59° to 77°F).  The 
investigational products are for investigational use only and are to be used only within the context of 
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p. 36 of 47
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M20-040 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
this study.  The study drug supplied for this study must be maintained under adequate security and 
stored under the conditions specified on the label until dispensed for subject use or destroyed on site as 
appropriate.
6.3 Method of Assigning Subjects to Treatment Groups
This study is a randomized, placebo-controlled, double-blind study. All eligible subjects will receive 
study drug for up to 48 weeks.
At the screening visit, all subjects will be assigned a unique subject number through the use of the IRT.
For subjects who do not meet the study selection criteria, the site personnel must access the IRT system 
and identify the subject as a screen failure.
As subjects are enrolled into a study, they will receive a subject number that will be retained throughout 
the remainder of the study.  Upon receipt of study drug, the site will acknowledge receipt in the IRT 
system. Contact information and user guidelines for IRT use will be provided to each site.
Additional information on randomization and drug assignment are provided in the Randomization/Drug 
Assignment section of the Protocol.
6.4 Selection and Timing of Dose for Each Subject
Subjects should take study drug as outlined in Section 3.18.
Each subject's dosing schedule should be closely monitored by the site at each study visit by drug 
accountability data.  This will ensure that all subjects enrolled into the study maintain their original 
dosing schedule beginning with the first dose of study drug (Baseline/Day 1).
If a subject should forget to take their study drug dose at their regularly scheduled dosing time, they 
should take the forgotten dose as soon as they remember the dose was missed as long as it is at least 
10 hours before their next scheduled dose.  If a subject only remembers the missed dose within 
10 hours before next scheduled dose, the subject should skip the missed dose and take the next dose at 
the scheduled time.
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p. 37 of 47
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M20-040 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
7 Appendices
7.1 PATIENT'S GLOBAL ASSESSMENT OF SKIN PAIN
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p. 38 of 47
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M20-040 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
7.2 HIDRADENITIS SUPPURATIVA SYMPTOM ASSESSMENT 
QUESTIONNAIRE
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p. 39 of 47
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M20-040 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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p. 40 of 47
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M20-040 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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p. 41 of 47
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M20-040 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
7.3 HIDRADENITIS SUPPURATIVA IMPACT ASSESSMENT 
QUESTIONNAIRE
Hidradenitis Suppurativa Impact Assessment (HSIA)
Instructions:  This questionnaire includes 18 questions about the impacts that you may experience 
associated with your Hidradenitis Suppurativa (HS).  Hidradenitis Suppurativa is a skin condition that 
affects areas with sweat glands such as the underarms, breasts, inner thighs, groin, and buttocks.  
People often refer to their HS as boils, cysts, or lesions on their skin.
Please clearly mark an "x" in the box (
) that best describes how you have been affected by your HS in 
the past 7 days.  There are no right or wrong answers to any of the questions.
1.
Over the past 7 days, how uncomfortable did your clothing make you feel because of your HS?
Not at all
Extremely
2.
Over the past 7 days, how hard was it for you to move your arms because of your HS?
Not at all
Extremely
3.
Over the past 7 days, how hard was it for you to exercise (for example, play sports, work out) 
because of your HS?
Note:  If you did not exercise because of your HS please mark a "10."
Not at all
Extremely
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p. 42 of 47
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M20-040 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
4.
Over the past 7 days, how hard was it for you to walk because of your HS?
Note:  If you did not walk because of your HS please mark a "10."
Not at all
Extremely
5.
Over the past 7 days, how hard was it for you to sit because of your HS?
Note:  If you did not sit down because of your HS please mark a "10."
Not at all
Extremely
6.
Over the past 7 days, how much did your HS interfere with your wanting to be around other 
people (for example, going to a party, being with friends or family)?
Not at all
Extremely
7.
Over the past 7 days, how much did your HS interfere with your ability to do things around the 
house (for example, cleaning, cooking, yard work)?
Not at all
Extremely
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p. 43 of 47
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M20-040 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
8.
Over the past 7 days, how self-conscious did you feel because of your HS?
Not at all
Extremely
9.
Over the past 7 days, how embarrassed did you feel because of your HS?
Not at all
Extremely
10. Over the past 7 days, how sad did you feel because of your HS?
Not at all
Extremely
11. Over the past 7 days, how worried did you feel because of your HS?
Not at all
Extremely
12. Over the past 7 days, how bothered did you feel because of your HS?
Not at all
Extremely
13. Over the past 7 days, how much did your feelings about your HS limit your desire to have sex 
(for example, because you felt unattractive, embarrassed, self-conscious, etc.)?
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p. 44 of 47
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M20-040 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
If this question is not applicable for you, please press "next."
Not at all
Extremely
14. Over the past 7 days, how much was your ability to have sex limited because of your HS 
symptoms (for example, pain, cysts, drainage, flare ups, bleeding, etc.)?
If this question is not applicable for you, please press "next."
Not at all
Extremely
15. Over the past 7 days, how satisfied have you been with your HS medications?
Not at all
Extremely
16. Over the past 7 days, how bothered did you feel by the scars from your past HS 
surgery/surgeries?
If this question is not applicable for you as you have not had surgery for your HS, please press 
"next."
Not at all
Extremely
17. Over the past 7 days, how many hours did you spend at work or school?
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p. 45 of 47
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M20-040 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
If this question is not applicable for you as you are not employed nor do you attend school, 
please press "next."
_______________ Hours
18. Over the past 7 days, how many hours did you miss from work or school because of your HS?  
Include hours you missed on sick days, times you went in late, left early, etc., because of your 
HS.
If this question is not applicable for you as you are not employed nor do you attend school, 
please press "next."
_______________ Hours
Source:  AO-AV141778-HSIA-English-USA-Version 2-for electronic use; 03 Feb 2020
Page 101 of 105
 


p. 46 of 47
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M20-040 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
7.4 DERMATOLOGY LIFE QUALITY INDEX
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p. 47 of 47
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M20-040 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
7.5 SCREENING TB RISK ASSESSMENT QUESTIONNAIRE
For Screening TB risk assessment, ask Part I and Part II questions.
Part 1
1.
Has an immediate family member or other close contact been newly diagnosed with or treated 
for active or latent tuberculosis during the last 3 months?
2.
Within the past year, have you, or an immediate family member, had any of the following 
problems lasting for 3 weeks or longer which remained unexplained:

Chronic Cough

Production of Sputum

Blood-Streaked Sputum

Weight Loss

Fever

Fatigue/Tiredness

Night Sweats

Shortness of Breath

(Reference:  https://www.cdc.gov/tb/topic/testing/diagnosingltbi.htm)
Part II
3.
Have you ever been diagnosed or treated for active or latent tuberculosis?
4.
Have you lived in or had prolonged travels to any of the following TB endemic regions?
Angola
China
India
Mozambique
Papua New Guinea
Thailand
Bangladesh
Congo
Indonesia
Myanmar
Philippines
UR Tanzania
Brazil
DPR Korea
Kenya
Namibia
Russian Federation
Viet Nam
Cambodia
DR Congo
Lesotho
Nigeria
Sierra Leone
Zambia
Central African Republic
Ethiopia
Liberia
Pakistan
South Africa
Zimbabwe
(Reference:  World Health Organization Global Tuberculosis Report 2018. Available from:  
https://www.who.int/tb/publications/global_report/en/)
5.
Have you lived or worked in a prison, refugee camp, homeless shelter, immigration center, or 
nursing home?
Page 103 of 105
 

SAP_001.pdf: 
Upadacitinib
M20-040 – Statistical Analysis Plan
Version 2.0 – 30 April 2021
1
Statistical Analysis Plan for Study M20-040
A Phase 2, Multicenter, Randomized, Placebo-
Controlled, Double-Blind Study to Evaluate 
Upadacitinib in Adult Subjects with Moderate to 
Severe Hidradenitis Suppurativa
Date:  30 April 2021
Version 2.0
 
NCT04430855


Upadacitinib
M20-040 – Statistical Analysis Plan
Version 2.0 – 30 April 2021
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........................................................................7
3.0
Endpoints..................................................................................8
3.1
Primary Endpoint(s)...................................................................................8
3.2
Secondary Endpoint(s)...............................................................................8
3.3
Other Efficacy Endpoint(s)........................................................................8
3.4
Safety Endpoint(s) .....................................................................................9
4.0
Analysis Populations ...............................................................9
5.0
Subject Disposition..................................................................9
6.0
Study Drug Duration and Compliance................................10
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ....................11
7.1
Demographics and Baseline Characteristics............................................11
7.2
Medical History .......................................................................................12
7.3
Prior and Concomitant Medications ........................................................12
8.0
Handling of Potential Intercurrent Events for the 
Primary Endpoint..................................................................13
9.0
Efficacy Analyses...................................................................13
9.1
General Considerations............................................................................13
9.2
Handling of Missing Data........................................................................14
9.2.1
Categorical Endpoints in Period 1 ...........................................................15
9.2.2
Continuous Endpoints in Period 1 ...........................................................16
9.2.3
Summary of Long-Term Efficacy............................................................17
9.3
Primary Efficacy Endpoint and Analyses ................................................18
9.3.1
Primary Efficacy Endpoint ......................................................................18
9.3.2
Main Analysis of Primary Efficacy Endpoint..........................................18
9.3.3
Sensitivity Analyses of the Primary Efficacy Endpoint ..........................19
 


Upadacitinib
M20-040 – Statistical Analysis Plan
Version 2.0 – 30 April 2021
3
9.4
Secondary Efficacy Analyses...................................................................21
9.4.1
Main Analyses of Secondary Efficacy Endpoints....................................21
9.5
Additional Efficacy Analyses ..................................................................22
9.5.1
Additional Categorical Endpoints in Period 1 .........................................22
9.5.2
Additional Continuous Endpoints in Period 1 .........................................22
9.5.3
Summary of Long-Term Efficacy............................................................23
9.6
Efficacy Subgroup Analyses....................................................................23
10.0
Safety Analyses ......................................................................24
10.1
General Considerations............................................................................24
10.2
Adverse Events ........................................................................................24
10.2.1
Treatment-Emergent Adverse Events ......................................................24
10.2.2
Adverse Event Overview .........................................................................25
10.2.3
Treatment-Emergent Adverse Events by SOC and/or PT .......................26
10.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure ..................................................................................................26
10.2.5
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation...............................................................................26
10.2.6
Adverse Events of Special Interest ..........................................................27
10.3
Analysis of Laboratory Data....................................................................28
10.4
Analysis of Vital Signs ............................................................................29
10.5
Safety Subgroup Analyses .......................................................................29
10.6
Other Safety Analyses..............................................................................30
11.0
Other Analyses.......................................................................30
12.0
Interim Analyses....................................................................30
12.1
Data Monitoring Committee....................................................................30
13.0
Overall Type-I Error Control ..............................................30
14.0
Version History......................................................................31
15.0
References...............................................................................31
List of Tables
Table 1.
Summary of the Estimand Attributes of the Primary Efficacy 
Endpoint...................................................................................................19
 


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Table 2.
SAP Version History Summary...............................................................31
List of Figures
Figure 1.
Study Schematic.........................................................................................7
List of Appendices
Appendix A.
Protocol Deviations..................................................................................33
Appendix B.
Definition of Adverse Events of Special Interest ....................................34
Appendix C.
Potentially Clinically Important Criteria for Safety Endpoints ...............36
Appendix D.
Random Seeds..........................................................................................38
Appendix E.
Non-Responder Imputation Incorporating Multiple Imputation to 
Handle Missing Data Due to COVID-19 Pandemic for 
Dichotomized Outcome Variables...........................................................39
Appendix F.
Simulations for Combining Subject-level Historical Placebo Data 
with In-trial Placebo Data ........................................................................53
Appendix G.
List of Matching Subjects ........................................................................60
 


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1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for upadacitinib 
Study M20-040 'A Phase 2, Multicenter, Randomized, Placebo-Controlled, Double-Blind 
Study to Evaluate Upadacitinib in Adult Subjects with Moderate to Severe Hidradenitis 
Suppurativa.'
Study M20-040 examines the efficacy and safety of upadacitinib 30 mg versus placebo for 
the treatment of signs and symptoms of moderate to severe hidradenitis suppurativa (HS) 
in adult subjects.
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 assess the efficacy and safety of upadacitinib 
30 mg QD in adult subjects with moderate to severe HS.  The primary efficacy objective 
will be assessed based on the achievement of HiSCR after 12 weeks of treatment with 
upadacitinib 30 mg when compared to placebo in the Intent-to-Treat (ITT) population, 
which consists of all randomized subjects.
Hypothesis corresponding to the primary endpoint is:
●
The proportion of subjects achieving HiSCR with upadacitinib is greater than 
that with placebo at Week 12.
 


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The estimand corresponding to the primary endpoint is defined using composite variable 
strategy:
●
Achievement of HiSCR at Week 12 without the initiation of antibiotics for HS-
related infections and without premature discontinuation of study drug due to 
lack of efficacy prior to Week 12.
2.2
Study Design Overview
This is a Phase 2, multicenter, randomized, double-blinded, parallel-group, placebo-
controlled study to evaluate the efficacy and safety of upadacitinib in adult subjects with 
moderate to severe HS.
The duration of the study will be up to 57 weeks and will include an approximately 35-
day screening period followed by a 48-week double-blinded treatment period and a 30-
day follow up visit after the last dose of study drug.
Subjects who meet eligibility criteria will be randomized in a 2:1 ratio to 1 of the 2 arms 
as shown below:
●
Upadacitinib 30 mg once daily (QD) (N = 40):  Daily oral doses of upadacitinib 
30 mg from the Baseline visit through Period 1 and Period 2.
●
Placebo (N = 20):  Placebo for upadacitinib from the Baseline visit up to the 
Week 12 visit (Period 1).  At Week 12, subjects will be switched to blinded 
upadacitinib 15 mg QD through Period 2.
The schematic of the study is shown in Figure 1.  Further details regarding study 
procedures are included in the Operations Manual (Appendix E).
The primary efficacy analysis will be conducted when all ongoing subjects have 
completed their Week 12 visit.
 


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Figure 1.
Study Schematic
PBO = placebo; UPA = upadacitinib
2.3
Treatment Assignment and Blinding
Subjects will be randomized to upadacitinib 30 mg QD or placebo in a 2:1 ratio.  
Randomization will be stratified by anti-TNF use prior to baseline (yes or no) and Hurley 
stage (< III or III).
All AbbVie personnel with direct oversight of the conduct and management of the trial 
(with the exception of AbbVie Drug Supply Management Team), the investigator, study 
site personnel, and the subject will remain blinded to each subject's treatment through 
Week 12.  Sites and subjects will remain blinded for the duration of the study.  
2.4
Sample Size Determination
The primary endpoint is the achievement of HiSCR at Week 12.  The primary analysis 
compares the proportion of subjects achieving HiSCR response to that of historical 
placebo (25% HiSCR response).  Assuming the Week 12 HiSCR response rate is 57% for 
the upadacitinib 30 mg arm, 40 subjects on upadacitinib will provide more than 95% 
power with a one-sample Chi-square test and one-sided alpha = 0.05 significance level.  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
    
 
 


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The historical placebo rate of 25% is assumed based on the response rate of placebo 
subjects satisfying the same eligibility criteria from the two Humira studies 
(Study M11-313 and Study M11-810). 
3.0
Endpoints
3.1
Primary Endpoint(s)
The primary endpoint is the achievement of HiSCR at Week 12.  HiSCR is defined as at 
least a 50% reduction in the total abscess and inflammatory nodule count (AN count) with 
no increase in abscess count and no increase in draining fistula count relative to Baseline.
3.2
Secondary Endpoint(s)
The secondary endpoint is the achievement of NRS30, defined as at least 30% reduction 
and at least 1 unit reduction from Baseline in Patient's Global Assessment (PGA) of Skin 
Pain (numeric rating scale [NRS]) – at worst at Week 12 among subjects with baseline 
NRS ≥ 3.
3.3
Other Efficacy Endpoint(s)
The primary and secondary endpoints will also be analyzed for all visits where 
measurements are taken other than Week 12.  In addition, the following endpoints will be 
analyzed at all visits noted in the Study Activities Table (Protocol Appendix D).
●
Experience of flare, defined as an increase in AN count of at least a 25% with a 
minimum increase of 2 relative to Baseline (flare);
●
Change from Baseline in Dermatology Life Quality Index (DLQI);
●
Change from baseline in Hidradenitis Suppurativa Symptom Assessment 
(HSSA);
●
Change from baseline in HS-related swelling, assessed based on the HSSA;
●
Change from baseline in HS-related odor, assessed based on the HSSA;
●
Change from baseline in HS-related worst drainage, assessed based on the 
HSSA;
 


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●
Change from baseline in Hidradenitis Suppurativa Impact Assessment (HSIA).
3.4
Safety Endpoint(s)
The following endpoints will be included in the safety analyses:
●
Treatment emergent adverse events (TEAEs);
●
Serious adverse events (SAEs);
●
Adverse events of special interest (AESIs);
●
Adverse events (AEs) leading to discontinuation;
●
Vital signs and laboratory tests.
4.0
Analysis Populations
The following populations will be used for the analyses.
The Intent-to-Treat (ITT) Population includes all randomized subjects.  The ITT 
Population will be used for all efficacy analyses.  Subjects will be included in the analysis 
according to the treatment groups that they are randomized to.
The following 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.
●
The all upadacitinib treated (ALL_UPA) Population is defined as subjects who 
received at least one dose of upadacitinib in the study.  This population will be 
used to provide a comprehensive summary of safety.
For safety analyses, subjects will be analyzed based on the treatment actually received.
5.0
Subject Disposition
The number of subjects for each of the following categories will be summarized, for 
overall and for each treatment group in ITT Population in Period 1:
 


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●
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;
The summary will also be provided for Period 2 for each of the following categories in 
ITT 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 reason (primary reason and all reasons) for each treatment 
group and overall.  Subjects with multiple reasons for premature discontinuation will be 
counted once in the calculation of the number and percentage of total.
In addition, the above summaries (except for the reason for premature discontinuation) 
will also be summarized by center in the accountability table.
The number of subjects and percentage of screen failure will be summarized by primary 
reason.
6.0
Study Drug Duration and Compliance
For each safety population, duration of treatment will be summarized for each treatment 
group and for all dose groups combined.  Duration of treatment is defined for each subject 
 


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as last dose date minus first dose date +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 will be summarized by treatment groups for Safety_1 Population 
and upadacitinib dose groups for ALL_UPA Population.  Treatment compliance is 
defined as the number of tablets actually taken divided by the number of tablets that 
should have been taken.  Percent compliance will be summarized.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications
Demographics, baseline or disease characteristics, medical history, and prior and 
concomitant medications will be summarized overall and by treatment group.  Categorical 
variables will be summarized with the number and percentage of subjects; percentages 
will be calculated based on the number of non-missing observations.  Continuous 
variables will be summarized with descriptive statistics (number of non-missing 
observations, mean and standard deviation, median, minimum and maximum).
7.1
Demographics and Baseline Characteristics
Demographics and baseline disease characteristics will be summarized for ITT 
Population. 
Continuous demographic variables include age, weight, height, and body mass index 
(BMI).  Categorical demographic variables include sex, ethnicity, race, age (<40, 40 – 65, 
≥ 65 years), weight (≤ 100 or > 100 kg), BMI (< 25, ≥ 25 - < 30 or ≥ 30 kg/m2), tobacco 
user (current, former, never, unknown), and alcohol user (current, former, never, 
unknown).
 


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Disease characteristics include HS disease duration in years, Baseline lesion counts (by 
lesion type), Baseline skin pain NRS (among all subjects and among subjects with 
baseline value ≥ 3), Baseline DLQI, Baseline HSSA, Baseline HSIA and Baseline hsCRP 
as continuous variables, prior exposure to TNF antagonists (yes, no) and baseline Hurley 
stage (< III, III), HS history (anatomic regions, types of lesions) 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 
statistical tables and clinical study report.  The number and percentage of subjects in each 
medical history category (by MedDRA system organ class and preferred term) will be 
summarized overall and by treatment group for ITT Population.  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 Safety_1 
Population.  A prior medication is defined as any medication taken prior to the date of the 
first dose of study drug.  A concomitant medication is defined as any medication that 
started prior to the date of the first dose of study drug and continued to be taken after the 
first dose of study drug or any medication that started on or after the date of the first dose 
of study drug, but not after the date of the last dose of study drug.  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.  Concomitant medications will be summarized for each safety 
population.
In addition, subjects' prior exposure to antibiotics (systemic and topical), biologics, Jak-
inhibitor, and other will be summarized for each treatment group and by reason of 
discontinuation.
 


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8.0
Handling of Potential Intercurrent Events for the 
Primary Endpoint
The primary efficacy endpoint, achievement of HiCSR at Week 12 (defined in 
Section 3.1) will be analyzed in the ITT Population and the following method will be used 
to address potential intercurrent events:
●
Intercurrent events of initiation of antibiotics for HS-related infections and
discontinuation of study drug due to lack of efficacy before Week 12 are 
included in the definition of primary endpoint; subjects who have either 
intercurrents above will be considered not achieving the response.  No other 
intercurrent events are considered.
9.0
Efficacy Analyses
9.1
General Considerations
All efficacy analyses will be conducted in ITT Population in each period.  All tests will be 
1-sided at an alpha level of 0.05.
The Primary Analysis will be conducted after all ongoing subjects have completed 
Week 12, data pertaining to Period 1 has been cleaned, and a database lock has occurred 
for the purpose of efficacy and safety analysis in Period 1.  This is the only and final 
efficacy analysis for Period 1.
In Period 1, all categorical variables at Week 12 and experience of flare in Period 1 will 
be analyzed using one sample Chi-square test comparing with historical placebo rate.  
Supplemental analyses will be conducted to compare in-trial data in upadacitinib group vs 
in-trial placebo data combined with historical placebo data for primary and secondary 
endpoints, and compare in-trial data in upadacitinib group vs in-trial placebo data for all 
categorical endpoints.
Continuous variables will be analyzed using Mixed-Effect Model Repeat Measurement 
(MMRM) (for endpoints other than DLQI) and Analysis of Covariance (ANCOVA) (for 
 


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DLQI) comparing with historical placebo mean change from Baseline at Week 12.  
Supplemental analyses will be conducted to compare in-trial data in upadacitinib group vs 
in-trial placebo data.
Long-term efficacy in the Period 2 will be summarized using the observed case approach.
Any subject who is randomized based on a wrong stratum will be analyzed according to 
the actual stratum the subject belongs to.
For variables other than PGA Skin Pain NRS, "Baseline" refers to the last non-missing 
observation on or before the date of the first administration of study drug or the date of 
randomization if no study drug is given.  The "Baseline" of PGA Skin Pain NRS is 
defined as the last non-missing weekly average score, calculated based on the daily scores 
from the past 7 days (with non-missing values in 4 or more days of the 7 day period), 
before the date of the first administration of study drug or on or before the date of 
randomization if no study drug is given.  
9.2
Handling of Missing Data
Missing data could occur due to various reasons, including missing visits/assessments, 
early withdrawal from the study, or missing due to COVID-19 infection or logistic 
restriction. 
The COVID-19 pandemic is interfering with the conduct of many ongoing trials, with 
potential impacts on treatment duration and the collection, analysis and the interpretation 
of clinical trial data.  Some protocol-specified visits in the clinical trials may be impacted 
due to COVID-19 infection or logistical restrictions during the pandemic.  For example, 
some scheduled visits may be missed due to self-quarantine or local government 
restrictions on travel; some visits may also be delayed or canceled due to healthcare 
resource constraints during the pandemic.  Impacted visits due to COVID-19 will be 
recorded in the database.  The probability of having missed visits and missing data due to 
COVID-19 infection or logistical restrictions related to the COVID-19 pandemic can be 
reasonably assumed to be unrelated to the unobserved values.  Therefore, for the purpose 
 


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of statistical analysis, it is reasonable to assume that these missing data are missing at 
random (MAR) and the statistical models that require MAR assumption are appropriate.  
Sensitivity analyses will be performed to assess the impact of missing data and the 
robustness of the conclusion.
Handling of intercurrent events and missing data for the efficacy analyses is described 
below.
9.2.1
Categorical Endpoints in Period 1
●
The primary approach for handling missing data in the analysis of categorical 
endpoints (including the primary endpoint) will use Non-Responder Imputation 
while incorporating Multiple Imputation (MI) to handle missing data due to 
COVID-19 (NRI-C).
The NRI-C will categorize any subject who does not have an evaluation 
during a pre-specified visit window (either due to missing assessment or 
due to early withdrawal from the study) as a non-responder for the visit.  
The only exceptions are:  1) when the subject is a responder both before 
and after the visit window, the subject will be categorized as a responder 
for the visit.  2) missing data due to COVID-19 infection or logistical 
restriction will be handled by Multiple Imputation.  Of note, the 
intercurrent events of initiation of antibiotics for HS-related infections or 
discontinuation of study drug due to lack of efficacy will lead the subjects 
being counted as non-responders at later visits.  Subjects whose 
change/percent change from Baseline cannot be calculated because of a 
missing Baseline will be considered as non-responders at all post-baseline 
visits.  When determining the HiSCR response status, a subject with 
missing Baseline value will be counted as a non-responder at any post-
baseline visit unless a subject's abscess, inflammatory nodule, and draining 
fistula counts are all zero at a specific visit, where the subject will be a 
HiSCR responder at that visit.  More details are provided in Appendix E.
●
A sensitivity analysis for categorical endpoints will use NRI with No special 
data handling for missing due to COVID-19 (NRI-NC).
 


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NRI-NC will be performed in the same way as NRI-C without the 
exception #2 above.  That is, missing due to COVID-19 infection or 
logistical restriction will also be counted as non-responders.
The NRI-C and NRI-NC will not be applicable to experience of flare in 
Period 1 since it is event-driven.  
●
Multiple Imputation (MI), a sensitivity analysis for the primary endpoint.  
Markov Chain Monte Carlo (MCMC) will be first applied to augment data into 
monotonic missing pattern and PROC MI will be used to generate 30 datasets 
using the regression method.  Taking abscess count as an example, the 
variables to be included in the imputation model are:  major stratum (prior 
exposure to anti-TNF [yes, no], Hurley Stage [< III, III]), Baseline, and 
measurements at each visit up to the end of the Period 1.  The random seed for 
MCMC and the random seed for PROC MI are specified in Appendix D.  The 
imputed post-baseline measurements will be rounded to the same precision as 
the observed data.  The same imputation strategy will be applied to the 
inflammatory nodule count and the draining fistula count.  HiSCR status will be 
determined accordingly.  Using the one sample Chi-square test, the imputed 
endpoint will be analyzed using each of the 30 datasets.  A pooled test statistic 
from the chi-square distributed statistics after analyzing each of the 30 imputed 
datasets will be used to test the difference between upadacitinib group and 
historical placebo rate with Rubin's strategy.  Note that measurements will be 
considered as missing after receiving antibiotics for HS-related infections or 
discontinued study drug due to lack of efficacy before MI.  Regardless of MI 
imputed values, subjects receiving antibiotics for HS-related infections or 
discontinued study drug due to lack of efficacy will be counted as non-
responders at later visits.
9.2.2
Continuous Endpoints in Period 1
For continuous endpoints except for DLQI, missing data will be handled using Mixed-
Effect Model Repeat Measurement (MMRM).
●
MMRM will be conducted using a mixed effect model including observed 
measurements at all visits.  For the comparison with historical placebo change 
 


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from Baseline, the dependent variable is change from Baseline, and the mixed 
model for Period 1 includes visit, main stratification factors at randomization 
(prior exposure to anti-TNF [yes, no], Hurley Stage [<III, III]), and the 
corresponding Baseline as a continuous variable.  For the comparison with in-
trial placebo data, the dependent variable is change from Baseline, and the 
mixed effect model for Period 1 includes treatment, visit, treatment by visit 
interaction, main stratification factors at randomization, and the corresponding 
Baseline as a continuous variable.  Subjects' observations after receiving 
antibiotics for HS-related infections or discontinued study drug due to lack of 
efficacy will be excluded from the analysis.  An unstructured variance 
covariance matrix (UN) will be used.  If the model cannot converge, an 
appropriate covariance structure matrix (e.g., autoregressive (1) or compound 
symmetry) will be used.  The parameter estimations are based on the method of 
restrictive maximum likelihood (REML).  The fixed effects will be used to 
report model-based means at corresponding visits.
No missing data handling will be used for DLQI in Period 1 since there is only one post-
baseline assessment in Period 1.  An ANCOVA model will be applied.  For the 
comparison with historical placebo change from Baseline, the dependent variable is 
change from Baseline in DLQI, and the model includes main stratification factors and the 
corresponding Baseline as a continuous variable.  For the comparison with in-trial placebo 
data, the dependent variable is change from Baseline in DLQI, and the model includes 
treatment, main stratification factors and the corresponding Baseline as a continuous 
variable.
9.2.3
Summary of Long-Term Efficacy
Long-term efficacy in the Period 2 will be summarized using the observed case approach.
●
Observed Case (OC) while on study drug:  The OC analysis will be used for the 
summaries of long-term efficacy, which will not impute values for missing 
evaluations, and thus a subject who does not have an evaluation on a scheduled 
visit will not be included in the OC analysis for that visit.  The OC analysis will 
be performed for all variables and will not include values after subjects 
 


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receiving antibiotics for HS-related infections or discontinued study drug due to 
lack of efficacy. 
9.3
Primary Efficacy Endpoint and Analyses
9.3.1
Primary Efficacy Endpoint
The primary endpoint is the achievement of HiSCR at Week 12.  HiSCR is defined as at 
least a 50% reduction in the total AN count with no increase in abscess count and no 
increase in draining fistula count relative to Baseline.
The corresponding statistical null hypothesis to the primary endpoint is that there is no 
difference between upadacitinib 30 mg and historical placebo rate, in the proportion of 
subjects achieving HiSCR at Week 12. 
9.3.2
Main Analysis of Primary Efficacy Endpoint
Analysis of the primary endpoint will be conducted in the ITT Population based on 
treatment as randomized.  Comparison of the primary endpoint will be made between 
upadacitinib 30 mg group and historical placebo rate (25%) using a one sample Chi-
square test at Week 12.  Point estimates, p-value and 95% CIs for the difference in 
proportions between upadacitinib 30 mg and the historical placebo rate (25%) will be 
provided. 
The attributes of the estimands corresponding to the primary efficacy endpoint are 
summarized in Table 1.
 


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Table 1.
Summary of the Estimand Attributes of the Primary Efficacy 
Endpoint
Estimand
Attributes of the Estimand
Treatment
Endpoint
Population
Intercurrent Events
Statistical 
Summary
Primary 
efficacy 
endpoint of 
HiSCR
Upadacitinib 
30 mg QD
Achievement 
of HiSCR at 
Week 12
without the 
initiation of 
antibiotics for 
HS-related 
infections or 
discontinuation 
of study drug 
due to lack of 
efficacy
All 
randomized 
subjects (ITT 
Population)
The intercurrent of 
initiation of antibiotics 
for HS-related 
infections or 
discontinuation of study 
drug due to lack of 
efficacy are included in 
the endpoint attribute 
using composite 
variable strategy.  No 
other intercurrent event 
is considered.
Difference 
between 
upadacitinib 
30 mg and 
placebo in 
the 
proportion 
of subjects 
achieving 
HiSCR at 
Week 12
9.3.3
Sensitivity Analyses of the Primary Efficacy Endpoint
Historical placebo data pre-selected by propensity score matching combined with in-trial 
placebo data will be used to estimate treatment effect of upadacitinib against placebo. 
Subjects with historical placebo data of HiSCR were pre-selected using propensity score 
matching from two Humira Phase 3 studies (M11-313 and M11-810) and the 
Risankizumab study (M16-833), whose study populations, entry criteria and study designs 
are similar to this study.
The propensity scores were estimated for all randomized subjects in this study and 
historical placebo subjects with selected common baseline demographics and 
characteristics variables:
●
Age
●
Gender 
●
Race
●
Smoking status
●
Baseline BMI
 


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●
Baseline AN count (abscess count and inflammatory nodule count)
●
Duration of HS since diagnosis
●
Baseline Hurley Stage
●
Baseline draining fistula
The "nearest neighbor matching" were performed based on a distance measure, caliper, 
with the propensity score for each subject calculated from the logistic regression. The 
number of synthetic placebo subjects was determined by the simulation results, for each 
in-trial placebo rate assumption, with pre-determined criteria that the number of synthetic 
placebo subjects not to exceed 68 (approximately 3 times the number of in-trial placebo 
subjects) and the one-sided false positive rate was controlled at 10% (simulation details 
can be found in Appendix F and the list of matching subjects can be found in 
Appendix G:
In-Trial Placebo Rate
Number of Synthetic Placebo Subjects
≤ 33%
68
>33% and ≤ 34%
23*
>34%
0
*
The 23 subjects with the highest rank in Appendix G Table A will be used in the analysis.
After database lock, comparison between the in-trial data of the upadacitinib group and 
the in-trial placebo data combined with the pre-selected historical placebo subjects' data 
will be performed. Frequencies and percentages will be summarized along with 95% 
confidence interval (CI).  Pairwise comparisons of upadacitinib vs. placebo will be made 
using CMH test.  Point estimates, p-value and 95% CIs for the difference in proportions 
between each upadacitinib group and placebo will be provided.  The stratification factors 
(prior exposure to anti-TNF [yes, no], Hurley Stage [<III, III]) will be adjusted in the 
model.
Comparison between the in-trial data of the upadacitinib group and the in-trial placebo 
subjects will also be performed.  The analysis method will be the same as described 
above.
 


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The NRI-C will be the primary approach for missing data handling in the analysis of the 
primary efficacy endpoint.  NRI-NC and MI will be used as sensitivity analysis.
9.4
Secondary Efficacy Analyses
9.4.1
Main Analyses of Secondary Efficacy Endpoints
The secondary endpoint NRS30, defined as the achievement of at least 30% reduction and 
at least 1 unit reduction from Baseline in Patient's Global Assessment (PGA) of Skin Pain 
(numeric rating scale [NRS]) – at worst at Week 12 among subjects with baseline NRS 
≥3.
NRS30 will be analyzed using the same method as for the primary endpoint and 
comparing with the historical placebo rate (22.5%) at Week 12.  The historical placebo 
rate of 22.5% is assumed based on the response rate of placebo subjects from the two 
Humira studies (Study M11-313 and Study M11-810), who satisfied the same eligibility 
criteria.
The same supplemental analysis to compare upadacitinib 30 mg group vs in-trial placebo 
group combined with pre-selected placebo subjects' data from the three existing trials will 
also be performed as described in Section 9.3.3.  The actual number of synthetic placebo 
subjects is determined as below (simulation details can be found in Appendix F and the 
list of matching subjects can be found in Appendix G):
In-Trial Placebo Rate
Number of Synthetic Placebo Subjects
≤ 36%
68
>36% and ≤ 37%
23*
>37
0
*
The 23 subjects with the highest rank in Appendix G Table B will be used in the analysis.
Comparison between the in-trial data of the upadacitinib group and the in-trial placebo 
subjects will also be performed.  The analysis method will be the same as described in 
Section 9.3.3.
 


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In addition, analgesic use will be handled as follows:
●
Prohibited analgesic (including opioids):  A subject will be counted as a non-
responder from the day that the subject initiates prohibited analgesic to 5 days 
after the end of such analgesic use.
●
Protocol-allowed analgesic use:
○
A subject who enter the study without concomitant analgesic will be 
counted as a non-responder from the day that the subject initiates a 
protocol-allowed analgesic to 2 days after the end of such analgesic use.
○
A subject who entered the study on a stable dose of a protocol-allowed 
concomitant analgesic will be counted as a non-responder from the first 
day of an analgesic dose increase to 2 days after the end of the dose 
increase.
The NRI-C will be the primary approach for missing data handling in the analysis of the 
secondary efficacy endpoint.  NRI-NC will be used as sensitivity analysis.
9.5
Additional Efficacy Analyses
9.5.1
Additional Categorical Endpoints in Period 1
The analysis of flare during Period 1 will be performed using the same method as for the 
primary endpoint, comparing with historical placebo rate of the occurrence of flare in 12 
weeks (34%).  The historical placebo rate is assumed based on the response rate of 
placebo subjects from the two Humira studies (Study M11-313 and Study M11-810), who 
satisfied the same eligibility criteria.  A supplemental analysis will be performed to 
compare upadacitinib 30 mg and in-trial placebo group.
9.5.2
Additional Continuous Endpoints in Period 1
Continuous endpoints except for DLQI will be analyzed using MMRM including 
observed measurements at all visits, as described in Section 9.2.  For HSSA total score, 
HS-related swelling, odor, worst drainage, and HSIA at Week 12, the comparison will be 
made between upadacitinib 30 mg group and the historical change from baseline at Week 
 


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12 values of -0.72, -0.8, -0.72, -0.89 or -0.83 (HSIA historical value is the average of 
Week 8 and Week 16 since there is no Week 12 measurement), respectively, using 
MMRM.  The historical change from baseline at Week 12 values are obtained based on 
the placebo subjects from Risankizumab Study M16-833, who satisfied the same 
eligibility criteria.
For change from baseline in DLQI at Week 12, the comparison will be made between 
upadacitinib 30 mg group and historical change from baseline (-2.5) using an ANCOVA 
model.  The historical change from baseline of -2.5 is assumed based on the mean change 
from Baseline of placebo subjects from the two Humira studies (Study M11-313 and 
Study M11-810), who satisfied the same eligibility criteria.
Continuous endpoints will also be analyzed using MMRM for endpoints other than DLQI 
and ANCOVA for DLQI to compare upadacitinib 30 mg QD with in-trial placebo group.  
9.5.3
Summary of Long-Term Efficacy
Long-term efficacy in Period 2 will be summarized by visit for ITT Population using the 
observed case approach, as described in Section 9.2.3.
9.6
Efficacy Subgroup Analyses
To evaluate the consistency of the efficacy over demographic and other baseline 
characteristics, summaries will be provided for the following subgroups for the primary 
efficacy endpoint.
●
Age group (< 40 years, ≥ 40 – < 65 years, ≥ 65 years)
●
Sex (male, female)
●
Race (white, non-white)
●
Smoking (current, ex or never)
●
Body mass index (normal:  < 25, overweight:  ≥ 25 – < 30, obese:  ≥ 30)
●
Duration of HS since diagnosis (by median)
●
Prior exposure to TNF antagonists (yes, no)
 


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●
Baseline Hurley stage (< III, III)
For age and BMI subgroups with fewer than 10% subjects will be combined with their 
adjacent subgroup.
10.0
Safety Analyses
10.1
General Considerations
Safety data will be summarized for each safety population.  Safety summaries will be 
presented by treatment group.  For ALL_UPA Population, upadacitinib 30 mg, 15 mg and 
a total group for all subjects on upadacitinib will be summarized.  For the safety analysis, 
subjects are assigned to a treatment group based on the treatment actually received, 
regardless of the treatment randomized.
A subject's actual treatment sequence will be determined by the most frequent dose 
regimen received in Period 1.
10.2
Adverse Events
Adverse events (AEs) will be summarized and presented using primary MedDRA System 
Organ Classes (SOCs) and preferred terms (PTs) according to the version of the MedDRA 
coding dictionary used for the study at the time of database lock.  The actual version of 
the MedDRA coding dictionary used will be noted in the AE tables and in the clinical 
study report.  Specific adverse events will be counted once for each subject for calculating 
percentages, unless stated otherwise.  In addition, if the same adverse event occurs 
multiple times within a subject, the highest severity and level of relationship to 
investigational product will be reported.
10.2.1
Treatment-Emergent Adverse Events
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 first dose in Period 2, whichever is 
 


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earlier.  For Period 2, 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 2.  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.
The number and percentage of subjects experiencing TEAEs 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:
●
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 
4.03)
●
Any serious TEAE (SAE)
●
Any treatment-emergent SAE related to study drug according to the
investigator
●
Any TEAE leading to discontinuation of study drug
●
TEAEs of Special Interest
●
Any TEAE leading to death
●
Any deaths
●
Deaths occurring ≤ 30 days after last dose of study drug
●
Deaths occurring > 30 days after last dose of study drug.
The overview of AEs per 100 patient-years of exposure will also be provided for the 
above categories.
 


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10.2.3
Treatment-Emergent Adverse Events by SOC and/or PT
TEAEs 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 severity and SOC and PT; and by subject number and SOC 
and PT.  Specific adverse events will be counted once for each subject for calculating 
percentages, unless stated otherwise.  In addition, if the same adverse event occurs 
multiple times within a subject, the highest severity and level of relationship to 
investigational product will be reported.
In addition, TEAEs will be summarized by PT and sorted by decreasing frequency for 
upadacitinib 30 mg group for Safety_1 Population, and by the total active group for 
ALL_UPA Population.
10.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure
Exposure-adjusted AEs per 100 patient-years will be provided by SOC and PT, where 
AEs per 100 patient-years of exposure are defined as the number of AEs divided by the 
total exposure in 100 patient-years.  The study drug exposure is defined as (last dose –
first dose) + 1.
10.2.5
SAEs (Including Deaths) and Adverse Events 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.
In addition, the event rate per 100 patient-years of exposure will also be provided by SOC 
and PT for each treatment emergent SAE and TEAE leading to study drug 
discontinuation.
 


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10.2.6
Adverse Events of Special Interest
Adverse events of special interest 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.  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
●
Anemia
●
Neutropenia
●
Lymphopenia
●
Herpes zoster
●
Renal dysfunction
●
Active tuberculosis
●
Adjudicated MACE
●
Adjudicated VTE
Detailed information about the search criteria are provided in Appendix B.
Tabular listings of adverse events of special interest will be provided.
In addition, the event rate per 100 patient-years of exposure will also be provided by SOC 
and PT for each AESI.
 


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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.
Mean change from baseline to each applicable post-baseline visit will be summarized for 
selected laboratory variables, with the number of observations, baseline mean, and visit 
mean for each safety population.  The change from baseline mean, standard error, and 
95% confidence interval will be presented for the mean change from baseline within each 
treatment group and difference between treatment groups (active vs. placebo).  Percent 
change from baseline in LDL-C, HDL-C, total cholesterol and ratio of LDL-C to HDL-C 
will also be summarized similarly. 
Changes in laboratory parameters will be tabulated using shift tables by NCI CTC criteria 
(Version 4.03) for each safety population.  A shift table from baseline to the worse value 
(based on NCI CTC criteria) during treatment will be created.  A similar shift table will be 
provided to summarize shifts from baseline to the final post-baseline value.
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 at least one laboratory value meeting the criteria will be 
summarized for each safety population.  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 the following 
criteria of potential clinical interest should be presented:
●
ALT ≥ 3 × ULN
●
ALT ≥ 5 × ULN
 


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●
ALT ≥ 10 × ULN
●
ALT ≥ 20 × ULN
●
AST ≥ 3 × ULN
●
AST ≥ 5 × ULN 
●
AST ≥ 10 × ULN 
●
AST ≥ 20 × ULN
●
TBL ≥ 2 × ULN
●
Alkaline phosphatase ≥ 1.5 × ULN
●
ALT and/or AST ≥ 3 × ULN and concurrent TBL ≥ 1.5 × ULN
●
ALT and/or AST ≥ 3 × ULN and concurrent TBL ≥ 2 × ULN
10.4
Analysis of Vital Signs
Vital sign measurements of systolic and diastolic blood pressure, pulse rate, and body 
temperature will be summarized for each safety population.
Mean 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.  
The change from baseline mean, standard error, and 95% confidence interval will be 
presented for the mean change from baseline within each treatment group and difference 
between treatment groups (active vs. placebo).
Vital sign variables will be evaluated based on PCI criteria (Appendix C).  For each vital 
sign PCI criterion, the number and percentage of subjects who have at least one vital sign 
value meeting the criteria will be summarized.  Listings will be provided to summarize 
subject-level vital sign data for subjects meeting PCI criteria.
10.5
Safety Subgroup Analyses
Not applicable.
 


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10.6
Other Safety Analyses
Not applicable.
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 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 nature of the phase 2 proof of concept study, all the endpoints will be tested at 
alpha = 0.05 (1-sided) and no alpha-spending is needed. 
 


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14.0
Version History
Table 2.
SAP Version History Summary
Version
Date
Summary
1.0
25 Sep 2020
Original version
2.0
30 Apr 2021

Added the supplemental analyses of the comparison 
between in-trial upadacitinib data with in-trial placebo data 
combined with historical placebo data for primary and 
secondary endpoints.

Added the supplemental analyses of the comparison 
between in-trial upadacitinib data with in-trial placebo data 
for all categorical endpoints.

Provided details for the MMRM and ANCOVA for 
continuous endpoints.

Added the comparisons of upadacitinib with single 
placebo change from baseline for HSSA total score and 
components and HSIA based on the estimates from Study 
M16-833. 

Clarified the population for the summary of exposure and 
concomitant medications.

Adjust the calculations of the study drug exposure in the 
TEAE per patient-years of exposure.
15.0
References
1.
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.
2.
FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-
19 Pandemic - Guidance for Industry, Investigators, and Institutional Review 
Boards.  FDA.  2020. 
3.
Statistical Considerations for Clinical Trials During the COVID-19 Public Health 
Emergency - Guidance for Industry.  FDA.  2020. 
4.
Points to consider on implications of Coronavirus disease (COVID-19) on 
methodological aspects of ongoing clinical trials.  EMA.  2020.
 


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5.
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. 
6.
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.
7.
White IR, Royston P, Wood AM.  Multiple imputation using chained equations:  
Issues and guidance for practice.  Stat Med.  2011;30(4):377-99.
8.
Rosenbaum PR, Rubin DB. Constructing a control group using multivariate 
matched sampling methods that incorporate the propensity score. The American 
Statistician. 1985;39(1):33-8.
9.
Austin PC. An introduction to propensity score methods for reducing the effects of 
confounding in observational studies. Multivariate Behav Res.
2011;46(3):399-424.
 


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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
CPK
U/L
> 5.0 × ULN
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.
Table C-3.
Criteria for Potentially Clinically Important Vital Sign Values
Vital Sign
Category
Criteria for Potential Clinically Significant Vital Signs
Systolic blood pressure
Low
Value ≤ 90 mmHg and decrease ≥ 20 mmHg from Baseline
High
Value ≥ 160 mmHg and increase ≥ 20 mmHg from Baseline
Diastolic blood pressure
Low
Value ≤ 50 mmHg and decrease ≥ 10 mmHg from Baseline
High
Value ≥ 100 mmHg and increase ≥ 10 mmHg from Baseline
Pulse
Low
Value ≤ 50 bpm and decrease ≥ 15 bpm from Baseline
High
Value ≥ 120 bpm and increase ≥ 15 bpm from Baseline
Weight 
High
> 7% increase from Baseline
Low
> 7% decrease from Baseline
 


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Appendix D.
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-C
Endpoints
Random Seed
MCMC procedure
PROC MI
Abscess count
1001
9001
Draining fistula count 
1002
9002
Inflammatory nodule count
1003
9003
NRS30
1004
9004
≥25% AN increase
1005
9005
B. Random Seeds for MI
Endpoints
Random Seed
MCMC procedure
PROC MI
Abscess count
1006
9006
Draining fistula count 
1007
9007
Inflammatory nodule count
1008
9008
 


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


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(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 guidance in March 2020:
●
"At this point in time it is not possible to give general applicable advice on 
how the different aspects related to the pandemic should be handled, as 
implications on clinical trials are expected to be manifold.  Impact on the data 
collection, analysis and interpretation of results for each trial will need a 
thorough case-by-case assessment."
●
"As a general principle, there are strong scientific reasons to conduct trials as 
planned and implement changes only when there is a convincing scientific 
reason that it improves interpretability of results."
1.4
Missing Data Handling for Missing Due to COVID-19 for 
Dichotomized Variables
In this document, a missing data handling method is proposed to handle missing data due 
to COVID-19 infection or logistical restrictions related to the COVID-19 pandemic under 
the general MAR framework.  In particular, we explain using multiple imputation (MI) to 
handle missing data due to COVID-19 in dichotomized variables in conjunction with non-
responder imputation (NRI) for missing data due to other reasons.
 


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2.0
Non-responder Imputation Incorporating Multiple 
Imputation (NRI-C)
2.1
Overall Description of the Method
For a dichotomized outcome variable with missing data, the NRI-C will categorize any 
subject who does not have evaluation during a pre-specified visit window as a non-
responder for the visit, with two exceptions: 
●
If the subject is a responder both before and after the pre-specified visit 
window in the particular Study Period, the subject will be categorized as a 
responder for the visit.
●
If the reason for missing (e.g., missed visits, incomplete visit, out-of-schedule 
visits, or discontinuations of study drug) is due to COVID-19, the information 
will be captured in the database and the subject's response status will be 
imputed using multiple imputation.
Of note, later visits of subjects receiving antibiotics for HS-related infections or 
discontinued study drug due to lack of efficacy will be set as missing before imputation.  
As a result, these assessments will not contribute to the imputation and the subjects will 
be counted as non-responders for the analysis at later visits.  When determining the 
HiSCR response status, a subject with missing Baseline value will be counted as a non-
responder at any post-baseline visit unless a subject's abscess, inflammatory nodule, and 
draining fistula counts are all zero at a specific visit, then the subject will be a HiSCR 
responder at that visit.  Non-responder imputation incorporating multiple imputation 
(NRI-C) for missing due to COVID-19 will be implemented as follows.
2.2
Multiple Imputation (MI) and MAR Assumption
When a dichotomized variable is derived from continuous scales, for example, HiSCR (as 
at least a 50% reduction in the total abscess and inflammatory nodule (AN) count with no 
increase in abscess count and no increase in draining fistula count relative to Baseline), 
the multiple imputation will be applied to the original scales of abscess, inflammatory 
nodule and draining fistula counts, assuming multivariate normal distributions.  Then the 
 


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dichotomized variable will be derived from the imputed values.  For demonstration 
purposes, we use HiSCR as an example in this Appendix E, and provide sample code for 
the imputation of abscess count for one sample Chi-square test and two sample CMH test 
in Appendix E Section 3.0.  The same imputation strategy will be applied to the 
inflammatory nodule count and the draining fistula count.  HiSCR status will be 
determined accordingly.
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., abscess count 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., abscess count 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 group, prior 
 


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exposure to anti-TNF category, Baseline Hurley Stage, Baseline abscess count, all post-
baseline visits of abscess count up to the end of the Study Period. Of note, categorical 
variables are included using the form of dummy variables. 
Repeat the imputation process K=30 times using the procedure described above to form 
K=30 monotone missing datasets, where K is determined as described in "Repetition of 
Imputations (K)."
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 group, prior exposure to anti-TNF category, Baseline 
Hurley Stage, Baseline abscess count, all post-baseline visits of abscess count 
up to the end of the Study Period. 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 
 


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a specific number of imputations.  The more imputations (K) are conducted, the more 
precise the parameter estimates will be.  For example, with a 1% power falloff tolerance 
in multiple imputation, as compared to an infinite number of imputations, multiple 
imputation requires 20 repetitions of imputation for 30% missing information and 40 
repetitions for 50% missing information (Graham, Olchowski, and Gilreath 2007).5  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 research5
suggested that the number of repetitions (K) should be at least equal to the percentage of 
missing (White et al., 2011).7
2.4
Derivation of Response Status and Non-Responder 
Imputation
Same as the abscess count, we also impute to obtain complete datasets for the 
inflammatory nodule count and the draining fistula count.  For each 'complete' dataset, the 
imputed post-baseline values will be rounded to the same precision as the observed data.  
HiSCR status will be determined accordingly.
The imputed response status for missing due to reasons other than COVID-19 will be 
overridden by non-responder imputation (Section 2.1) to ensure that multiple imputation 
is only applied to missing due to COVID-19:
●
Using NRI-C approach, all missing due to reasons other than COVID-19 will 
be categorized as non-responders, including visits after a subject receives 
antibiotics for HS-related infections or discontinued study drug due to lack of 
efficacy.  When determining the HiSCR response status, a subject with 
missing Baseline value will be counted as a non-responder at any post-baseline 
visit unless a subject's abscess, inflammatory nodule, and draining fistula 
counts are all zero at a specific visit, then the subject will be a HiSCR 
responder at that visit. 
 


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●
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 SPP-specified visit 
window in the particular Study Period.
2.5
Analysis
The statistical analysis will use the Chi-square test or CMH test adjusted by the actual 
stratification factors.
2.5.1
Analysis of Each Dataset
For each of the K 'complete' datasets, the Chi-square test or 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
For the comparison between upadacitinib 30 mg and historical placebo rate, the chi-square 
distributed statistics from each of the K datasets will be pooled using the procedure of 
Rubin (1987) and Li et al. (1991).  Denote by 
 chi-square distributed statistics with 
degrees of freedom estimated in each of the K imputed datasets.  A pooled test statistics 
can be obtained as follows:
	 =
̅
 − + 1
 −1 ̅	
1 + ̅	
where ̅ =

 ∑




;  ̅	 = 1 +



 ∑

 − ∑








The pooled p-value for the hypothesis test based on 	 can be obtained using F 
distribution with  and  as numerator and denominator degrees of freedom, respectively, 
as follows:
	 =  , ! > 	#;    	 = $
%( −1) (1 +

)̅!*

 


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For the comparison between in-trial data from upadacitinib group and the in-trial placebo 
data combined with subject-level historical data, the results from the K 'complete' datasets 
will be synthesized using the SAS procedure PROC MIANALYZE, following Rubin's 
formula (Rubin, 1987),6 to derive the MI estimator of the treatment difference for the final 
inferences.
We fit the analysis model to the kth 'complete' dataset, denoting the estimate of the 
treatment difference q by +, from the kth 'complete' dataset, and denoting the 
corresponding estimate of the variance as Vk.
The MI estimator of q (point estimator obtained from PROC MIANALIZE), +,-., is the 
average of the K individual estimators:
+,-. = 1
 / +,.


The estimated variance of +,-., is a combination of the between- and within-imputation 
variability as follows:
-. = 1 + 1 +

 2,
where 1 =

 ∑



is the within-imputation variability and 2 =

 ∑
3+, −+,-.4



is the between-imputation variance. 
It has been shown6 that the statistic
5 = +,-. −+
-.
 


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has an approximate 67 distribution where 8 = ( −1) 1 +
9
:

.  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 COUNT_2; SET COUNT;
  /*THE MCMC STATMENT BELOW ASSUMES MULTI-VARIATE NORMAL*/
  /*  USE ALL DATA IN THE IMPUTATION MODEL*/
  IF HURLEY=1 THEN HURLEY1 = 1 ELSE HURLEY1 = 0; /* CREATE DUMMY 
VARIABLE FOR HURLEY STAGE 1*/
  IF HURLEY=2 THEN HURLEY2 = 1 ELSE HURLEY2 = 0; /* CREATE DUMMY 
VARIABLE FOR HURLEY STAGE 2*/
RUN;
/*AUGMENTATION STEP -- TO HAVE 30 MONOTONE MISSING DATASETS*/
PROC MI DATA= COUNT_2 OUT= COUNT_MONO NIMPUTE=30 SEED= 1001 /*RANDOM 
SEED PRE-DEFINED*/
  ROUND=. . . . 1 1 1 1 1 /*VALUE ROUND TO INTEGER*/
  MIN=. . . . 0 0 0 0 0  /*MINIMUM VALUE OF COUNT IS 0*/
  MAX=. . . . . . . . .   /*MAXIMUM VALUE*/
MCMC IMPUTE=MONOTONE ;
/*NOTE: CATEGORICAL VARIABLES SUCH AS HURLEY1 HURLEY2 ARE DUMMY, CREATED 
ABOVE*/
/*NOTE: ALL OTHER NON-DUMMIED COVARIATES MUST BE CONTINUOUS*/
VAR TRT01PN TNFN HURLEY1 HURLEY2 BASE WK2 WK4 WK8 WK12;
/*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= COUNT_MONO OUT= COUNT_FULL NIMPUTE=1 SEED= 9001  /*RANDOM 
SEED PRE-DEFINED*/
 


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  ROUND=. . . 1 1 1 1 1 /*VALUE ROUND TO INTEGER*/
  MIN=. . . 0 0 0 0 0   /*MINIMUM VALUE OF COUNT IS 0*/
  MAX=. . . . . . . .    /*MAXIMUM VALUE*/
  MINMAXITER=1000;
  /*CLASS CATEGORICAL VARIABLES*/
  CLASS TRT01P TNFN HURLEY;
  VAR TRT01P TNFN HURLEY BASE WK2 WK4 WK8 WK12;
  MONOTONE REG (WK2 WK4 WK8 WK12);  /* IMPUTED SEQUENTIALLY, FROM WK 1 
TO 16, WITH COVARIATES CONSTRUCTED FROM THE CORRESPONDING PRECEDING 
VARIABLES*/
  BY _IMPUTATION_;                   /*FOR EACH OF THE 30 MONOTONE 
MISSING DATASETS, IMPUTE A 'COMPLETE' DATASET*/
RUN;
/*We will get the imputed "complete" datasets for abscess, inflammatory 
nodule, and draining fistula counts. For sample code below, we denote 
the following variables: ABS12, INF12 and DRA12 as the corresponding 
lesion count at Week 12; and AN12 as the sum of ABS12 and INF12. 
Determine the HiSCR status at Week 12.  */
DATA ALL; SET COUNT_FULL;
    IF 0<= AN12 <=0.5*AN_BASE AND ABS12<=ABS_BASE AND DRA12 <= DRA_BASE 
THEN HISCR_12=1;
    ELSE HISCR_12=0;
RUN; 
/***********************************************************************
*/
/*         DATA HANDLING STEPS TO MERGE COVID-19 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 WITH TRADITIONAL 
NRI*/
DATA ALLF; SET ALL;
  /*COVID19_XX='Y' IF MISSING AT WEEK XX IS DUE TO COVID-19; IF NOT, 
OVERRIDE WITH TRADITIONAL NRI*/
  /*VARIABLE HISCR_NRI_12: TRADITIONAL NRI DATA AT WEEK 12, WHICH COVERS 
THE SPECIAL HANDLING SUCH AS THE BEFORE-AND-AFTER EXCEPTION IN THE 
PARTICULAR STUDY PERIOD*/
  IF COVID19_MISS NE 'Y' THEN HISCR_12 = HISCR_NRI_12;
RUN;
PROC SORT DATA=ALLF; BY _IMPUTATION_ SUBJID; RUN;
 


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/****************/
/*ANALYSIS MODEL*/
/****************/
/*KEY CODE: ANALYZING EACH 'COMPLETE' DATASET*/
/***********************************/
/********************************/
/*FOR ONE SAMPLE CHI-SQUARE TEST*/
/********************************/
ODS OUTPUT ONEWAYCHISQ=CHI;
PROC FREQ DATA=ADEFF;
  BY _IMPUTATION_;
  TABLES CRIT2FN/CHISQ TESTP=(0.75 0.25) ;
RUN;
DATA CHI;
  SET CHI;
  KEEP _IMPUTATION_ NVALUE1 LABEL1;
RUN;
/*GET CHI-SQUARE STATISTICS*/
DATA CHISQ_VALUE;
  SET CHI(WHERE = (LABEL1 = "Chi-Square"));
  VALUE = NVALUE1;
  DROP NVALUE1;
RUN; 
/*GET DEGREE OF FREEDOM*/
DATA CHISQ_DF;
  SET CHI(WHERE = (LABEL1 = "DF"));
  DF = NVALUE1;
  DROP NVALUE1;
RUN;
DATA CHISQ;
  MERGE CHISQ_VALUE CHISQ_DF;
  BY _IMPUTATION_;
  A=1;
RUN; 
/*CALCULATE MEAN OF CHI-SQUARE STATISTICS*/
PROC MEANS DATA = CHISQ MEAN NOPRINT;
  VAR VALUE;
  OUTPUT OUT = M_CHISQ MEAN = M_VALUE N = COUNT;
RUN;
DATA M_CHISQ;
 


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  SET M_CHISQ;
  A=1;
RUN;
DATA CHISQ1;
  MERGE CHISQ M_CHISQ;
  BY A;
  MEAN_VALUE = M_VALUE;
  M = COUNT;
  DROP _FREQ_ _TYPE_ M_VALUE COUNT;
RUN; 
DATA TEMP;
  SET CHISQ1;
  SQRT_VALUE=SQRT(VALUE);
RUN;
/*CALCULATE MEAN OF SQUARE ROOT OF CHI-SQUARE STATISTICS*/
PROC MEANS DATA = TEMP MEAN NOPRINT;
  VAR SQRT_VALUE;
  OUTPUT OUT=M_CHISQ1 MEAN=M_SQRT_VALUE;
RUN;
DATA M_CHISQ1;
  SET M_CHISQ1;
  A=1;
RUN;
DATA CHISQ2;
  MERGE CHISQ1 M_CHISQ1;
  BY A;
  MEAN_SQRT=M_SQRT_VALUE;
  DROP _FREQ_ _TYPE_ M_SQRT_VALUE;
RUN;
DATA CHISQ3;
  SET CHISQ2;
  RX = (1+1/M)*(((VALUE**0.5) - MEAN_SQRT)**2)/(M-1);
RUN; 
/*CALCULATE MEAN OF RX*/
PROC MEANS DATA = CHISQ3 MEAN NOPRINT;
  VAR RX;
  OUTPUT OUT = T_RX SUM = T_RX;
RUN;
DATA T_RX;
  SET T_RX;
  A=1;
 


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RUN;
DATA CHISQ4;
  MERGE CHISQ3 T_RX;
  BY A;
  RX_RESULT = T_RX;
  DROP _FREQ_ _TYPE_ T_RX;
RUN; 
PROC SORT DATA=CHISQ4 NODUPKEY; 
  BY MEAN_VALUE DF RX_RESULT M MEAN_SQRT;
RUN;
/*CALCULATE P VALUE*/
DATA P_CHISQ;
  SET CHISQ4;
  DROP RX;
  DX = ((MEAN_VALUE/DF) - (M+1)*RX_RESULT/(M-1))/(1+RX_RESULT);
  VX = (DF **(-3/M)) * (M-1) * ((1 + 1/RX_RESULT) ** 2);
  PVAL = 1 - CDF("F", DX, DF, VX);
RUN; 
/*************************/
/*FOR TWO SAMPLE CMH TEST*/
/*************************/
/*INDIVIDUAL-LEVEL DATA --> # OF RESPONDERS & # OF SUBJECTS, TO BE READ-
IN TO PROC STDRATE */
PROC FREQ DATA=ALLF;
  BY _IMPUTATION_;
  TABLES TRT01PN*STRATA*HISCR_12/LIST NOCUM NOPRINT OUT=COUNT_TABLE;
RUN;
DATA COUNT_TABLE; SET COUNT_TABLE;
  DROP PERCENT;
RUN;
PROC TRANSPOSE DATA=COUNT_TABLE OUT=FREQ_TABLE PREFIX=RESP;
ID HISCR_12;
BY _IMPUTATION_ TRT01PN STRATA;
VAR COUNT;
RUN;  
DATA FREQ_TABLE1; SET FREQ_TABLE;
  CASE=RESP1;
  SIZE=SUM(RESP0, RESP1);
  KEEP _IMPUTATION_ TRT01PN STRATA CASE SIZE;
RUN;
/*CALCULATE THE COMMON RISK DIFF FOR EACH COMPLETE DATASET*/
PROC STDRATE DATA=FREQ_TABLE2
  METHOD=MH STAT=RISK EFFECT=DIFF;
 


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  BY _IMPUTATION_;
  POPULATION GROUP=TRT01PN EVENT=CASE TOTAL=SIZE;
  STRATA STRATA / 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;
 


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Appendix F.
Simulations for Combining Subject-level Historical Placebo Data 
with In-trial Placebo Data
1.0
Introduction
In randomized controlled trials, randomization ensures that the different arms of the trial 
tend to be balanced, both in terms of measured and unmeasured characteristics of the 
population.  Thus, the only systematic difference between treated and untreated patients is 
the exposure to treatment.  This allows one to obtain unbiased estimates of the average 
treatment effect within the context of the study design.  In the studies such that the 
treatment effect will be estimated with the combination of in-trial placebo subjects and 
historical placebo subjects, the distribution of subject characteristics is likely to vary 
systematically between the in-trial subjects and historical subjects and is often related to 
patient prognosis, patient characteristics, and physician preference.  Thus, confounding 
may occur.
Propensity score matching method (Rosenbaum and Rubin, 1985) matches in-trial 
patients with synthetic placebo subjects based on propensity scores such that matched in-
trial subjects and placebo subjects are comparable in terms of covariates used in 
propensity score determination.  This process mimics randomization to create 
two comparable groups with a caution of limitation that the matching is conditional on 
included covariates.
To provide the guidance on how many synthetic placebo subjects can be matched for the 
primary and secondary analysis (HiSCR and NRS30), simulations have been conducted to 
evaluate the power and false positive rate of combining the data from historical placebo 
subjects and in-trial subjects under different scenarios.
2.0
Methods
The simulation procedures are outlined in the following sections.
 


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2.1
Simulation of Baseline Covariates and Treatment Groups
Within each simulation, the following baseline covariates were generated for the 68 in-
trial subjects from multivariate normal distribution:
●
Age
●
Baseline AN count 
●
Baseline BMI
●
Duration of HS since diagnosis
●
Baseline draining fistula
●
Gender 
●
Race
●
Smoking status
The multivariate normal distribution with mean vector µ, standard deviation ; and 
correlation matrix ∑ is defined as below (covariates in the order as listed above):
<= = (35.8, 21.8, 35.2,11,3.56,0,0,0)
;= = (11.91, 20.73, 8.65, 8.4, 5.14, 1,1,1)
The means and standard deviations for the continuous variables were estimated based on 
the baseline information from the in-trial subjects.  For the binary variables, random 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 


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samples were generated using standard normal distribution and the binary outcome of 0 or 
1 was determined by the proportions estimated from the in-trial subjects.
Based on the baseline information from 68 in-trial subjects, the two stratification factors, 
baseline Hurley Stage (<III, III), and the indicator of prior exposure to anti-TNF treatment 
(Yes, No) were generated assuming that 5% of the subjects are Hurley Stage <III and 
have prior exposure to anti-TNF treatment, 10% of the subjects are Hurley Stage III and 
have prior exposure to anti-TNF treatment, 55% of the subjects are Hurley Stage <III and 
do not have prior exposure to anti-TNF treatment, and 35% of the subjects are Hurley 
Stage III and do not have prior exposure to anti-TNF treatment.
Treatment groups (upadacitinib 30 mg and placebo) were generated in a 2:1 ratio within 
each of the 4 strata.  With a total of 68 subjects, it was assumed that 45 subjects received 
upadacitinib 30 mg, and 23 subjects received placebo.
2.2
Matching Historical Placebo Subjects Using Propensity 
Score
In the matching phase, placebo subjects from existing studies (Study M11-313, 
Study M11-810, Study M16-833) were matched in a fixed ratio with in-trial subjects 
using propensity score method with pre-selected baseline covariates.  Nearest neighbor 
matching method was used.
Different numbers of matched subjects were evaluated:
Number of Matched Subjects
Matching Ratio
(in-trial:  matching)
Control Set
23
1:1
In-trial placebo subjects (N=23)
46
1:2
In-trial placebo subjects (N=23)
68
1:1
All in-trial subjects (N=68)
 


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3.0
Scenarios and Simulation Results for Primary 
Endpoint (HiSCR) and Secondary Endpoint (NRS30)
3.1
HiSCR
Different scenarios with regard to the variations in the in-trial placebo rate relative to the 
historical placebo rate (28%) were considered:  in-trial placebo subjects perform worse 
than historical placebo subjects by 10% or 5%, in-trial placebo subjects perform similarly 
as the historical placebo subjects, and in-trial placebo subjects perform better than 
historical placebo subjects by 5% or 10%, as summarized in the following table.
Scenario
Placebo Rate
Upadacitinib Rate*
In-trial PBO rate = Historical rate -10%
0.18
0.59
In-trial PBO rate = Historical rate - 5%
0.23
0.59
In-trial PBO rate = Historical rate
0.28
0.59
In-trial PBO rate = Historical rate + 5%
0.33
0.59
In-trial PBO rate = Historical rate + 10%
0.38
0.59
*
Assume that upadacitinib performs at least as good as min TPP.
One-sided power and false positive rates for each scenario and different numbers of 
matched subjects were calculated, and the results from 10000 simulations (random seed:  
12345) are summarized in the following table:
 


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Power
False Positive Rate
Number of Matched 
Subjects
In-Trial 
Only
Number of Matched 
Subjects
In-Trial 
Only
Scenario
23
46
68
UPA vs 
PBO:  
45:23
23
46
68
UPA vs 
PBO:  
45:23
In-trial PBO rate = 
Historical rate -
10%
0.978
0.984
0.984
0.977
0.013
0.004
0.002
0.082
In-trial PBO rate = 
Historical rate - 5%
0.957
0.973
0.977
0.926
0.027
0.014
0.009
0.075
In-trial PBO rate = 
Historical rate
0.925
0.954
0.966
0.837
0.051
0.04
0.033
0.072
In-trial PBO rate = 
Historical rate + 5%
0.877
0.933
0.951
0.701
0.087
0.093
0.091
0.07
In-trial PBO rate = 
Historical rate + 
6%*
0.865
0.927
0.948
0.672
0.095
0.105
0.108
0.07
In-trial PBO rate = 
Historical rate + 
10%
0.811
0.904
0.935
0.549
0.133
0.168
0.189
0.069
*
To determine the number of matched subjects, additional scenario of historical rate + 6% was also evaluated and 
the power and false positive rate are given in the table.
The simulation results show that power with matched placebo subjects from historical 
data is higher than that with in-trial placebo subjects only in all of the scenarios.  Power 
increases with the increase in the number of matched placebo subjects.  In the meantime, 
when the in-trial placebo rate is lower than or similar to the historical placebo rate, the 
false positive rates are controlled at approximately 0.05.  When the in-trial placebo rate is 
higher than historical placebo rate, the false positive rate increases with the increase in the 
number of matched subjects.  The inflation in the false positive rate is larger when higher 
in-trial placebo rate is observed.  The number of matched subjects is therefore determined 
by both achieving a high power and maintaining a slightly inflated false positive rate.
To determine the number of matched placebo subjects in the analysis, the following two 
criteria should be satisfied:
 


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●
One sided false positive rate is controlled at 10%;
●
Not to exceed 68 (approximately 3 times the number of in-trial placebo 
subjects).
The numbers of matched placebo subjects are given in the following table:
In-Trial PBO Rate
Number of Matched Subjects
≤ 33%
68
>33% and ≤ 34%
23
>34%
0
3.2
NRS30
With historical placebo rate at 26%, the following scenarios of the proportion of subjects 
achieving NRS30 at Week 12 were evaluated to assess the power and false positive rates 
with different number of matched subjects:
Scenario
Placebo Rate
Upadacitinib Rate*
In-trial PBO rate = Historical rate – 10%
0.16
0.46
In-trial PBO rate = Historical rate – 5%
0.21
0.46
In-trial PBO rate = Historical rate
0.26
0.46
In-trial PBO rate = Historical rate + 5%
0.31
0.46
In-trial PBO rate = Historical rate + 10%
0.36
0.46
*
Assume that upadacitinib performs at least as good as min TPP.
One-sided power and false positive rates for each scenario and different numbers of 
matching subjects were calculated, and the results from 10000 simulations (random seed:  
12345) are summarized in the following table:
 


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Power
False Positive Rate
Number of Matched 
Subjects
In-Trial 
Only
Number of Matched 
Subjects
In-Trial 
Only
Scenario
23
46
68
UPA vs 
PBO:  
45:23
23
46
68
UPA vs 
PBO:  
45:23
Historical rate -
10%
0.813
0.788
0.775
0.899
0.006
0.001
0
0.094
Historical rate - 5%
0.721
0.723
0.724
0.769
0.014
0.006
0.003
0.084
Historical rate 
(Base case)
0.625
0.65
0.668
0.603
0.03
0.018
0.012
0.077
Historical rate + 5%
0.521
0.573
0.607
0.434
0.057
0.045
0.038
0.077
Historical rate + 
10%
0.41
0.492
0.542
0.279
0.089
0.098
0.096
0.073
Historical rate + 
11%*
0.391
0.476
0.528
0.249
0.099
0.112
0.115
0.073
*
To determine the cutoff number in the matched subjects, additional scenario of historical rate + 11% is also 
conducted and the power and false positive rate are given in the above table.
The same conclusion can be reached with the results provided from the simulations.
The numbers of matched placebo subjects are given in the following table using the same 
criteria as for HiSCR:
In-Trial PBO Rate
Number of Matched Subjects
≤ 36%
68
>36% and ≤ 37%
23
>37%
0
 


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Appendix G.
List of Matching Subjects
Table A.
List of matching subjects for HiSCR:
Subject ID
Distance
Rank
2.57E-06
1
8.96E-05
2
0.000158
3
0.000268
4
0.000327
5
0.000411
6
0.000466
7
0.000475
8
0.000638
9
0.000688
10
0.000781
11
0.000937
12
0.000982
13
0.000998
14
0.001223
15
0.001303
16
0.001496
17
0.001548
18
0.001571
19
0.001755
20
0.001853
21
0.001972
22
0.00217
23
0.002261
24
0.002472
25
0.002498
26
0.002688
27
0.002832
28
0.002928
29
 


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Subject ID
Distance
Rank
0.003055
30
0.003187
31
0.004881
32
0.005842
33
0.006369
34
0.006551
35
0.007607
36
0.008428
37
0.009143
38
0.011198
39
0.012126
40
0.012508
41
0.013673
42
0.014632
43
0.015039
44
0.015057
45
0.015973
46
0.016307
47
0.0166
48
0.016938
49
0.018109
50
0.018142
51
0.018631
52
0.025821
53
0.026235
54
0.027435
55
0.030238
56
0.035562
57
0.036589
58
0.04232
59
0.045276
60
0.049032
61
 


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Subject ID
Distance
Rank
0.058936
62
0.072734
63
0.142095
64
0.199571
65
0.203572
66
0.212218
67
0.253149
68
Note:
the subject's rank is based on the distance, a subject with the closer distance has a higher rank.
Table B.
List of matching subjects for NRS30:
Subject ID
Distance
Rank
0.000269
1
0.000516
2
0.000929
3
0.001143
4
0.001297
5
0.001443
6
0.001773
7
0.002621
8
0.002963
9
0.003434
10
0.003834
11
0.004059
12
0.004439
13
0.004735
14
0.004945
15
0.005183
16
0.006073
17
0.00641
18
0.006571
19
0.00688
20
0.008785
21
 


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Subject ID
Distance
Rank
0.011996
22
0.012155
23
0.012481
24
0.012774
25
0.013329
26
0.014019
27
0.018572
28
0.019276
29
0.019987
30
0.020912
31
0.022264
32
0.022325
33
0.027872
34
0.029373
35
0.030355
36
0.034626
37
0.035711
38
0.037138
39
0.040258
40
0.041608
41
0.046707
42
0.048336
43
0.049609
44
0.050289
45
0.050512
46
0.051712
47
0.051713
48
0.05409
49
0.055272
50
0.055707
51
0.056069
52
0.057397
53
 


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Subject ID
Distance
Rank
0.058898
54
0.059654
55
0.06074
56
0.061507
57
0.064318
58
0.068315
59
0.074845
60
0.09129
61
0.09648
62
0.099541
63
0.100568
64
0.100701
65
0.102387
66
0.106828
67
0.112646
68
Note:
the subject's rank is based on the distance, a subject with the closer distance has a higher rank.