Clinical trial NCT04451772
Conditions: Systemic Lupus Erythematosus (SLE)
Keywords: Systemic Lupus Erythematosus ABBV-599 ABBV-105 ABT-494 Elsubrutinib Upadacitinib
Sponsor: AbbVie
Start date: 2020-07-27; Completion date: 2024-01-03
Enrollment: 185 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Systemic Lupus Erythematosus (SLE) is an immune-mediated disease associated with inflammation of multiple organ systems. This study will evaluate how well elsubrutinib and upadacitinib given alone or as the ABBV-599 combination (elsubrutinib/upadacitinib) works within the body, in participants who completed study M19-130. This study will assess the change in disease symptoms.

ABBV-599 is an investigational drug being developed for the treatment of Systemic Lupus Erythematosus (SLE). This study is "double-blinded", which means that neither the trial participants nor the study doctors will know who will be given which study drug. Study doctors put the participants into 1 of 4 groups called treatment arms. Each group receives a different treatment. Adult participants with a diagnosis of SLE will be enrolled. Around 260 participants will be enrolled in the study in approximately 100 sites worldwide.

Participants will receive the following for up to 56 weeks:

Participants will receive oral elsubrutinib capsules and/or oral upadacitinib tablets once daily for up to 56 weeks. Participants who were receiving elsubrutinib and/or upadacitnib in M19-130 will continue to receive the same treatment in this study. Participants who were receiving placebo in M19-130 will be re-randomized to one of the 2 combination treatment arms in this study.

Arm 1: Elsubrutinib Dose A and Upadacitinib Dose A Arm 2: Elsubrutinib Dose A and Upadacitinib Dose B

There may be higher burden for participants in this trial compared to their standard of care. Participants will attend monthly visits 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.

Detailed description:

Arms: arm 1: Participants received elsubrutinib 60 mg capsules once a day by mouth and upadacitinib 30 mg film-coated tablets once a day by mouth for 48 weeks in Study M19-130. Participants continued on this regimen in the current study (M20-186) for up to 56 weeks. arm 2: Participants received placebo capsules for elsubrutinib once a day by mouth and upadacitinib 30 mg film-coated tablets once a day by mouth for 48 weeks in Study M19-130. Participants continued on this regimen in the current study (M20-186) for up to 56 weeks. arm 3: Participants received placebo capsules for elsubrutinib once a day by mouth and placebo film-coated tablets for upadacitinib once a day by mouth for 48 weeks in Study M19-130. Participants received elsubrutinib 60 mg capsules once a day by mouth and upadacitinib 30 mg film-coated tablets once a day in the current study (M20-186) for up to 56 weeks. arm 4: Participants received elsubrutinib 60 mg capsules once a day by mouth and upadacitinib 15 mg film-coated tablets once a day by mouth for 48 weeks in Study M19-130. Participants continued on this regimen in the current study (M20-186) for up to 56 weeks. arm 5: Participants received elsubrutinib 60 mg capsules once a day by mouth and placebo film-coated tablets for upadacitinib once a day by mouth for 48 weeks in Study M19-130. Participants continued on this regimen in the current study (M20-186) for up to 56 weeks. arm 6: Participants received placebo capsules for elsubrutinib once a day by mouth and placebo film-coated tablets for upadacitinib once a day by mouth for 48 weeks in Study M19-130. Participants received elsubrutinib 60 mg capsules once a day by mouth and upadacitinib 15 mg film-coated tablets once a day by mouth for 48 weeks in the current study (M20-186) for up to 56 weeks.
Interventions: intervention 1: Elsubrutinib intervention 2: Placebo for Elsubrutinib intervention 3: Upadacitinib intervention 4: Placebo for Upadacitinib
Intervention descriptions: intervention 1: Capsule; Oral intervention 2: Capsule; Oral intervention 3: Film-coated tablet; Oral intervention 4: Film-coated tablet; Oral

Protocol documents:
Prot_000.pdf: 


  
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TABLE OF CONTENTS
1
SYNOPSIS
5
2
INTRODUCTION
10
2.1
BACKGROUND AND RATIONALE
10
2.2
BENEFITS AND RISKS TO SUBJECTS
11
3
OBJECTIVES AND ENDPOINTS
13
3.1
PRIMARY ENDPOINT
13
3.2
SECONDARY ENDPOINTS
13
3.3
ADDITIONAL EFFICACY ENDPOINTS
13
3.4
SAFETY ENDPOINTS
14
4
INVESTIGATIONAL PLAN
15
4.1
OVERALL STUDY DESIGN AND PLAN
15
4.2
DISCUSSION OF STUDY DESIGN
17
5
STUDY ACTIVITIES
18
5.1
ELIGIBILITY CRITERIA
18
5.2
CONTRACEPTION RECOMMENDATIONS
20
5.3
PROHIBITED MEDICATIONS AND THERAPY
22
5.4
PRIOR AND CONCOMITANT THERAPY
24
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
25
5.6
FOLLOW-UP AFTER SUBJECT DISCONTINUATION OF STUDY DRUG OR FROM STUDY
27
5.7
STUDY DRUG
28
5.8
RANDOMIZATION/DRUG ASSIGNMENT
29
5.9
PROTOCOL DEVIATIONS
30
6
SAFETY CONSIDERATIONS
30
6.1
COMPLAINTS AND ADVERSE EVENTS
30
6.2
TOXICITY MANAGEMENT
36
6.3
DATA MONITORING COMMITTEE
40
7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
41
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7.1
STATISTICAL AND ANALYTICAL PLANS
41
7.2
DEFINITION FOR ANALYSIS POPULATIONS
41
7.3
STATISTICAL ANALYSES FOR EFFICACY
41
7.4
STATISTICAL ANALYSES FOR SAFETY
42
7.5
INTERIM ANALYSIS
42
7.6
OVERALL TYPE I ERROR CONTROL
42
7.7
SAMPLE SIZE DETERMINATION
42
8
ETHICS
43
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD
43
8.2
ETHICAL CONDUCT OF THE STUDY
43
8.3
SUBJECT CONFIDENTIALITY
43
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
43
10
DATA QUALITY ASSURANCE
44
11
COMPLETION OF THE STUDY
44
12
REFERENCES
45
LIST OF TABLES
TABLE 1.
EXAMPLES OF COMMONLY USED STRONG CYP3A OR CYP1A2 INHIBITORS AND INDUCERS
23
TABLE 2.
INVESTIGATIONAL STUDY DRUG(S)
29
TABLE 3.
ADVERSE EVENTS REQUIRING SUPPLEMENTAL REPORTS
32
TABLE 4.
SPECIFIC TOXICITY MANAGEMENT GUIDELINES FOR ABNORMAL LABORATORY VALUES
38
LIST OF FIGURES
FIGURE 1.
STUDY SCHEMATIC
17
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LIST OF APPENDICES
APPENDIX A.
STUDY-SPECIFIC ABBREVIATIONS AND TERMS
47
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
51
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
52
APPENDIX D.
ACTIVITY SCHEDULE
53
APPENDIX E.
DESCRIPTION OF EFFICACY MEASURES
57
APPENDIX F.
LOCAL REQUIREMENTS
59
APPENDIX G.
PROTOCOL SUMMARY OF CHANGES
60
APPENDIX H.
OPERATIONS MANUAL
62
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2 INTRODUCTION
2.1 Background and Rationale
Why This Study Is Being Conducted
The ABBV-599 (elsubrutinib/upadacitinib) combination is an innovative combination therapy that 
targets non-overlapping signaling pathways implicated in systemic lupus erythematosus (SLE).  As 
described below, Janus kinase 1 (JAK1) inhibition via upadacitinib is expected to disrupt T-cell activation 
and Type I interferon (IFN) signaling, whereas elsubrutinib (ABBV-105) is expected to inhibit B-cell 
activation and immune complex-driven activation of dendritic cells (and neutrophils).  As such, the 
ABBV-599 (elsubrutinib/upadacitinib) combination has the potential for differentiated efficacy in SLE 
through concurrent inhibition of multiple pathogenic nodes.
Autoantibody generation by pathogenic B cells, which is dependent on B-cell receptor signaling, is a 
hallmark of autoimmune diseases, such as rheumatoid arthritis (RA) and SLE.1
Bruton's tyrosine kinase (BTK) is a non-receptor tyrosine kinase expressed in multiple immune cell types 
associated with the pathogenesis of SLE and other autoimmune diseases.  Bruton's tyrosine kinase is 
required for the propagation of pro-inflammatory signals downstream of immunoreceptors that 
promote autoimmune disease pathogenesis.
The hematopoietic expression and signaling function of BTK downstream of numerous receptors has 
raised interest in pharmacologic targeting of BTK for immune-mediated inflammatory diseases.2  The 
potential clinical value of BTK inhibition has been supported by studies in preclinical models of arthritis 
and lupus.3,4  These have demonstrated:  1) complete abrogation of arthritis in the collagen-induced 
arthritis model when initiated at disease onset, consistent with the effect of BTK inhibition on 
autoantibody production,3,4 2) efficacy in myeloid-mediated animal arthritis models, consistent with the 
effects of BTK inhibition on macrophage, mast cell, dendritic cell, and neutrophil activity,3,4 and 
3) marked reductions of proteinuria in mouse models of lupus, consistent with the effect of BTK 
inhibition on autoantibody production and/or myeloid cell activation.5-7
Upadacitinib (ABT-494), an oral Janus kinase (JAK) inhibitor, was approved in 2019 under the brand 
name Rinvoq™ for the treatment of patients with RA in the United States (US), the European Union (EU), 
and Japan.  Upadacitinib is being investigated in separate clinical studies in other indications, which 
include psoriatic arthritis, active axial spondyloarthritis, ulcerative colitis, Crohn's disease, atopic 
dermatitis, giant cell arteritis, and polyarticular course juvenile idiopathic arthritis.
Clinical Hypothesis
Inhibition of JAK1 pathways in combination with BTK pathways in SLE will provide greater clinical 
efficacy compared with inhibition of each individual pathway when they are added to current standard 
of care while maintaining an acceptable safety profile.
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2.2 Benefits and Risks to Subjects
Both upadacitinib and elsubrutinib have the potential, when added to current standard of care, to offer 
clinically meaningful efficacy over the current standard of care for the treatment of SLE with an 
acceptable safety profile.  The ABBV-599 (elsubrutinib/upadacitinib) combination of BTK inhibition by 
elsubrutinib and JAK1 inhibition by upadacitinib has the potential to provide even greater clinical 
efficacy compared with either monotherapy while maintaining an acceptable safety profile.
Upadacitinib is approved as a single-ingredient agent for the treatment of RA and is being developed for 
other inflammatory diseases, several of which are in Phase 3 development.  Preclinical models and 
clinical samples from Phase 1 studies with upadacitinib have demonstrated that upadacitinib has 
minimal impact on the Janus kinase 2 (JAK2) and Janus kinase 3 (JAK3) at efficacious drug levels, in 
contrast to its inhibitory effects on JAK1.  The enhanced selectivity of upadacitinib for JAK1 may offer an 
improved benefit/risk profile compared with less selective JAK inhibition in patients with 
immune-mediated inflammatory diseases due to reduced JAK2-related effects such as inhibition of 
erythropoiesis and inhibition of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, 
the latter of which plays a critical role in a myelopoietic response to microbial infection.  In addition, 
there is reduced potency of upadacitinib against JAK3 thereby minimizing the reduction in natural killer 
(NK) cells.  Hence, the JAK2- and JAK3-sparing properties of upadacitinib may manifest as a reduced risk 
of anemia and infection compared with less selective JAK inhibitors such as tofacitinib (Xeljanz®) and 
baricitinib (Olumiant®).  On the basis of this differentiated selectivity profile for the inhibition of JAK 
kinases, there is potential for an improved benefit/risk profile of upadacitinib compared with other JAK 
inhibitors currently in clinical trials.
Identified risks for upadacitinib are summarized in the upadacitinib Investigator's Brochure8 and include:  
serious infections, opportunistic infections and tuberculosis (TB), and herpes zoster.  Potential risks for 
upadacitinib include:  malignancies, including lymphoma and non-melanoma skin cancer (NMSC), 
gastrointestinal (GI) perforations, major adverse cardiovascular events (MACE), hematologic changes 
(anemia, neutropenia, and lymphopenia), increased serum creatinine and renal dysfunction, hepatic 
events and increased hepatic transaminases, elevated creatine phosphokinase (CPK), embolic and 
thrombotic events (non-cardiac, non-central nervous system [CNS]), and fetal risks.
As of 15 December 2019, 171 healthy volunteers have received at least 1 dose of elsubrutinib; the most 
common side effect reported was headache, mild in severity.
As of 06 May 2020, from the Phase 2 RA and SLE studies, there are no identified safety risks for 
elsubrutinib or for ABBV-599 (elsubrutinib/upadacitinib) combination.
A detailed description of the preclinical pharmacology, metabolism, and toxicology datasets can be 
found in the elsubrutinib9 and upadacitinib8 Investigator's Brochures.  The results of genetic toxicology 
testing indicate that elsubrutinib and upadacitinib are not genotoxic.  Preclinical embryofetal 
development studies indicate that elsubrutinib and/or upadacitinib are embryotoxic, fetotoxic, and/or 
teratogenic.
Systemic lupus erythematosus patients are known to have an increased risk of thrombosis.  Based on 
this and the potential risk of thrombosis with the use of JAK inhibitors, the use of estrogen-containing 
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contraceptives may further increase the risk of thrombotic events; therefore, the choice of 
contraceptive should be carefully considered.
In LTE Study M20-186, benefit/risk assessment of treatment groups for rollover may require subjects to 
be reassigned or discontinued based on the outcome of the unblinded interim analysis from the feeder 
Study M19-130 (See Section 4 Investigational Plan).  Routine safety evaluations of all treatment groups
will be performed.  These include assessments of deaths, serious adverse events (SAEs), non-serious 
adverse events (AEs), withdrawals, and pregnancies, as well as routine monitoring by physical 
examinations, vital sign measurements, electrocardiograms, (ECGs), and clinical laboratory testing 
(hematology, chemistry, and urinalysis).
For the safety of subjects, the following exclusions and ongoing assessments are included in the 
protocol:

Exclusion of subjects with chronic or recent infections including active TB.

Evaluating subjects for TB [TB as assessed by IFN Gamma Release Assay (IGRA QuantiFERON®-TB 
Gold In-Tube test or equivalent), and/or a purified protein derivative (tuberculin) (PPD) test (or 
both if required per local guidelines)].

If different national regulations exist for evaluating TB while being on immunosuppressive 
treatment, these national regulations will be applied, respectively.

If a subject develops a serious infection (including coronavirus disease 2019 [COVID-19]) or 
serious opportunistic infection (excludes non-serious oropharyngeal candidiasis) with study 
treatment, study drug should be interrupted, and appropriate treatment of the infection should 
be initiated.

Review SAEs of infection on a real-time basis and query for additional information as clinically 
indicated.

A supplemental herpes zoster form will be used to collect additional information for any herpes 
zoster events.
See Section 3.4 for detailed safety endpoints and Section 6.3 for information on the Data Monitoring 
Committee (DMC).
For further details, please see findings from completed studies, including safety data in the elsubrutinib9
and upadacitinib8 Investigator's Brochures.
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 elsubrutinib and upadacitinib on the course of 
COVID-19 are not well-defined.  Further guidance regarding COVID-19 infection is provided in 
Section 6.2.
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3 OBJECTIVES AND ENDPOINTS
Objectives and Hypothesis
Primary
The primary objective is to evaluate the longer-term safety and tolerability of elsubrutinib and 
upadacitinib given alone or as the ABBV-599 (elsubrutinib/upadacitinib) combination in SLE subjects 
who have completed the M19-130 Phase 2 study.
There is no planned hypothesis to be tested for this long-term extension (LTE) study.
Secondary
The secondary objective is to obtain longer-term efficacy data beyond Week 48 and to more fully assess 
the benefit/risk of each assigned treatment over time.
3.1 Primary Endpoint
There is no primary efficacy endpoint since this is the extension to the feeder Study M19-130.
3.2 Secondary Endpoints
Secondary efficacy endpoints for this study, measured at specified study visits, include the following:
1.
Achievement of SLE Responder Index (SRI)-4
2.
Achievement of British Isles Lupus Assessment Group (BILAG)-Based Combined Lupus 
Assessment (BICLA) response
3.
Steroid burden, assessed as change from M19-130 Baseline
4.
Number of mild, moderate, or severe flares per patient-year (respectively and overall) by Safety 
of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLE Disease Activity Index 
(SLEDAI) flare index (SFI), assessed by number and types of flare per subject 
3.3 Additional Efficacy Endpoints
Additional efficacy endpoints for this study, measured at specified study visits, include the following:
1.
Achievement of Lupus Low Disease Activity State (LLDAS)
2.
Achievement of ≥ 4-point decrease in SLEDAI-2K compared with M19-130 Baseline
3.
Achievement of 50% reduction of tender or swollen lupus joints (of those starting with total 
≥6 affected joints) from M19-130 Baseline
4.
Achievement of 50% reduction in Cutaneous Lupus Erythematosus Disease Area and Severity 
Index (CLASI) activity score (of those starting with CLASI ≥ 10 at M19-130 Baseline)
5.
Change in SLEDAI-2K from M19-130 Baseline
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6.
Change in BILAG from M19-130 Baseline
7.
Change in Physician's Global Assessment (PhGA) from M19-130 Baseline
8.
Change in Patient Global Assessment (PtGA) from M19-130 Baseline
9.
Change in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue from M19-130 
Baseline
10. Change in 36-Item Short Form Health Survey (SF-36) from M19-130 Baseline
11. Change in Lupus Quality of Life questionnaire (LupusQoL) from M19-130 Baseline
12. Change in Pain Numerical Rating Scale (NRS) from M19-130 Baseline
13. Number of withdrawals from study drug due to lack of efficacy
For more information on the description of efficacy measures, refer to Appendix E.
3.4 Safety Endpoints
The following safety evaluations will be performed for the entire study duration as measures of safety 
and tolerability:

AE monitoring

Physical examinations

Vital sign measurements

ECGs

Clinical laboratory testing (hematology, chemistry, and urinalysis)
Serious adverse events will be assessed at any dose that results in a death, inpatient hospitalization or 
prolongation of existing hospitalization, persistent or significant disability/incapacity, or a congenital 
anomaly (see Section 6.1 for more details).
The following areas of safety interest will be routinely assessed to identify any major safety findings 
related to immunosuppression or potential risks associated with the individual classes of therapy:  
serious and/or opportunistic infections, herpes zoster, active TB, malignancies (all types), adjudicated GI 
perforations, adjudicated cardiovascular events (e.g., MACE), anemia, neutropenia, lymphopenia, renal 
dysfunction, hepatic disorders, and adjudicated embolic and thrombotic events (non-cardiac, non-CNS) 
including venous thromboembolic events defined as pulmonary embolism and deep vein thrombosis 
(see Section 6.1 for more details).
Specific toxicity management measures will be utilized, as described in Section 6.2, for serious 
infections, serious GI events, cardiovascular events (MACE), malignancy, ECG abnormalities, and select 
laboratory abnormalities.  In addition, a 30-day follow-up phone call from the last dose of study drug 
should occur to determine the status of any ongoing AEs/SAEs, or the occurrence of any new AEs/SAEs.
Additional safety monitoring measures include an independent Cardiovascular Adjudication Committee 
(CAC) (see Section 6.1) and an internal DMC (see Section 6.3).
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4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
This is a multicenter, double-blind LTE Phase 2 study to investigate the longer-term safety and efficacy of 
elsubrutinib and upadacitinib given alone or as the ABBV-599 (elsubrutinib/upadacitinib) combination in 
subjects with moderately to severely active SLE.  The study population will consist of approximately 195 
to 260 individuals with moderately to severely active SLE despite standard of care therapy.
Subjects who participated in Study M19-130 may be offered the opportunity to consent for this study.  
The number of subjects participating in this study will not be greater than the number randomized into 
Study M19-130.  Subjects discontinuing study drug prematurely in Study M19-130 are not eligible to 
participate in the LTE study.
In Study M19-130, subjects were randomized in a 1:1:1:1:1 ratio to one of 5 treatment groups: 

Elsubrutinib 60 mg once a day (QD) and upadacitinib 30 mg QD (projected n = 65)

Elsubrutinib 60 mg QD and upadacitinib 15 mg QD (projected n = 65)

Elsubrutinib 60 mg QD and upadacitinib placebo QD (projected n = 65)

Elsubrutinib placebo QD and upadacitinib 30 mg QD (projected n = 65)

Elsubrutinib placebo QD and upadacitinib placebo QD (projected n = 65) 
Prior to the planned Study M19-130 Interim Analysis, qualified subjects entering into LTE Study M20-186 
stayed in their original treatment group from Study M19-130 if on an ABBV-599 
(elsubrutinib/upadacitinib) combination, elsubrutinib 60 mg monotherapy, or upadacitinib 30 mg 
monotherapy.  Those originally assigned to the placebo group in Study M19-130 were randomized
centrally in a 1:1 ratio to the 2 ABBV-599 (elsubrutinib/upadacitinib) combination treatment groups.
Prior to the planned Study M19-130 Interim Analysis, there were 4 treatment groups in this LTE study:

Group 1:  Elsubrutinib 60 mg QD and upadacitinib 30 mg QD

Group 2:  Elsubrutinib 60 mg QD and upadacitinib 15 mg QD

Group 3:  Elsubrutinib 60 mg QD and upadacitinib placebo QD

Group 4:  Elsubrutinib placebo QD and upadacitinib 30 mg QD
A planned unblinded interim analysis for Study M19-130 was scheduled when 50% of the planned 
subjects completed their Week 24 assessments.  The objective of this analysis was to reassess the 
treatment regimens in Study M19-130 and the benefit/risk for rollover into LTE Study M20-186.
The Study M19-130 Interim Analysis was performed by an independent team at AbbVie that was 
separate and apart from the blinded study team for Study M19-130.  The M19-130 study team will 
remain blinded through the Study M19-130 Week 24 Primary Analysis.
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An Interim Unblinding Plan (IUP) was developed separately describing the analyses to be performed and 
included execution logistics, an unblinded analysis team, and the data chain of custody to protect the 
integrity of the study.
An Internal Executive Review Committee (IERC) reviewed the interim unblinded results as specified in 
the IERC charter and decided which treatment group(s) should be continued in Study M19-130 and for 
rollover into LTE Study M20-186.  Study sites and subjects remained blinded to treatment assignment in 
Study M19-130 and LTE Study M20-186 throughout the studies.
Based on the benefit/risk assessment of the planned Study M19-130 Interim Analysis, subjects in 1 or 
more groups of LTE Study M20-186 may be discontinued.  Subjects in any discontinued group(s) should 
return for a Premature Discontinuation (PD) visit and have a follow-up phone call 30 days after the last 
study drug dose.
Subjects originally assigned to the placebo group in Study M19-130 will be rolled over and will be 
randomized to an active treatment group in LTE Study M20-186.
This study includes a 56-week double-blind treatment period with study visits conducted at Weeks 48, 
56, 64, 72, 80, 88, 96, and 104 (from the Baseline visit of Study M19-130), and a subsequent telephone 
follow-up call 30 days after the last visit to determine the status of any ongoing AEs/SAEs or the 
occurrence of any new AEs/SAEs.  The plan is to extend the trial if data support the safety and efficacy 
endpoints during the 56-week LTE study duration.
An interim analysis for LTE Study M20-186 may be performed to aid data interpretation and to facilitate 
interactions with regulatory authorities.
The schematic of the study is shown in Figure 1.  Further details regarding study procedures are located 
in the Operations Manual (Appendix H).  See Section 5 for information regarding eligibility criteria.
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Figure 1.
Study Schematic
QD = once daily
4.2 Discussion of Study Design
Choice of Control Group
There will not be any placebo control in LTE Study M20-186.  Subjects in LTE Study M20-186 will roll 
over from Study M19-130.  The objective of this LTE study is to evaluate longer-term safety and 
tolerability of elsubrutinib, upadacitinib, and ABBV-599 (elsubrutinib/upadacitinib) combination in SLE, 
and thus the primary comparison will be relative to the safety profile observed in each treatment group 
during the initial randomized study.
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  All safety and 
efficacy measurements in this study are standard for assessing disease activity in subjects with SLE being 
treated with immunosuppressive therapies.  All clinical and laboratory procedures in this study are 
standard and generally accepted.
Suitability of Subject Population
After the planned Study M19-130 Interim Analysis, this rollover LTE study will enroll subjects who have 
successfully completed 48 weeks of treatment in Study M19-130 on placebo or a treatment group that is 
still active.  Only those subjects who have met all of the specified eligibility criteria will have an option to 
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enter the LTE study to receive continued therapy, provided the subject is willing and the investigator 
believes that continuing therapy is appropriate.
Selection of Doses in the Study
The dose selection in Study M19-130 was based on analysis of pharmacokinetic, pharmacodynamic, 
safety, and efficacy (upadacitinib only) data from Phase 1 studies in healthy volunteers for elsubrutinib, 
Phase 2 and Phase 3 studies for upadacitinib in RA, as well as a published study of baricitinib in SLE.8-10
The 60 mg dose of elsubrutinib is intended to target exposures at or greater than those needed to 
achieve maximal peripheral BTK occupancy.  Following QD dosing of elsubrutinib 60 mg, peak and 
trough BTK occupancy at steady-state are predicted to be 99% and 89%, respectively.  Furthermore, the 
elsubrutinib dose of 60 mg (administered alone or with upadacitinib 30 mg) has been shown to be safe 
and well-tolerated in Phase 1 studies in healthy subjects.
The selected dosing regimens of upadacitinib are 15 and 30 mg QD (testing both dose levels in the 
ABBV-599 [elsubrutinib/upadacitinib] combination and only the higher dose in the upadacitinib 
monotherapy treatment group).  These doses are based on the well-tolerated safety profile of 
upadacitinib in Phase 3 RA studies as well as extrapolation of data from a recently published 
Phase 2 study of baricitinib in SLE.10  In that study, the baricitinib 2 mg QD dosing regimen demonstrated 
negligible efficacy while the 4 mg QD regimen provided evidence of therapeutic benefit; indicating that 
higher doses of baricitinib may be needed to demonstrate efficacy in SLE compared with RA.10  
Furthermore, comparison of in vitro cellular inhibition of Type I IFN signaling showed comparable 
potency between upadacitinib and baricitinib (i.e., comparable concentration producing 50% inhibition 
[IC50] values).  Predicted plasma-concentration time profiles for upadacitinib and baricitinib indicate that 
the upadacitinib 15 mg QD dosing regimen is predicted to result in plasma concentrations that provide 
higher inhibitory efficacy (e.g., time above IC50) compared with the baricitinib 2 mg QD dosing regimens; 
whereas the upadacitinib 30 mg QD regimen is predicted to provide similar or higher inhibitory efficacy 
compared with the baricitinib 4 mg QD dosing regimen.
Doses selected for continuation in the LTE study may be modified or discontinued at any time based on 
the outcome of the planned Study M19-130 Interim Analysis and at AbbVie's discretion.
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.
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Consent
1. Subjects or their legally authorized representative (if required per local regulations) must 
understand and personally, voluntarily sign and date an informed consent, approved by an 
independent ethics committee (IEC)/institutional review board (IRB), prior to the initiation of 
any study-specific procedures.  In Japan, subjects under 20 years of age must voluntarily sign 
and date an informed consent, in addition to their parent or legal guardian.  Legally authorized 
representation will not apply in the case of Germany and France, and protected persons such as 
minors, adults under guardianship, pregnant women, persons deprived of their liberty and 
persons incapable or unable to express their consent cannot be included in the study.
2. Subjects are willing and able to comply with procedures required in this protocol.
Demographic and Laboratory Assessments
3. Subjects have completed Study M19-130 on study drug and have not developed any 
laboratory or clinical discontinuation criteria as defined in that study.
Relevant Study M19-130 eligibility requirements applicable to LTE Study M20-186 are as follows:
a.
Must be on stable background treatment throughout the study with antimalarial(s), 
prednisone (or prednisone-equivalent) (≤ 20 mg), azathioprine (≤ 150 mg), mycophenolate 
(≤ 2 g), leflunomide (≤ 20 mg), cyclosporine, tacrolimus, and/or MTX (≤20 mg).

The combination of background treatment with antimalarial(s) and/or prednisone (or 
equivalent) is permitted 

and a single, but not multiple, additional immunosuppressant from the list above, is 
permitted.
b.
Must not have any active, chronic, or recurrent viral or bacterial infection that, based on the 
investigator's clinical assessment, makes the subject an unsuitable candidate for the study.
c.
Must not have active TB.
d.
Must not have a history of any malignancy except for successfully treated NMSC or localized 
carcinoma in-situ (CIS) of the cervix.
e.
Must not currently have clinically significant (per investigator's judgment) drug or alcohol 
abuse.
f.
Must not have a history of GI perforation (other than appendicitis or penetrating injury), 
diverticulitis, or significantly increased risk for GI perforation per investigator judgment.
g.
Must not have any conditions that could interfere with drug absorption including but not 
limited to short bowel syndrome (e.g., subjects with a history of gastric bypass surgery are 
excluded).  Subjects with a history of gastric banding/segmentation are not excluded.
h.
Must not be a recipient of an organ transplant.
i.
Must not have history of clinically significant medical conditions or any other reason that in 
the opinion of the investigator would interfere with the subject's participation in this study 
or would make the subject an unsuitable candidate to receive study drug.
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j.
Must not have a history of an allergic reaction or significant sensitivity to constituents of the 
study drugs (and its excipients) and/or other products in the same class.
k.
Must not have any clinically relevant or significant ECG abnormalities at LTE 
Baseline/M19-130 Week 48, including ECG with QT interval corrected for heart rate (QTc) 
using Fridericia's correction formula (QTcF) > 480 msec.  In subjects with ventricular 
conduction delay (QRS > 120 msec), cardiologist consultation is required.
l.
Women of childbearing potential (WOCBP) must have a negative urine pregnancy test at LTE 
Baseline/M19-130 Week 48 prior to the first dose of study drug.
m. If female, subject must be either postmenopausal, OR permanently surgically sterile OR for 
WOCBP practicing at least 1 protocol-specified method of birth control (Section 5.2), that is 
effective from Study Day 1 through at least 30 days after the last dose of study drug and in 
agreement with local regulations
n.
Women must not be pregnant, breastfeeding, or considering becoming pregnant during the 
study and for at least approximately 30 days after the last dose of study drug.
o.
Subjects must not require vaccination with any live vaccine during study participation 
including at least 30 days after the last dose of study drug (see Section 5.3 for additional 
information on vaccines).
4. Latent TB for which the subject refuses to or cannot take prophylaxis.
Subject History
5. No history of clinically significant medical conditions or any other reason that the investigator 
determines would interfere with the subject's participation in this study or would make the 
subject an unsuitable candidate to receive study drug.
Concomitant Medications
6. Subject must not have been treated with any investigational drug (except those used in 
Study M19-130) within 30 days or 5 half-lives of the drug (whichever is longer) prior to the first 
dose of study drug or be currently enrolled in any study (except in the preceding 
Study M19-130) or planning to enroll in another interventional clinical study while participating 
in this study.
5.2 Contraception Recommendations
Contraception Requirements for Females
Systemic lupus erythematosus patients are known to have an increased risk of thrombosis.  There is a 
potential risk of thrombosis with the use of JAK inhibitors.  The use of estrogen-containing 
contraceptives may further increase the risk of thrombotic events; therefore, the choice of 
contraceptive should be carefully considered.
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Subjects must follow the following contraceptive guidelines as specified:

Females, Non-Childbearing Potential
Women do not need to use birth control during or following study drug treatment if considered 
of non-childbearing potential due to meeting any of the following criteria:

Postmenopausal, age > 55 years with no menses for 12 or more months without an 
alternative medical cause.

Postmenopausal, age ≤ 55 years with no menses for 12 or more months without an 
alternative medical cause AND a follicle-stimulating hormone (FSH) level > 40 IU/L.

Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy, or 
hysterectomy).

Women of Childbearing Potential 

WOCBP must avoid pregnancy while taking study drug(s) and for at least 30 days after the 
last dose of study drug.  They must commit to one of the following highly effective methods 
of birth control with:

Combined (estrogen- and progestogen-containing) hormonal contraception (oral, 
intravaginal, transdermal, injectable) associated with the inhibition of ovulation.

Progestogen-only hormonal contraception (oral, injectable, implantable) associated 
with inhibition of ovulation.

Bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a 
hysterosalpingogram confirms success of the procedure).  For Japan:  only bilateral tubal 
ligation.

Vasectomized partner, provided the partner has received medical confirmation of 
surgical success, and is the sole sexual partner of the WOCBP trial participant.

Intrauterine device (IUD).

Intrauterine hormone-releasing system (IUS).

Practice true abstinence (if acceptable per local requirements):  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).
For the local requirements for contraception in Japan, please refer to Appendix F.
If required per local practices, WOCBP 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.

Male or female condom with or without spermicide.
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
Cap, diaphragm, or sponge with spermicide.

A combination of male condom with a cap, diaphragm, or sponge with spermicide 
(double-barrier method).
A condom is required in the following countries:  United Kingdom (UK), Germany, and Spain.
If during the course of the study a woman becomes surgically sterile or post-menopausal (defined 
above) and complete documentation is available, contraceptive measures as defined above are no 
longer required.
It is important to note that the contraception requirements described above are specifically intended to 
prevent pregnancy during exposure to the investigational therapies (elsubrutinib and/or upadacitinib).  
For concomitant immunosuppressive agent(s) (i.e., MTX, azathioprine, mycophenolate, leflunomide, 
etc.) that have been prescribed per standard of care prior to study entry and are allowed to be 
continued during the study, contraception should continue while the subject is on the concomitant 
immunosuppressive agent(s).  The duration of contraception after discontinuation of these 
immunosuppressive agent(s) should be based on the local product labeling.  Urine pregnancy testing 
shall be performed at monthly intervals in the study activity schedule.
Additional local requirements may apply and should be followed accordingly.
Contraception Requirements for Males
There are no contraception recommendations for males participating in the study.
5.3 Prohibited Medications and Therapy
In addition to the medications listed in the eligibility criteria, the following are prohibited while subjects 
are on study drug:

Cyclophosphamide

Belimumab

Rituximab

Granulocyte-colony stimulating factor (GCSF)

Intravenous immunoglobulin (IVIG)

Strong cytochrome P450 3A isoform subfamily (CYP3A) or cytochrome P450 1A2 isoform 
subfamily (CYP1A2) inhibitors and inducers (examples found in Table 1)

Traditional Chinese medicines

High-potency narcotics (unless administered during a hospitalization) including (but not limited 
to):

Oxycodone

Oxymorphone
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
Fentanyl

Levorphanol

Buprenorphine

Methadone

Hydromorphone

Morphine

Meperidine

Of note, low-potency narcotics are permitted to optimize SLE medications (see Section 5.4 for 
details).
Table 1.
Examples of Commonly Used Strong CYP3A or CYP1A2 Inhibitors and Inducers
Strong CYP3A Inhibitors
Strong CYP3A Inducers
Boceprevir
Cobicistat
Clarithromycin
Conivaptan
Grapefruit (fruit or juice)
Indinavir
Itraconazole
Ketoconazole
Lopinavir/Ritonavir
Mibefradil
Nefazodone
Nelfinavir
Posaconazole
Ritonavir
Saquinavir
Telaprevir
Telithromycin
Troleandomycin
Voriconazole
Carbamazepine
Phenytoin
Rifampin  
Rifapentine
St. John's Wort
Strong CYP1A2 Inhibitors
Strong CYP1A2 Inducers
Fluvoxamine
Ciprofloxacin
Enoxacin
Zafirlukast
Rifampin
CYP3A = Cytochrome P450 3A isoform subfamily; CYP1A2 = Cytochrome P450 1A2 isoform subfamily
Vaccines
Although not mandated by the protocol, vaccines recommended by local guidelines should be 
considered.  Live vaccines are not permitted during the study.  If the subject and investigator choose to 
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administer live vaccines, these vaccinations must be completed or administered at least 30 days after 
last dose of study drug.
Examples of live vaccines include, but are not limited to, the following:

Monovalent live influenza A (H1N1) (intranasal);

Seasonal trivalent live influenza (intranasal);

Herpes zoster (i.e., Zostavax®);

Rotavirus;

Varicella (chicken pox);

Measles-mumps-rubella or measles mumps rubella varicella;

Oral polio vaccine;

Smallpox;

Yellow fever;

Bacille Calmette-Guérin (BCG);

Typhoid.
Examples of common vaccines that are inactivated, toxoid or biosynthetic, include but are not limited 
to:  injectable influenza vaccine, Shingrix™ (herpes zoster), pneumococcal, and pertussis (Tdap) vaccines.
5.4 Prior and Concomitant Therapy
Subjects taking the following concomitant medications/therapy are required to follow the directives 
below: 
Allowed Concomitant Medications/Therapy 
Comments/Notes
Methotrexate
≤ 20 mg/week with concomitant folic acid ≥5 mg/week
Azathioprine
≤ 150 mg/ day
Mycophenolate mofetil 
≤ 2,000 mg/day
Mycophenolate sodium
≤ 1,440 mg/day
Hydroxychloroquine
≤ 400 mg/day
Chloroquine
≤ 500 mg/day
Quinacrine
≤ 100 mg/day
Leflunomide 
≤20 mg/day
Cyclosporine 
Dosed by serum levels
Tacrolimus 
Dosed by serum levels
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Corticosteroids (prednisone – equivalent)
≤ 20 mg per day, decrease no faster than 5 mg QD per 
week
Rescue Concomitant Medications/Therapy 
Comments/Notes
Corticosteroids (prednisone-equivalent)
Continued reduction of corticosteroids is an important 
goal of therapy, as medically indicated, throughout this 
long-term study.
Subjects must remain on their background therapy throughout the entirety of the study.  The only 
permitted change of background therapy is steroid tapering.  If applicable, subjects should continue on 
their stable doses of nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and low-potency 
narcotics.  For NSAIDs, acetaminophen/paracetamol, tramadol, codeine, hydrocodone, and 
propoxyphene that are part of background therapy, changes in dose, including initiation, are not 
allowed, with the exception of protocol-defined rescue therapy.  The following medications taken as 
needed (PRN) are allowed, but should not be taken within the 24 hours prior to any study visit:  NSAIDs, 
acetaminophen/paracetamol, tramadol, codeine, hydrocodone, and propoxyphene.  In the event of 
tolerability (or other safety) issues, the doses of NSAID and/or acetaminophen may be decreased or 
discontinued with substitution of another NSAID.
Note:  If medication supply issues result in a change in background therapy due to pandemic changes, 
substitutions meeting protocol requirements are permitted and must be approved by the AbbVie 
Therapeutic Area Medical Director (TA MD).
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 enrollment or receives during the study 
must be recorded through the post-treatment visit (30-day follow-up phone call).
Any questions regarding concomitant or prior therapy should be raised to the AbbVie TA MD.  
Information regarding potential drug interactions with elsubrutinib and/or upadacitinib can be located 
in the individual elsubrutinib and upadacitinib Investigator's Brochures.
5.5 Withdrawal of Subjects and Discontinuation of Study
Subjects can request to be discontinued from participating in the study at any time for any reason 
including but not limited to disease progression or lack of response to treatment.  The investigator may 
discontinue any subject's study treatment at any time for any reason, including but not limited to, 
disease progression, lack of response to treatment, safety concerns, or failure to comply with the 
protocol.  See Section 6.2 for toxicity management criteria.
Subjects will be discontinued from study drug immediately if any of the following occur:

Development or worsening of lupus manifestation requiring introduction of certain prohibited 
medications or dosages when continuation of the study drug would place the subject at risk, as 
determined by the AbbVie TA MD.  Introduction of the following in addition to study drug will 
require discontinuation of study drug immediately:

Cyclophosphamide
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
Belimumab

Rituximab

More than one of the following in combination:  azathioprine, mycophenolate, leflunomide, 
MTX, cyclosporine, or tacrolimus

Plasmapheresis

High dose steroids (≥ 60 mg prednisone-equivalent oral or parenteral)

IVIG

Clinically significant abnormal laboratory results or AEs, which rule out continuation of the study 
drug, as determined by the investigator or the AbbVie TA MD.

Serious infections (e.g., pneumonia, sepsis) which cannot be adequately controlled by 
anti-infective treatment or would put the subject at risk for continued participation in the trial, 
as determined by the investigator or the AbbVie TA MD.

The investigator believes it is in the best interest of the subject.

The subject decides to withdraw from study drug or the study, or the Sponsor decides to 
discontinue 1 or more treatment groups after the planned Study M19-130 Interim Analysis.

Inclusion or exclusion criterion violation was noted after the subject started study drug, when 
continuation of the study drug would place the subject at risk as determined by the AbbVie TA 
MD.

Subject develops an ECG change considered clinically significant and with reasonable possibility 
of relationship to study drug or a confirmed absolute QTcF value > 500 msec or confirmed 
increase of ≥ 60 msec from Study M19-130 Baseline.

Subject's QTcF increases from Baseline ≥ 60 msec, the investigator will evaluate, confirm the 
value, and treatment should be stopped.

Subject develops active TB at any time during the study.

Subject with latent TB who is non-compliant with or refuses to initiate TB prophylaxis.

The subject becomes pregnant while on study drug.

Malignancy, except for localized NMSC or CIS of the cervix.

Subject is significantly non-compliant with study procedures, including inconsistent study drug 
dosing, which would put the subject at risk for continued participation in the trial as determined 
by the investigator or the AbbVie TA MD.

Subject develops a GI perforation.

If a diagnosis of deep vein thrombosis, pulmonary embolus, or non-cardiac, non-neurologic 
arterial thrombosis is confirmed.

Subject develops active neuropsychiatric SLE (excluding lupus headache) as defined by the CNS 
portion of SLEDAI-2K or BILAG.

Subject develops Class IV lupus nephritis (confirmed by biopsy).
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In order to minimize missing data for efficacy and safety assessments, subjects who prematurely 
discontinue study drug treatment should, if possible:

Continue in the study without receiving study drug

Have all procedures performed outlined in the PD visit, preferably within 2 weeks of study drug 
discontinuation

Continue with their regular study visit schedule
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 electronic case report form (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.
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.
AbbVie may terminate this study prematurely at any time, either in its entirety or partially (discontinue 
1 or more treatment groups), at any site.  The study may be terminated in case of an unacceptable risk, 
relevant toxicity, or a negative change in the benefit/risk assessment including the occurrence of AEs of 
which the character, severity, or frequency is new in comparison to the existing risk profile.  In addition, 
data deriving from other clinical trials or toxicological studies which negatively influence the benefit/risk
assessment might cause discontinuation or termination of the study.  In the event the study is partially 
terminated, all subjects in the terminated treatment arm(s) will be asked to return for a PD visit and to 
perform a 30-day follow-up phone call after the last dose of study drug.  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.
5.6 Follow-Up After Subject Discontinuation of Study Drug or from 
Study
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, unless subjects 
have decided to discontinue the 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.
Discontinuation of Study Drug and Continuation of Study Participation
During the study, 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 PD visit as 
soon as possible, preferably within 2 weeks.  Afterwards, subjects should follow the regular visit 
schedule as outlined in Appendix D and Section 2.1 of the Operations Manual and adhere to all study 
procedures except for dispensing study drug.  As the subject has discontinued study drug, all rescue and 
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efficacy discontinuation criteria may no longer apply.  If at any point a subject no longer wants to 
provide assessments (withdrawal of informed consent) following discontinuation of study drug, a 
second PD visit is not required.
Premature Discontinuation from Study (Withdrawal of Informed Consent)
Subjects may withdraw from the study completely (withdrawal of informed consent) for any reason at 
any time.  If a subject prematurely discontinues study drug treatment AND study participation 
(withdrawal of informed consent), the procedures outlined for the PD visit should be completed as soon 
as possible, preferably within 2 weeks of study drug discontinuation, and preferably prior to initiation of 
another therapy.  In addition, if subject is willing, a 30-day follow-up call after the last dose of study drug 
may be completed to ensure all treatment-emergent AEs/SAEs have been resolved.
If a subject withdraws from study follow-up or withdraws permission for the collection of their personal 
data, the study staff may still use available public records to obtain information about survival status 
only, as appropriate per local regulations.
5.7 Study Drug 
Based on the Sponsor's discretion, doses of the investigational study drug (s) selected for continuation in 
the LTE study may be reassigned or discontinued at any time based on the outcome assessment of the 
planned Study M19-130 Interim Analysis.
Investigational study drug(s) should be taken at approximately the same time each day (Table 2).  
Subjects will be instructed to take study drugs orally, which includes only 1 capsule of elsubrutinib or 
matching placebo from each of the 3 dispensed bottles per day, with or without food, and only 1 tablet 
of upadacitinib or matching placebo from the dispensed bottle per day, with or without food.  Subjects 
will be instructed to take only 1 capsule or tablet from each dispensed bottle per day.  If subjects forget 
to take their elsubrutinib, upadacitinib, or matching placebo dose at their regularly scheduled dosing 
time, they should take the forgotten dose as soon as they remember as long as it is at least 10 hours 
before their next scheduled dose.  Otherwise, they should take the next dose at the next scheduled 
dosing time. 
Subject dosing will be recorded on a subject dosing diary.  The subject will be instructed to return all 
drug bottles (even if empty) to the study site personnel at each study visit.  Study site personnel will 
document compliance.
Medications other than elsubrutinib, upadacitinib, or matching placebo will not be provided by AbbVie.  
AbbVie-provided study drug should not be substituted or alternately sourced unless otherwise directed 
by AbbVie.  
Elsubrutinib, upadacitinib, and matching placebo will be packaged in bottles with quantities sufficient to 
accommodate study design.  Each kit will be labeled per local requirements and this label must remain 
affixed to the kit.  Upon receipt, study drug should be stored as specified on the label and kept in a 
secure location.  Each kit will contain a unique kit number.  This kit number is assigned to a subject via 
interactive response technology (IRT) and encodes the appropriate study drug to be dispensed at the 
subject's corresponding study visit.  Site staff will complete all blank spaces on the label before 
dispensing to subjects.  Study drug will only be used for the conduct of this study.
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Table 2.
Investigational Study Drug(s)
Investigational 
Product
Investigational 
Product
Investigational 
Product Placebo
Investigational 
Product Placebo
Investigational 
product name
Elsubrutinib 
(ABBV-105)
Upadacitinib 
(ABT-494)
Elsubrutinib 
(ABBV-105) Placebo
Upadacitinib 
(ABT-494) Placebo
Active ingredient
Elsubrutinib (ABBV-
105)
Upadacitinib (ABT-
494)
Not applicable
Not applicable
Mode/Route of 
Administration 
Oral
Oral
Oral 
Oral 
Dosage Form
Capsule
Film-coated tablet
Capsule 
Film-coated tablet
Dose and units
20 mg
15 mg, 30 mg
Not applicable 
Not applicable
Frequency of 
administration
Daily
Daily
Daily
Daily
Storage Conditions
Room temperature 
(15°–25°C)
Room temperature 
(15°–25°C)
Room temperature 
(15°–25°C)
Room temperature 
(15°–25°C)
Note:
Potential doses of the investigational study drug(s) for rollover may be reassigned or discontinued based on the 
outcome of the planned Study M19-130 Interim Analysis benefit/risk assessment or planned Study M19-130 Week 24 
Primary Analysis.
5.8 Randomization/Drug Assignment
AbbVie reassessed the treatment assignments in the LTE Study M20-186 based on data from the 
planned Study M19-130 Interim Analysis.  Based on the outcome of the planned Study M19-130 Interim 
Analysis, subjects in LTE Study M20-186 may be prematurely discontinued due to lack of efficacy 
observed in individual treatment groups at the Sponsor's discretion.
All subjects were assigned a unique identification number by the IRT at the Screening visit for 
Study M19-130.  Prior to the planned Interim Analysis for Study M19-130, subjects entering LTE 
Study M20-186 who were originally assigned to the blinded ABBV-599 (elsubrutinib/upadacitinib) 
combination groups or the elsubrutinib or upadacitinib monotherapy groups in Study M19-130 were to 
continue on their current treatment for the duration of the study.  After the planned Study M19-130 
Interim Analysis, subjects who were originally assigned to placebo will be randomized to an active 
treatment group.
The investigator, study site personnel, and the subject will remain blinded to each subject's treatment 
assignment throughout Study M19-130 and LTE Study M20-186.  AbbVie personnel with direct oversight 
of the conduct and management of the trial (with the exception of AbbVie Drug Management Team) will 
remain blinded to study treatment through Week 24 of Study M19-130; the study team will become 
unblinded to study treatment in both studies after the Primary Analysis at Week 24 of Study M19-130 is 
completed.  To maintain the blind, the elsubrutinib capsules and matching placebo capsules and 
upadacitinib tablets and matching placebo tablets provided for the study will be identical in appearance.
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The IRT will provide access to unblinded subject treatment assignment from Study M19-130 or 
LTE Study M20-186 in the case of a medical emergency.
5.9 Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol except when necessary to 
eliminate an immediate hazard to study subjects.  The investigator is responsible for complying with all 
protocol requirements, written instructions, and applicable laws regarding protocol deviations.  If a 
protocol deviation occurs (or is identified, including those that may be due to the COVID-19 pandemic), 
the investigator is responsible for notifying IEC/IRB, regulatory authorities (as applicable), and AbbVie.
In Japan, the investigator will record all the protocol deviations in the appropriate medical records at the 
site.
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.
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Such an event can result from use of the drug as stipulated in the protocol, as well as from accidental or 
intentional overdose, drug abuse, or drug withdrawal.  Any worsening of a pre-existing condition or 
illness is considered an AE.  Worsening in severity of a reported AE should be reported as a new AE.  
Laboratory abnormalities and changes in vital signs are considered to be AEs only if they result in 
discontinuation from the study, necessitate therapeutic medical intervention, meet protocol-specific 
criteria (see Section 6.2 regarding toxicity management), and/or if the investigator considers them to be 
AEs.  Worsening SLE including flares will be captured and analyzed via the disease activity forms (SLEDAI, 
BILAG, CLASI, and SFI) and will be analyzed as part of efficacy.  As such, worsening SLE and flares will not 
be captured as AEs unless they result in serious outcomes.
The investigators will monitor each subject for clinical and laboratory evidence of AE 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 the surgery/procedure has been 
pre-planned prior to study entry.  However, if the pre-existing condition deteriorates unexpectedly 
during the study (e.g., surgery performed earlier than planned), then the deterioration of the condition 
for which the elective surgery/procedure is being done will be considered an AE.  If the subject 
undergoes elective surgery, the study drug should be interrupted at least 1 week prior to the planned 
surgery.  If the subject must undergo emergency surgery, the study drug should be interrupted at the 
time of the surgery.  For both elective and emergency surgery, allow reintroduction of study drug once 
the physician has examined the surgical site and determined that it has healed and there is no sign of 
infection.
If any of the following events (Table 3) are reported, then the following supplemental report must be 
completed.
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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.
Adverse Event Collection
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.  
The following definitions will be used for Serious Adverse Reactions (SAR) and Suspected Unexpected 
Serious Adverse Reaction (SUSAR):
SAR
Defined as all noxious and unintended responses to an Investigational Medicinal 
Product (IMP) related to any dose administered that result in death, are 
life-threatening, require inpatient hospitalization or prolongation of existing 
hospitalization, result in persistent or significant disability or incapacity, or are a 
congenital anomaly or birth defect.
SUSAR
A suspected unexpected SAR:  refers to individual SAE case reports from clinical 
trials where a causal relationship between the SAE and the IMP was suspected 
by either the sponsor or the investigator, is not listed is the applicable 
Reference Safety Information (RSI), and meets one of the following serious 
criteria:  results in death, is life-threatening, requires hospitalization or 
prolongation of an existing hospitalization, results in persistent or significant 
disability or incapacity, or is a congenital anomaly or birth defect.  
AbbVie will be responsible for SUSAR reporting for the IMP in accordance with global and local 
requirements.
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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 adverse events of special interest (AESI) will be routinely monitored during the study:

Serious infections

Opportunistic infections

Herpes zoster

Active TB 

Malignancy (all types)

Adjudicated GI perforations

Adjudicated cardiovascular events (e.g., MACE)

Anemia

Neutropenia

Lymphopenia

Renal dysfunction

Hepatic disorders

Adjudicated embolic and thrombotic events (non-cardiac, non-CNS) including venous 
thromboembolic events defined as pulmonary embolism and deep vein thrombosis.
Adverse Event Severity and Relationship to Study Drug
Investigators will rate the severity of each AE according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 5, which can be accessed at:  
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_reference_
8.5x11.pdf.
If no specific grading criteria are provided for the reported event, then the event should be as follows:

Mild (Grade 1):  asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated;

Moderate (Grade 2):  minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL) (instrumental ADL refer to preparing 
meals, shopping for groceries or clothes, using the telephone, managing money, etc.);

Severe (Grade 3 - 5):

Grade 3:  severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL 
(self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden);
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
Grade 4:  Life-threatening consequences; urgent intervention indicated;

Grade 5:  Death related to AE.
The investigator will use the following definitions to assess the relationship of the AE to the use of study 
drug:
Reasonable 
Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is 
sufficient evidence (information) to suggest a causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is 
insufficient evidence (information) to suggest a causal relationship.
For causality assessments, events assessed as having a reasonable possibility of being related to the 
study drug will be considered "associated."  Events assessed as having no reasonable possibility of being 
related to the study drug will be considered "not associated."  In addition, when the investigator has not 
reported a causality or deemed it not assessable, AbbVie will consider the event associated.
If an investigator's opinion of no reasonable possibility of being related to study drug is given, an
"Other" cause of event must be provided by the investigator for the SAE.
In Japan, the Principal Investigator will provide documentation of all SAEs to the Director of the 
investigative site and to the Sponsor.
Cardiovascular Adjudication Committee 
An independent CAC will adjudicate all blinded cardiovascular and cerebrovascular events, 
embolic/thrombotic events, and deaths, as defined in the CAC charter.
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.  Subjects who become pregnant during the study must be 
discontinued from the study drug (Section 5.5).  If a pregnancy occurs in a study subject or in the partner 
of a study subject, information regarding the pregnancy and the outcome will be collected.
In the event of pregnancy occurring in a subject's partner during the study, written informed consent 
from the partner must be obtained prior to collection of any such information.  AbbVie will provide a 
separate consent form for this purpose.  Pregnancy in a subject's partner will be collected from the date 
of the first dose in LTE Study M20-186 through 30 days following the last dose of study drug.
The pregnancy outcome of an elective or spontaneous abortion, stillbirth, or congenital anomaly is 
considered an SAE and must be reported to AbbVie within 24 hours after the site becomes aware of the 
event.
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6.2 Toxicity Management
The toxicity management of the AEs including AESI consists of safety monitoring (review of AEs on an 
ongoing basis, and periodic/ad hoc review of safety issues by an internal independent safety DMC), 
interruption of study drug dosing with appropriate clinical management if applicable, and 
discontinuation of the subjects from study drug.
The management of specific AEs and laboratory parameters is discussed below and described in Table 4.  
This includes AEs of serious infections, opportunistic infections, GI perforations, cardiovascular events 
(MACE), thromboembolic events, malignancies, and ECG abnormalities.  This also includes the following 
laboratory abnormalities:  hemoglobin, absolute neutrophil count (ANC), platelet count, alanine 
transaminase (ALT) or aspartate transaminase (AST), serum creatinine, CPK, lymphocyte count, total
white blood cell (WBC) count, and urine protein to creatinine ratio (UPCR).
For all other AEs or laboratory-related AEs, study drug will be interrupted immediately if a subject 
experiences a confirmed severe (Grade 3) clinical AE or SAE for which the investigator considers the 
relationship to the study drug to be a reasonable possibility.  For confirmed Grade 4 AEs for which the 
investigator considers the relationship to the study drug to be a reasonable possibility and the event 
does not improve back to at least Grade 2, then the study drug must be discontinued.
Product complaints concerning the investigational product must be reported to AbbVie within 
1 business day of the study site's knowledge of the event.  Product complaints occurring during the 
study will be followed up to a satisfactory conclusion.
All follow-up information is to be reported to the Sponsor (or an authorized representative) and 
documented in source as required by the Sponsor.  Product complaints associated with AEs will be 
reported in the study summary.  All other complaints will be monitored on an ongoing basis.
Management of Serious Infections
Subjects should be closely monitored for the development of signs and symptoms of infection during 
and after treatment with study drug.  Study drug should be interrupted if a subject develops a serious 
infection (including COVID-19) or a serious opportunistic infection (excludes non-serious oropharyngeal 
candidiasis).  A subject who develops a new infection during treatment with study drug should undergo 
prompt diagnostic testing appropriate for an immunocompromised subject.  As appropriate, 
antimicrobial therapy should be initiated, and the subject should be closely monitored.  Study drug may 
be restarted once the infection has been successfully treated.  Subjects who develop active TB must be 
discontinued from the study drug.
Canada only:  Investigators should be advised to follow local public health guidelines in order to prevent 
subjects enrolled in these trials from acquiring TB.
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 
appropriate COVID-19 eCRFs should be completed.  If a subject has a confirmed or suspected COVID-19 
infection and study drug was interrupted, the investigator should contact the AbbVie TA MD before 
reintroducing study drug.
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Management of Herpes Zoster
If a subject develops herpes zoster, the investigator should consider temporarily interrupting study drug 
until the episode resolves.
Management of Serious Gastrointestinal Events
Subjects presenting with the onset of signs or symptoms of a serious GI event should be evaluated 
promptly for early diagnosis and treatment.  If the diagnosis of GI perforation is confirmed, the subject 
must be discontinued from the study drug.
Management of Cardiovascular Events
Subjects presenting with potential cardiovascular events should be appropriately assessed and carefully
monitored.  These events will be reviewed and adjudicated by an independent CAC in a blinded manner.
Management of Malignancy
Subjects who develop malignancy other than NMSC or CIS of the cervix must be discontinued from the 
study drug.  Information including histopathological results should be queried for the confirmation of 
the diagnosis.  Periodic skin examination is recommended for subjects who are at increased risk for skin 
cancer.
Management of ECG Abnormality
Subjects must be discontinued from study drug for an ECG change considered clinically significant and 
with reasonable possibility of relationship to study drug OR a confirmed absolute QTcF value > 500 msec 
or confirmed increase of ≥ 60 msec from Baseline.
Management of Muscle-Related Symptoms
If a subject experiences symptoms suggestive of myositis or rhabdomyolysis, CPK and aldolase 
measurements should be requested and will be provided after review by the AbbVie TA MD with clinical 
management and/or study drug interruption as deemed appropriate by the treating physician.  Please 
refer to Table 4 below for further instructions.
Management of Thrombosis Events
Subjects who develop symptoms of thrombosis should be promptly evaluated and treated 
appropriately.  If the diagnosis of deep vein thrombosis, pulmonary embolus, or non-cardiac, 
non-neurologic arterial thrombosis is confirmed, the subject must be discontinued from study drug.
Management of Select Laboratory Abnormalities
For any given laboratory abnormality, the investigator should assess the subject and 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 4 and may require a 
supplemental eCRF to be completed (see Section 6.1).  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 4, the repeat testing must occur as soon as possible.
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Table 4.
Specific Toxicity Management Guidelines for Abnormal Laboratory Values
Laboratory Parameters
Toxicity Management Guidelines
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, the subject may remain on study drug at the 
investigator's discretion.
If confirmed, continue to withhold study drug until hemoglobin value 
returns to normal reference range or its baseline value.
Absolute neutrophil count (ANC)
If confirmed < 750 cells/µL by repeat testing with new sample, interrupt 
study drug dosing until ANC value returns to normal reference range or 
its baseline value.  Subjects who meet this criterion should be evaluated 
for an alternative etiology and closely monitored for infections.

The alternative etiology should be documented appropriately in the 
eCRF.  If restarting study drug, documentation should include the 
reason rechallenge is expected to be safe.
Platelet count
If confirmed < 30,000 platelets/µL by repeat testing with new sample, 
interrupt study drug dosing until platelet count returns to normal
reference range or its baseline value.
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Laboratory Parameters
Toxicity Management Guidelines
Aspartate transaminase (AST) or 
alanine transaminase (ALT)

Interrupt study drug immediately if confirmed ALT or AST > 3 × ULN 
by repeat testing with new sample and either a total bilirubin 
> 2 × ULN or an INR > 1.5.

INR will only need to be measured in subjects with ALT or AST 
> 3 × ULN by the central laboratory.  A repeat test of INR is not 
needed for determination if above toxicity management 
criteria are met.

Interrupt study drug immediately if confirmed ALT or AST > 3 × ULN 
by repeat testing with new sample along with appearance of 
fatigue, nausea, vomiting, right upper quadrant pain, or tenderness, 
fever, rash, and/or eosinophilia (> 5%).

Interrupt study drug immediately if ALT or AST > 5 × ULN by repeat 
testing with new sample.

Interrupt study drug immediately if ALT or AST > 8 × ULN and 
contact the AbbVie TA MD.
Subjects who meet any of the above criteria should be evaluated for an 
alternative etiology of the ALT or AST elevation and managed as 
medically appropriate.  The investigator should contact the AbbVie TA 
MD to discuss the management of a subject when an alternative 
etiology has been determined.  The alternative etiology should be 
documented appropriately in the eCRF; study drug should be 
discontinued if no alternative etiology can be found.
For any confirmed ALT or AST elevations > 3 × ULN, complete 
supplemental hepatic eCRF.

Subjects with HBc Ab+ status (irrespective of HBs Ab status) and 
negative HBV DNA at Study M19-130 Screening who develop the 
following should have HBV DNA by PCR testing performed within 
1 week:

ALT > 5 × ULN OR

ALT or AST > 3 × ULN if an alternative cause is not readily 
identified. 
A positive result for HBV DNA PCR testing in these subjects will require 
immediate interruption of study drug (per local guidelines) and a 
hepatologist consultation should occur within 1 week for 
recommendation regarding subsequent treatment.
Serum Creatinine

If serum creatinine is > 1.5 × the baseline value and > ULN, repeat 
the test for serum creatinine (with subject in an euvolemic state) to 
confirm the results.  If the results of the repeat testing still meet this 
criterion then interrupt study drug and re-start study drug once 
serum creatinine returns to ≤ 1.5 × baseline value and ≤ ULN.

If confirmed new serum creatinine ≥ 2 mg/dL, interrupt study drug 
and re-start study drug once serum creatinine returns to normal 
reference range or its baseline value.
For the above serum creatinine elevation scenarios, complete 
supplemental renal eCRF(s).
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Laboratory Parameters
Toxicity Management Guidelines
Creatine Phosphokinase (CPK)

CPK and aldolase will be measured at every visit, but results will be 
blinded to sites and subjects, as CPK elevation is a known class 
effect of JAK inhibitors and the results could be unblinding to the 
sites.  If symptomatic myositis is suspected, the site may send a 
request to the AbbVie TA MD for CPK and/or aldolase results to be 
unblinded.  Request must be approved by the AbbVie TA MD.

If confirmed CPK ≥ 4 × ULN accompanied by symptoms suggestive of 
myositis or rhabdomyolysis, interrupt study drug, complete 
supplemental CPK eCRF, and contact the AbbVie TA MD.
Lymphocyte Count Decreased

If confirmed Grade 4 (< 200/mm3) by repeat testing with new 
sample, interrupt study drug dosing until lymphocyte count returns 
to at least Grade 2 (< 800 to 500/mm3) or its baseline value.
White Blood Count Decreased

If confirmed Grade 4 (<1000/mm3) by repeat testing with new 
sample, interrupt study drug dosing until white blood cell count 
returns to at least Grade 2 (< 3000 to 2000/mm3) or its baseline
value.
Urine Protein to Creatinine Ratio

If > 2 g/day equivalent (2 mg/mg), repeat by testing with new 
sample, and if confirmed, a renal biopsy will be required.

If Class IV lupus nephritis is confirmed, subject must be permanently 
discontinued from study drug.
DNA = Deoxyribonucleic acid; eCRF = Electronic case report form; HBc Ab+ = Hepatitis B core antibody positive; HBs 
Ab = Hepatitis B surface antibody; HBV = Hepatitis B virus; INR = International normalized ratio; JAK = Janus kinase; 
PCR = Polymerase chain reaction; TA MD = Therapeutic Area Medical Director; ULN = Upper limit of normal
For all other AEs or laboratory-related AEs, study drug will be interrupted immediately if a subject 
experiences a confirmed severe (Grade 3) clinical AE or SAE for which the investigator considers the 
relationship to the study drug to be a reasonable possibility.  For confirmed Grade 4 AEs for which the 
investigator considers the relationship to the study drug to be a reasonable possibility and the event 
does not improve back to at least Grade 2, then the study drug must be discontinued.
6.3 Data Monitoring Committee
An internal safety DMC composed of persons independent of the RCT Study M19-130 and LTE 
Study M20-186 teams and with relevant expertise in their field will review unblinded safety data.  The 
primary responsibility of the DMC will be to protect the safety of the subjects participating in this LTE 
study.  When needed, high-level unblinded efficacy data may also be requested by the DMC and 
reviewed so that the DMC can assess benefit/risk of any emerging safety differences. 
A separate DMC charter for LTE Study M20-186 is available and describes the roles and responsibilities 
of the DMC members, frequency of data reviews, planned interim analyses, relevant safety data to be 
assessed, and expectations for blinded communications for LTE Study M20-186.
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7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
7.1 Statistical and Analytical Plans
Complete and specific details of the statistical analysis will be described and fully documented in the 
Statistical Analysis Plan (SAP).  The SAP will be finalized prior to the database lock.  The statistical 
analyses will be performed using SAS (SAS Institute Inc., Cary, North Carolina, USA).
7.2 Definition for Analysis Populations
The Full Analysis Set (FAS) includes all subjects received at least 1 dose of study drug in 
LTE Study M20-186.  The FAS will be used for efficacy and baseline analyses.  Subjects will be grouped 
according to treatment sequence as randomized for Studies M19-130 and M20-186.
The Safety Analysis Set includes all subjects who received at least 1 dose of study drug in 
LTE Study M20-186.  Subjects will be grouped according to treatment sequence actually received.  The 
Safety Analysis Set will be used for safety analyses.
7.3 Statistical Analyses for Efficacy
Analysis of secondary efficacy endpoints will be conducted on the FAS based on treatment sequence as 
randomized for Study M19-130 and continued/reassigned to rollover into LTE Study M20-186.  The 
analysis will be based on As Observed (AO) data, and no imputation will be conducted.  The treatment 
groups will be described as follows whenever applicable indicating treatments from Study M19-130 to 
LTE Study M20-186:

Group 1:  Elsubrutinib 60 mg / upadacitinib 30 mg to elsubrutinib 60 mg / upadacitinib 30 mg

Group 2:  Elsubrutinib 60 mg / upadacitinib 15 mg to elsubrutinib 60 mg / upadacitinib 15 mg 

Group 3:  Elsubrutinib 60 mg to elsubrutinib 60 mg

Group 4:  Upadacitinib 30 mg to upadacitinib 30 mg

Group 5a:  Placebo to elsubrutinib 60 mg / upadacitinib 30 mg

Group 5b:  Placebo to elsubrutinib 60 mg / upadacitinib 15 mg
The Baseline for all secondary efficacy analyses in this study will be the Baseline in Study M19-130.
There is no primary efficacy endpoint and no formal statistical tests will be applied.  Only descriptive 
statistics will be used for all efficacy endpoints.  Descriptive statistics will be provided for each treatment 
group for all visits.  These include the number of observations; mean with 95% confidence interval, 
standard deviation, median, minimum, and maximum for continuous endpoints (or the change from 
baseline measurements); and frequencies and percentages with 95% confidence interval for binary 
endpoints.
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No missing data imputation will be applied.  All efficacy analyses will be based on AO analysis, and thus a 
subject who does not have an evaluation at the analysis time point will not be included.  Missing 
value/visit information due to COVID-19 will be collected and reported.
Details on other efficacy analyses will be provided in the SAP.
7.4 Statistical Analyses for Safety
All safety analyses will be performed on the Safety Analysis Set.
All treatment-emergent adverse events (TEAEs), SAEs, AEs leading to discontinuation, and AESI will be 
collected during the study.  A TEAE is defined as an event with onset or worsening after the first study 
dose of study drug and within 30 days after the last dose of study drug administration.  The number and 
percentages of subjects experiencing TEAEs will be tabulated using the Medical Dictionary for Drug 
Regulatory Activities (MedDRA®) System Organ Class (SOC) and preferred term (PT).  Summaries 
(including percentages and events per 100 patient-years) of SAEs, deaths, AEs leading to 
discontinuation, and AESI will be provided as well.  For selected laboratory and vital sign parameters, 
mean change from Baseline and the percentage of subjects with evaluations meeting pre-defined 
criteria for Potentially Clinically Important values will be summarized.
7.5 Interim Analysis
An interim analysis may be performed as needed in order to provide long-term safety data to inform the 
benefit-risk assessment of elsubrutinib, upadacitinib, and ABBV-599 (elsubrutinib/upadacitinib) 
combination.  All endpoints will be summarized using descriptive statistics, and summaries will be 
displayed both overall and split by treatment groups indicating treatments from Study M19-130 to 
LTE Study M20-186.  The detailed interim analysis plan will be provided in the SAP.
7.6 Overall Type I Error Control
Not applicable for this study.
7.7 Sample Size Determination
The sample size will be determined by the number of available subjects who were randomized into 
Study M19-130 and are eligible for the current study.  All eligible subjects who completed 
Study M19-130 will be enrolled in this study if the subject signs and dates the informed consent.  It is 
anticipated that between 60% and 80% of subjects from Study M19-130 (195 to 260 subjects) will be 
enrolled in this LTE study.
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8 ETHICS
8.1 Independent Ethics Committee/Institutional Review Board 
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the IEC/IRB for review and approval.  Approval of both the protocol and the informed
consent form(s) must be obtained before any subject is enrolled.  Any amendment to the protocol will 
require review and approval by the IEC/IRB before the changes are implemented to the study.  In 
addition, all changes to the consent form(s) will be IEC/IRB approved.
In Japan, the investigator will prepare the consent form and explanatory material required to obtain 
subject's consent to participate in the study with the cooperation of the sponsor and will revise these 
documents as required.  The prepared or revised consent forms and explanatory material will be 
submitted to the sponsor.  Approval of the IRB will be obtained prior to use in the study.
In Japan, when important new information related to the subject's consent becomes available, the 
investigator will revise the consent form and explanatory material based on the information without 
delay and will obtain the approval of the IRB prior to use in the study.  The investigator will provide the 
information, without delay, to each subject already participating in the study, and will confirm the 
intention of each subject to continue the study or not.  The investigator shall also provide a further 
explanation using the revised form and explanatory material and shall obtain written consent from each 
subject of their own free will to continue participating in the study.
8.2 Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, Operations Manual, International Council 
for Harmonisation (ICH) guidelines, applicable regulations, and guidelines governing clinical study 
conduct and the ethical principles that have their origin in the Declaration of Helsinki.  Responsibilities of 
the investigator are specified in Appendix B.
8.3 Subject Confidentiality
To protect subjects' confidentiality, all subjects and their associated samples will be assigned numerical 
study identifiers or "codes."  No identifiable information will be provided to AbbVie.
9 SOURCE DOCUMENTS AND CASE REPORT FORM 
COMPLETION
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported.  All source documents should be attributable, legible, contemporaneous, original, 
accurate, and complete to ensure accurate interpretation of data.  Clinical site monitoring is conducted 
to ensure that the rights and well-being of human subjects are protected, that the reported trial data 
are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the 
currently approved protocol, ICH Good Clinical Practice (GCP), and applicable local regulatory 
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requirement(s).  During the COVID-19 pandemic, remote data review and verification 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 investigator will conduct the study in compliance with the protocol and complete the study within 
the timeframe specified in the contract between the investigator (and Director of the site in Japan) and 
AbbVie.  Continuation of this study beyond this date must be mutually agreed upon in writing by both 
the investigator (and Director of the site in Japan) and AbbVie.  The investigator will provide a final 
report to the IEC/IRB following conclusion of the study and will forward a copy of this report to AbbVie 
or their representative.
The investigator (and Director of the site in Japan) must retain any records related to the study 
according to local requirements.  If the investigator is not able to retain the records, he/she must notify 
AbbVie to arrange alternative archiving options.
AbbVie will select the signatory investigator from the investigators who participate in the study.  
Selection criteria for this investigator will include level of participation as well as significant knowledge 
of the clinical research, investigational drug, and study protocol.
This study will be conducted in compliance with the protocol, GCP and all other applicable regulatory 
requirements, including the archiving of essential documents.
The end-of-study is defined as the date of the last subject's last visit, or date of the last follow-up 
contact, whichever is later.
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12
REFERENCES
1.
Kil LP, de Bruijn MJ, van Nimwegen M, et al. Btk levels set the threshold for B-cell activation and 
negative selection of autoreactive B cells in mice. Blood. 2012;119(16):3744-56.
2.
Flemming A. Target discovery: Blocking BTK in B-cell disorders. Nat Rev Drug Discov. 2010;9(9):681.
3.
Chang BY, Huang MM, Francesco M, et al. The Bruton tyrosine kinase inhibitor PCI-32765 
ameliorates autoimmune arthritis by inhibition of multiple effector cells. Arthritis Res Ther. 
2011;13(4):R115.
4.
Di Paolo JA, Huang T, Balazs M, et al. Specific Btk inhibition suppresses B cell- and myeloid cell-
mediated arthritis. Nat Chem Biol. 2011;7(1):41-50.
5.
Hutcheson J, Vanarsa K, Bashmakov A, et al. Modulating proximal cell signaling by targeting Btk 
ameliorates humoral autoimmunity and end-organ disease in murine lupus. Arthritis Res Ther. 
2012;14(6):R243.
6.
Mina-Osorio P, LaStant J, Keirstead N, et al. Suppression of glomerulonephritis in lupus-prone NZB x 
NZW mice by RN486, a selective inhibitor of Bruton's tyrosine kinase. Arthritis Rheum. 
2013;65(9):2380-91.
7.
Rankin AL, Seth N, Keegan S, et al. Selective inhibition of BTK prevents murine lupus and antibody-
mediated glomerulonephritis. J Immunol. 2013;191(9):4540-50.
8.
AbbVie. Upadacitinib Investigator's Brochure Edition 11. 18 August 2020.
9.
AbbVie. ABBV-105 Investigator's Brochure Edition 4. 03 February 2020.
10. Wallace DJ, Furie RA, Tanaka Y, et al. Baricitinib for systemic lupus erythematosus: a double-blind, 
randomised, placebo-controlled, phase 2 trial. Lancet. 2018;392(10143):222-31.
11. Furie RA, Petri MA, Wallace DJ, et al. Novel evidence-based systemic lupus erythematosus 
responder index. Arthritis Rheum. 2009;61(9):1143-51.
12. Wallace DJ, Strand V, Furie R, et al. Evaluation of treatment success in systemic lupus erythematosus 
clinical trials: development of the British Isles Lupus Assessment Group-based Composite Lupus 
Assessment Endpoint. Presented at: ACR 2011: Poster 2265. Arthritis Rheum. 2011;63:S885-6.
13. Franklyn K, Lau CS, Navarra SV, et al. Definition and initial validation of a Lupus Low Disease Activity 
State (LLDAS). Ann Rheum Dis. 2016;75(9):1615-21.
14. Gladman DD, Ibanez D, Urowitz MB. Systemic lupus erythematosus disease activity index 2000. J 
Rheumatol. 2002;29(2):288-91.
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15. Yee CS, Farewell V, Isenberg DA, et al. British Isles Lupus Assessment Group 2004 index is valid for 
assessment of disease activity in systemic lupus erythematosus. Arthritis Rheum. 2007;56(12):4113-
9.
16. Albrecht J, Taylor L, Berlin JA, et al. The CLASI (Cutaneous Lupus Erythematosus Disease Area and 
Severity Index): an outcome instrument for cutaneous lupus erythematosus. J Invest Dermatol. 
2005;125(5):889-94.
17. Petri M, Buyon J, Kim M. Classification and definition of major flares in SLE clinical trials. Lupus. 
1999;8(8):685-91.
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APPENDIX A. STUDY-SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
Ab
Antibody
ADL
Activities of daily living
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine transaminase
ANC
Absolute neutrophil count
anti-dsDNA
anti-double stranded DNA
AO
As observed
AST
Aspartate transaminase
BCG
Bacilli Calmette-Guérin
BICLA
BILAG-Based Combined Lupus Assessment
BILAG
British Isles Lupus Assessment Group
BTK
Bruton's tyrosine kinase
CAC
Cardiovascular Adjudication Committee
CBC
Complete blood count
Cardiac (eCRF)
Cardiovascular (electronic Case Report Form)
CIS
Carcinoma in-situ
CLASI
Cutaneous Lupus Erythematosus Disease Area and Severity Index
CNS
Central nervous system
COVID-19
Coronavirus disease 2019
CPK
Creatine phosphokinase
CRF
Case report form
CTCAE
Common Terminology Criteria for Adverse Events
CXR
Chest x-ray
CYP3A
Cytochrome P450 3A isoform subfamily
CYP1A2
Cytochrome P450 1A2 isoform subfamily
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
dsDNA
Double stranded deoxyribonucleic acid
DSUR
Development Safety Update Report
EC
Ethics Committee
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ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EMR
Electronic medical records
EU
European Union
EudraCT
European Clinical Trials Database
FACIT
Functional Assessment of Chronic Illness Therapy
FAS
Full Analysis Set
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
GCSF
Granulocyte-colony stimulating factor
GFR
Glomerular filtration rate
GI
Gastrointestinal
GM-CSF
Granulocyte-macrophage colony-stimulating factor
GOT
Glutamic oxaloacetic transaminase
GPT
Glutamic pyruvic transaminase
HBc Ab/Ab+
Hepatitis B core antibody/antibody positive
HBs Ab
Hepatitis B surface antibody
HBV
Hepatitis B virus
HRQoL
Health-related quality of life
IC50
Inhibitory concentration producing 50% inhibition
ICH
International Council for Harmonisation
ID
Identification
IEC
Independent Ethics Committee
IERC
Internal Executive Review Committee
IFN
Interferon
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IMP
Investigational medicinal product
INR
International normalized ratio
IRB
Institutional Review Board
IRT
Interactive response technology
IU
International unit
IUD
Intrauterine device
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IUP
Interim Unblinding Plan
IUS
Intrauterine hormone-releasing system
IVIG
Intravenous immunoglobulin
JAK
Janus kinase
JAK1
Janus kinase 1
JAK2
Janus kinase 2
JAK3
Janus kinase 3
LLDAS
Lupus Low Disease Activity State
LTE
Long-term extension
LupusQoL
Lupus Quality of Life questionnaire
MACE
Major adverse cardiovascular event
MedDRA
Medical Dictionary for Regulatory Activities
MI
Myocardial infarction
MTX
Methotrexate
NA
No assessment
NCI
National Cancer Institute
NK
Natural killer
NMSC
Non-melanoma skin cancer
NRS
Numerical Rating Scale
NSAID
Nonsteroidal anti-inflammatory drug
PCR
Polymerase chain reaction
PD
Premature discontinuation
PhGA
Physician's Global Assessment
PHI 
Protected health information
PII
Personally identifiable information
PMN
Polymorphonuclear white blood cells
PPD
Purified protein derivative (tuberculin)
PRN
As needed
PRO
Patient-reported outcome
PT
Preferred term
PtGA
Patient Global Assessment
QD
Once a day
QoL
Quality of life
QTc
QT interval corrected for heart rate
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QTcF
QT interval corrected for heart rate using Fridericia's formula
RA
Rheumatoid arthritis
RBC
Red blood cell
RCT
Randomized controlled trial
RSI
Reference Safety Information 
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SAR
Serious adverse reaction
SELENA
Safety of Estrogens in Lupus Erythematosus National Assessment
SF-36
36-Item Short Form Health Survey
SF-36v2
36-Item Short Form Health Survey version 2
SFI
SLEDAI Flare Index
SLE
Systemic Lupus Erythematosus
SLEDAI
Systemic Lupus Erythematosus Disease Activity Index
SJC
Swollen joint count
SOC
System Organ Class
SRI
SLE Responder Index
SUSAR
Suspected unexpected serious adverse reaction
TA MD
Therapeutic Area Medical Director
TB
Tuberculosis
TEAE
Treatment-emergent adverse event
TJC
Tender joint count
UK
United Kingdom
ULN
Upper limit of normal
UPCR
Urine protein to creatinine ratio
US
United States 
WBC
White blood cell
WOCBP
Women of childbearing potential
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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M20-186:  A Phase 2, Long-Term Extension (LTE) Study with Elsubrutinib and Upadacitinib 
Given Alone or in Combination (ABBV-599) in Subjects with Moderately to Severely Active Systemic 
Lupus Erythematosus Who Have Completed the M19-130 Phase 2 Randomized Controlled Trial (RCT)
Protocol Date:  26 October 2021
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation 
(ICH) Good Clinical Practices (GCP) and local regulations and guidelines governing the study at the site 
location.  In signing the Investigator Agreement, the investigator is agreeing to the following:
1.
Conducting the study in accordance with ICH GCP, the applicable regulatory requirements, 
current protocol and operations manual, and making changes to a protocol only after notifying 
AbbVie and the appropriate Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC), except when necessary to protect the subject from immediate harm.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed consent and 
ethics committees (e.g., IEC or IRB) review and approval of the protocol and its amendments.
4.
Reporting complaints that occur in the course of the investigation(s) to AbbVie.
5.
Reading the information in the Investigator's Brochure/safety material provided, including the 
instructions for use and the potential risks and side effects of the investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the study about 
their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making those records 
available for inspection by representatives of AbbVie and/or the appropriate regulatory agency, 
and retaining all study-related documents until notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and approved the initial 
clinical protocol and all of its amendments.
9.
Reporting promptly, all changes in the research activity and all unanticipated problems involving 
risks to human subjects or others, to the appropriate individuals (e.g., coordinating investigator, 
institution director) and/or directly to the ethics committees and AbbVie.
10. Providing direct access to source data documents for study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s).
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
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APPENDIX C. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
Pharmaceutical Development, Immunology
Pharmaceutical Development, Immunology
Clinical Study Leadership
Data and Statistical Sciences
Data and Statistical Sciences
Medical Writing (Protocol Author)
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APPENDIX D. ACTIVITY SCHEDULE
The following table shows the required activities across all subject encounters.  The individual activities 
are described in detail in the Operations Manual.  Allowed modifications due to COVID-19 are detailed 
within the Operations Manual.
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anti-dsDNA = anti-double stranded DNA; BILAG = British Isles Lupus Assessment Group; CBC = Complete blood count; CLASI = Cutaneous Lupus Erythematosus Disease Area and 
Severity Index; DNA = Deoxyribonucleic acid; ECG = Electrocardiogram; FACIT = Functional Assessment of Chronic Illness Therapy; IgG = Immunoglobulin G; IgM = Immunoglobulin 
M; LTE = Long-term extension; LupusQoL = Lupus Quality of Life questionnaire; NRS = Numerical Rating Scale; PPD = Purified protein derivative; PtGA = Patient Global Assessment; 
SF-36 = 36-Item Short Form Health Survey; SELENA = Safety of Estrogens in Lupus Erythematosus National Assessment; SJC = Swollen joint count; SLEDAI = Systemic Lupus 
Erythematosus Disease Activity Index; TB = Tuberculosis; TJC = Tender joint count; US = United States; WOCBP = Women of childbearing potential
*
Tests/study activities are only to be performed if not done as part of Study M19-130.
**
The 30-day follow up call will be calculated from the last study drug administration date/last visit.
a.
Subjects in US who are already enrolled in the LTE study can be tokenized beyond the LTE Baseline/M19-130 Week 48 visit once they consent to be tokenized.
b.
The patient-reported outcome instruments should be completed prior to drug administration at LTE Baseline/M19-130 Week 48 and prior to any discussion of AEs or any 
review of laboratory findings.  The subject should complete the questionnaires before site personnel perform any clinical assessments and before any interaction with site 
personnel has occurred to avoid biasing the subject's response.
c.
A chest x-ray (CXR) will be obtained annually for subjects with TB risk factors as identified by the TB risk assessment form or for subjects with a newly positive PPD or 
QuantiFERON-TB Gold test.
d.
A complete physical examination will be performed during the LTE Baseline/M19-130 Week 48 visit.  Physical examinations at other visits can be symptom-directed.
e.
A urine pregnancy test will be performed locally for all females of childbearing potential prior to the first dose of study drug in LTE Study M20-186 and at a minimum of monthly 
intervals (either at study visits or at home between scheduled study visits).  The results of the monthly at-home tests must be communicated to the site.  If any urine pregnancy 
test is positive, a serum pregnancy test will be performed by the central laboratory.
f.
This is a clinician-reported outcome that is completed on the tablet. 
g.
Not required if subject discontinues study drug but remains in the study.
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APPENDIX E. DESCRIPTION OF EFFICACY MEASURES
Measure
Definition
Scale
Systemic Lupus Erythematosus 
Responder Index
(SRI)11
Composite responder index based on 
improvement in disease activity 
(number following SRI indicates 
numerical improvement in SLEDAI-2K 
score) without worsening of the 
overall condition (no worsening in 
Physician's Global Assessment [PhGA], 
< 0.3 point increase) or the 
development of significant disease 
activity in new organ systems (no new 
BILAG A or > 1 new BILAG B).
Not Applicable
British Isles Lupus Assessment 
Group Based Combined Lupus 
Assessment
(BICLA)12
Composite responder index based on 
improvement in organ systems 
(improvement in all initial A and B 
scores, no more than one new BILAG B 
score) without worsening of the 
overall condition (no worsening in 
PhGA, < 0.3 point increase) and no 
worsening of SLEDAI-2K score.
Not Applicable
Lupus Low Disease Activity State
(LLDAS)13
A state of low disease activity based 
on SLEDAI score (SLEDAI-2K score ≤ 4 
excluding SLEDAI-2K activity in major 
organ systems), absence of systemic 
lupus erythematosus (SLE) disease 
activity in major organ systems and 
new disease activity, PhGA ≤1, and 
concomitant medication usage 
(steroid dose ≤ 7.5 mg QD and 
toleration of immunosuppressive 
drugs at standard maintenance doses).
Not Applicable
Systemic Lupus Erythematosus 
Disease Activity Index 2000
(SLEDAI-2K)14
Global SLEDAI that focuses on 
high-impact disease manifestations 
across 9 organ systems.  It includes 
24 clinical and laboratory variables 
with manifestations weighted by the 
affected organ system.
Scores range from 0 to 105, with 
higher scores indicating more 
severe disease
British Isles Lupus Assessment 
Group
(BILAG) 200415
Global SLEDAI designed on the basis of 
the physician's intention to treat, 
focusing on changes in disease 
manifestations.  The instrument 
assesses 97 clinical signs, symptoms, 
and laboratory parameters across 
9 organ systems.
Letter score assigned to each 
organ system with following 
indications:  A = severe, 
B = moderate, C = mild, 
D = inactive with prior history, 
and E = inactive with no history
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Measure
Definition
Scale
Cutaneous Lupus Erythematosus 
Disease Area and Severity Index
(CLASI)16
Index used to assess cutaneous 
manifestations of SLE summarizing the 
activity of the disease.
Scores range from 0 to 70, with 
higher scores indicating more 
severity
SELENA SLEDAI Flare Index (SFI)17
An index defining SLE flares using 
changes in the SLEDAI score, 
definitions of worsening signs and 
symptoms, treatment changes, and 
Physician's Global Assessment of 
Disease Activity.
Mild/moderate or severe flare
Physician's Global Assessment of 
Disease Activity17
Physician's assessment of patient's 
overall disease activity due to SLE, as 
compared with all possible patients 
with SLE.  The benchmarks of the 
visual analog scale are 0, 1, 2, and 3 on 
the line corresponding to no, mild, 
moderate, and severe SLE disease 
activity, respectively.
Visual-analog scale ranging from 
0 to 3, with higher values 
indicating more severe disease
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APPENDIX F. LOCAL REQUIREMENTS
Clarification for Japan Contraception Recommendations
Women of childbearing potential (WOCBP) must avoid pregnancy while taking study drug(s) and for at 
least 30 days after the last dose of study drug.  They must commit to one of the following highly 
effective methods of birth control with:

Combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal,* 
transdermal,* injectable*) associated with the inhibition of ovulation.

Progestogen-only hormonal contraception (oral,** injectable,* implantable*) associated with 
inhibition of ovulation.

Bilateral tubal occlusion/ligation (in Japan, only bilateral tubal occlusion).

Vasectomized partner, provided the vasectomized partner has received medical confirmation of 
surgical success, and is the sole sexual partner of the WOCBP trial participant.

Intrauterine device (IUD).

Intrauterine hormone-releasing system (IUS).

Practice true abstinence (if acceptable per local requirements):  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] 
is not acceptable).
*
Not approved in Japan.
**
Not applicable in Japan due to the approval only for emergency contraception.
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APPENDIX G. PROTOCOL SUMMARY OF CHANGES
Protocol 
Date
Version 1.0
14 May 2020
Version 2.0
21 July 2020
Version 3.0
28 October 2020
Version 3.1 (China Only)
15 January 2021
The purpose of this version is to correct minor clerical errors for consistency throughout the protocol in 
addition to the following:
PROTOCOL
1.
Rationale:  After the planned Study M19-130 Interim Analysis assessment was completed, 
AbbVie selected treatment groups to move forward in LTE Study M20-186 based upon efficacy 
results.  These changes were necessary to reflect the possible treatment groups that may be 
active in LTE Study M20-186 after the planned Study M19-130 Interim Analysis.

Section 1 Synopsis and Section 4.1 Overall Study Design and Plan

Updated secondary objective and investigational plan to reflect changes that were made 
as a result of the planned Study M19-130 Interim Analysis.  Clarity was provided
regarding reassignment of subjects in the placebo groups of Study M19-130. Also, in 
Section 4.1 the Study Schematic was updated to reflect "Pre Interim Analysis."

Section 3 Objectives and Endpoints

Updated secondary objective to provide clarity regarding changes that were made as a 
result of the planned Study M19-130 Interim Analysis.

Section 4.2 Discussion of Study Design

Clarified that subjects will need to successfully complete 48 weeks of Study M19-130 on 
placebo or a group that is currently active after the planned Study M19-130 Interim 
Analysis and meet all eligibility criteria to be considered eligible to enroll into LTE Study 
M20-186

Section 5.7 Study Drug

At the Sponsor's discretion, doses of study drug(s) selected for continuation in LTE Study 
M20-186 may be reassigned or discontinued at any time based on the outcome 
assessment of the Study M19-130 Interim Analysis.

Section 5.8 Randomization/Drug Assignment

Based on the outcome of the planned Interim Analysis for Study M19-130, subjects in 
LTE Study M20-186 may be prematurely discontinued at the Sponsor's discretion.

Section 7.5 Interim Analysis

Added clarification regarding how endpoints will be displayed if an interim analysis for 
LTE Study M20-186 is performed.
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2.
Rationale:  If the study is partially terminated, details for follow-up of subjects were provided.

Section 5.5 Withdrawal of Subjects and Discontinuation of Study

Added if the study is partially terminated, a subject in a terminated group will be asked 
to return for a PD visit and to perform a 30-day follow-up phone call after the last dose 
of study drug.
OPERATIONS MANUAL
3.
Rationale:  Alignment with protocol-required screening

Section 3.11 Clinical Laboratory Tests

Added HBV DNA (quantitative) to infection screening in Table 1 Clinical Laboratory 
Tests.
In addition to these modifications, minor typographical edits and corrections were made throughout the
protocol and operations manual for consistency, and other revisions were made for clarity and
readability (e.g., addition of abbreviations).
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SAP_001.pdf: 
ABBV-599
M20-186 – Statistical Analysis Plan
Version 2.0 – 02 January 2024
1
Statistical Analysis Plan
Study M20-186
A Phase 2, Long-Term Extension (LTE) Study with 
Elsubrutinib and Upadacitinib Given Alone or in 
Combination (ABBV-599) in Subjects with 
Moderately to Severely Active Systemic Lupus 
Erythematosus Who Have Completed the M19-130 
Phase 2 Randomized Controlled Trial (RCT)
Date: 02 January 2024
Version 2.0
 
NCT04451772


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Table of Contents
1.0
Introduction...........................................................................5
2.0
Study Design and Objectives ................................................5
2.1
Objectives and Hypotheses..................................................................... 5
2.2
Study Design Overview.......................................................................... 6
2.3
Treatment Assignment and Blinding....................................................... 6
2.4
Sample Size Determination .................................................................... 8
3.0
Endpoints...............................................................................8
3.1
Primary Efficacy Endpoint ..................................................................... 8
3.2
Secondary Efficacy Endpoints................................................................ 8
3.3
Other Efficacy Endpoints ....................................................................... 9
3.4
Safety Endpoints .................................................................................... 9
3.5
Additional Endpoint(s) ......................................................................... 10
4.0
Analysis Populations ...........................................................10
5.0
Subject Disposition..............................................................10
6.0
Study Drug Duration and Compliance ..............................11
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ...................13
7.1
Demographics and Baseline Characteristics.......................................... 13
7.2
Medical History.................................................................................... 16
7.3
Prior and Concomitant Medications...................................................... 16
8.0
Efficacy Analyses.................................................................17
8.1
General Considerations......................................................................... 17
8.2
Handling of Missing Data..................................................................... 18
8.3
Primary Efficacy Endpoint and Analyses.............................................. 18
8.4
Secondary Efficacy Analyses ............................................................... 18
8.5
Additional Efficacy Analyses ............................................................... 18
8.6
Efficacy Subgroup Analyses................................................................. 19
9.0
Safety Analyses....................................................................19
9.1
General Considerations......................................................................... 19
9.2
Adverse Events..................................................................................... 19
9.2.1
Treatment-Emergent Adverse Events.................................................... 20
 


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9.2.2
Adverse Event Overview...................................................................... 20
9.2.3
Treatment-Emergent Adverse Events by SOC and/or PT...................... 21
9.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure .............................................................................................. 22
9.2.5
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation ........................................................................... 22
9.2.6
Adverse Events of Special Interest........................................................ 22
9.2.7
Adverse Events by "Reasonably Possibly Related" Relationship........... 22
9.2.8
Frequent (> 5%) Adverse Events and Reasonably Possibly 
Related Adverse Events by Preferred Term in Decreasing 
Frequency............................................................................................. 22
9.2.9
Listing of Adverse Events..................................................................... 23
9.3
Analysis of Laboratory Data................................................................. 23
9.4
Analysis of Vital Signs......................................................................... 25
9.5
Safety Subgroup Analyses.................................................................... 25
9.6
Other Safety Analyses .......................................................................... 25
10.0
Other Analyses ....................................................................25
11.0
Interim Analysis ..................................................................25
11.1
Interim Analysis ................................................................................... 25
11.2
Data Monitoring Committee................................................................. 26
12.0
Overall Type-I Error Control.............................................26
13.0
Version History ...................................................................26
14.0
References............................................................................26
List of Tables
Table 1.
SAP Version History Summary ............................................................ 26
List of Figures
Figure 1.
Study Schematic..................................................................................... 6
 


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List of Appendices
Appendix A.
Protocol Deviations .............................................................................. 27
Appendix B.
Definition of Adverse Events of Special Interest................................... 28
Appendix C.
Potentially Clinically Important Criteria for Vital Sign Values ............. 30
 


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1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for ABBV-599 
Study M20-186.
Study M20-186 evaluates the long-term safety, tolerability, and efficacy of elsubrutinib 
and upadacitinib given alone or as the ABBV-599 (elsubrutinib/upadacitinib) combination 
in SLE subjects who have completed the Phase 2 Study M19-130.
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) under the UNIX operating system.
2.0
Study Design and Objectives
2.1
Objectives and Hypotheses
Primary
The primary objective is to evaluate the longer-term safety and tolerability of elsubrutinib 
and upadacitinib given alone or as the ABBV-599 (elsubrutinib/upadacitinib) combination 
in SLE subjects who have completed the M19-130 Phase 2 study.
There is no planned hypothesis to be tested for this long-term extension (LTE) study.
Secondary
The secondary objective is to obtain longer-term efficacy data beyond Week 48 with the 
treatments studied in the RCT (monotherapies and combination) to more fully assess the 
risk/benefit of each treatment over time.
 


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2.2
Study Design Overview
This is a double-blind LTE Phase 2 study to investigate the longer-term safety and 
efficacy of elsubrutinib and upadacitinib given alone or as the ABBV-599 
(elsubrutinib/upadacitinib) combination in subjects with moderately to severely active 
SLE. The study population will consist of approximately 195 to 260 individuals who 
entered Study M19-130 with moderately to severely active SLE despite standard of care 
therapy and who have completed Study M19-130.
The schematic of the study is shown in Figure 1.
Figure 1.
Study Schematic
QD = once daily
2.3
Treatment Assignment and Blinding
Prior to the planned Study M19-130 Interim Analysis, qualified subjects entering into 
LTE Study M20-186 stayed in their original treatment group from Study M19-130 if on 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


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an ABBV-599 (elsubrutinib/upadacitinib) combination, elsubrutinib 60 mg monotherapy, 
or upadacitinib 30 mg monotherapy. Those originally assigned to the placebo group in 
Study M19-130 were randomized centrally in a 1:1 ratio to the 2 ABBV-599 
(elsubrutinib/upadacitinib) combination treatment groups.
Prior to the planned Study M19-130 Interim Analysis, there were 4 treatment groups in 
this LTE study:
●
Group 1: Elsubrutinib 60 mg QD and upadacitinib 30 mg QD
●
Group 2: Elsubrutinib 60 mg QD and upadacitinib 15 mg QD
●
Group 3: Elsubrutinib 60 mg QD and upadacitinib placebo QD
●
Group 4: Elsubrutinib placebo QD and upadacitinib 30 mg QD
A planned unblinded interim analysis for Study M19-130 was performed when 50% of 
the planned subjects completed their Week 24 assessments. The objective of this analysis 
was to reassess the treatment regimens in Study M19-130 and the benefit/risk for rollover 
into Study M20-186.
Based on the benefit/risk assessment of the planned Study M19-130 Interim Analysis, 
subjects in 1 or more groups of LTE Study M20-186 may be discontinued. Subjects in any 
discontinued group(s) should return for a Premature Discontinuation (PD) visit and have a 
follow-up phone call 30 days after the last study drug dose.
This study includes a 56-week double-blind treatment period with study visits conducted 
at Weeks 48, 56, 64, 72, 80, 88, 96, and 104 (from the Baseline visit of Study M19-130), 
and a subsequent telephone follow-up call 30 days after the last visit to determine the 
status of any ongoing AEs/SAEs or the occurrence of any new AEs/SAEs. The plan is to 
extend the trial if data support the safety and efficacy endpoints during the 56-week LTE 
study duration.
The M19-130 Primary Analysis will be performed when all subjects have completed the 
Week 24 visit. The M20-186 study team will become unblinded after the M19-130 
 


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Week 24 Primary Analysis has been completed. Study sites and subjects will remain 
blinded to treatment assignment in Study M19-130 and Study M20-186 throughout the 
studies.
2.4
Sample Size Determination
This is the LTE study for Study M19-130. All eligible subjects who completed 
Study M19-130 will be enrolled in this study if the subject signs and dates the informed 
consent. Based on discontinuation criteria mandating efficacy in Study M19-130, it is 
anticipated that between 60% and 80% of subjects from Study M19-130 (195 to 
260 subjects) will be enrolled in this LTE study.
3.0
Endpoints
3.1
Primary Efficacy Endpoint
There is no primary efficacy endpoint since this is the extension to the feeder 
Study M19-130. The primary objective is to investigate the longer-term safety of the 
ABBV-599 combination in patients with active SLE.
3.2
Secondary Efficacy Endpoints
●
SLE Responder Index (SRI)-4
●
British Isles Lupus Assessment Group (BILAG)-Based Combined Lupus 
Assessment (BICLA)
●
Steroid burden, assessed as change from M19-130 baseline
●
Number of mild/moderate, or severe flares per patient-year (respectively and 
overall) by Safety of Estrogens in Lupus Erythematosus National Assessment 
(SELENA) SLEDAI Flare Index (SFI), assessed by number and types of flare 
per subject compared across treatment groups
 


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3.3
Other Efficacy Endpoints
The secondary efficacy endpoints are listed in Section 3.2. The additional efficacy 
endpoints are:
●
Lupus Low Disease Activity State (LLDAS)
●
≥ 4-point decrease in SLEDAI-2K compared with M19-130 Baseline
●
Achievement of 50% reduction of tender or swollen lupus joints (of those 
starting with total ≥ 6 affected joints) from M19-130 Baseline
●
Achievement of 50% reduction in Cutaneous Lupus Erythematosus Disease 
Area and Severity Index (CLASI) activity score (of those starting with CLASI 
≥ 10 at M19-130 Baseline)
●
Change in SLEDAI-2K from M19-130 Baseline
●
Change in BILAG from M19-130 Baseline
●
Change in Functional Assessment of Chronic Illness Therapy - Fatigue 
(FACIT-F) from M19-130 Baseline
●
Change in 36-Item Short Form Health Survey (SF-36) PCS and MCS from 
M19-130 Baseline
●
Change in Lupus Quality of Life questionnaire (LupusQoL) from M19-130 
Baseline
●
Change in Pain Numerical Rating Scale (NRS) from M19-130 Baseline
3.4
Safety Endpoints
The following safety evaluations will be performed for the entire study duration as 
measures of safety and tolerability:
●
AE monitoring
●
Physical examinations
●
Vital sign measurements
●
ECGs
●
Clinical laboratory testing (hematology, chemistry, and urinalysis)
 


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3.5
Additional Endpoint(s)
No additional endpoints will be analyzed in the SAP.
4.0
Analysis Populations 
The following population sets will be used for the analyses.
The Full Analysis Set (FAS) includes all subjects who completed Study M19-130 and 
received at least 1 dose of assigned study drug in Study M20-186. The FAS will be used 
for efficacy and baseline analyses. Subjects will be grouped according to treatment 
sequence as randomized for Study M19-130 and continued/reassigned to rollover into 
Study M20-186.
The Safety Analysis Set also includes all subjects who completed Study M19-130 and 
received at least 1 dose of assigned study drug in Study M20-186. Subjects will be 
grouped according to treatment sequence actually received. A subject's actual treatment 
will be determined by the most frequent dose regimen received. The Safety Analysis Set 
will be used for safety analyses.
5.0
Subject Disposition
The total number of subjects who were enrolled and treated will be summarized.
A summary of subject accountability will be provided where the number of subjects in 
each of the following categories will be summarized for each treatment group:
●
Subjects enrolled in the study;
●
Subjects who took at least one dose of study drug;
●
Subjects who completed protocol-specified treatment;
●
Subjects who prematurely discontinued study drug (all reasons and primary 
reason).
 


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For end of study participation, the number and percentage of subjects who completed the 
protocol defined follow-up period (or did not with associated reasons) will be summarized 
overall and by treatment group.
The treatment groups will be described as follows indicating treatments from 
Study M19-130 to extension Study M20-186:
●
Group 1: Elsubrutinib 60 mg/upadacitinib 30 mg to elsubrutinib 
60 mg/upadacitinib 30 mg
●
Group 2: Elsubrutinib 60 mg/upadacitinib 15 mg to elsubrutinib 
60 mg/upadacitinib 15 mg
●
Group 3: Elsubrutinib 60 mg to elsubrutinib 60 mg
●
Group 4: Upadacitinib 30 mg to upadacitinib 30 mg
●
Group 5a: Placebo to elsubrutinib 60 mg/upadacitinib 30 mg
●
Group 5b: Placebo to elsubrutinib 60 mg/upadacitinib 15 mg
Treatment groups above are subject to change depending on potential M20-186 treatment 
re-assignments after M19-130 Interim Analysis.
6.0
Study Drug Duration and Compliance
Study Drug Duration
A summary of study drug duration (days) will be provided by each treatment arm for the 
Safety Analysis Set.
The duration of exposure to study drug will be summarized for each group as specified in 
Section 5.0, with the number of subjects, mean, standard deviation, median, minimum and 
maximum values. In addition, the number and percentage of subjects exposed to study 
drug will be summarized for Study M20-186 treatment period based on the following 
duration intervals:
●
≥ 1 day
 


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●
≥ 57 days
●
≥ 113 days
●
≥ 169 days
●
≥ 225 days
●
≥ 281 days
●
≥ 337 days
●
≥ 393 days
The exposure to study drug in days for Study M20-186 period is calculated as:
Exposure = (date of last study medication in Study M20-186 – date of first study 
medication in Study M20-186 + 1)
Compliance
Study drug compliance will be summarized for each treatment group for FAS population. 
Descriptive statistics will be provided including sample size, mean, standard deviation, 
median, minimum and maximum.
Treatment compliance (TC) will be calculated using the following formula:
●
The total number of tablets/capsules taken will be calculated as the total 
number of tablets/capsules dispensed minus the total number of 
tablets/capsules returned.
Note: If the bottle is not returned, total number of tablets/capsules returned is 
assumed to be 0.
●
In M20-186: number of tablets per day is 1 and number of capsules per day 
is 3.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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 for the FAS overall and by treatment group 
as described in Section 5.0. 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
The following demographic and baseline characteristics, as measured at baseline of the 
Study M19-130 study, will be summarized.
Demographic Characteristics
●
Sex (male, female)
●
Age (years)
●
Age category [18 – < 40 years old, 40 – < 65 years old, ≥ 65 years old]
●
Ethnicity (Hispanic or Latino, Not Hispanic or Latino)
●
Race (White, Black or African American, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Asian, Other)
●
Geographic region (North America, South/Central America, Western Europe, 
Eastern Europe, Asia Japan, Asia Other, Other)
●
Weight (kg)
●
Weight Categories (< 60 kg, ≥ 60 kg)
●
Height (cm)
●
BMI (kg/m2)
●
Body Mass Index (BMI) Category (kg/m2) (BMI < 25, BMI ≥ 25)
 


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Other Baseline Characteristics
The following continuous variables will be summarized:
●
SLEDAI-2K score
●
Patient's Global Assessment of Disease Activity score
●
Physician's Global Assessment of Disease Activity score
●
LupusQoL score
●
SF-36 score
●
Time since onset of lupus (years), which will be calculated as follows:
Time since onset of lupus (years) = year of first dose – year of initial diagnosis 
of SLE
●
Number of tender joints (from 28-tender joint count)
●
Number of swollen joints (from 28-swollen joint count)
●
Daily dose of corticosteroid (mg/day)
●
CLASI Total Activity Score
●
CLASI Total Damage Score
●
Complement C3 and C4 levels
●
Anti-dsDNA level
●
Urine protein to urine creatinine ratio
●
Serum immunoglobulin (Ig)G and IgM concentrations
●
Creatinine
The following categorical variables will be summarized:
●
Anti-dsDNA status (positive defined as ≥ 30 IU/mL) (positive, negative)
●
SLEDAI-2K status (< 10, ≥10)
●
British Isles Lupus Assessment Group (BILAG) organ system involvement at 
baseline (yes or no for each organ system domain). Involvement requires a 
baseline BILAG disease activity score of A or B.
 


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●
BILAG A organ system involvement at baseline (yes or no for each organ 
system domain).
●
SLEDAI-2K organ system involvement at baseline (yes or no for each organ 
system domain).
●
C3 status (less than the lower limit of normal [LLN] (< 90.0 mg/dL)
●
C4 status (less than LLN [< 10.0 mg/dL])
●
Anti-Smith antibodies (≥ 30 AU/mL) (yes, no)
●
Corticosteroid use (yes or no), and within those taking corticosteroids, 
< 10 mg/day or ≥ 10 mg/day.
●
Corticosteroid use (yes or no), and within those taking corticosteroids, 
< 7.5 mg/day or ≥ 7.5 mg/day.
●
Immunosuppressant use (yes or no):
○
Mycophenolate use (yes or no)
○
Azathioprine use (yes or no)
○
Methotrexate use (yes or no)
○
Tacrolimus use (yes or no)
○
Cyclosporine use (yes or no)
○
Leflunomide use (yes or no)
●
Antimalarial use (yes or no):
○
Hydroxychloroquine (yes or no)
○
Chloroquine (yes or no)
○
Quinacrine (yes or no)
Clinical Tests at Screening
●
Chest x-ray
●
Tuberculin PPD skin test, QuantiFERON TB Gold test
●
Serum pregnancy test
 


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Immunization History
●
Herpes Zoster immunization
●
Hepatitis B immunization
Tobacco/Nicotine and Alcohol Use
●
Tobacco/Nicotine Use (current, former, never, or unknown)
●
Alcohol Use (current, former, never, or unknown)
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. Medical history data will be summarized and 
presented for the FAS population using body systems and conditions/diagnoses as 
captured on the CRF. The body systems will be presented in alphabetical order and the 
conditions/diagnoses will be presented in alphabetical order within each body system. The 
number and percentage of subjects with a condition/diagnosis will be summarized for 
each treatment group as well as overall. Subjects reporting more than one 
condition/diagnosis within a body system will be counted only once for that body system. 
No statistical comparison will be performed for medical history reporting.
7.3
Prior and Concomitant Medications
Prior and concomitant medications will be summarized by each treatment group as well as 
overall for the FAS.
Prior medications are those medications taken prior to the first dose of study drug in 
Study M19-130. This includes medications with a start date before the first study drug 
administration date, regardless of the end date of these medications. Medications taken on 
the day of the first dose of study drug are not counted as prior medications.
 


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Concomitant medications are those medications, other than study drug, taken after the 
first dose of study drug in Study M20-186 and within 1 day of the last dose of study drug.
This includes medications with a start date between first study drug administration in 
Study M20-186 and last study drug administration + 1 day, as well as, medications with a 
start date prior to first dose of study drug in Study M20-186 and which are ongoing after 
first dose of study drug. Medications taken on the day of the first dose of study drug in 
Study M20-186 are counted as concomitant medications.
The number and percentage of subjects who received a prior medication and the number 
and percentage of subjects who received a concomitant medication will be tabulated 
separately by the generic name assigned by the most current version of the World Health 
Organization (WHO) Drug Dictionary.
8.0
Efficacy Analyses
8.1
General Considerations
Analysis of efficacy endpoints will be conducted on the FAS based on treatment sequence 
as randomized for Study M19-130 and continued/reassigned to rollover into 
Study M20-186. For all efficacy endpoints, the descriptive statistics will be provided by 
treatment group. The statistics include number of observations, mean, standard deviation, 
minimum, median, and maximum for continuous variables; and number and percentage of 
subjects for categorical variables.
The analysis treatment groups will be described as follows indicating treatments from 
Study M19-130 to extension Study M20-186:
●
Group 1: Elsubrutinib 60 mg/upadacitinib 30 mg to elsubrutinib 
60 mg/upadacitinib 30 mg
●
Group 2: Elsubrutinib 60 mg/upadacitinib 15 mg to elsubrutinib 
60 mg/upadacitinib 15 mg 
●
Group 3: Elsubrutinib 60 mg to elsubrutinib 60 mg
●
Group 4: Upadacitinib 30 mg to upadacitinib 30 mg
 


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●
Group 5a: Placebo to elsubrutinib 60 mg/upadacitinib 30 mg
●
Group 5b: Placebo to elsubrutinib 60 mg/upadacitinib 15 mg
Analysis treatment groups above are subject to change depending on potential M20-186 
treatment re-assignments after M19-130 Interim Analysis.
The Baseline for all efficacy analyses in this study will be the Baseline in Study M19-130, 
i.e., the last non-missing observation before the first administration of study drug in 
Study M19-130 or randomization in Study M19-130 if no study drug is given.
8.2
Handling of Missing Data
The analysis will be based on As Observed data, and no imputation will be conducted.
8.3
Primary Efficacy Endpoint and Analyses
There are no primary efficacy endpoints or analyses for this study.
8.4
Secondary Efficacy Analyses
Descriptive statistics will be provided for each treatment group for all visits. These 
include the number of observations, mean with 95% confidence interval, standard 
deviation, median, minimum and maximum for continuous endpoints and count 
endpoints; and frequencies and percentages with 95% confidence interval for binary 
endpoints.
No missing data imputation will be applied. All efficacy analyses will be based on As 
Observed (AO) analysis, and thus a subject who does not have an evaluation at the 
primary analysis time point will not be included.
8.5
Additional Efficacy Analyses
No additional efficacy analyses are planned.
 


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8.6
Efficacy Subgroup Analyses
No subgroup analyses will be performed.
9.0
Safety Analyses
9.1
General Considerations
Safety analyses will include reporting of adverse events, laboratory, and vital signs 
measurements based on data in Study M20-186. Safety analyses will be carried out using 
the Safety Analysis Set.
The following summary statistics will be presented for subjects who have both baseline 
and post-baseline values for laboratory parameters and vital signs: the mean value at 
Baseline and at each respective protocol specified visit, and the mean, standard deviation 
and median for changes from Baseline. Categorical data will be summarized using 
frequencies and percentages. The number of non-missing values will be given. Missing 
safety data will not be imputed.
For safety analysis, Baseline is defined as the last available measurement before 
Study M19-130 study drug administration if the subjects took active treatment in
Study M19-130, and the last available measurement before Study M20-186 study drug 
administration if the subjects took placebo in Study M19-130.
9.2
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 maximum toxicity grade and level of relationship to 
investigational product will be reported.
 


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9.2.1
Treatment-Emergent Adverse Events
To summarize data from Study M20-186, a treatment-emergent Adverse Event (TEAE) is 
defined as an adverse event with an onset date that is on or after the first dose of study 
drug from Study M20-186, and no more than 30 days after the last dose of study drug 
from Study M20-186.
Events where the onset date is the same as Study M20-186 study drug start date are 
assumed to be treatment-emergent, unless the Study M20-186 study drug start time and 
the adverse event start time are collected and the adverse event start time is prior to the 
Study M20-186 study drug start time. If an incomplete onset date was collected for an 
adverse event, the event will be assumed to be treatment-emergent unless there is other 
evidence that confirms that the event was not treatment-emergent (e.g., the event end date 
was prior to the study drug start date). All treatment-emergent AEs will be summarized 
overall, as well as by primary MedDRA SOC and Preferred Term. The SOCs will be 
presented in alphabetical order, and the PTs will be presented in alphabetical order within 
each SOC.
The number and percentage of subjects experiencing TEAEs will be summarized.
9.2.2
Adverse Event Overview
The number and percentage of subjects experiencing TEAEs will be summarized by 
treatment group as specified in Section 6.0 and overall.
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 treatment-emergent AE
●
Any treatment-emergent AE related to study drug according to the investigator
●
Any severe treatment-emergent AE
●
Any serious treatment-emergent AE
●
Any treatment-emergent AE leading to discontinuation of study drug
 


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●
Any treatment-emergent AE leading to death
●
TEAE of special interest (AESIs) (as defined in Appendix B)
●
Any COVID-19 related AE
●
All deaths
●
COVID-19 related deaths
Additional AEs may be considered for tabulation/summary based on recommendations 
from Clinical and Safety as deemed appropriate.
The number and percentage of subjects experiencing at least one event of treatment-
emergent AEs will be summarized for each treatment group. In addition, an overview of 
AEs per 100 patient-years of study exposure will be presented for the AE categories 
defined above. The number of TEAEs reported, the total number of years of study drug 
exposure, and the TEAE rate per 100 patient-years will be presented.
9.2.3
Treatment-Emergent Adverse Events by SOC and/or PT
Treatment-emergent adverse events will be summarized by SOC and PT; by maximum 
relationship to study drug as assessed by the investigator (e.g., reasonable possibility or no 
reasonable possibility) and SOC and PT; by maximum toxicity grade 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 maximum toxicity grade and 
level of relationship to investigational product will be reported.
In addition, treatment-emergent adverse events will be summarized by PT and sorted by 
decreasing frequency for the total active group.
 


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9.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure
TEAEs occurring during Study M20-186 will be summarized by event rate per 
100 subject years, defined as
100 * (Number of TEAEs)/(Total Patient Years)
where total patient years is defined as the sum of the study drug exposure of all subjects 
normalized by 365.25 and rounded to 1 decimal place.
9.2.5
SAEs (Including Deaths) and Adverse Events Leading to 
Study Drug Discontinuation
SAEs (including deaths) and AEs leading to study drug discontinuation will be 
summarized by SOC and PT and in listing format.
9.2.6
Adverse Events of Special Interest
Adverse events of special interest (AESI) will be summarized by SOC and PT and will be 
based on standardized or company MedDRA queries (SMQs or CMQs). AESI are 
categorized in Appendix B. Tabular listings of AESIs will be provided.
9.2.7
Adverse Events by "Reasonably Possibly Related" 
Relationship
TEAEs and reasonably possibly related AEs occurring for more than 2% of the subjects in 
any of the treatment groups will also be summarized by MedDRA SOC and PT. If a 
subject has an AE with an unknown relationship, then the AE will be counted as 'related.'
9.2.8
Frequent (> 5%) Adverse Events and Reasonably Possibly 
Related Adverse Events by Preferred Term in Decreasing 
Frequency
TEAEs and reasonably possibly related AEs occurring for more than 5% of the subjects in 
any of the treatment arms will be summarized by MedDRA PT in decreasing frequency 
separately.
 


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9.2.9
Listing of Adverse Events
The following additional summaries of AEs will be prepared.
●
Listing of Subjects with Treatment-Emergent AESIs
●
Listing of Subjects with Pretreatment SAEs
●
Listing of Subjects with Treatment-Emergent SAEs
●
Listing of Treatment-Emergent AEs that led to discontinuation of study drug
●
Listing of all deaths.
9.3
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.
Each laboratory variable will be summarized for all time points (starting with Baseline) 
with the number of non-missing observations, mean and standard deviation, median, 
minimum and maximum.
Mean change from Baseline to each applicable post-Baseline visit will be summarized for 
selected laboratory variables, with the number of observations, Baseline mean, and visit 
mean, at each visit in Study M20-186 for each treatment group. The change from Baseline 
mean, standard error, and 95% confidence interval will be presented for the mean change 
from Baseline within each treatment group.
Shift tables will be provided for each hematology, clinical chemistry parameter. Shifts 
from Baseline to the following endpoints will be considered: post-Baseline value and final 
value. This analysis will be performed only for category of "low or normal" at Baseline 
which shift to 'high' and category of "high or normal" at Baseline which shift to category 
of 'low.'
 


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For selected laboratory variables including hemoglobin, neutrophils, lymphocytes, 
platelets, creatinine, ALT, AST, CPK, LDL cholesterol, HDL cholesterol, total 
cholesterol, and triglycerides, a listing of all observations collected will be generated for 
subjects that had at least one post-Baseline observation meeting pre-defined criteria for 
potentially clinically important values. The number and percentage of subjects in each 
treatment group who have at least one post-Baseline observation meeting the pre-defined 
criteria for potentially clinically important values will be provided for each variable. The 
criteria for potentially clinically important laboratory values will be determined by NCI 
CTCAE version 4.03 of greater than Grade 3 or greater than Grade 4.
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 will be summarized by "as treated" treatment group:
●
ALT ≥ 3 × ULN
●
ALT ≥ 5 × ULN
●
ALT ≥ 10 × ULN
●
ALT ≥ 20 × ULN
●
AST ≥ 3 × ULN
●
AST ≥ 5 × ULN
●
AST ≥ 10 × ULN
●
AST ≥ 20 × ULN
●
Total Bilirubin Level (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
A listing of possible Hy's Law cases, defined as those who meet all of the following 
conditions simultaneously, will be provided: ALT > 3 × ULN or AST > 3 × ULN that is 
associated with an increase in bilirubin ≥ 2 × ULN and alkaline phosphatase < 2 × ULN.
 


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9.4
Analysis of Vital Signs
Vital sign measurements of systolic and diastolic blood pressure, pulse rate, body 
temperature, and weight will be summarized.
Each vital sign variable will be summarized for all time points with the number of 
non-missing observations, mean and standard deviation, median, minimum and 
maximum. Mean change from Baseline to each applicable post-Baseline visit 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.
Vital sign variables will be evaluated based on potentially clinically important (PCI) 
criteria (Appendix C). For each vital sign PCI criterion, the number and percentage of 
subjects who have a vital sign value meeting the criteria will be summarized. Listings will 
be provided to summarize subject-level vital sign data for subjects meeting PCI criteria.
9.5
Safety Subgroup Analyses
No planned safety subgroup analyses.
9.6
Other Safety Analyses
ECG is collected at Screening and Weeks 64, 80, and 96. The number and percentage of 
subjects with QTcF prolongation (QTcF > 500 msec) will be summarized by treatment 
groups using Safety Analysis Set population.
10.0
Other Analyses
No other analyses are planned.
11.0
Interim Analysis
11.1
Interim Analysis
No interim analysis is planned.
 


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11.2
Data Monitoring Committee
An internal safety DMC composed of persons independent of the Study M19-130 and 
Study M20-186 protocols and with relevant expertise in their field will review unblinded 
safety data from the ongoing studies. The primary responsibility of the DMC will be to 
protect the safety of the subjects participating in Study M19-130 and in this study. When 
needed, high-level unblinded efficacy data may also be requested by the DMC and 
reviewed so that the DMC can assess benefit:risk of any emerging safety differences.
A separate DMC charter for Studies M19-130 and M20-186 was prepared outside of the 
protocols and described the roles and responsibilities of the DMC members, frequency of 
data reviews, planned interim analyses, relevant safety data to be assessed, and 
expectations for blinded communications for Studies M19-130 and M20-186.
12.0
Overall Type-I Error Control
No hypothesis tests will be conducted for the efficacy analysis.
13.0
Version History
Table 1.
SAP Version History Summary
Version
Date
Summary
1.0
12 August 2020
Original version
2.0
02 January 2024
1.
Updated to align with the updates in the protocol after M19-130 
interim analysis.
2.
Update analysis of study drug duration and analysis of safety to 
use M20-186 data only. Integrated data will be summarized 
later in the submission of SLE Phase 3 program.
14.0
References
1. Julious SA. Two-sided confidence intervals for the single proportion: comparison
of seven methods by Robert G. Newcombe. Stat Med. 2005;24(21):3383-4.
 


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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 CMQ
Herpes Zoster
CMQ
"Herpes Zoster"
Active Tuberculosis
CMQ
"Active Tuberculosis"
Possible Malignancy
SMQ
Narrow
"Malignancies"
Malignancy
SMQ
Narrow
"Malignant Tumours"
Malignancies excluding NMSC
SMQ
Narrow
"Malignant Tumours" removing
NMSC output
Non-Melanoma Skin Cancer (NMSC)
SMQ
Narrow
"Skin Malignant Tumours"
removing Melanoma CMQ
Adjudicated GI perforations
Based on adjudicated results (the 
identification of events to be 
adjudicated are described in the 
GI Perforation charter)
Adjudicated cardiovascular events:
MACE*
        Cardiovascular Death
        Non-fatal Myocardial Infarction
        Non-fatal Stroke
Undetermined/Unknown Cause of 
Deaths
Other Cardiovascular events
Output from 
CAC
Anemia
CMQ
"Non-Hemolytic and Non-
Aplastic Anemias"
Neutropenia
CMQ
"Hematological Toxicity –
Neutropenia"
Lymphopenia
CMQ
"Hematological Toxicity -
Lymphopenia"
 


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AESI
Type of 
MedDRA 
Query
Broad or 
Narrow 
Search
SMQ/CMQ Search Criteria
Renal dysfunction
SMQ
Narrow
"Acute Renal Failure"
Hepatic disorders
SMQ
Narrow
"Drug Related Hepatic 
Disorders"
Adjudicated Thrombotic Events:
VTE**
        Deep Vein Thrombosis
        Pulmonary Embolism
Other Venous Thrombosis
Output from 
CAC
*
MACE:  Major Adverse Cardiovascular Events, defined as cardiovascular death, non-fatal myocardial infarction 
and non-fatal stroke.
**
VTE:  Venous thromboembolic events, defined as deep vein thrombosis (DVT) and pulmonary embolism (PE) 
(fatal and non-fatal).
 


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Appendix C.
Potentially Clinically Important Criteria for Vital Sign Values
Vital Sign
Category
Criteria for Potential Clinically Important 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
Weight
High
> 7% increase from baseline
Low
> 7% decrease from baseline