Conditions: Systemic Lupus Erythematosus (SLE)
Keywords: Systemic Lupus Erythematosus (SLE) ABBV-105 Upadacitinib ABBV-599 Elsubrutinib
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 341
Healthy volunteers: no

Brief summary:
The main objective of this study was to evaluate the safety and efficacy of elsubrutinib, upadacitinib (UPA), and ABBV-599 (elsubrutinib/upadacitinib) High Dose and Low Dose combinations vs placebo for the treatment of signs and symptoms of Systemic Lupus Erythematosus (SLE) in participants with moderately to severely active SLE and to define doses for further development.

Detailed description:

Arms:
arm 1: Placebo capsule for elsubrutinib once a day by mouth for up to 48 weeks; placebo film-coated tablet for upadacitinib once a day by mouth for up to 48 weeks arm 2: 60 mg elsubrutinib capsule once a day by mouth for up to 48 weeks; 30 mg upadacitinib film-coated tablet once a day by mouth for up to 48 weeks arm 3: Placebo capsule for elsubrutinib once a day by mouth for up to 48 weeks; 30 mg upadacitinib film-coated tablet once a day by mouth for up to 48 weeks arm 4: 60 mg elsubrutinib capsule once a day by mouth for up to 24 weeks; 15 mg upadacitinib film-coated tablet once a day by mouth for up to 24 weeks arm 5: 60 mg elsubrutinib capsule once a day by mouth for up to 24 weeks; placebo film-coated tablet for upadacitinib once a day by mouth for up to 24 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 document:
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
STUDY OBJECTIVES AND ENDPOINTS
12
3.1
OBJECTIVE AND HYPOTHESES
12
3.2
PRIMARY ENDPOINT
13
3.3
SECONDARY ENDPOINTS
13
3.4
ADDITIONAL EFFICACY ENDPOINTS
13
3.5
SAFETY
14
3.6
PHARMACOKINETIC ENDPOINTS
15
3.7
BIOMARKER RESEARCH
15
4
INVESTIGATIONAL PLAN
16
4.1
OVERALL STUDY DESIGN AND PLAN
16
4.2
DISCUSSION OF STUDY DESIGN
18
5
STUDY ACTIVITIES
19
5.1
ELIGIBILITY CRITERIA
19
5.2
CONTRACEPTION RECOMMENDATIONS
24
5.3
PROHIBITED MEDICATIONS AND THERAPY
26
5.4
CONCOMITANT THERAPY
28
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
29
5.6
FOLLOW-UP AFTER SUBJECT DISCONTINUATION OF STUDY DRUG OR FROM STUDY
31
5.7
STUDY DRUG
32
5.8
RANDOMIZATION/DRUG ASSIGNMENT
33
5.9
PROTOCOL DEVIATIONS
34
5.10
DATA MONITORING COMMITTEE
35
6
SAFETY CONSIDERATIONS
35
6.1
COMPLAINTS AND ADVERSE EVENTS
35
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6.2
TOXICITY MANAGEMENT
40
7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
45
7.1
STATISTICAL AND ANALYTICAL PLANS
45
7.2
DEFINITION FOR ANALYSIS POPULATIONS
46
7.3
STATISTICAL ANALYSES FOR EFFICACY
46
7.4
STATISTICAL ANALYSES FOR SAFETY
47
7.5
INTERIM ANALYSIS
48
7.6
OVERALL TYPE I ERROR CONTROL
48
7.7
SAMPLE SIZE ESTIMATION
48
8
ETHICS
49
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD (IEC/IRB)
49
8.2
ETHICAL CONDUCT OF THE STUDY
49
8.3
SUBJECT CONFIDENTIALITY
49
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
49
10
DATA QUALITY ASSURANCE
50
11
COMPLETION OF THE STUDY
50
12
REFERENCES
50
LIST OF TABLES
TABLE 1.
EXAMPLES OF COMMONLY USED STRONG CYP3A OR CYP1A2 INHIBITORS AND INDUCERS
27
TABLE 2.
STUDY DRUG
33
TABLE 3.
ADVERSE EVENTS REQUIRING SUPPLEMENTAL REPORTS
37
TABLE 4.
SPECIFIC TOXICITY MANAGEMENT GUIDELINES FOR ABNORMAL LABORATORY VALUES
43
LIST OF FIGURES
FIGURE 1.
STUDY SCHEMATIC
18
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LIST OF APPENDICES
APPENDIX A.
STUDY SPECIFIC ABBREVIATIONS AND TERMS
53
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
58
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
59
APPENDIX D.
ACTIVITY SCHEDULE
60
APPENDIX E.
DESCRIPTION OF EFFICACY MEASURES
65
APPENDIX F.
LOCAL REQUIREMENTS
67
APPENDIX G.
PROTOCOL SUMMARY OF CHANGES
68
APPENDIX H.
OPERATIONS MANUAL
70
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significant disease activity in new organ systems (no new British Isles 
Lupus Assessment Group ([BILAG]) A or > 1 new BILAG B).
Secondary Endpoints: 
1.
Achievement of SRI-4 at Week 24
2.
Achievement of BILAG-Based Combined Lupus Assessment 
(BICLA) response at Week 24
3.
Achievement of Lupus Low Disease Activity State (LLDAS) at 
Week 24
4.
Steroid burden, assessed as change from Baseline at Week 24
5.
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 
through Week 24
Additional Endpoints (for efficacy, at all visits unless otherwise noted):
1.
Achievement of SRI-4 
2.
Achievement of SRI-5, -6, -7, -8 and steroid dose ≤ 10 mg 
prednisone equivalent QD at Weeks 24 and 48
3.
Achievement of SRI-5, -6, -7, -8
4.
Achievement of BICLA response
5.
Achievement of LLDAS
6.
Achievement of ≥4-point decrease in SLEDAI-2K from Baseline
7.
Steroid burden, assessed as change from Baseline
8.
Number of mild, moderate, or severe flares per patient-year 
(respectively and overall) by SELENA SFI, assessed by number 
and types of flare per subject through Week 24 and Week 48
9.
Time to first flare by SELENA SFI after first study drug 
administration up to Week 24 and Week 48
10. Achievement of 50% reduction of tender or swollen lupus joints 
defined as ≥ 50% decrease in either tender or swollen joints (of 
those starting with total ≥ 6 affected joints)
11. Achievement of 50% reduction in Cutaneous Lupus 
Erythematosus Disease Area and Severity Index (CLASI) activity 
score (of those starting with CLASI ≥ 10)
12. Change in SLEDAI-2K from Baseline
13. Change in BILAG from Baseline
14. Change in PhGA from Baseline
15. Change in Patient Global Assessment (PtGA) from Baseline
16. Change from Baseline in Functional Assessment of Chronic 
Illness Therapy (FACIT)-Fatigue at Weeks 2, 12, 24, and 48
17. Change from Baseline in 36-Item Short Form Health Survey 
(SF-36) at Weeks 2, 12, 24, and 48
18. Change from Baseline Lupus Quality of Life questionnaire 
(LupusQoL) at Weeks 2, 12, 24, and 48
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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 RA, SLE, and other autoimmune diseases.  BTK 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 including 
RA.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 that displays unique selectivity for the JAK1 
receptor, 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 currently being developed 
for the treatment of:  adult patients with Crohn's disease (CD), ulcerative colitis (UC), psoriatic arthritis, 
active axial spondyloarthritis (axSpA), giant cell arteritis (GCA), adult and pediatric patients with 
moderate to severe atopic dermatitis, and pediatric patients with polyarticular course juvenile idiopathic 
arthritis (JIA).
Clinical Hypothesis
It is anticipated that inhibition of either JAK1 or BTK will result in amelioration of lupus disease activity 
with increased efficacy delivered by the ABBV-599 (elsubrutinib/upadacitinib) combination.
BTK inhibition by elsubrutinib and JAK1 inhibition by upadacitinib are expected to disrupt B cell 
activation, T cell activation, and Type I IFN signaling as well as block local immune complex-driven tissue 
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damage that contributes to inflammation.  Given the diverse immunologic mechanisms at play in SLE, 
the ABBV-599 (elsubrutinib/upadacitinib) combination on background standard of care has the potential 
to provide greater clinical efficacy compared to current standard of care while maintaining an 
acceptable safety profile.
2.2 Benefits and Risks to Subjects
The ABBV-599 (elsubrutinib/upadacitinib) combination of BTK inhibition by elsubrutinib and JAK1 
inhibition by upadacitinib has the potential to provide greater clinical efficacy when added to current 
standard of care while maintaining an acceptable safety profile.
Upadacitinib is approved as a single-ingredient agent for the treatment of RA and is being developed for
the treatment of 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.  Review of the available safety data has 
determined the following common AEs (upper respiratory tract infection, increased blood creatine 
phosphokinase [CPK], herpes zoster, nausea, cough, herpes simplex, neutropenia, pneumonia, 
hypercholesterolemia, and pyrexia) to be possibly causally related to treatment with upadacitinib.  
Events of deep vein thrombosis and pulmonary embolism have been reported in patients receiving JAK 
inhibitors including upadacitinib.  Phase 3 RA clinical data have determined the following as important 
identified risks for upadacitinib therapy: serious infections (including opportunistic infections and 
tuberculosis [TB]) and herpes zoster.  Upadacitinib offers a favorable benefit/risk ratio in the treatment 
of adult RA, which supports further clinical development of upadacitinib in other immunoinflammatory 
indications (e.g., SLE, CD, UC, atopic dermatitis, psoriatic arthritis, axSpA, JIA, and GCA).
A detailed description of the preclinical toxicology, metabolism, and toxicology datasets can be found in 
the elsubrutinib8 and upadacitinib9 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.
In Phase 1 Studies M16-356 (single doses of elsubrutinib ranging from 2 to 125 mg), M16-357 (multiple 
doses of elsubrutinib ranging from 3 to 60 mg), and M16-044 (co-administration of upadacitinib 30 mg 
with elsubrutinib ranging from 10 to 60 mg), elsubrutinib alone or elsubrutinib co-administration with 
upadacitinib was well-tolerated with no severe or serious adverse events (SAEs) observed in healthy 
adult subjects.  The most common adverse event (AE) reported was headache, which was distributed 
evenly across cohorts including placebo and without apparent dose effect.
SLE 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 contraceptives may further 
increase the risk of thrombotic events; therefore, the choice of contraceptive should be carefully 
considered.
Taken together, the safety data from the Phase 1 program support further development of elsubrutinib
given alone or in combination with upadacitinib (ABBV-599 [elsubrutinib/upadacitinib] combination) in 
Phase 2 in subjects with SLE.
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In Study M19-130, routine safety evaluations of all treatment groups will be performed.  These include 
assessments of deaths, SAEs, non-serious 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 screening exclusions and ongoing assessments are included in 
the protocol:

Exclusion of subjects with chronic or recent infections;

Screen subjects for TB; exclude subjects with active TB or latent TB without history of 
appropriate prophylaxis [latent 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 screening for latent TB while being on 
immunosuppressive treatment, these national regulations will be applied, respectively.

Subjects will also be screened for human immunodeficiency virus (HIV) and hepatitis B (HB) and 
C infections.

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 3.5 for detailed safety monitoring and information on the Data Monitoring Committee 
(DMC).
For further details, please see findings from completed studies, including safety data in the elsubrutinib8
and upadacitinib9 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.
3 STUDY OBJECTIVES AND ENDPOINTS
3.1 Objective and Hypotheses
The main objective of this study is to evaluate the safety and efficacy of elsubrutinib, upadacitinib, and 
the ABBV-599 (elsubrutinib/upadacitinib) combination vs placebo for the treatment of signs and 
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symptoms of SLE at 24 and 48 weeks in subjects with moderately to severely active SLE and to define
dose(s) for further development.
The hypotheses corresponding to the main objective are that elsubrutinib, upadacitinib, and the 
ABBV-599 (elsubrutinib/upadacitinib) combination are expected to provide better efficacy than placebo 
and to be well-tolerated in subjects with moderately to severely active SLE.
3.2 Primary Endpoint
The following is the primary efficacy endpoint:
1.
Achievement of SLE Responder Index (SRI)-4 and steroid dose ≤ 10 mg prednisone equivalent
once a day (QD) at Week 24
SLE Responder Index (SRI)-4 is defined as ≥ 4-point reduction in Systemic Lupus Erythematosus Disease 
Activity Index 2000 (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 British Isles Lupus Assessment Group [BILAG] A or > 1 new 
BILAG B).
3.3 Secondary Endpoints
The following secondary efficacy endpoints will be evaluated:
1.
Achievement of SRI-4 at Week 24
2.
Achievement of BILAG-Based Combined Lupus Assessment (BICLA) response at Week 24
3.
Achievement of Lupus Low Disease Activity State (LLDAS) at Week 24
4.
Steroid burden, assessed as change from Baseline at Week 24
5.
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 through Week 24
3.4 Additional Efficacy Endpoints
The following additional efficacy endpoints will be evaluated at all visits unless otherwise noted:
1.
Achievement of SRI-4 
2.
Achievement of SRI-5, -6, -7, -8 and steroid dose ≤ 10 mg prednisone equivalent QD at Weeks 24 
and 48
3.
Achievement of SRI-5, -6, -7, -8
4.
Achievement of BICLA response
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5.
Achievement of LLDAS
6.
Achievement of ≥4-point decrease in SLEDAI-2K from Baseline
7.
Steroid burden, assessed as change from Baseline
8.
Number of mild, moderate, or severe flares per patient-year (respectively and overall) by 
SELENA SFI, assessed by number and types of flare per subject through Week 24 and Week 48.
9.
Time to first flare by SELENA SFI after first study drug administration up to Week 24 and 
Week 48
10. Achievement of 50% reduction of tender or swollen lupus joints defined as ≥ 50% decrease in 
either tender or swollen joints (among those starting with total ≥ 6 affected joints)
11. Achievement of 50% reduction in Cutaneous Lupus Erythematosus Disease Area and Severity 
Index (CLASI) activity score (of those starting with CLASI ≥10)
12. Change in SLEDAI-2K from Baseline
13. Change in BILAG from Baseline
14. Change in PhGA from Baseline
15. Change in Patient Global Assessment (PtGA) from Baseline
16. Change from Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue at 
Weeks 2, 12, 24, and 48
17. Change from Baseline in 36-Item Short Form Health Survey (SF-36) at Weeks 2, 12, 24, and 48
18. Change from Baseline Lupus Quality of Life questionnaire (LupusQoL) at Weeks 2, 12, 24, and 48
19. Change from Baseline Pain Numerical Rating Scale (NRS) at Weeks 2, 12, 24, and 48
3.5 Safety
Routine safety evaluations include AE monitoring, physical examinations, vital sign measurements, ECGs, 
and clinical laboratory testing (hematology, chemistry, and urinalysis) as a measure of safety and 
tolerability for the entire study duration.
SAEs 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.
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
gastrointestinal (GI) perforations, adjudicated cardiovascular events (e.g., major adverse cardiovascular 
event [MACE]), anemia, neutropenia, lymphopenia, renal dysfunction, hepatic disorders, and 
adjudicated embolic and thromboembolic events (non-cardiac, non-central nervous system [CNS])
including venous thrombotic events defined as pulmonary embolism and deep vein thrombosis.  Specific 
toxicity management measures will be utilized, as described in Section 6.2, for serious infections, serious 
GI events, cardiovascular events (MACE), malignancies, ECG abnormalities, and select laboratory 
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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.
An unblinded internal DMC will be established to ensure the overall integrity and conduct of the study.  
DMC reviews will be conducted at regular intervals (see Section 5.10 for more details).  Regular 
systematic reviews of emerging safety data from all clinical studies with elsubrutinib, upadacitinib, and 
ABBV-599 (elsubrutinib/upadacitinib) combination will be conducted by AbbVie.
An independent external Cardiovascular Adjudication Committee (CAC) will adjudicate all blinded 
cardiovascular and cerebrovascular events, embolic/thrombotic events, and deaths, as defined in the 
CAC charter.
3.6 Pharmacokinetic Endpoints
Elsubrutinib and upadacitinib plasma concentrations will be summarized at each sampling time point 
(Appendix D) using descriptive statistics.  A mixed-effects modeling approach may be used to estimate 
the population central value and the empirical Bayesian estimates of the individual values for 
elsubrutinib and upadacitinib oral clearance (CL/F) and volume of distribution (Vss/F).  Additional 
parameters and pharmacokinetic (PK)/pharmacodynamic relationships may be estimated if useful in the 
interpretation of the data.
3.7 Biomarker Research
Biospecimens (whole blood, peripheral blood mononuclear cells [PBMCs], plasma, and serum) will be 
collected at specified time points (Appendix D) throughout the study to evaluate known and/or novel 
disease-related or drug-related biomarkers.  Types of biomarkers may include nucleic acids, proteins, 
lipids, RNA, DNA, and/or metabolites.  The objective of this research is to analyze samples for 
biomarkers that will help to understand SLE, related conditions, and response to treatment with 
elsubrutinib, upadacitinib, and ABBV-599 (elsubrutinib/upadacitinib) combination or similar compounds.  
Research on samples collected in Germany will be limited to SLE, elsubrutinib, upadacitinib, and 
ABBV-599 (elsubrutinib/upadacitinib) combination.  Biomarker samples will not be collected at sites in 
China as specified in Appendix D.
Type I IFN is a key driver of disease pathogenesis in lupus, and high IFN signature is associated with 
active SLE.10,11  Approximately 60% of lupus patients express an elevated Type I IFN gene signature in the 
blood, suggesting higher Type I IFN activity in these individuals.  JAK1 inhibition is expected to disrupt 
Type I IFN signaling; therefore, lupus patients expressing the Type I gene signature may be more likely to 
benefit from treatment with ABBV-599 (elsubrutinib/upadacitinib) combination.  A Type I IFN RNA 
signature consisting of 4 genes (IFI6, IFI27, IFIT1, and MX1) will be evaluated using a validated assay with 
a cut point set at ≥-0.25 for IFN high vs < -0.25 for IFN low (-0.25 is the upper limit of the cut point)
using the Type I IFN Gene Expression Assay Score.  In the event an IFN score cannot be collected or 
analyzed at Screening due to COVID-19 lab access, that subject will still be enrolled in the study and 
assigned a score of Not Applicable for the Screening visit.  Samples drawn at the Week 4 and Week 24 
visits may be used for analysis, if collected.
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These results robustly dichotomize the IFN high and low population.  The assay will be performed on 
Screening samples and at subsequent time points unless precluded by local regulations or restrictions 
(IFN signature samples will not be collected at sites in China).  Screening values will be used as a 
criterion for subject enrichment with the goal of enrolling 80% of the study subjects with high composite 
score.  Stratifying the study to include approximately 80% high IFN score population will allow for 
increased confidence in the subject population.
Two assays to monitor BTK activity will be included.  A BTK phosphorylation assay (BTK Y223) will be 
performed on whole blood from all subjects, and serial PBMC pellets will be isolated from a subset of 
subjects to monitor BTK occupancy.  Whole blood will be collected for fluorescence-activated cell sorting 
B cell immunophenotyping as well as T lymphocyte, B lymphocyte, and natural killer lymphocyte (TBNK) 
measurement.
Research may also include analysis of genes, epigenetics, gene expression, and proteomic biomarkers 
that may associate with SLE, related conditions, or the subject's response to treatment.  This research is 
exploratory in nature and the results may not be included with the clinical study report.  Required 
biomarker samples will be collected and analyzed from all subjects, unless precluded by local regulations 
or restrictions (for such cases, optionality of collection/analysis is given through an appropriate 
Informed Consent Form).
4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
This is a multi-center, randomized, double-blind, and placebo-controlled Phase 2 study, with a Week 24 
primary endpoint, to investigate the safety and efficacy of elsubrutinib and upadacitinib given alone or 
in combination (ABBV-599 [elsubrutinib/upadacitinib] combination) in subjects with moderately to 
severely active SLE.  The study will continue through Week 48 to further assess maintenance of efficacy 
and safety of each treatment beyond 24 weeks.
Approximately 325 male and female subjects, 18 to 65 years of age, inclusive, with a diagnosis of 
moderately to severely active SLE (clinical diagnosis of SLE at least 24 weeks prior to Screening, meeting 
at least 4 of the 11 revised Criteria for Classification of SLE according to the 1997 Update of the 1982 
American College of Rheumatology [ACR] OR meeting at least 4 of the 2012 Systemic Lupus 
Erythematosus International Collaborating Clinics [SLICC] classification criteria, including at least 
1 clinical criterion and 1 immunologic criterion) despite standard of care therapy will be randomized in a 
1:1:1:1:1 ratio of 5 treatment groups, as follows:

Group 1:  Elsubrutinib 60 mg QD and upadacitinib 30 mg QD (n = 65)

Group 2:  Elsubrutinib 60 mg QD and upadacitinib 15 mg QD (n = 65)

Group 3:  Elsubrutinib 60 mg QD and upadacitinib placebo QD (n = 65)

Group 4:  Elsubrutinib placebo QD and upadacitinib 30 mg QD (n = 65)

Group 5:  Elsubrutinib placebo QD and upadacitinib placebo QD (n = 65)
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Randomization will be stratified based on the following factors:

Baseline corticosteroid dose above 10 mg prednisone-equivalent (≤ 10 mg or > 10 mg)

Screening SLEDAI-2K (< 10 or ≥ 10)

High vs low vs not applicable IFN score (approximately 80% high) (this stratification factor does 
not apply to subjects in China)

Baseline immunosuppressant (azathioprine, tacrolimus, cyclosporine, methotrexate [MTX], 
mycophenolate, or leflunomide) (yes/no)
The study duration will include a 42-day maximum screening period and a 48-week randomized, 
placebo-controlled, double-blind, parallel-group treatment period with a 30-day follow-up phone call.  
Sites and subjects will remain blinded throughout the study.  The Week 24 Primary Analysis will be 
performed when all subjects have completed the Week 24 visit or have discontinued the study.  The 
study team will remain blinded until the Week 24 Primary Analysis.  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.  
The schematic of the study is shown in Figure 1  Further details regarding study procedures are located 
in the Operations Manual.  See Section 5 for information regarding eligibility criteria.
A long-term extension (LTE) study will be conducted under a separate protocol (LTE Study M20-186) at 
sites where it is permitted by the local Competent Authority and Ethics Committee.  Subject rollover 
from the initial randomized portion of the study will occur at Week 48.
When 50% of the planned subjects completed the Week 24 assessments, an unblinded interim analysis 
was performed by an independent team at AbbVie.  Details are provided in Section 7.5, Interim Analysis.  
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Figure 1.
Study Schematic
BL = Baseline; QD = once a day
4.2 Discussion of Study Design
Choice of Control Group
This is a parallel-group study consisting of 5 treatment groups receiving elsubrutinib, upadacitinib, 
ABBV-599 (elsubrutinib/upadacitinib) combination, or matching placebo to assess the safety and 
efficacy of elsubrutinib or upadacitinib given alone or in combination (as the ABBV-599 
[elsubrutinib/upadacitinib] combination) once daily for 48 weeks in subjects with moderately or severely 
active SLE.  Placebo will serve as a reference for efficacy assessment while the additional efficacy of the
ABBV-599 (elsubrutinib/upadacitinib) combination will utilize in-study comparison to the elsubrutinib
and upadacitinib treatment groups.
Appropriateness of Measurements
All efficacy and safety measurements in this study are standard for assessing disease activity in subjects 
with SLE being treated with immunosuppressant therapies.  The first safety evaluation is at Week 2, and 
at all subsequent visits.  All clinical and laboratory procedures in this study are standard and generally 
accepted.
Suitability of Subject Population
Eligible for this study are adult male or female subjects, 18 to 65 years of age, inclusive, with a clinical 
diagnosis of SLE at least 24 weeks prior to Screening, meeting at least 4 of the 11 revised Criteria for 
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Classification of SLE according to the 1997 Update of the 1982 ACR OR meeting at least 4 of the 
2012 SLICC classification criteria, including at least 1 clinical criterion and 1 immunologic criterion, and at 
least one of the following at Screening:  positive antinuclear antibody (ANA) (titer ≥ 1:80), anti-double 
stranded DNA (dsDNA), or anti-Smith antibodies.  The selection criteria identify individuals with active 
SLE that are the intended target population for treatment with elsubrutinib and/or upadacitinib, based 
on the current knowledge of these drugs.
Selection of Doses in the Study
The dose selection in this study is based on analysis of PK, pharmacodynamics, safety, and efficacy 
(upadacitinib only), data from Phase 1 studies in healthy volunteers for elsubrutinib and ABBV-599
(elsubrutinib/upadacitinib) combination, Phase 2 and Phase 3 studies for upadacitinib in RA, as well as a 
published Phase 2 study of baricitinib in SLE.8,9,12
The 60 mg dose of elsubrutinib is intended to target exposures at or greater than those needed to 
achieve maximal peripheral BTK occupancy.  Following once-daily 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 mg and 30 mg QD (testing both dose levels in the 
ABBV-599 [elsubrutinib/upadacitinib] combination and only the higher dose in the upadacitinib 
monotherapy group).  In addition to evaluation of upadacitinib 30 mg QD monotherapy, the selected 
ABBV-599 (elsubrutinib/upadacitinib) combination regimens will enable evaluation of upadacitinib dose
response in combination with elsubrutinib.  These doses are based on the demonstrated efficacy and 
well-tolerated safety profile of upadacitinib at these 2 doses in Phase 3 RA studies.  Additionally, these 
doses are supported by extrapolation of data from a recently published Phase 2 study of baricitinib in 
SLE.  In that study, the baricitinib 2 mg QD dosing regimen demonstrated negligible efficacy while the 
4 mg QD regimen provided evidence of therapeutic benefit compared to placebo.  In vitro cellular 
inhibition of Type I IFN signaling in CD3+ T cells and CD14+ monocytes 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 
modestly higher inhibitory efficacy (e.g., time above IC50) compared to the baricitinib 2 mg QD dosing 
regimen; whereas the upadacitinib 30 mg QD regimen is predicted to provide similar or higher inhibitory 
efficacy compared to the baricitinib 4 mg QD dosing regimen.
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 screening or 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.
Demographic and Laboratory Assessments
2. Adult male or female, 18 to 65 years of age, inclusive, at Screening.
3. Must not have laboratory values meeting the following criteria within the screening period 
prior to the first dose of study drug: 

Serum aspartate transaminase (AST) > 2.0 × upper limit of normal (ULN);

Serum alanine transaminase (ALT) > 2.0 × ULN;

Estimated glomerular filtration rate (GFR) by simplified 4-variable Modification of Diet in 
Renal Disease (MDRD) formula < 40 mL/min/1.73 m2;

Absolute neutrophil count (ANC) < 1,000/µL;

Platelet count < 50,000/µL;

Hemoglobin < 9 g/dL.
4. Must not have positive titers for all 3 antiphospholipid antibodies known to be associated 
with venous thrombotic events at Screening:  lupus anticoagulant, anti-beta 2 glycoprotein 1, 
and anticardiolipin antibody.
5. Are willing and able to comply with procedures required in this protocol.
Disease Activity
6. Clinical diagnosis of SLE at least 24 weeks prior to Screening, meeting at least 4 of the 
11 revised Criteria for Classification of SLE according to the 1997 Update of the 1982 ACR OR
meeting at least 4 of the 2012 SLICC classification criteria, including at least 1 clinical criterion 
and 1 immunologic criterion.
7. At Screening, must have at least one of the following:

ANA+ (titer ≥1:80) 

anti-dsDNA+ 

anti-Smith+ 
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8. SLEDAI-2K ≥6 despite background therapy as reported and independently adjudicated 
(clinical score ≥4, excluding lupus headache and/or organic brain syndrome) at Screening:

If 4 points of the required entry points are for arthritis, there must also be a minimum of 
3 tender and 3 swollen joints.

If 4 points of the required clinical score are for proteinuria attributable to active lupus 
nephritis, it must be > 0.5 g/day equivalent (0.5 mg/mg).

If subject has rash and Principal Investigator (PI) considers it to be attributable to SLE, 
subject must consent to skin photograph collection for adjudication.

Score must be re-confirmed at the Baseline visit.
9. PhGA ≥1 during screening period.
10. The subject must be on background treatment throughout the study.  The background 
treatment must be stable for 30 days prior to Baseline and 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.
Subject History
11. Must not have active lupus nephritis (progressive Class IV or >1 g/day equivalent [1 mg/mg] 
proteinuria) or have undergone induction therapy within the last 6 months.
12. Must not be receiving hemodialysis (or other forms of renal replacement therapy).
13. Must not have active neuropsychiatric SLE as defined by the CNS portion of SLEDAI-2K or 
BILAG (excluding lupus headache).
14. 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, 
including hepatitis B virus (HBV) or hepatitis C virus (HCV), recurrent or disseminated (even a 
single episode) herpes zoster, disseminated (even a single episode) herpes simplex, or HIV.  
Active HBV, HCV, and HIV are defined as:

HBV:  hepatitis B surface antigen (HBs Ag) positive (+) or detected sensitivity on the HBV 
DNA polymerase chain reaction (PCR) qualitative test for hepatitis B core antibody (HBc Ab) 
positive (+) subjects; (and for hepatitis B surface antibody [HBs Ab] positive [+] subjects in 
China and Japan only);

HCV:  HCV RNA detectable in any subject with anti-HCV antibody (HCV Ab).

HIV:  confirmed positive anti-HIV antibody (HIV Ab) test.
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15. Must not have active TB or latent TB and did not complete a full course of prophylaxis for 
latent TB.
16. Must not have a history of any malignancy except for successfully treated non-melanoma 
skin cancer (NMSC) or localized carcinoma in-situ (CIS) of the cervix.
17. Must not have a history of clinically significant (per Investigator's judgment) drug or alcohol 
abuse within the last 6 months.
18. 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.
19. 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.
20. Must not be a recipient of an organ transplant.
21. 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.
22. Must not have had an active infection(s) requiring treatment with parenteral anti-infectives 
within 30 days, or oral anti-infectives within 14 days prior to the first dose of study drug.
23. Must not have confirmed COVID-19:  the Baseline visit must be at least 14 days from onset 
of signs/symptoms or positive SARS-CoV-2 test; symptomatic subjects must have recovered, 
defined as resolution of fever without use of antipyretics and improvement in symptoms.
24. Must not have suspected COVID-19:  subjects with signs/symptoms suggestive of COVID-19, 
known exposure, or high-risk behavior should undergo molecular (e.g., PCR) testing to rule out 
SARS-CoV-2 infection or must be asymptomatic for 14 days from a potential exposure.
25. 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.
26. Must not have a history of any of the following cardiovascular conditions:

Recent history (within past 6 months) cerebrovascular accident (CVA), myocardial infarction 
(MI), coronary stenting, coronary bypass surgery.

Uncontrolled hypertension as defined by a persistent systolic blood pressure (BP) 
> 160 mmHg or diastolic BP > 100 mmHg.  For subjects with known hypertension, the 
subject's BP must be stable for at least 30 days on current, stable anti-hypertensive 
medications.

Any other condition which, in the opinion of the Investigator, would put the subject at risk 
by participating in the protocol.
27. Must not have any clinically relevant or significant ECG abnormalities at Screening, 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.
28. For Japan subjects only:  must not have positive result of beta-D-glucan or 2 consecutive 
indeterminate results of beta-D-glucan (screening for Pneumocystis jiroveci infection).
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Contraception
29. Women of childbearing potential (WOCBP) must not have a positive serum pregnancy test at 
the Screening visit and must have a negative urine pregnancy test at Baseline prior to the 
first dose of study drug.  Note:  Subjects with borderline serum pregnancy tests at Screening 
must have a serum pregnancy test ≥3 days later to document continued lack of positive result.
30. 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.
31. 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.
Prior/Concomitant Medications
32. Must not be using intravenous (IV) or intramuscular (IM) corticosteroids greater than or 
equal to a 40 mg prednisone-equivalent bolus within 30 days of planned randomization.  Must 
not have been treated with intra-articular, trigger point or tender point, intra-bursa, or 
intra-tendon sheath corticosteroids in the preceding 8 weeks prior to the first dose of study 
drug.
33. Subjects must be naïve or have discontinued, if not currently benefiting from, the following 
prior to the first dose of study drug per the applicable washout period below or should be at 
least 5 times the mean terminal elimination half-life of a drug:

≥ 6 months for plasmapheresis

≥ 3 months for belimumab (Benlysta®)

≥ 1 year for rituximab OR ≥6 months if B cells have returned to ≥50 B cells per microliter

≥ 3 months for cyclophosphamide

≥ 4 weeks for abatacept, any anti-tumor necrosis factor (TNF) therapy, and all other 
biologics 
34. Subjects must not have received intravenous immunoglobulin (IVIG) within 30 days prior to 
the first dose of study drug.
35. Must not have prior exposure for 14 days or more or any prior intolerance to a JAK inhibitor 
(including but not limited to upadacitinib, tofacitinib, baricitinib, and filgotinib) or a BTK 
inhibitor.  The washout period for JAK and BTK inhibitors prior to the first dose of study drug is 
≥30 days or 5 times the half-life, whichever is longer.
36. To avoid combinations of immunosuppressive medications that are not permitted during the 
study (see criterion 10, above), subjects with prior exposure to the following medications may 
need to complete a washout period prior to enrollment as specified below or should be at least 
5 times the mean terminal elimination half-life of a drug: 

≥ 4 weeks prior to first dose of study drug for MTX, azathioprine, tacrolimus, cyclosporine, 
mycophenolate.
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
≥ 8 weeks prior to first dose of study drug for leflunomide if no elimination procedure was 
followed, or adhere to an elimination procedure (i.e., 11 days with cholestyramine, or 
30 days washout with activated charcoal or as per local label).
37. Must not have previous exposure to IFN kinoid vaccination.
38. Must not have prior exposure within 3 months of study Baseline to anti-IFN therapies, 
including anti-IFN and anti-IFN receptor.
39. Must not have been treated with any investigational drug within 30 days, or 5 half-lives of 
the drug (whichever is longer), prior to the first dose of study drug or be currently enrolled in 
another clinical study.
40. Subjects must have discontinued all high-potency opiates at least 1 week and traditional 
Chinese medicine for at least 30 days prior to the first dose of study drug.
41. Subjects must not have received any live vaccine within 30 days (56 days for Japan) prior to 
the first dose of study drug (see Section 5.3 for additional information on vaccines).
5.2 Contraception Recommendations
Contraception Requirements for Females
SLE 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.
Subjects must follow the following contraceptive guidelines as specified:

Women, 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)
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, initiated at 
least 30 days prior to Study Day 1.
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
Progestogen-only hormonal contraception (oral, injectable, implantable) associated with 
inhibition of ovulation, initiated at least 1 month prior to Study Day 1.

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 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).
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, initiated at least 30 days prior to Study Day 1.

Male or female condom with or without spermicide.

Cap, diaphragm, or sponge with spermicide.

A combination of male condom with a cap, diaphragm, or sponge with spermicide 
(double-barrier method).
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 labelling.  Urine pregnancy testing 
shall be performed at monthly intervals in the study activity schedule.
Additional local requirements may apply and should be followed accordingly.
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Contraception Requirements for Males
There are no contraception recommendations for males participating in the study.
5.3 Prohibited Medications and Therapy
Medications and therapies with a washout period specified in Section 5.1 (eligibility criteria) are 
prohibited while subjects are on study drug.
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)

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

Elective surgery within the first 24 weeks.  Further details regarding elective surgery are 
provided in Section 6.1 Complaints and Adverse Events.

High-potency narcotics (unless administered during a hospitalization) including (but not limited 
to): 

Oxycodone

Oxymorphone

Fentanyl

Levorphanol

Buprenorphine

Methadone

Hydromorphone

Morphine

Meperidine

Of note, low-potency narcotics are permitted to optimize SLE medications (see Section 5.4 for 
more details). 
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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 
administer live vaccines, these vaccinations must be completed (per local label) 30 days (56 days for 
Japan) before first dose of study drug with appropriate precautions 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;
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
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 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/wk with concomitant folic acid ≥ 5 mg/wk
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
Corticosteroids (prednisone-equivalent)
≤ 20 mg/day, decrease no faster than 5 mg QD per week
Rescue Concomitant Medications/Therapy 
Comments/Notes
Corticosteroids (prednisone-equivalent)
Increase of no more than 5 mg QD per week regardless of 
Baseline dose, maximum dose of 25 mg, through Week 8
 
 
 
 
 
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Subject 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.
Subjects must be able to safely discontinue any prohibited medications 30 days prior to initial study drug 
administration.  Subjects must be consented for the study prior to discontinuing any prohibited 
medications for the purpose of meeting study eligibility.
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 on Toxicity Management for toxicity management criteria.
At Week 24, the Investigator must assess and document in source if continuing in the study is in the best 
interest of the subject.
Subjects will be discontinued from study drug immediately if any of the following occur:
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
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.  The following will require discontinuation of study drug 
immediately:

Cyclophosphamide

Belimumab

Rituximab

More than one of the following in combination:  azathioprine, mycophenolate, leflunomide, 
MTX, cyclosporine, or tacrolimus;

Plasmapheresis

High-dose corticosteroids (≥ 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 requests withdrawal from study drug or the study, or the Sponsor decides to 
discontinue 1 or more treatment groups after the interim analysis.

Inclusion or exclusion criteria violation was noted after the subject started study drug, when 
continuation of the study drug would place the subject at risk as determined by the AbbVie TA 
MD.

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 Baseline.

Subject's QTcF increases from Baseline ≥ 60 msec, the investigator will evaluate, confirm the 
value, and treatment should be stopped.

Subject develops active or latent TB at any time during the study.

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.
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
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).
In order to minimize missing data for efficacy and safety assessments, subjects who prematurely 
discontinue study drug treatment should:

Continue in the study without receiving study drug

Have all procedures performed outlined in the Premature Discontinuation (PD) visit, preferably 
within 2 weeks of study drug discontinuation

Continue with their regular study visit schedule
No PK or biomarker samples should be collected after the PD visit.
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 discontinued or 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 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.  These subjects 
are not eligible for the LTE Study M20-186.  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 
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
procedures except for dispensing study drug.  As the subject has discontinued study drug, all rescue and 
efficacy discontinuation criteria no longer apply.  If at any point a subject no longer wants to provide 
assessments (withdrawal of informed consent) following discontinuation of study drug, a second PD visit 
is not required.  Subjects who discontinue study drug treatment are not eligible for the LTE 
Study M20-186.
Premature Discontinuation of 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 participation (withdrawal of informed consent), 
the procedures outlined for the PD visit should be completed as soon as possible, preferably within 2 
weeks, and preferably prior to initiation of another therapy.  In addition, if subject is willing, a 30-day 
follow-up phone call after the last dose of study drug may be completed to ensure all 
treatment-emergent AEs/SAEs have been resolved.
For subjects to be considered lost to follow-up, reasonable attempts must be made to obtain 
information on the subject's final status.  At a minimum, 2 telephone calls must be made and 1 certified 
letter must be sent and documented in the subject's source documentation.
If a subject withdraws from study follow up or withdraws permission for the collection of their personal 
data, the study staff may still use available public records to obtain information about survival status 
only, as appropriate per local regulations.
In the event a subject withdraws consent from the clinical study, biomarker research will continue 
unless the subject explicitly requests analysis to be stopped.  When AbbVie is informed that samples are 
withdrawn from research, samples will not be analyzed, no new biomarker analysis data will be 
collected, and the samples will be destroyed.  Data generated from biomarker research, before subject 
withdrawal of consent, will remain part of the study results.
5.7 Study Drug
Elsubrutinib, upadacitinib, or matching placebo manufactured by AbbVie (Table 2) will be administered 
on Day 1 (Baseline) and should be taken at approximately the same time each day.  Subjects will be 
instructed to take study drugs orally, which includes only 1 capsule of elsubrutinib or placebo from each 
of the 3 dispensed bottles per day, with or without food, and only 1 tablet of upadacitinib or 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 should 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 containers (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.
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No use or disclosure outside AbbVie is permitted without prior written authorization from 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.
Table 2.
Study Drug
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)
N/A
N/A
Mode/Route of 
Administration (ROA)
Oral
Oral
Oral
Oral
Dosage Form
Capsule
Film-Coated Tablet
Capsule
Film-Coated Tablet
Dose and units
20 mg
15 mg, 30 mg
N/A
N/A
Frequency of 
administration
Daily
Daily
Daily
Daily
Storage Conditions
Room temperature 
(15 - 25°C)
Protect from 
freezing
Room temperature 
(15 - 25°C)
Room temperature 
(15 - 25°C)
Protect from 
freezing
Room temperature 
(15 - 25°C)
N/A = not applicable
5.8 Randomization/Drug Assignment
Approximately 325 subjects who meet eligibility criteria will be randomized in a 1:1:1:1:1 ratio to 1 of 
5 treatment groups:

Group 1:  Elsubrutinib 60 mg QD and upadacitinib 30 mg QD (n = 65)

Group 2:  Elsubrutinib 60 mg QD and upadacitinib 15 mg QD (n = 65)

Group 3:  Elsubrutinib 60 mg QD and upadacitinib placebo QD (n = 65)

Group 4:  Elsubrutinib placebo QD and upadacitinib 30 mg QD (n = 65)

Group 5:  Elsubrutinib placebo QD and upadacitinib placebo QD (n = 65)
All subjects will be assigned a unique identification number by the IRT at the Screening visit.  For 
subjects who rescreen, the screening number assigned by the IRT at the initial Screening visit should be 
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used.  The IRT will assign a randomization number that will encode the subject's treatment group 
assignment according to the randomization schedule generated by the statistics department at AbbVie.
Randomization will be stratified based on the following factors:

Baseline corticosteroid dose above 10 mg prednisone-equivalent (≤10 mg or > 10 mg)

Screening SLEDAI-2K (< 10 or ≥ 10).

High vs low vs not applicable IFN score (approximately 80% high)

This stratification factor does not apply to subjects in China.

Baseline immunosuppressant (azathioprine, tacrolimus, cyclosporine, MTX, mycophenolate, or 
leflunomide) (yes/no)
Once approximately 20% of total subjects have been randomized who are IFN signature low, further 
enrollment of such subjects may be suspended.  Please refer to rationale in Section 3.7.
The investigator, study site personnel, and the subject will remain blinded to each subject's treatment 
throughout the study.  AbbVie personnel with direct oversight of the conduct and management of the 
trial (with the exception of AbbVie Drug Supply Management Team) will remain blinded through 
Week 24 and will become unblinded only after the primary efficacy analysis at Week 24 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.
In the event of a medical situation that requires unblinding of the study drug assignment, the 
Investigator is requested to contact the AbbVie TA MD prior to breaking the blind as long as it does not 
compromise subject safety.  However, if an urgent therapeutic intervention is necessary which warrants 
breaking the blind prior to contacting the AbbVie TA MD, the Investigator can directly access the IRT 
system to break the blind without AbbVie notification or agreement.  Unblinding is available in the IRT 
system via the Unblind Subject transaction, which is available to the Investigator.  If the IRT system is 
unavailable, unblinding may occur by contacting EndPoint technical support via either phone (preferred) 
or email (support@endpointclinical.com).  For country-specific phone numbers, please see the following 
website:  http://www.endpointclinical.com/help-desk/.  In the event that the blind is broken before 
notification to the AbbVie TA MD, we request that the AbbVie TA MD be notified within 24 hours of the 
blind being broken.  Also, the date and reason that the blind was broken must be recorded in the source 
documents and electronic case report form (eCRF), as applicable.
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 independent ethics committee (IEC)/independent review 
board (IRB), regulatory authorities (as applicable), and AbbVie.
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In Japan, the investigator will record all the protocol deviations in the appropriate medical records at the 
site.
5.10 Data Monitoring Committee 
An internal DMC will be composed of persons independent of the Study M19-130 protocol and with 
relevant expertise in their field who will review unblinded safety data from the ongoing study.  The 
primary responsibility of the DMC will be to protect the safety of the subjects participating in this study.  
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 will be 
prepared outside of the protocol before the first subject is enrolled in the study and will describe the 
roles and responsibilities of the DMC members, frequency of data reviews, relevant safety data to be 
assessed, and expectations for blinded communications.  Communications from the DMC to the study 
team will not contain information that could potentially unblind the study team to subject treatment 
assignments.
AbbVie utilizes an internal DMC charter template which closely follows that used for external DMCs and 
applies the same rigor describing DMC roles and responsibilities, DMC procedures, and the maintenance 
of data integrity.  Each internal DMC will be appropriately constituted with DMC members who have 
relevant expertise in SLE and have no involvement in the development of compound(s) that are the 
subject of the study to ensure objective decision making.  Specifically, all DMC members of 
Study M19-130 will be well-versed in safety aspects of drug development with years of experience in the 
pharmaceutical industry.  As described in the DMC charter for Study M19-130, the DMC's sole remit is to 
safeguard the interests of trial subjects and make recommendations regarding study continuation, study 
modification, or study termination.
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.
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Product complaints concerning the investigational product and/or device must be reported to AbbVie 
within 1 business day of the study site's knowledge of the event.  Product complaints occurring during 
the study will be followed up to a satisfactory conclusion.
Medical Complaints/Adverse Events and Serious Adverse Events
An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not the event is considered causally related to the use of the 
product.
Such an event can result from the 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 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 SELENA SLEDAI Flare Index) 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 AEs on a routine basis 
throughout the study.  All AEs will be followed to a satisfactory conclusion.
An elective surgery/procedure scheduled to occur during a study will not be considered an AE if the 
surgery/procedure is being performed for a pre-existing condition and the surgery/procedure has been 
pre-planned prior to study entry.  Elective surgery is not permitted during the study until the primary 
endpoint has been assessed.  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 are reported (Table 3), then the following supplemental report must be 
completed.
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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 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 PI will provide documentation of all SAEs to the Director of the investigative site and to the 
Sponsor.
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 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 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 a SAE and must be reported to AbbVie within 24 hours after the site becomes aware of the 
event.
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 unblinded review of safety issues by an internal safety DMC), 
interruption of study drug dosing with appropriate clinical management if applicable, and 
discontinuation of the subjects from study drug.
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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, ANC, platelet count, ALT or 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 or latent 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 must contact the AbbVie TA MD before 
reintroducing study drug.
Management of Herpes Zoster
If a subject develops herpes zoster, the Investigator should consider temporarily interrupting study drug 
until the episode resolves.
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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 Fridericia's correction 
formula (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 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 Complaints and Adverse Events).  All abnormal 
laboratory tests that are considered clinically significant by the investigator will be followed to a 
satisfactory resolution.  If a repeat test is required per Table 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 
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 × 
upper limit of normal (ULN) by repeat testing with new sample and 
either a total bilirubin > 2 × ULN or an international normalized ratio 
(INR) > 1.5.

INR will only need to be measured in subjects with ALT or AST 
> 3 × ULN by the central lab.  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 
Therapeutic Area MD (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+ (irrespective of HBs Ab status) and negative 
HBV DNA at Screening who develop the following should have HBV 
DNA by PCR testing performed within one 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 one 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 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 Cell 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 > 1 g/day equivalent (1 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.
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.
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).  An unblinded interim analysis will be performed by an independent team 
at AbbVie after 50% of the planned subjects have completed Week 24 assessments.  The study team will 
remain blinded until the Week 24 Primary Analysis.  The Week 24 Primary Analysis will be conducted 
after all ongoing subjects have completed Week 24 assessments or have discontinued the study to 
inform next phase studies.  The Final Analysis will be conducted when all subjects have completed the 
study.
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Efficacy and safety analysis may be revised accordingly based on the IERC decision at the interim 
analysis. 
Details will be included in the SAP.
7.2 Definition for Analysis Populations
The Full Analysis Set (FAS) includes all randomized subjects who have received at least 1 dose of study 
drug.  Subjects will be grouped according to treatment as randomized.  The FAS will be used for all 
efficacy and baseline analysis.
The Safety Analysis Set consists of all subjects who have received at least 1 dose of study drug.  For the 
Safety Analysis Set, subjects are assigned to a treatment group based on the treatment actually 
received, regardless of the treatment randomized.
7.3 Statistical Analyses for Efficacy
Primary Endpoint Analysis
The primary efficacy endpoint, the achievement of SRI-4 and steroid dose ≤ 10 mg prednisone
equivalent QD at Week 24, will be assessed for each active treatment group vs the placebo group.  The 
treatment difference will be evaluated using a Cochran-Mantel-Haenszel (CMH) test stratified by
randomization stratification factors.  ABBV-599 (elsubrutinib/upadacitinib) combination treatment 
groups will be compared to placebo and the monotherapy treatment groups.  Additional comparisons or 
analyses will be conducted as appropriate.  There will be no multiplicity adjustment for the multiple 
comparisons.
The Week 24 Primary Analysis will be performed when all subjects have completed the Week 24 
assessments or have discontinued the study.  The Final Analysis will be performed after all subjects have 
completed all study assessments including the 30-day follow-up phone call.
Non-Responder Imputation while incorporating Multiple Imputation to handle missing data due to 
COVID-19 (NRI-C) will be applied for primary endpoint analysis.  As observed (AO) analysis will be 
performed as the sensitivity analysis for the primary endpoint.
Secondary and Additional Endpoint Analysis
All secondary and additional efficacy endpoints described in Section 3.3 and Section 3.4 will be analyzed 
as follows:
Categorical variables will be tabulated by the number and frequency.  Between-treatment group 
comparison will be evaluated in the same way as the primary endpoint analysis.
All continuous endpoints will be evaluated through the change from Baseline.  For continuous endpoints 
with multiple post-Baseline visits, the treatment effect will be assessed through Mixed-effect Model 
Repeated Measures (MMRM) with treatment, visit and treatment-by-visit interaction, main stratification 
factors, and the continuous fixed covariate of baseline measurement.  An unstructured variance 
covariance matrix will be used.  For continuous endpoints with single post-Baseline visit analysis, the 
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treatment effect may be assessed through analysis of covariance with baseline value, treatment, and 
stratification factors as covariates.  In addition, the descriptive statistics for continuous variables will be 
provided including sample size, mean, standard deviation, median, minimum, and maximum.
For the count endpoints (e.g., number of flares), negative binomial regression model will be used to 
assess treatment effect with treatment, visit, and stratification factors as covariates.
The Cox Proportional Hazards model will be used to assess the treatment effect for the time-to-event 
endpoint, i.e., time to flare.
Missing Data Imputation Definition
Censoring:  For the time-to-event endpoint, i.e., time to flare, missing data will be considered as 
censored at the last available time for the information.
NRI-C:  The NRI-C will categorize any subject who does not have an evaluation during a pre-specified 
visit window as a non-responder for the visit, except for missing data due to COVID-19 infection or 
logistical restriction, which will be handled by Multiple Imputation.  In addition, subjects who 
prematurely discontinue from study drug will be considered as non-responders for all subsequent visits 
after discontinuation.  Subjects will also be classified as non-responders as described in Section 5.4.
As Observed:  As observed analysis will not impute values for missing evaluations, and thus a subject 
who does not have an evaluation on a scheduled visit will be excluded from the AO analysis for that visit.  
Regardless of premature discontinuation of study drug, all observed data will be used in the analysis.  As 
observed analysis may be used for both categorical variables and continuous variables for sensitivity 
analysis.
Mixed-Effect Model Repeated Measurements: MMRM analysis will be conducted using a mixed-effect 
model for continuous variables.  Data collected after study drug discontinuation or initiation of rescue 
treatment will not be included.  The mixed model includes the categorical fixed effects of treatment, 
visit and treatment-by-visit interaction, main stratification factors, and the continuous fixed covariate of 
baseline measurement.  An unstructured variance covariance matrix will be used.  The parameter 
estimations are based on the assumption of data being missing at random and using the method of 
restricted maximum likelihood (REML).
7.4 Statistical Analyses for Safety
Safety analyses will be carried out using the Safety Analysis Set, which includes all subjects who receive 
at least 1 dose of study drug.  Subjects will be grouped to the treatment actually received.  Safety will be 
assessed by AEs, physical examination, laboratory assessments, ECGs, and vital signs.  Frequency tables 
and lists of subjects with treatment-emergent adverse events (TEAEs) by preferred term as in the 
Medical Dictionary for Regulatory Activities (MedDRA®) dictionary, by system organ class, by severity, 
and by relationship to the study drug as assessed by the Investigator will be provided.  The changes from 
Baseline in vital signs, physical examination results, and clinical laboratory values will be analyzed in a 
descriptive manner.  Shift of laboratory values from Baseline to defined time points will be tabulated.  
Pre-treatment AEs will be summarized separately.
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All 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 MedDRA system organ class and preferred term. Summaries 
(including percentages and event per 100 patient-year) of SAEs, deaths, AEs leading to discontinuation, 
and AESI will be provided as well.  For selected laboratory and vital signs parameters, mean change from 
Baseline and percentage of subjects with evaluations meeting pre-defined criteria for Potentially 
Clinically Important values will be summarized.
7.5 Interim Analysis
A planned unblinded interim analysis 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 LTE Study M20-186. 
The interim analysis was performed by an independent team at AbbVie that is separate and apart from 
the blinded study team.  The M19-130 study team will remain blinded through the Week 24 Primary 
Analysis. 
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.  
7.6 Overall Type I Error Control
All tests will be performed as pairwise comparison at a 2-sided statistical significance level of α = 0.1.  No 
multiplicity adjustment will be applied because this is a Phase 2 study.
7.7 Sample Size Estimation
The planned sample size for this study is 325 subjects in total, with 65 subjects for each of the 5 groups, 
determined based on the primary endpoint, the composite of SRI-4 and steroid dose ≤ 10 mg 
prednisone equivalent QD at Week 24.  Assuming at Week 24 the placebo response rate is 25%, a 
two-sided χ2 test with α = 10% will provide 78% to 91% power to detect a difference of 20% to 25% 
between an active treatment group and the placebo group.
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8 ETHICS
8.1 Independent Ethics Committee/Institutional Review Board 
(IEC/IRB)
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the IEC/IRB for review and approval.  Approval of both the protocol and the informed 
consent form(s) must be obtained before any subject is enrolled.  Any amendment to the protocol will 
require review and approval by the IEC/IRB before the changes are implemented to the study.  In 
addition, all changes to the consent form(s) will be IEC/IRB approved.
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 
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are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the 
currently approved protocol, ICH Good Clinical Practice (GCP), and applicable local regulatory 
requirement(s).  During the COVID-19 pandemic, remote data review 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.
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.
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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. ABBV-105 Investigator's Brochure Edition 4. 03 February 2020.
9.
AbbVie. Upadacitinib Investigator's Brochure Edition 11. 18 August 2020.
10. Crow MK. Type I interferon in the pathogenesis of lupus. J Immunol. 2014;192(12):5459-68.
11. Connelly KL, Kandane-Rathnayake R, Huq M, et al. Longitudinal association of type 1 interferon-
induced chemokines with disease activity in systemic lupus erythematosus. Sci Rep. 2018;8(1):3268.
12. 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.
13. Furie RA, Petri MA, Wallace DJ, et al. Novel evidence-based systemic lupus erythematosus 
responder index. Arthritis Rheum. 2009;61(9):1143-51.
14. 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.
15. 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.
16. Gladman DD, Ibanez D, Urowitz MB. Systemic lupus erythematosus disease activity index 2000. J 
Rheumatol. 2002;29(2):288-91.
17. 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.
18. 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.
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19. 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
ACR
American College of Rheumatology
ADL
Activities of daily living
AE
Adverse event
AESI
Adverse events of special interest
Ag
Antigen
ALT
Alanine transaminase
ANA
Antinuclear antibody
ANC
Absolute neutrophil count
anti-dsDNA
Anti-double stranded DNA
AO
As observed
AST
Aspartate transaminase
axSpA
Axial spondyloarthritis
BCG
Bacilli Calmette-Guérin
BICLA
BILAG-Based Combined Lupus Assessment
BILAG
British Isles Lupus Assessment Group
BL
Baseline
BP
Blood pressure
BTK
Bruton's tyrosine kinase
CAC
Cardiovascular Adjudication Committee
Cardiac
Cardiovascular
CD
Crohn's disease
CIS
Carcinoma in-situ
CL/F
Apparent clearance
CLASI
Cutaneous Lupus Erythematosus Disease Area and Severity Index
CMH
Cochran-Mantel-Haenszel
CNS
Central nervous system
COVID-19
Coronavirus disease 2019
CPK
Creatine Phosphokinase
CRF
Case report form
CT
Computed tomography
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CTCAE
Common Terminology Criteria for Adverse Events
CVA
Cerebrovascular accident
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
ECG
Electrocardiogram
eCRF
Electronic case report form
EU
European Union
EudraCT
European Clinical Trials Database
FACIT
Functional Assessment of Chronic Illness Therapy
FAS
Full analysis set
FSH
Follicle-stimulating hormone
GCA
Giant cell arteritis
GCP
Good clinical practice
GCSF
Granulocyte-colony stimulating factor
GFR
Glomerular filtration rate
GI
Gastrointestinal
GM-CSF
Granulocyte-macrophage colony-stimulating factor
HB
Hepatitis B
HBc Ab
Hepatitis B core antibody
HBs Ag
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HCV Ab
Hepatitis C virus antibody
HIV
Human immunodeficiency virus
HIV Ab
HIV antibody
IC50
Inhibitory concentration producing 50% inhibition
ICH
International Council for Harmonisation
IEC
Independent ethics committee
IEC/IRB
Independent Ethics Committee/Institutional Review Board
IERC
Internal Executive Review Committee
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IFN
Interferon
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IM
Intramuscular
IMP
Investigational Medicinal Product
IRB
Institutional review board
IRT
Interactive response technology
IU
International Unit
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous
IVIG
Intravenous immunoglobulin
JAK
Janus kinase
JAK1
Janus kinase 1
JAK2
Janus kinase 2
JAK3
Janus kinase 3
JIA
Juvenile idiopathic arthritis
LLDAS
Lupus Low Disease Activity State
LTE
Long-term extension
LupusQoL
Lupus Quality of Life questionnaire
MACE
Major adverse cardiovascular event
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MI
Myocardial infarction
MMRM
Mixed-effect Model Repeated Measures
MTX
Methotrexate
N/A
Not applicable
NCI
National Cancer Institute
NMSC
Non-melanoma skin cancer
NRI-C
Non-Responder Imputation while incorporating Multiple Imputation to handle missing 
data due to COVID-19 
NRS
Numerical rating scale
NSAID
Nonsteroidal anti-inflammatory drug 
OC
Observed Case
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PBMC
Peripheral blood mononuclear cell
PCR
Polymerase chain reaction
PD
Premature Discontinuation
PhGA
Physician's Global Assessment
PI
Principal Investigator
PK
Pharmacokinetic(s)
PPD
Purified protein derivative (tuberculin)
PRN
As needed
PRO
Patient-reported outcome
PtGA
Patient global assessment
QD
Once a day
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate using Fridericia's formula
RA
Rheumatoid arthritis
RCT
Randomized clinical trial 
REML
Restricted maximum likelihood
RNA
Ribonucleic acid
ROA
Route of administration
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
SFI
SLEDAI Flare Index
SLE
Systemic lupus erythematosus
SLEDAI
Systemic Lupus Erythematosus Disease Activity Index
SLEDAI-2K
Systemic Lupus Erythematosus Disease Activity Index 2000
SJC
Swollen joint count
SLICC
Systemic Lupus Erythematosus International Collaborating Clinics
SRI
SLE Responder Index
SUSAR
Suspected unexpected serious adverse reaction
TA MD
Therapeutic Area MD
TB
Tuberculosis
TBNK
T lymphocytes, B lymphocytes, and natural killer lymphocytes
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TEAE
Treatment-emergent adverse event
TJC
Tender joint count
TNF
Tumor necrosis factor
UC
Ulcerative colitis
UK
United Kingdom
ULN
Upper limit of normal
UPCR
Urine protein to creatinine ratio
US
United States
vs
versus
Vss/F
Apparent volume of distribution at steady state
WBC
White blood cells
WOCBP
Women of Childbearing Potential
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CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M19-130:  A Phase 2 Study to Investigate the Safety and Efficacy of Elsubrutinib and 
Upadacitinib Given Alone or in Combination (ABBV-599 Combination) in Subjects with Moderately to 
Severely Active Systemic Lupus Erythematosus
Protocol Date:  25 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
 
Director, Clinical Pharmacokinetics
Clinical Pharmacology and 
Pharmacometrics
Therapeutic Area Head 
Data and Statistical Sciences
Director, Statistics
Data and Statistical Sciences
Group Medical Director 
Immunology Clinical Development
Therapeutic Area Medical Director
Immunology Clinical Development
Study Project Manager
Clinical Program Development
Principal Medical Writer
Medical Writing
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n.
Pre-dose and post-dose collection.
o.
Blood samples collected and analyzed from all subjects unless precluded by local regulations or restrictions.
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APPENDIX E. DESCRIPTION OF EFFICACY MEASURES
Measure
Definition
Scale
Systemic Lupus Erythematosus 
Responder Index
(SRI)13
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 
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)14
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)15
A state of low disease activity based 
on SLEDAI score (SLEDAI-2K score ≤ 4 
excluding SLEDAI-2K activity in major 
organ systems), absence of SLE 
disease activity in major organ systems 
and new disease activity, Physician's 
Global Assessment (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)16
Global SLE disease activity index 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) 200417
Global SLE disease activity index 
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)18
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)19
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 Activity19
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, initiated at least 30 days 
prior to Study Day 1.

Progestogen-only hormonal contraception (oral,** injectable,* implantable*) associated with 
inhibition of ovulation, initiated at least 1 month prior to Study Day 1.

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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STUDY M19-130  |  Version 7.0  |  EudraCT 2019-000638-20
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APPENDIX G. PROTOCOL SUMMARY OF CHANGES
Previous Protocol Versions
Protocol
Date
Version 1.0
15 April 2019
Version 2.0
02 July 2019
Version 3.0
25 July 2019
Version 4.0
12 December 2019
Version 4.1 (China Only)
21 April 2020
Administrative Change 1
13 November 2019
Administrative Change 2
20 February 2020
Administrative Change 3
07 April 2020
Version 5.0
04 June 2020
Version 5.1 (China Only)
15 July 2020
Version 6.0
15 October 2020
Version 6.1 (China Only)
10 November 2020
PROTOCOL
The purpose of this version is to correct minor clerical errors for consistency throughout the protocol in 
addition to the following:
1.
Rationale:  To clarify the adjustment of treatment groups in Study M19-130 as a result of the 
completed 50% interim analysis at Week 24.

Section 1 Synopsis and Section 4.1  Overall Study Design and Plan

Added Study M19-130 to the objective to reassess treatment regimens and details 
regarding the IERC review.

Section 3.5 Safety

Removed mention of additional multi-disciplinary Safety review team and added details 
to Section 7.5.

Section 5.5 Withdrawal of Subjects and Discontinuation of Study

Clarified that the Sponsor may "partially" terminate the study, meaning 1 or more 
treatment groups may be terminated.
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STUDY M19-130  |  Version 7.0  |  EudraCT 2019-000638-20
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
Section 7.5 Interim Analysis

Added Study M19-130 to the objective to reassess treatment regimens and also added 
details regarding IERC that was identified and reviewed which treatment group(s) 
should be continued in Study M19-130 and for rollover into LTE Study M20-186.
2.
Rationale:  If the study is partially terminated (i.e., only certain groups are discontinued), 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 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:  To clarify that not all subjects will be eligible for roll over.

Section 5.2 Treatment After End of Study

Added clarification that only "eligible" subjects will be permitted to rollover from the 
initial randomized portion of the study.
4.
Rationale:  To clarify, the Study Team does not have access to HIV results, but AbbVie field 
personnel ("monitors") do have access to site laboratory results, including HIV testing.

Section 3.13 Clinical Laboratory Tests

Removed from the HIV section the statement "Abbvie will not receive results from the 
testing and will not be made aware of any positive results."
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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APPENDIX H. OPERATIONS MANUAL
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p. 2 of 42
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-130 Version 7.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
1 CONTACTS
Sponsor/
Emergency 
Medical Contact
 MD
Therapeutic Area Medical Director
AbbVie
1 North Waukegan Road
North Chicago, IL 60064
EMERGENCY 24 hour Number:  
+1 (973) 784-6402
Office:
Mobile:
Fax:
Email:
Safety Concerns
Immunology Safety Team
1 North Waukegan Road 
North Chicago, IL 60064
Phone:
+1 (847) 938-8737
Email:
GPRD_SafetyManagement_Immunology@abbvie.co
m
SAE Reporting 
outside of RAVE
Email:
PPDINDPharmacovigilance@abbvie.co
m
Fax:
+1 (847) 938-0660
Protocol 
Deviations
AbbVie Inc.
1 North Waukegan Road
North Chicago, IL 60064
Phone:
Fax:
Email:
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p. 3 of 42
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-130 Version 7.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Certified Clinical 
Laboratories
For sites in North America:
Labcorp Drug Development
8211 Scicor Drive
Indianapolis, IN 46214
For Sites in Europe:
Labcorp Drug Development
7 rue Marcinhes 
1217 Geneva 
Meyrin Switzerland
For sites in Asia-Pacific:
Labcorp Drug Development
1 International Business Park
The Synergy, #04-14
Singapore 609917
Labcorp Drug Development Central 
Laboratory Services, Inc.
1st Floor, No.6 Building,
151 Li Bing Road,
Zhangjiang Hi-Tech Park,
Shanghai 201203
P.R. of China
CB Lab
c/o BML General Laboratory
1361-1 Matoba/Kawagoe-shi
Saitama 350-1101, Japan
Japan Toll free:  0120-123-905
Phone:
+1 (866) 762-6209
Fax:
+ 1 (317) 616-2362
Phone (local calls):
+41 58 822 7000
Fax:
+41 58 822 6999
Phone:
65-6560-8793
Fax:
65-6565-5901
Phone:
+86 21 5137 1111
Fax:
+86 21 51371301
Phone:
+81-3-6837-9536
Fax:
+81-3-6220-3667
For country-specific lab contact information, please 
refer to Labcorp Lab Manual. 
Pharmacokinetic 
Lab
Attn:  AbbVie Sample Receiving
c/o:  Delivery Services
1150 S. Northpoint Blvd. 
Waukegan, IL 60085
Phone:
+1 (847) 937-0889
Fax:
+1 (847) 938-9898
Exploratory 
Sample Lab
Cambridge Biomedical Inc.
Maloy Mangada
Project 214A 
1320 Soldiers Field Road
Boston, MA 02135
Phone:
+1 (617) 456-0870
Fax:
+1 (617) 456-0701
Interferon 
Signature
DxTerity Diagnostics
Attn:  Olga Derbeneva
19500 S. Rancho Way
Suite 112
Compton, CA 90220
Phone:
310-537-7857
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p. 4 of 42
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-130 Version 7.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
TABLE OF CONTENTS
1
CONTACTS
2
2
PROTOCOL ACTIVITIES BY VISIT
6
2.1
INDIVIDUAL TREATMENT PERIOD VISIT ACTIVITIES
6
2.2
INDIVIDUAL POST-TREATMENT PERIOD VISIT ACTIVITIES
18
3
STUDY PROCEDURES
19
3.1
SUBJECT INFORMATION AND INFORMED CONSENT
20
3.2
MEDICAL HISTORY AND PRIOR/CONCOMITANT MEDICATIONS
20
3.3
ADVERSE EVENT ASSESSMENT AND ADVERSE EVENTS OF SPECIAL INTEREST
20
3.4
SKIN PHOTOGRAPHS
20
3.5
PATIENT-REPORTED OUTCOMES
21
3.6
PHARMACOKINETIC SAMPLING
22
3.7
BIOMARKER RESEARCH SAMPLING
22
3.8
12-LEAD ELECTROCARDIOGRAM
23
3.9
HEIGHT AND WEIGHT
23
3.10
VITAL SIGNS
24
3.11
PHYSICAL EXAMINATION AND ASSESSMENTS
24
3.12
DISPENSE STUDY DRUG
26
3.13
CLINICAL LABORATORY TESTS
26
3.14
SUBJECT WITHDRAWAL FROM STUDY
33
3.15
UNSCHEDULED VISITS
33
4
SAFETY MANUAL
34
4.1
METHODS AND TIMING OF SAFETY ASSESSMENT
34
4.2
RECORDING DATA AND ANALYSES OF SAFETY FINDINGS
34
4.3
REPORTING ADVERSE EVENTS AND INTERCURRENT ILLNESSES
34
5
COUNTRY-SPECIFIC REQUIREMENTS
36
5.1
SUSAR REPORTING
36
5.2
TREATMENT AFTER END OF STUDY
36
6
STUDY DRUG
36
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-130 Version 7.0
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6.1
TREATMENTS ADMINISTERED
36
6.2
PACKAGING AND LABELING
37
6.3
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS
38
6.4
SELECTION AND TIMING OF DOSE FOR EACH SUBJECT
38
7
REFERENCES
38
LIST OF FIGURES
FIGURE 1.
INTERPRETATION AND MANAGEMENT OF HBV SEROLOGIC TEST RESULTS
32
LIST OF APPENDICES
APPENDIX A.
STUDY SPECIFIC ABBREVIATIONS AND TERMS
39
APPENDIX B.
SCREENING TB RISK ASSESSMENT QUESTIONNAIRE (SAMPLE FORM)
42
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p. 6 of 42
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-130 Version 7.0
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2 PROTOCOL ACTIVITIES BY VISIT
2.1 Individual Treatment Period Visit Activities
This section presents a list of activities performed during each visit, organized by visit.  The dot pattern 
on the upper right indicates the place of the visit in the overall Treatment Period Activity Schedule.
Activities are grouped by category (Interview, Exam, etc.).  Further information about each activity is 
provided in Section 3.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-130 Version 7.0
CONFIDENTIAL INFORMATION
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3 STUDY PROCEDURES
Screening Period
Within 42 days prior to the Baseline visit, subjects will receive a full explanation of the study design and 
study procedures, provide a written informed consent, and undergo the screening procedures outlined 
in the Activity Schedule in Protocol Appendix D.  With the exception of the QuantiFERON TB-Gold and
purified protein derivative (PPD) tests (requirements outlined in Section 3.13), otherwise exclusionary 
laboratory values can be re-tested once during the screening period.  If the re-tested lab value(s) 
remain(s) exclusionary, the subject will be considered a screen failure.  Redrawing samples if previous 
samples were unable to be analyzed would not count as a retest since previous result was never 
obtained.
Re-Screening
Subjects who initially screen-fail for the study are permitted to be re-screened once following reconsent.  
For additional re-screening, AbbVie Therapeutic Area Medical Director (TA MD)/Scientific Director 
approval is required.  All screening procedures, with the exceptions noted below, will be repeated 
during re-screening.  The subject must meet all of the eligibility criteria at the time of re-screening in 
order to qualify for the study.  There is no minimum period of time that a subject must wait to re-screen 
for the study, except for the SARS-CoV-2 infection criteria.
Subjects who do not meet SARS-CoV-2 infection eligibility criteria must be screen failed and may only 
re-screen after they meet the following SARS-CoV-2 infection viral clearance criteria: 

At least 14 days since first molecular test (e.g., PCR) result have passed in asymptomatic subjects 
or 14 days since onset of signs/symptoms, defined as resolution of fever without use of 
antipyretics and improvement in symptoms. 
If the subject had an initial screening evaluation including the following assessments, the below tests 
will not be required to be repeated for re-screening, provided the conditions noted in Protocol 
Section 5.1 (Eligibility Criteria) are met, there are no changes in the subject's medical history that 
warrant re-testing, and no more than 90 days have passed:

Hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) 
serology

Interferon (IFN)-Gamma Release Assay (IGRA; QuantiFERON Tuberculosis [TB] Gold In-Tube test 
or equivalent) and/or a PPD test (or both if required per local guidelines)

Interferon signature, antinuclear antibody (ANA) test/anti-Smith Antibody (Ab)

Immunoglobulin G (IgG), immunoglobulin M (IgM)

Cotinine measurement

Chest x-ray (CXR)

Electrocardiogram (ECG)
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p. 20 of 42
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-130 Version 7.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
3.1 Subject Information and Informed Consent
The investigator or his/her representative will explain the nature of the study to the subject and answer 
all questions regarding this study.  Prior to any study-related screening procedures being performed on 
the subject or any medications being discontinued by the subject in order to participate in this study, 
the informed consent statement will be reviewed, signed, and dated by the subject or their legally 
authorized representative, the person who administered the informed consent, and any other 
signatories according to local requirements.  A copy of the signed informed consent will be given to the 
subject and the original will be placed in the subject's medical record.  An entry must also be made in 
the subject's dated source documents to confirm that informed consent was obtained prior to any 
study-related procedures and that the subject received a signed copy.
Information regarding benefits for subjects and information regarding provisions for treating and/or 
compensating subjects who are harmed as a consequence of participation in the study can be found in 
the informed consent form.
3.2 Medical History and Prior/Concomitant Medications
A complete list of prior/concomitant medications and medical history including demographics, history of 
tobacco (e.g., smoking and/or vaporizing or other routes of administration or nicotine substitutes), 
alcohol, and drug use will be taken at Screening.  The subject's prior/concomitant medications and 
medical history, including history of herpes zoster vaccination (and the name of the specific vaccine) will 
be updated at the Study Day 1 visit.  This updated medical history will serve as the baseline for clinical 
assessment.  Concomitant medications will be reviewed at each study visit listed in Section 2.1.
3.3 Adverse Event Assessment and Adverse Events of Special Interest
Please refer to Section 4 for adverse events (AEs) and Section 6 of the protocol for adverse events of 
special interest (AESI).
3.4 Skin Photographs
Subjects with rash at Screening, considered by the investigator to be due to systemic lupus 
erythematosus (SLE), should have photographs taken at Screening for adjudication.  For those subjects 
who have confirmed (by adjudication) Lupus rash at screening, photographs will also be taken at 
Week 24.  Subject must voluntarily provide consent, approved by an institutional review 
board/independent ethics committee (IRB/IEC), after the nature of the skin photographs has been 
explained and the subject has had an opportunity to ask questions.  If the subject presents with a rash 
requiring adjudication at Screening, the subject must consent to skin photographs or they will not be 
allowed to participate in the study.  Subjects who agree to skin photographs are consenting to 
photographs at Screening and at Week 24 (for those who have confirmed Lupus rash by adjudication).
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-130 Version 7.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
3.5 Patient-Reported Outcomes
Subjects will complete the self-administered patient-reported outcome (PRO) instruments (when 
allowed per local regulatory guidelines).  Subjects should be instructed to follow the instructions 
provided with the instrument and to provide the best possible response to each item.  Site personnel 
shall not provide interpretation or assistance to subjects other than encouragement to complete the 
tasks.  Site personnel will encourage completion of the instrument at all specified visits and will ensure 
that a response is entered for all items.
The PRO instrument should be completed prior to drug administration on Day 1 and prior to any 
discussion of AEs or any review of laboratory findings.  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.
LupusQoL
The Lupus Quality of Life questionnaire (LupusQoL) is a disease-specific health-related quality of life 
(HRQoL) PRO instrument.  It has 8 domains including physical health, emotional health, body image, 
pain, planning, fatigue, intimate relationships, and burden on others.  Item responses are based on a 
5-point Likert scale ranging from 0 = "All the time" to 4 = "Never."  These 8 domains are measured via 
34 items and are scored separately.  Scores range from 0 (worst HRQoL) to 100 (best HRQoL).
Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue
The Functional Assessment of Chronic Illness Therapy (FACIT) system is a collection of quality of life 
(QoL) questionnaires targeted to the management of cancer and other chronic illnesses.  The 
FACIT-Fatigue questionnaire was developed to assess fatigue associated with anemia.  It consists of 
13 fatigue-related questions.  The responses to the 13 items on the FACIT-Fatigue questionnaire are 
each measured on a 5-point Likert scale.  The responses to the answers are the following:  (i) not at all:  
0 points; (ii) a little bit:  1 point; (iii) somewhat:  2 points; (iv) quite a bit:  3 points; (v) very much:  
4 points.  Items are summed, and reverse scored when appropriate, to provide a total score ranging
from 0 to 52, where higher scores represent better QoL.  
SF-36
The SF-36v2 is a general health-related quality of life (HRQoL) instrument with extensive use in multiple 
disease states.  The SF-36v2 instrument comprises 36 total items (questions) targeting a subject's 
functional health and well-being in 8 dimensions (physical functioning, role physical, bodily pain, general 
health, vitality, social functioning, role emotional, and mental health).  Scoring is totaled into a Physical 
Component Summary and a Mental Component Summary.  Higher SF-36v2 scores indicate a better state 
of health.  
Patient Global Assessment of Disease Activity (PtGA)
The PtGA is a single-item assessment in which subjects are asked to rate the overall effect that lupus has 
on them at the time the assessment is completed.  The PtGA is a visual analog scale with scores ranging 
from 0 to 100 and high scores indicating greater disease activity.
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Pain Numerical Rating Scale (NRS)
The pain NRS is a single-item questionnaire in which subjects are asked to rate the overall pain level.  
The pain NRS scores range from 0 to 10, with higher scores indicating a higher level of pain.
3.6 Pharmacokinetic Sampling
Starting 3 days prior to each clinical site visit, subjects are advised to take the study drug dose at the 
time that matches their scheduled visit time at the clinical site.  Following the clinical visit, subjects may 
continue taking study drug dose according to their regular schedule.
On the day of the study visit, subjects will take their dose of study drug at the clinical site and 1 blood 
sample for pharmacokinetic (PK) assessments should be collected within specified time intervals at each 
visit below as follows:

At Baseline, between 0.5 and 2 hours following dosing;

At Week 4, between 2 and 6 hours following dosing;

At Week 12, pre-dose;

At Week 20, between 0.5 and 2 hours following dosing; and

At Week 24, between 2 and 6 hours following dosing;

Premature Discontinuation (PD), at any time during the visit.
3.7 Biomarker Research Sampling
Blood samples will be collected for biomarker research.  Refer to Section 2.1 for the schedule of 
biomarker research sample collections.  All biomarker samples should be labeled and shipped as 
outlined in the study-specific laboratory manual.  AbbVie (or people or companies working with AbbVie) 
will use and store the samples and data in a secure storage space with adequate measures to protect 
confidentiality.  The samples may be retained while research on elsubrutinib (ABBV-105), upadacitinib
(ABT-494), ABBV-599 (elsubrutinib/upadacitinib) combination (or drugs of this class), or SLE and related 
conditions continues, but for no longer than 20 years after study completion, or per local requirement. 
Whole blood for Bruton's tyrosine kinase (BTK) Y223 phosphorylation assay will be collected twice at 
Baseline, pre-dose and post-dose collection.  This biomarker will also have Week 12, Week 24, and PD
visits collection.  The collection window at Baseline (post-dose only), Week 12 (pre-dose), Week 24 
(post-dose), and at PD visits should be the same as collection of blood samples for PK assessment. 
At select study sites, whole blood for BTK occupancy will be collected twice at Baseline, pre-dose and 
post-dose collection.  This biomarker will also have Week 12, Week 24, and at PD visits collection (in a 
subset of sites/subjects).  The collection window at Baseline (post-dose only), Week 12 (pre-dose), 
Week 24 (post-dose), and at PD visits should be the same as collection of blood samples for PK 
assessment. 
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Whole blood for immunophenotyping (T lymphocytes, B lymphocytes, and natural killer lymphocytes 
[TBNK], B cell subsets) will be collected pre-dose at Baseline, and at any time during the visit at Week 4, 
Week 12, Week 24, and PD.
Whole blood for plasma, serum, viable peripheral blood mononuclear cells (PBMCs), DNA, and RNA, will 
be collected pre-dose at Baseline, and at any time during the visit at Week 2, Week 4, Week 12, 
Week 24, Week 48, or at PD. 
Interferon signature will be collected at Screening, Week 4, Week 24, and at PD.
3.8 12-Lead Electrocardiogram
A 12-lead electrocardiogram (ECG) will be performed at the designated study visits as specified in 
Section 2.1.  The ECG should be performed prior to blood collection.
The ECGs will be evaluated by an appropriately trained physician at the site ("local reader").  The local 
reader from the site will sign and date all ECG tracings and will provide his/her global interpretation as a
written comment on the tracing using the following categories:

Normal ECG

Abnormal ECG – not clinically significant

Abnormal ECG – clinically significant
Only the local reader's evaluation of the ECG will be collected and documented in the subject's source 
folder.  The automatic machine reading (i.e., machine-generated measurements and interpretation that 
are automatically printed on the ECG tracing) will not be collected.
ECGs with QT interval corrected for heart rate using Fridericia's correction formula (QTcF) should be 
reported (or calculated) and documented in the source documents and later transcribed on to the 
appropriate electronic case report form (eCRF) if QTcF prolongation is observed.
A valid QTcF cannot be calculated in subjects who have a pacemaker or supraventricular or ventricular 
conduction abnormalities.  In cases of QTcF prolongation, the baseline QTcF will need to be entered into 
the appropriate eCRF for comparison as well.  In addition, any clinically significant findings will be 
documented in the source documents and later transcribed on to the appropriate eCRF.  Each signed 
original ECG will be monitored by the responsible site monitor and kept with a subject's source 
documents onsite.
Subjects can have a repeat ECG at any time during the study as warranted based on the opinion of the 
investigator.
3.9 Height and Weight
Height will be measured at Screening only.  Body weight will be measured at scheduled visits as 
specified in Section 2.1.  The subject will wear lightweight clothing and no shoes during weighing.
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3.10 Vital Signs
Vital sign determinations of systolic and diastolic blood pressure (BP), pulse rate, respiratory rate, and 
body temperature will be obtained at visits as specified in Section 2.1.  Blood pressure, pulse rate, and 
respiratory rate should be measured after the subject has been sitting for at least 3 minutes and prior to 
drawing lab samples. 
3.11 Physical Examination and Assessments
A physical examination will be performed at the designated study visits as specified in Section 2.1.  The 
complete physical examination performed on Study Day 1 will serve as the baseline physical 
examination for the entire study.  Physical examinations at subsequent study visits can be 
symptom-directed.  Any significant physical examination findings after the first dose will be recorded as 
AEs.  All findings, whether related to an AE or part of each subject's medical history, will be captured on 
the appropriate eCRF page.
At any time, a symptom-directed physical examination can be performed as deemed necessary by the 
investigator.
Chest x-ray (CXR)
A CXR (posterior-anterior and lateral views) is required for all subjects at Screening to rule out the 
presence of TB or other clinically relevant findings.  The CXR will not be required if the subject had a 
previous normal CXR (posterior-anterior and lateral views) or computed tomography (CT) scan of the 
chest within 90 days of Screening, provided all source documentation is available at the site, as outlined 
below and provided nothing has changed in the subject's medical history to warrant a repeat test.  A 
radiologist or pulmonologist must perform and document an assessment of the CXR at Screening (If 
allowed per local regulation, a qualified physician can perform and document an assessment of the CXR 
at Screening.).  The Principal Investigator (PI) will indicate the clinical significance of any findings and will 
sign and date the report.  In the assessment of the CXR, the PI or their delegate must indicate the 
presence or absence of (1) calcified granulomas, (2) pleural scarring/thickening, and (3) signs of active 
TB.  If the CXR or prior chest CT scan demonstrates changes suggestive of previous TB (e.g., calcified 
nodule, fibrotic scar, apical or basilar pleural thickening) or other findings that are clinically significant, 
the PI should contact the AbbVie TA MD before enrolling the subject.
Subjects can have a repeat CXR at any time during the study as warranted based on the opinion of the 
investigator.
TB risk assessment 
Done at Screening only (see Section 3.13 for more information about TB testing and Appendix B).
Physician Global Assessment of Disease Activity (PhGA)
The physician will rate global assessment of the subject's current disease activity, ranging from 0 to
3 independent of the subject's self-assessment using the visual analogue scale, which consists of a 
horizontal 3-inch line anchored at either end by opposite adjectives reflecting the spectrum/severity of 
the parameters assessed at visits specified in Section 2.1.
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Swollen and Tender Joint Count Assessment
An assessment of 28 joints will be done by directed physical examination at visits specified in 
Section 2.1.  Joint swelling will be classified as present ("1"), absent ("0"), replaced ("9"), or no 
assessment ("NA").  Joint tenderness will additionally be classified as present ("1"), absent ("0"), 
replaced ("9"), or "NA."
Any injected joints will be considered as "not assessed" ("NA") for 3 months from the time of the 
intra-articular injection.
If possible, the swollen joint count (SJC) and tender joint count (TJC) should be performed by an 
independent and blinded joint assessor who should not perform any other study-related procedures.
In order to minimize variability, the same independent joint assessor should evaluate the subject at each 
visit for the duration of the trial as much as possible.  A back-up independent joint assessor should be 
identified.  The independent joint assessors should be a qualified medical professional (e.g., nurse, 
physician's assistant, physician).  Any other joint assessor must be trained and competent in performing 
such assessments.  It is the responsibility of the investigator to ensure that all assessors are qualified and 
trained to perform joint assessments.  If the independent assessor is not available, the preidentified 
back-up assessor should perform such assessments.
SLE Disease Activity Index (SLEDAI)-2K assessment
The SLEDAI-2K is a global index that evaluates disease activity over the previous 30 days and includes 
24 items collecting specific manifestations in 9 organ systems:  neurological, musculoskeletal, renal, 
mucocutaneous, general, heart, respiratory, vascular, and hematological.  The SLEDAI-2K scores all 
active (not merely emerging) rash, alopecia, oral ulcers, and proteinuria, and collects disease aspects as 
present or absent.  Thus, it may not reflect partial improvement.
British Isles Lupus Activity Group (BILAG) assessment 2004
The British Isles Lupus Assessment Group (BILAG) 2004 evaluates specific manifestations over the 
previous four weeks in a total of 8 organs systems, 9 in the revised Index:  constitutional, 
mucocutaneous, neuropsychiatric, musculoskeletal, cardiorespiratory, gastrointestinal (GI), ophthalmic, 
renal, and hematological.  Activity in each organ system is scored as:  A = severe disease; B = moderate 
activity; C = mild disease; D = previous involvement, currently inactive; E = no previous activity.  The 
BILAG also is used to evaluate the occurrence of flares in patients with SLE.  A severe flare is defined as a 
score of A, new appearance and a moderate flare is defined with a score of B, and a reoccurrence is 
defined with a score of D or E.
The BILAG-Based Combined Lupus Assessment (BICLA)
The BILAG-Based Combined Lupus Assessment (BICLA) is a composite index used in clinical trials.  This 
differs from the SLE Responder Index (SRI) in that the BILAG-2004 index is the driver of efficacy.  BICLA 
requires patients to meet response criteria across the BILAG-2004 index, SLEDAI-2K, and PhGA.  To be 
classified as a BICLA responder, patients must meet the following criteria:  BILAG-2004 index 
improvement in all A and B scores, no more than one new BILAG B score, no worsening of the total 
SLEDAI-2K score from Baseline, no significant deterioration (not > 10% worsening) in the 100 mm visual 
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analogue PhGA and no treatment failure.  The BICLA also identifies deterioration in clinical features and 
excludes treatment failures.
Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) assessment
The CLASI is a simple, single-page tool that separately quantifies disease activity and damage.  Each part 
of the body is listed separately, from the scalp to the feet, in addition to sections focusing on mucous 
membrane involvement and alopecia.  Scores for each area are assigned based on the most severe 
lesion within the area of interest.  Of note, affected body parts are weighted equally regardless of 
surface area and number of lesions present.  The selection of these equally weighted segments was 
designed to reflect the impact of more common areas of SLE skin involvement.  Unlike the SLEDAI and 
BILAG, interim disease between visits is not accounted for, only the condition on the day of the 
examination.
SELENA SLEDAI Flare Index assessment
The SELENA SLEDAI Flare Index (SFI), developed by the SELENA trials, is a composite outcome of SELENA; 
distinguishing mild/moderate, and severe flares; integrating specific descriptors, medication changes, 
the Physician Global Assessment of Disease Activity (PhGA), and changes in the total SLEDAI score.1
3.12 Dispense Study Drug
Study drug will be dispensed to subjects beginning at Baseline (Day 1) and as specified in Section 2.1.  
The first dose of study drug will be administered after all other Baseline (Day 1) procedures are 
completed.  At the visits specified in Section 2.1, the site personnel will review and retain a copy of the 
subject dosing diary, review returned study drug kits, and empty study drug packaging to verify 
compliance.
Elsubrutinib capsules, upadacitinib tablets, and matching placebo capsules and tablets should be dosed 
together at approximately the same time each day and taken with or without food.
3.13 Clinical Laboratory Tests
The blood samples for serum chemistry tests should be collected following a minimum 8-hour fast prior 
to study drug intake (with the exception of the Screening visit, which may be nonfasting).  Subjects 
whose visits occur prior to the morning dose of study drug should be instructed to fast after midnight 
until the blood sample is collected in the morning and thereafter take their study drug with food.  
Subjects whose visits occur after the morning dose of study drug should be instructed to fast after 
breakfast until the study visit occurs.  At the Study Day 1 visit, a fasting blood sample should be collected 
prior to the first dose of study drug.  Blood samples should still be drawn if the subject did not fast for at 
least 8 hours.  Fasting or nonfasting status will be recorded in the source documents and on the 
laboratory requisition.  The baseline laboratory test results for clinical assessment for a particular test 
will be defined as the last measurement prior to the initial dose of study drug.
A certified laboratory will be utilized to process and provide results for the clinical laboratory tests.  
Laboratory reference ranges will be obtained prior to the initiation of the study.
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Instructions regarding the collection, processing, and shipping of these samples will be provided by the 
central laboratory.
If a laboratory test value is outside the reference range and the investigator considers the laboratory 
result to be clinically significant, the investigator will:

repeat the test to verify the out-of-range value;

follow the out-of-range value to a satisfactory clinical resolution; or

discontinue the subject from study drug or require the subject to receive treatment; in this case, 
the laboratory result will be recorded as an AE.
If renal and hematological laboratory results required for physician indices are not available (e.g., 
specimen hemolyzed, specimen lost in transit, specimen received beyond stability, etc.), re-draw should 
occur within 7 days of notification from Labcorp Drug Development that results are unavailable.
Clinical Laboratory Testsa
HEMATOLOGY
CLINICAL CHEMISTRY
URINALYSIS
Hematocrit
Hemoglobin
Red Blood Cell (RBC) count/
  Erythrocytes
White Blood Cell (WBC) count/
  Leukocytes
Platelet count/Thrombocytes
Prothrombin
Partial thromboplastin
Differential Automatic (absolute
  count):
Neutrophils
Eosinophils
Basophils
Monocytes
Lymphocytes
Manual Differential (ONLY IF 
  Automated Differential is 
  abnormal):
Neutrophils, bands (stabs)
Neutrophils, polymorphonuclear
  (PMN)
Eosinophils
Basophils
Monocytes
Lymphocytes
Electrolytes
Calcium
Sodium
Potassium
Chloride
Bicarbonate
Substrates
Glucose
Blood urea nitrogen
Creatinine (Glomerular Filtration
  Rate [GFR])
Bilirubin Total
Bilirubin Direct (if total is 
  elevated) 
Bilirubin Indirect (if total is 
  elevated)
Albumin
Cholesterol, total
Low-density lipoprotein cholesterol
High-density lipoprotein cholesterol
Triglycerides
Follicle-stimulating hormone (FSH)b
Cotinine
Enzymes
Aspartate transaminase (AST/GOT)
Alanine transaminase (ALT/GPT)
Alkaline phosphatase
Creatine phosphokinase (CPK)c
Aldolasec
Dipstick Urinalysis
Urine Nitrite
Urine Protein
Urine Glucose
Urine Ketone
Urobilinogen
Urine Bilirubin
Urine RBC/Erythrocytes
Urine WBC/Leukocytes
Urine pH
Urine creatinine
Urine-Sediment (microscopic 
  examination, only if urine analysis
  abnormal)
Urine Sediment Bacteria
Urine Cast in Sediment
Urine Squamous Epithelial Cells 
Urine Sediment Crystals, 
  Unspecified
Urine Sediment RBC/Erythrocytes 
Urine Sediment WBC/Leukocytes
Urine
Urine Protein to Creatinine Ratio
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INFECTION SCREENING
PREGNANCY TESTING
PHARMACOKINETIC/
PHARMACODYNAMIC
HBs Ag (qualitative)
HBs Ab (qualitative)
Anti-HBc total (qualitative)
HBV DNA (quantitative) 
HCV Ab (qualitative)
HCV RNA (quantitative)
HIV-1 and HIV-2 Ab (qualitative)
QuantiFERON®-TB and/or PPD
Beta-D-glucan (for Japan subjects
  only)
Urine pregnancy test (local)
Serum pregnancy test
Plasma elsubrutinib and
  upadacitinib concentration
CENTRAL LABa
SPECIALTY LAB
B cell subsets and TBNK cells
ANA
Anti-Smith
Anti-dsDNA
Complement C3, C4
IgG and IgM
Anticardiolipin antibody
Anti-beta 2 glycoprotein 1
  antibody
Lupus anticoagulant
Blood sample for BTK occupancy 
analyses (only select number of 
sites and subjects in the US)
Blood sample for BTK Y223
IFN signature
Ab = antibody; ANA = antinuclear antibody test; COVID-19 = coronavirus disease 2019; BTK = Bruton's tyrosine kinase; 
dsDNA = double-stranded deoxyribonucleic acid; GOT = glutamic oxaloacetic transaminase; GPT = glutamic pyruvic 
transaminase; HBV = hepatis B virus; HBc = Hepatitis B core (antibody); HBs Ab = hepatitis B surface antibody; HBs Ag = hepatitis 
B surface antigen; HCV = hepatitis C virus; HIV = human immunodeficiency virus; IFN = interferon; IgG = immunoglobulin G; 
IgM = immunoglobulin M; JAK = Janus kinase; PPD = purified protein derivative; TA MD = Therapeutic Area Medical Director; 
TB = tuberculosis; TBNK = T lymphocytes, B lymphocytes, and natural killer lymphocytes; US = United States
a.
Tests may also be performed by a certified local lab if sending samples to the central lab is not possible due to 
COVID-19-related restrictions.  
b.
Performed only at Screening.
c.
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.
Pregnancy Testing (Serum and Urine)
Pregnancy testing should not be performed for women who are not of childbearing potential, as 
described above.
A quantitative serum pregnancy test will be performed at Screening and a urine pregnancy test will be 
performed at Baseline.
The serum pregnancy test will be sent to and performed by the central laboratory.  If the serum 
pregnancy test is positive the subject is considered a screen failure.  If the serum pregnancy test is 
borderline, it should be repeated ≥ 3 days later to determine eligibility.
If the repeat serum pregnancy test is:

Positive, the subject is considered a screen failure;

Negative, the subject can be enrolled into the trial;
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
Still borderline, ≥ 3 days later, this will be considered documentation of continued lack of a 
positive result and the subject can be enrolled into the study (unless prohibited per local 
requirements) in the absence of clinical suspicion of pregnancy and other pathological causes of 
borderline results.
Urine pregnancy tests will be performed at all scheduled visits.  An at-home pregnancy test is required if 
a scheduled study visit is missed.  The results of at-home testing must be communicated to the site.  
More frequent pregnancy tests can be performed throughout the study at the investigator's discretion 
or if required per local/country requirements.

If the Baseline urine pregnancy test is negative, then dosing with study drug may begin.

If the Baseline or post-Baseline urine pregnancy test is positive, dosing with study drug must be 
withheld, and a serum pregnancy test is required (as stated above).

Unless a woman is suspected to have become pregnant, additional pregnancy testing beyond 
the monthly testing during the clinical trial is not required.
At each visit, the study staff should review the pregnancy avoidance recommendations with each female 
of childbearing potential and document this discussion in the subject's source records.
Clinical Chemistry
A minimum 8-hour fast is recommended for blood samples to be drawn for chemistry.  If a subject is not 
able to fast when necessary due to unforeseen circumstances, the nonfasting status will be recorded in 
study source documentation.
Urinalysis
Dipstick urinalysis will be completed by the central laboratory at all required visits.  Specified abnormal 
macroscopic urinalyses defined as leukocytes, nitrite, protein, ketones, or blood greater than negative, 
or glucose greater than normal will be followed up with a microscopic analysis at the central laboratory.
TB Testing/TB Prophylaxis
The TB screening tests provide diagnostic test results to be interpreted in the context of the subject's 
epidemiology, history, exam findings, etc., and it is the responsibility of the investigator to determine if a 
subject has previous, active, or latent TB.  Expert consultation for the evaluation and/or management of 
TB may be considered per investigator discretion.
At Screening, all subjects will be assessed for evidence of increased risk for TB by a risk assessment form 
(see Appendix B) and tested for TB infection by QuantiFERON-TB Gold test.  The PPD skin test should be 
utilized only when a QuantiFERON-TB Gold test is not possible for any reason (unless both tests are 
required per local guidelines).  IGRA equivalent test may be used as available and if compliant with local 
TB guidelines.  The site staff will complete the TB risk assessment form and enter the data into an 
appropriate eCRF.
If a subject had a negative QuantiFERON-TB Gold (and/or PPD) test (or IGRA equivalent such as 
T-SPOT.TB test) within 90 days prior to Screening and source documentation is available, the test does 
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not need to be repeated, provided nothing has changed in the subject's medical history to warrant a 
repeat test.  These cases may be discussed with the AbbVie TA MD.  The results of the TB test(s) will be 
retained at the site as the original source documentation.
Subjects with a negative TB test and CXR not suggestive of active TB or prior TB exposure may be 
enrolled.
Subjects with a positive TB test must be assessed for evidence of active TB or latent TB, including signs 
and symptoms and CXR.  Subjects with no signs or symptoms and a CXR not suggestive of active TB may 
be enrolled if the subject has documentation of a full course of prophylaxis (at least 6 months of 
treatment with isoniazid per investigator discretion based on local guidelines) or treatment for TB.  
Subjects with a prior history of latent TB who have documented completion of a full course of anti-TB 
therapy will be allowed to enter the study provided nothing has changed in the subject's medical history 
to warrant repeat treatment.  If documentation of a full course prophylaxis or treatment for TB is not 
available, the subject should be excluded from the study and be referred to a physician for evaluation 
and treatment.
Subjects with evidence of active TB must not be enrolled.
Any newly positive TB screen after the subject has started the study should be reported as an AE of 
latent TB or active TB (as applicable), and subject must be discontinued from the study drug.
TB Testing

Subjects with documentation of prior positive result of QuantiFERON-TB Gold Test (or 
equivalent) and/or PPD are not required to repeat either test at Screening and should be 
considered positive.

For regions that require both PPD and QuantiFERON-TB Gold testing, both will be performed.  If 
either PPD or QuantiFERON-TB Gold tests are positive, the TB test is considered positive.

The PPD Skin Test (also known as a TB Skin Test or Mantoux Test) should be utilized only when a 
QuantiFERON-TB Gold Test is not possible for any reason (unless both tests are required per 
local guidelines).

If the QuantiFERON-TB Gold Test is NOT possible (or if both the QuantiFERON-TB Gold Test and 
the PPD are required per local guidelines), the PPD will be performed.  The PPD should be read 
by a licensed healthcare professional between 48 and 72 hours after administration.  A subject 
who does not return within 72 hours will need to be rescheduled for another skin test.  The 
reaction will be measured in millimeters (mm) of induration, and induration ≥ 5 mm is 
considered a positive reaction.  The absence of induration will be recorded as "0 mm" not 
"negative."  Subjects who have had an ulcerating reaction to the PPD in the past should not be 
re-exposed, and the PPD should be considered positive.

If the QuantiFERON-TB Gold test is indeterminate, then the investigator should perform a local 
QuantiFERON-TB Gold test (or through the central laboratory if not locally available) to rule out 
a positive test result.  If testing remains indeterminate or is positive, then the subject is 
considered to be positive for the purpose of this study.  If the testing result is negative, then the 
subject is considered to be negative.
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
Interpretation of a positive TB test in low risk subjects:  In cases where the QuantiFERON-TB 
Gold Plus test by the central laboratory is positive and the investigator considers the subject at 
low risk for TB (i.e., no risk factors identified using the Part I and Part II questions of the TB risk 
assessment questionnaire at Screening) and has no clinical suspicion of TB, the investigator may 
perform a local QuantiFERON-TB Gold Plus test (or repeat testing through the central laboratory 
if not locally available) to confirm the positive test result.  If the repeat testing result is negative, 
the investigator may consider the test to be negative based on his/her clinical judgment; if the 
repeat testing result is positive or indeterminate, the test is considered positive.

If different national regulations exist for screening for latent TB while being on 
immunosuppressive treatment, these national regulations will be applied, respectively.
Hepatitis Screen
All subjects will be tested for the presence of HBV and HCV at Screening.
Hepatitis B Virus:
Subjects will be tested for the presence of HBV at Screening using the following tests:

Hepatitis B surface antigen (HBs Ag)

Hepatitis B core antibody (HBc Ab/anti-HBc)

Hepatitis B surface antibody (HBs Ab/anti-HBs)
A positive result for HBs Ag will be exclusionary.
A negative result for HBs Ag will trigger automatic reflex testing for core antibodies (HBc Ab) and surface 
antibodies (HBs Ab).

A negative test result for HBc Ab does not require HBV DNA PCR qualitative testing, and the 
subject may be enrolled (Figure 1, Scenarios A and B).

For a subject who has had an HBV vaccination (should document in the medical history), a 
positive test result for HBs Ab is expected.  The HBV DNA PCR qualitative testing is not required, 
and the subject may be enrolled (Figure 1, Scenario B).*

A positive test result for HBc Ab requires HBV DNA PCR testing (automatic reflex testing) 
(Figure 1, Scenarios C and D).

A result that exceeds detection sensitivity by central laboratory will be considered a positive 
result for HBV DNA and will be exclusionary.

A subject with a negative result for HBV DNA may be enrolled.

Where mandated by local requirements:  A positive result for HBs Ab requires HBV DNA PCR 
testing.

A result that exceeds detection sensitivity by central laboratory will be considered a positive 
result for HBV DNA and will be exclusionary.

A subject with a negative result for HBV DNA may be enrolled.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-130 Version 7.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

For subjects with HBs Ab+ and/or HBc Ab+ and negative HBV DNA at Screening, HBV DNA 
PCR test should be performed every 12 weeks.  HBV DNA PCR testing every 12 weeks is not 
necessary when the subject has a history of HBV vaccine and HBs Ab+ and HBc Ab–.

At any time during the study for subjects with HBc Ab+ (irrespective of HBs Ab status) and 
negative HBV DNA at Screening, a positive result for HBV DNA PCR testing accompanied by the 
following will require immediate interruption of study drug (per local guidelines) and a 
hepatologist consultation should occur within one week for recommendation regarding 
subsequent treatment:

Alanine transaminase (ALT) > 5 × upper limit of normal (ULN) OR 

ALT/Aspartate transaminase (AST) > 3 × ULN and either a total bilirubin > 2 × ULN or 
international normalized ratio (INR) > 1.5 OR

ALT/AST > 3 × ULN along with clinical signs of possible hepatitis.
Figure 1.
Interpretation and Management of HBV Serologic Test Results
HBc Ab = hepatitis B core antibody; HBs Ab = hepatitis B surface antibody; HBs Ag = hepatitis B surface antigen; 
HBV = hepatitis B virus; PCR = polymerase chain reaction 
*
A positive test result for HBs Ab is expected for subjects who have had an HBV vaccination.  For subjects without a history 
of HBV vaccination (and for subjects in Japan and China or where mandated by local requirements), a positive result for 
HBs Ab/anti-HBs requires HBV DNA PCR testing.
Hepatitis C Virus
Blood samples for HCV serology will be obtained at the Screening visit.  A positive HCV Ab will trigger an
HCV RNA test.  A subject will not be eligible for study participation if test results indicate active 
hepatitis C (HCV RNA detectable in any subject with anti HCV Ab).
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p. 33 of 42
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-130 Version 7.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
HIV
Subjects with HIV infection (positive HIV test) are excluded from study participation.  HIV testing will be 
performed at Screening, unless prohibited by local regulations.  The investigator must discuss any local 
reporting requirements to local health agencies with the subject.  The site will report confirmed positive 
results to their health agency per local regulations, if necessary.  If a subject has a confirmed positive 
result, the investigator must discuss with the subject the potential implications to the subject's health, 
and subject should receive or be referred for clinical care promptly.  
COVID-19 Pandemic-Related Acceptable Protocol Modifications
If travel restrictions or other changes in local regulations, or changes in shipping logistics in light of the 
coronavirus disease 2019 (COVID-19) pandemic prevent the subject from having blood drawn and 
analyzed for laboratory testing at the study site, if possible, arrange for subjects to have laboratory work 
done at a local lab, hospital, or other facility.  Local lab results should be obtained along with reference 
ranges and kept within the subjects' source documentation.  Local lab results should be reviewed by the 
investigator as soon as possible.
If laboratory samples cannot be obtained, study drug administration may be continued for 1 month 
provided the investigator has reviewed all prior laboratory results and confirms and discusses with the 
subject that there is no safety concern for the subject to continue use of the study drug in the absence 
of current labs.  The subject should be scheduled for laboratory draws as soon as feasible.
3.14 Subject Withdrawal from Study
All attempts must be made to determine the date of the last study drug dose and the primary reason for 
discontinuation of study drug or study participation.  The information will be recorded on the 
appropriate eCRF page.  However, these procedures should not interfere with the initiation of any new 
treatments or therapeutic modalities that the investigator feels are necessary to treat the subject's 
condition.  Following discontinuation of study drug, the subject will be treated in accordance with the 
investigator's best clinical judgment, irrespective of whether or not the subject decides to continue 
participation in the study.
3.15 Unscheduled Visits
An Unscheduled Visit should be performed when the subject comes in for a medical visit for evaluation 
and assessment.  During Unscheduled Visits, blood and urine samples may be obtained for the 
laboratory tests listed in Section 3.13, or for other tests, at the investigator's discretion.
Visits for dispensing new study drug in case of temperature excursion, loss or damage are not 
considered an Unscheduled Visit.  In addition, visits to only retest a lab will not be considered an 
Unscheduled Visit.
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p. 34 of 42
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-130 Version 7.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
4 SAFETY MANUAL
4.1 Methods and Timing of Safety Assessment
All serious and nonserious AEs which could be related to study procedures (e.g., infection at blood draw 
site, done during Screening) will be collected from the time the subject signed the study-specific 
informed consent until study drug administration.  From the time of study drug administration until 
30 days after discontinuation of study treatment, all AEs and SAEs will be collected whether solicited or 
spontaneously reported by the subject.  After 30 days following completion of study treatment and 
throughout the Post-Treatment Period, all spontaneously reported SAEs will be collected (nonserious 
AEs will not be collected).
4.2 Recording Data and Analyses of Safety Findings
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  The 
number and percentage of subjects with treatment-emergent adverse events (TEAEs; i.e., any event that 
begins or worsens in severity after initiation of study drug through 30 days post-study drug dosing) will 
be tabulated by primary MedDRA system organ class (SOC) and preferred term (PT) and compared 
between arms using Fisher's exact test.  The tabulation of the number of subjects with TEAEs by severity 
grade and relationship to study drug also will be provided.  Subjects reporting more than 1 AE for a given 
MedDRA PT will be counted only once for that term using the most severe grade according to the 
severity grade table and the most related according to the relationship to study drug tables.  Subjects 
reporting more than 1 type of event within an SOC will be counted only once for that SOC.
4.3 Reporting Adverse Events and Intercurrent Illnesses
In the event of a serious adverse event (SAE), whether associated with study drug or not, the 
investigator will notify Clinical Pharmacovigilance within 24 hours of the site being made aware of the 
SAE by entering the SAE data into the Electronic data capture system.  SAEs that occur prior to the site 
having access to the RAVE® system, or if RAVE is not operable, should be documented on the SAE 
nonCRF forms and emailed (preferred route) or faxed to Clinical Pharmacovigilance within 24 hours of 
the site being made aware of the SAE.
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p. 36 of 42
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-130 Version 7.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Supplemental study case report forms should be completed in the event of COVID-19-related missed 
visits, study drug interruptions or discontinuations, or AEs (including capture of specific signs/symptoms 
of infection and testing results).
COVID-19 infections should be captured as AEs.  If the event meets the criteria for an SAE, then follow 
the SAE reporting directions per the protocol and above.  The following COVID-19-related supplemental 
eCRFs should be completed:

COVID-19 Supplemental Signs/ Symptoms

COVID-19 Status Form
If a subject has a confirmed or suspected COVID-19 infection and study drug was interrupted, the 
investigator should contact the sponsor emergency medical contact listed above before reintroducing 
study drug.
5 COUNTRY-SPECIFIC REQUIREMENTS
5.1 SUSAR Reporting
AbbVie will be responsible for SUSAR reporting for the IMP in accordance with global and local 
guidelines; Appendix A of the Investigator Brochure for elsubrutinib and for upadacitinib will serve as
the Reference Safety Information (RSI).  The RSI in effect at the start of a drug safety update report 
reporting period serves as the RSI during the reporting period.  For follow-up reports, the RSI in place at 
the time of occurrence of the 'suspected' Serious Adverse Reaction will be used to assess expectedness.
5.2 Treatment After End of Study
For active subjects randomized to elsubrutinib, upadacitinib, or ABBV-599 (elsubrutinib/upadacitinib) 
combination, subjects will continue on study treatment throughout the study for a period of up to 
48 weeks, or until premature discontinuation of study drug.  At the subject's last study visit, the 
investigator will discuss the appropriate subsequent treatment with the subject.  A long-term extension 
(LTE) study (Study M20-186) is planned to be conducted under a separate protocol at sites where it is 
permitted by the local Competent Authority and Ethics Committee.  Eligible subject rollover from the 
initial randomized portion of the study will occur at Week 48. 
6 STUDY DRUG
6.1 Treatments Administered
The study drug (elsubrutinib, upadacitinib, and/or matching placebo) will be dispensed in the form of a 
capsule (elsubrutinib or matching placebo), or film-coated tablet (upadacitinib or matching placebo) at 
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p. 37 of 42
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-130 Version 7.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
the visits listed in Section 2.1.  Subjects will be instructed to take study drugs at the same time every 
day.
Study drug will be provided by AbbVie as elsubrutinib 20 mg capsules, upadacitinib 15 mg and 30 mg 
film-coated tablets, and matching placebo capsules and film-coated tablets.
Study drug will be taken orally as 3 capsules of elsubrutinib and/or matching placebo and 1 film-coated 
tablet of upadacitinib and/or matching placebo once daily with or without food.
Study drug must not be dispensed without contacting the interactive response technology (IRT) system.  
Study drug may only be dispensed to subjects enrolled in the study through the IRT system.  At the end 
of the Treatment Period or at the PD visit, the site will contact the IRT system to provide visit date 
information and study drug return information for each kit.
For study drug interruption, the following rules apply:
1.
If the subject undergoes elective surgery, the study drug should be interrupted 1 week prior to 
the planned surgery.  
2.
Up to Week 24, allow study drug interruption up to 10 consecutive days for AEs, emergency 
surgery, and abnormal labs.  After Week 24, allow study drug interruption up to 30 consecutive 
days for AEs, emergency surgery, and abnormal labs.  Elective surgery will not be allowed during 
the first 24 weeks of the study.  If subject misses or is anticipated to miss > 10 days of study drug
during the first 24 weeks of the study or > 30 days of study drug after Week 24, it will be 
considered a protocol deviation and reported as described in the protocol.
3.
If the subject must undergo emergency surgery, the study drug should be interrupted at the 
time of the surgery.  After emergency surgery, allow reintroduction of study drug once the 
surgeon has examined the surgical site and determined that it has healed and there is no sign of 
infection.
At the end of the Treatment Period or at the PD visit, the site will contact the IRT system to provide visit 
date information and study drug return information for each kit.
6.2 Packaging and Labeling
All study drugs will be supplied in bottles.
Each bottle will be labeled as required per country requirements.
The labels must remain affixed to the bottles.  All blank spaces should be completed by site staff prior to 
dispensing to subject.
Storage and Disposition of Study Drug
Study drug must be stored at controlled room temperature (15° to 25°C/59° to 77°F).  Elsubrutinib and 
placebo must be protected from freezing.
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p. 38 of 42
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-130 Version 7.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
The investigational products are for investigational use only and are to be used only within the context 
of this study.  The study drug supplied for this study must be maintained under adequate security and 
stored under the conditions specified on the label until dispensed for subject use or destroyed on site as 
appropriate.
6.3 Method of Assigning Subjects to Treatment Groups
This is a Phase 2, 48-week, multi-center, randomized, double-blind, placebo-controlled study.  All eligible 
subjects will receive the study drug for 48 weeks.
At the Screening visit, all subjects will be assigned a unique subject number through the use of the IRT.  
For subjects who do not meet the study selection criteria, the site personnel must contact the IRT 
system and identify the subject as a screen failure.
Subjects who are enrolled will retain their subject number assigned at the screening visit throughout the 
study.  Upon receipt of study drug, the site will acknowledge receipt in the IRT system.
Contact information and user guidelines for IRT use will be provided to each site.
6.4 Selection and Timing of Dose for Each Subject
Three capsules of elsubrutinib or matching placebo and 1 tablet of upadacitinib or matching placebo 
tablet will be dosed together once daily.  All subjects should take all doses of study drug around the 
same time each day, with or without food.
7 References
1.
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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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-130 Version 7.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX A. STUDY SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
NA
No assessment
Ab
Antibody
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine transaminase
ANA
Antinuclear antibody
Anti-dsDNA
Anti-double stranded DNA
AST
Aspartate transaminase
BICLA
BILAG-Based Combined Lupus Assessment
BILAG
British Isles Lupus Activity Group
BTK
Bruton's tyrosine kinase
CBC
Complete blood count
CLASI
Cutaneous Lupus Erythematosus Disease Area and Severity Index
COVID-19
Coronavirus disease 2019
CT
Computed tomography
CXR
Chest x-ray
DNA
Deoxyribonucleic acid
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic case report form
FACIT
Functional Assessment of Chronic Illness Therapy
FSH
Follicle-stimulating hormone
HBc Ab
Hepatitis B core antibody
HBs Ab
Hepatitis B surface antibody
HBs Ag
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HCV Ab
Hepatitis C virus antibody
HIV
Human immunodeficiency virus
HRQoL
Health-related quality of life
IEC
Independent ethics committee
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p. 40 of 42
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-130 Version 7.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
IFN
Interferon
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IMP
Investigational Medicinal Product
INR
International normalized ratio
IRB
Institutional review board
IRT
Interactive response technology
LTE
Long-term extension
LupusQoL
Lupus Quality of Life questionnaire
MedDRA
Medical Dictionary for Regulatory Activities
NRS
Numerical Rating Scale
PBMC
Peripheral blood mononuclear cell
PCR
Polymerase chain reaction
PD
Premature Discontinuation
PhGA
Physician Global Assessment
PI
Principal Investigator
PK
Pharmacokinetic
PMN
Polymorphonuclear white blood cells
PPD
Purified protein derivative
PRO
Patient-reported outcome
PT
Preferred term
PtGA
Patient Global Assessment
QoL
Quality of life
QTcF
QTc using Fridericia's correction formula
RBC
Red blood cells
RNA
Ribonucleic acid
RSI
Reference Safety Information
SAE
Serious adverse event
SF-36
SF-36 Health Survey
SJC
Swollen joint count
SLE
Systemic lupus erythematosus
SLEDAI
SLE Disease Activity Index
SOC
System organ class
SUSAR
Suspected unexpected serious adverse reaction
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p. 41 of 42
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-130 Version 7.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
TB
Tuberculosis
TBNK
T lymphocytes, B lymphocytes, and natural killer lymphocytes
TJC
Tender joint count
ULN
Upper limit of normal
UPCR
Urine protein to creatinine ratio
US
United States
WBC
White blood cells
WOCBP
Women of childbearing potential
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p. 42 of 42
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-130 Version 7.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX B. SCREENING TB RISK ASSESSMENT 
QUESTIONNAIRE (SAMPLE FORM)
For Screening TB risk assessment, ask Part I and Part II questions.
For Annual TB risk assessment, only ask the Part I questions.
Part 1
1.
Has an immediate family member or other close contact been newly diagnosed with or treated 
for active or latent tuberculosis during the last 3 months?
2.
Within the past year, have you, or an immediate family member, had any of the following 
problems lasting for 3 weeks or longer which remained unexplained:

Chronic Cough

Production of Sputum

Blood-Streaked Sputum

Weight Loss

Fever

Fatigue/Tiredness

Night Sweats

Shortness of Breath
(Reference:  https://www.cdc.gov/tb/topic/testing/diagnosingltbi.htm)
Part II
3.
Have you ever been diagnosed or treated for active or latent tuberculosis?
4.
Have you lived in or had prolonged travels to any of the following TB endemic regions?
Angola
China
India
Mozambique
Papua New Guinea
Thailand
Bangladesh
Congo
Indonesia
Myanmar
Philippines
UR Tanzania
Brazil
DPR Korea
Kenya
Namibia
Russian Federation
Viet Nam
Cambodia
DR Congo
Lesotho
Nigeria
Sierra Leone
Zambia
Central African Republic
Ethiopia
Liberia
Pakistan
South Africa
Zimbabwe
(Reference:  World Health Organization Global Tuberculosis Report 2018. Available from:  
https://www.who.int/tb/publications/global_report/en/)
5.
Have you lived or worked in a prison, refugee camp, homeless shelter, immigration center, or 
nursing home?
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SAP_001.pdf: 
ABBV-599
M19-130 – Statistical Analysis Plan
Version 4.0 – 26 July 2022
1
Statistical Analysis Plan
Study M19-130
Systemic Lupus Erythematosus:  A Phase 2 Study to 
Investigate the Safety and Efficacy of Elsubrutinib 
and Upadacitinib Given Alone or in Combination 
(ABBV-599 Combination) in Subjects with 
Moderately to Severely Active Systemic Lupus 
Erythematosus
Date:  26 July 2022
Version 4.0
 
NCT03978520


ABBV-599
M19-130 – Statistical Analysis Plan
Version 4.0 – 26 July 2022
2
Table of Contents
1.0
Introduction...........................................................................5
2.0
Study Design and Objectives ................................................5
2.1
Objectives, Hypotheses and Estimands................................................... 5
2.2
Study Design Overview.......................................................................... 7
2.3
Treatment Assignment and Blinding....................................................... 8
2.4
Sample Size Determination .................................................................. 10
3.0
Endpoints.............................................................................10
3.1
Primary Endpoint(s) ............................................................................. 10
3.2
Secondary Endpoint(s) ......................................................................... 10
3.3
Other Efficacy Endpoint(s)................................................................... 11
3.4
Safety Endpoint(s)................................................................................ 13
4.0
Analysis Populations ...........................................................14
5.0
Subject Disposition..............................................................14
6.0
Study Drug Duration and Compliance ..............................15
6.1
Study Drug Duration ............................................................................ 15
6.2
Study Drug Compliance ....................................................................... 16
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ...................16
7.1
Demographics and Baseline Characteristics.......................................... 17
7.2
Medical History.................................................................................... 19
7.3
Prior and Concomitant Medications...................................................... 20
8.0
Efficacy Analyses.................................................................20
8.1
General Considerations......................................................................... 20
8.2
Handling of Potential Intercurrent Events ............................................. 22
8.2.1
Premature Discontinuation of Study Drug ............................................ 22
8.2.2
Initiation of Rescue Medications or Initiation or Dose Escalation 
of SLE-Related Corticosteroid.............................................................. 22
8.3
Handling of Missing Data..................................................................... 23
8.4
Primary Efficacy Endpoint and Analyses.............................................. 26
8.4.1
Primary Efficacy Endpoint ................................................................... 26
8.4.2
Main Analysis of Primary Efficacy Endpoint(s).................................... 26


ABBV-599
M19-130 – Statistical Analysis Plan
Version 4.0 – 26 July 2022
3
8.4.3
Sensitivity and Supplementary Analyses of the Primary Efficacy 
Endpoint............................................................................................... 28
8.5
Secondary Efficacy Endpoints and Analyses ........................................ 28
8.5.1
Secondary Efficacy Endpoints.............................................................. 28
8.5.2
Main Analyses of Secondary Efficacy Endpoints.................................. 29
8.5.3
Sensitivity and Supplementary Analyses for Secondary Efficacy 
Endpoints ............................................................................................. 32
8.6
Additional Efficacy Analyses ............................................................... 32
8.7
Efficacy Subgroup Analyses................................................................. 33
9.0
Safety Analyses....................................................................34
9.1
General Considerations......................................................................... 34
9.2
Adverse Events..................................................................................... 35
9.2.1
Treatment-Emergent Adverse Events.................................................... 35
9.2.2
Adverse Event Overview...................................................................... 36
9.2.3
Treatment-Emergent Adverse Events by SOC and/or PT...................... 37
9.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure .............................................................................................. 37
9.2.5
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation ........................................................................... 38
9.2.6
Adverse Events of Special Interest........................................................ 38
9.2.7
Adverse Events by "Reasonably Possibly Related" Relationship........... 38
9.2.8
Frequent (> 5%) Adverse Events and Reasonably Possibly 
Related Adverse Events by Preferred Term in Decreasing 
Frequency............................................................................................. 39
9.2.9
Listing of Adverse Events..................................................................... 39
9.3
Analysis of Laboratory Data................................................................. 39
9.4
Analysis of Vital Signs......................................................................... 41
9.5
Safety Subgroup Analyses.................................................................... 42
9.6
Other Safety Analyses .......................................................................... 42
10.0
Other Analyses ....................................................................42
11.0
Interim Analysis ..................................................................42
11.1
Data Monitoring Committee................................................................. 42
11.2
Interim Analysis ................................................................................... 43
11.2.1
Interim Analysis Population ................................................................. 43


ABBV-599
M19-130 – Statistical Analysis Plan
Version 4.0 – 26 July 2022
4
11.2.2
Subject Disposition, Demographics and Disease Characteristics, 
and Treatment Compliance................................................................... 44
11.2.3
Efficacy Analyses................................................................................. 45
11.2.4
Safety Analyses.................................................................................... 46
12.0
Overall Type-I Error Control.............................................47
13.0
Version History ...................................................................47
14.0
References............................................................................48
List of Tables
Table 1.
Summary of the Estimand Attributes of the Primary Efficacy 
Endpoint(s)........................................................................................... 27
Table 2.
Summary of the Estimand Attributes of the Secondary Efficacy 
Endpoints ............................................................................................. 30
Table 3.
Subgroups ............................................................................................ 34
Table 4.
SAP Version History Summary ............................................................ 47
List of Figures
Figure 1.
Study Schematic..................................................................................... 8
List of Appendices
Appendix A.
Protocol Deviations .............................................................................. 49
Appendix B.
Definition of Adverse Events of Special Interest................................... 50
Appendix C.
Potentially Clinically Important Criteria for Safety Endpoints .............. 52
Appendix D.
Attributes of the Estimand for Primary and Secondary Endpoints......... 53
Appendix E.
Random Seeds...................................................................................... 55


ABBV-599
M19-130 – Statistical Analysis Plan
Version 4.0 – 26 July 2022
5
1.0
Introduction
This statistical analysis plan (SAP) describes the proposed statistical analyses to be 
completed by the Data and Statistical Sciences Department for ABBV-599 
Study M19-130 Primary Analysis performed after all subjects have completed the 
Week 24 visit or have discontinued the study and the Final Analysis performed after all 
subjects have completed or discontinued the study.
Pharmacokinetic and Biomarker analyses will be performed separately and reported in a 
separate document, as applicable, to further aid data interpretation.
The SAP will be updated if there are any protocol changes identified that impact the 
efficacy or safety analysis.
Unless noted otherwise, all analyses will be performed using SAS version 9.4 or later 
(SAS Institute Inc., Cary, NC  27513) under the UNIX operating system.
This SAP Version 3 includes changes to the analyses described in the amended RCT 
Study M19-130 (Version 7) protocol.  Details are outlined in Section 13.0.
2.0
Study Design and Objectives
2.1
Objectives, Hypotheses and Estimands
The main objective is to evaluate the safety and efficacy of elsubrutinib, upadacitinib and 
the ABBV-599 (elsubrutinib/upadacitinib) combination vs. placebo for the treatment of 
signs and symptoms of Systemic Lupus Erythematosus (SLE) at 24 and 48 weeks in
subjects with moderately to severely active SLE and to define dose(s) for further 
development.
Primary Efficacy Objective
The primary efficacy objective is to demonstrate a higher rate of achievement of SRI-4 
and steroid dose ≤ 10 mg prednisone equivalent once a day (QD) at Week 24 of active 


ABBV-599
M19-130 – Statistical Analysis Plan
Version 4.0 – 26 July 2022
6
treatment groups (elsubrutinib, upadacitinib and ABBV-599 combination) when 
compared to placebo based on Full Analysis Set (FAS) as defined in Section 4.0.
Hypothesis corresponding to the primary efficacy objective and endpoint is:
●
The proportion of subjects achieving SRI-4 and steroid dose ≤ 10 mg 
prednisone equivalent QD treated with active treatment groups (elsubrutinib, 
upadacitinib and ABBV-599 combination) is greater than those treated with 
placebo at Week 24.
The estimand corresponding to the primary efficacy objective is defined as follows:
●
Difference in the proportion of subjects achieving SRI-4 and steroid dose 
≤10 mg prednisone equivalent QD regardless of premature discontinuation of 
study drug and without initiation of rescue medications (see Section 8.2) 
between active treatment groups (elsubrutinib, upadacitinib and ABBV-599 
combination) and placebo in FAS.
Secondary Efficacy Objective
The secondary efficacy objective is to demonstrate higher efficacy of active treatment 
groups (elsubrutinib, upadacitinib and ABBV-599 combination) when compared to 
placebo with respect to the secondary endpoints as specified in Section 3.2.  The 
secondary efficacy objectives will be assessed based on FAS.
Hypotheses corresponding to the secondary efficacy objectives and endpoints are: 
●
For each binary secondary endpoint, a greater proportion of subjects with 
improvement for the endpoint is achieved in active treatment groups
(elsubrutinib, upadacitinib and ABBV-599 combination) when compared to 
that of placebo.
●
For each continuous secondary endpoint, greater mean change from baseline 
for the endpoint is achieved with active treatment groups (elsubrutinib, 
upadacitinib and ABBV-599 combination) when compared to that of placebo.


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The estimands corresponding to the secondary efficacy objectives are defined as follows:
●
For each binary secondary endpoint, the estimand is the difference in the 
proportion of subjects achieving the endpoint regardless of premature 
discontinuation of study drug and without initiation of rescue medications (see 
Section 8.2) between active treatment groups (elsubrutinib, upadacitinib and 
ABBV-599 combination) and placebo in FAS.
●
For each continuous secondary endpoint, the estimand is the difference in the 
mean change from baseline of the endpoint regardless of premature 
discontinuation of study drug and if subjects would not initiate rescue 
medications (See Section 8.2) between active treatment groups (elsubrutinib, 
upadacitinib and ABBV-599 combination) and placebo in FAS.
2.2
Study Design Overview
This is a multi-center, randomized, double-blind, and placebo-controlled Phase 2 study, 
with a Week 24 primary endpoint, to investigate the safety and efficacy of elsubrutinib 
and upadacitinib given alone or in combination (ABBV-599 [elsubrutinib/upadacitinib] 
combination) in subjects with moderately to severely active systemic lupus 
erythematosus.
The schematic of the study is shown in Figure 1.


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Figure 1.
Study Schematic
QD = once daily
2.3
Treatment Assignment and Blinding
Approximately 325 male and female subjects, 18 to 65 years of age, inclusive, with a 
diagnosis of moderately to severely active SLE (clinical diagnosis of SLE at least 
24 weeks prior to Screening, meeting at least 4 of the 11 revised Criteria for Classification 
of SLE according to the 1997 Update of the 1982 ACR OR meeting at least 4 of the 
2012 Systemic Lupus Erythematosus International Collaborating Clinics [SLICC] 
classification criteria, including at least 1 clinical criterion and 1 immunologic criterion) 
despite standard of care therapy will be randomized in a 1:1:1:1:1 ratio of 5 treatment 
groups, as follows:
●
Group 1:  Elsubrutinib 60 mg QD and upadacitinib 30 mg QD (n = 65)
●
Group 2:  Elsubrutinib 60 mg QD and upadacitinib 15 mg QD (n = 65)
●
Group 3:  Elsubrutinib 60 mg QD and upadacitinib placebo QD (n = 65)


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Group 4:  Elsubrutinib placebo QD and upadacitinib 30 mg QD (n = 65)
●
Group 5:  Elsubrutinib placebo QD and upadacitinib placebo QD (n = 65)
Randomization will be stratified based on the following factors:
●
Baseline corticosteroid dose above 10 mg prednisone-equivalent (≤ 10 mg or 
> 10 mg)
●
Screening Systemic Lupus Erythematosus Disease Activity Measure 
(SLEDAI)-2K (< 10 or ≥ 10)
●
High versus low interferon score versus not applicable (approximately 80% 
high)
○
This stratification factor does not apply to subjects in China.
●
Baseline immunosuppressant (azathioprine, tacrolimus, cyclosporine, 
methotrexate [MTX], mycophenolate) (yes/no)
Once approximately 20% of total subjects have been randomized who are interferon 
signature low, further screening of such subjects may be suspended.  Interferon 
stratification will be utilized in all participating countries/regions except China due to 
local constraints.
The study duration will include a 42-day maximum screening period and a 48-week 
randomized, placebo-controlled, double-blind, parallel-group treatment period with a 
30-day follow-up phone call.  An interim analysis was performed after the first 50% of the 
subjects completed Week 24 visit or withdrew from the study by an independent team at 
AbbVie as planned (Section 11.2).  The Week 24 Primary Analysis will be performed 
when all subjects have completed the Week 24 visit or have discontinued the study. The 
study team will remain blinded until the Week 24 Primary Analysis.  The sites and 
subjects will remain blinded throughout the remainder of the study.  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.


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2.4
Sample Size Determination
The planned sample size for this study is 325 subjects in total, with 65 subjects for each of 
the 5 arms, determined based on the primary endpoint, the composite of SLE Responder 
Index (SRI)-4 (See Section 3.1) and steroid dose ≤ 10 mg prednisone equivalent QD at 
Week 24.  Assuming at Week 24 the placebo response rate is 25%, a two-sided Chi-
squared Test with alpha=10% will provide 78% to 91% power to detect a difference of 
20% to 25% between the active treatment groups and the placebo group.
3.0
Endpoints
3.1
Primary Endpoint(s)
The following is the primary efficacy endpoint:
●
Achievement of SRI-4 and steroid dose ≤ 10 mg prednisone equivalent once a 
day (QD) at Week 24
SLE Responder Index (SRI)-4 is defined as follows with all criteria compared to baseline:
●
≥ 4-point reduction in Systemic Lupus Erythematosus Disease Activity Index 
2000 (SLEDAI-2K) score.
●
No worsening of the overall condition (< 0.3 point increase in Physician's 
Global Assessment [PhGA]) 
●
No new BILAG A or more than 1 new BILAG B disease activity scores (i.e., 
no organ system changes from baseline B/C/D/E to A and no more than 1 organ 
system changes from baseline C/D/E to B).
3.2
Secondary Endpoint(s)
The following secondary efficacy endpoints will be evaluated:
1.
Achievement of SRI-4 at Week 24.


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2.
Achievement of BILAG-Based Combined Lupus Assessment (BICLA) response at 
Week 24.
3.
Achievement of Lupus Low Disease Activity State (LLDAS) at Week 24
4.
Steroid burden, assessed as change from Baseline at Week 24
5.
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
(mild/moderate, severe, and any) per subject through Week 24
3.3
Other Efficacy Endpoint(s)
The following additional efficacy endpoints will be evaluated at all visits unless otherwise 
noted:
1.
Achievement of SRI-4.
2.
Achievement of SRI-5, -6, -7, -8 and steroid dose ≤ 10 mg prednisone equivalent 
QD at Weeks 24 and 48.
3.
Achievement of SRI-7/-8 among subjects who have baseline SLEDAI-2K score 
>=7/>=8 and steroid dose ≤ 10 mg prednisone equivalent QD at Weeks 24 and 
48.
4.
Achievement of SRI-5, -6, -7, -8.
5.
Achievement of SRI-7/-8 among subjects who have baseline SLEDAI-2K score 
>=7/>=8.
6.
Achievement of BICLA response.
7.
Achievement of LLDAS.
8.
Achievement of ≥4-point decrease in SLEDAI-2K from Baseline.
9.
Steroid burden, assessed as change from Baseline.


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10.
Number of mild, moderate, or severe flares per patient-year (respectively and 
overall) by SELENA SFI, assessed by number and types of flare per subject
through Week 24 and Week 48.
11.
Time to first flare (any severity) by SELENA SFI after first study drug 
administration up to Week 24 and Week 48.
12.
Achievement of 50% reduction of tender or swollen lupus joints defined as ≥ 50% 
decrease in either tender or swollen joints (among those starting with total 
≥6 affected joints).
13.
Achievement of 50% reduction in Cutaneous Lupus Erythematosus Disease Area 
and Severity Index (CLASI) activity score (of those starting with CLASI ≥ 10).
14.
Change in SLEDAI-2K from Baseline.
15.
Change in BILAG total score from Baseline.
16.
Change in PhGA from Baseline.
17.
Change in Patient Global Assessment (PtGA) from Baseline.
18.
Change from Baseline in Functional Assessment of Chronic Illness Therapy 
(FACIT)-Fatigue at Weeks 2, 12, 24, and 48.
19.
Change from Baseline in 36-Item Short Form Health Survey (SF-36) at Weeks 2, 
12, 24, and 48.
20.
Change from Baseline Lupus Quality of Life questionnaire (LupusQoL) at 
Weeks 2, 12, 24, and 48.
21.
Change from Baseline Pain Numerical Rating Scale (NRS) at Weeks 2, 12, 24,
and 48.
22.
Achievement of SRI-4 and steroid dose ≤ 10 mg prednisone equivalent QD.
23.
The annualized BILAG-based flare rate through Week 24 and through Week 48.


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24.
Achievement of ≥ 50% improvement in joint counts (defined as ≥ 50% decrease in 
the swollen and tender joint count from baseline in patients with ≥ 8 swollen and 
≥8 tender joints at baseline).
25.
Achievement of Clinical SLEDAI (defined as ≥ 4-point reduction in clinical 
components (no laboratory components) of the SLEDAI) Among subjects with 
baseline SLEDAI-2K clinical score ≥ 4.
26.
Achievement of prednisone equivalent steroid daily dose ≤7.5 mg among subjects 
with daily dose ≥10 mg at Baseline through Week 48.
27.
Achievement of prednisone equivalent steroid daily dose ≤7.5 mg sustained from 
Week 36 to Week 48 among subjects with daily dose ≥10 mg at Baseline.
28.
Achievement of no increase in SLEDAI-2K total score from baseline.
29.
Achievement of < 0.3 point increase in PhGA from baseline.
30.
Achievement of no new BILAG A or more than 1 new BILAG B comparing to 
baseline (as defined in SRI-4).
31.
Achievement of improvement in all baseline BILAG A and BILAG B (as defined 
in BICLA)
3.4
Safety Endpoint(s)
Safety evaluations include adverse event (AE) monitoring, physical examinations, vital 
sign measurements, electrocardiograms (ECGs), and clinical laboratory testing 
(hematology, chemistry, and urinalysis) as measures of safety and tolerability for the 
entire study duration.
An independent external Cardiovascular Adjudication Committee (CAC) will adjudicate 
all blinded cardiovascular and cerebrovascular events, embolic/thrombotic events and 
deaths, as defined in the CAC charter.


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4.0
Analysis Populations
The Full Analysis Set (FAS) includes all randomized subjects who have received at least 
1 dose of study drug.  Subjects will be grouped according to treatment as randomized.  
The FAS will be used for all efficacy analyses and summary of baseline characteristics.
The Safety Analysis Set consists of all subjects who have received at least 1 dose of study 
drug.  For the Safety Analysis Set, subjects are assigned to a treatment group based on the 
treatment actually received, regardless of the treatment randomized.
5.0
Subject Disposition
The total number of subjects who were screened, enrolled (randomized), 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 (randomized) in the study.
●
Subjects who took at least one dose of study drug.
●
Subjects who completed study drug up to Week 24.
●
Subjects who completed study drug up to Week 48.
●
Subjects who prematurely discontinued study drug (all reasons and primary 
reason).
●
Subjects who completed Week 24 visits.
●
Subjects who completed the study.
●
Number of subjects who elect to participate in the long-term extension 
Study M20-186.
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.


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6.0
Study Drug Duration and Compliance
6.1
Study Drug Duration
The duration of exposure to study drug will be summarized by each treatment group using 
the Safety Analysis Set population.
●
Duration of exposure = the last study drug dose date – the first study drug dose 
date + 1.
For the Safety Analysis Set, duration of treatment will be summarized for each treatment 
group and for all investigational study drug dose groups combined.  The duration of 
treatment is defined for each subject as last dose date minus first dose date + 1.  Duration 
of treatment will be summarized using the number of subjects, mean, standard deviation, 
minimum, median and maximum for duration of Study M19-130.  In addition, the number 
and percentage of subjects exposed to study drug will be summarized for the following 
exclusive duration intervals:
●
≥ 1 day
●
≥ 29 days
●
≥ 57 days
●
≥ 85 days
●
≥ 113 days
●
≥ 141 days
●
≥ 169 days
●
≥ 197 days
●
≥ 225 days
●
≥ 253 days
●
≥ 281 days
●
≥ 309 days
●
≥ 337 days


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6.2
Study Drug Compliance
Study drug compliance will be summarized for each treatment group for SA 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 for tablets and 
capsules respectively:
●
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 M19-130:  number of tablets per day is 1 and number of capsules per day 
is 3.
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.  
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).


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7.1
Demographics and Baseline Characteristics
The following demographic and baseline characteristics, as measured at baseline of the 
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)
●
Body Mass Index (BMI) (kg/m2)
●
BMI Category (kg/m2) (BMI < 25, BMI ≥ 25)
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:


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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 prednisone equivalent 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
●
Serum creatinine
The following categorical variables will be summarized:
●
Anti-dsDNA status (positive defined as >= 30 IU/mL)
●
SLEDAI-2K status (< 10 or ≥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.
●
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 or 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.


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●
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
●
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.  


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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.  These include 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.  Concomitant 
medications are those medications, other than study drug, taken after the first dose of 
study drug and within 1 day of the last dose of study drug.  This includes medications 
with a start date between first study drug administration and last study drug administration 
+ 1 day, as well as medications with a start date prior to first dose of study drug and which 
are ongoing after first dose of study drug.  Medications taken on the day of the first dose 
of study drug 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
All efficacy analysis will be performed in the FAS.
AbbVie may terminate this study prematurely at any time, either in its entirety or partially 
(discontinue 1 or more treatment groups based on interim analysis), at any site.  In the 


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event the study is partially terminated, efficacy analysis will be performed separately for 
the terminated treatment groups and for the continued treatment groups:
Terminated Treatment Groups
For terminated group(s), the descriptive statistics will be provided by treatment group for 
the following efficacy endpoints using observed case (OC) (defined in Section 8.3) 
through Week 48:
●
Achievement of SRI-4 and steroid dose ≤ 10 mg prednisone equivalent QD.
●
Achievement of SRI-4.
●
Achievement of BICLA.
●
Number of mild, moderate, or severe flares per patient-year (respectively and 
overall) by SELENA SFI, assessed by number and types of flare per subject 
through Week 24 and Week 48.
●
Steroid burden, assessed as change from Baseline.
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.
Continued Treatment Groups
For continued treatment groups, the primary and secondary efficacy endpoints will be 
analyzed at the alpha level of 0.1 (two-sided).  Multiplicity control is not planned for this 
study.
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.


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Unless otherwise specified, any subject who is randomized based on a wrong stratum will
be analyzed according to the actual stratum that the subject belongs to.
"Baseline" refers to the last non-missing observation before the first administration of
study drug, or randomization if no study drug is given.
8.2
Handling of Potential Intercurrent Events
Potential intercurrent events considered in this study include 1) premature discontinuation 
of the study drug; 2) initiation of rescue medications; 3) initiation or dose escalation of 
SLE-related corticosteroid. Intercurrent events will be handled using the following 
methods for the efficacy analysis:
8.2.1
Premature Discontinuation of Study Drug
Data collected will be used regardless of premature discontinuation of the study drug.
8.2.2
Initiation of Rescue Medications or Initiation or Dose 
Escalation of SLE-Related Corticosteroid
Data collected on or after the occurrence of the rescue medications or initiation or dose 
escalation of SLE-related corticosteroid will be handled using the methods below for the 
efficacy analysis:
1.
 
2.
 
 
 
3.
 
 


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4.
 
5.
 
6.
 
Intercurrent events above apply to all categorical endpoints.  For continuous endpoints, 
data after intercurrent events above will be excluded from modeling (i.e., predicted from 
the model for analysis).
8.3
Handling of Missing Data
Missing data could occur due to various reasons, including missing visits/assessments, 
early withdrawal from the study, or missing due to Coronavirus disease 2019
(COVID-19) infection or logistic restriction.
The COVID-19 pandemic is interfering with the conduct of many ongoing trials, with 
potential impacts on treatment duration and the collection, analysis and the interpretation 
of clinical trial data. Some protocol-specified visits in the clinical trials may be impacted 
due to COVID-19 infection or logistical restrictions during the pandemic. For example, 
some scheduled visits may be missed due to self-quarantine or local government 
restrictions on travel; some visits may also be delayed or canceled due to healthcare 
resource constraints during the pandemic. Impacted visits due to COVID-19 will be 
recorded in the database. The probability of having missed visits and missing data due to 
COVID-19 infection or logistical restrictions related to the COVID-19 pandemic can be 
reasonably assumed to be unrelated to the unobserved values. Therefore, for the purpose 
of statistical analysis, it is reasonable to assume that these missing data are missing at 
random (MAR) and the statistical models that require MAR assumption are appropriate. 
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under the scenario without the impact of COVID-19 pandemic. Number of subjects with 
missing values due to COVID-19 will be presented.
Missing data and intercurrent events will be handled using the following methods for the 
efficacy analysis.
Non-Responder Imputation (NRI) incorporating Multiple Imputation (MI) to handle 
missing data due to COVID-19 (NRI-C)
●
The NRI-C will categorize any subject who does not have an evaluation during 
a pre-specified visit window (either due to missing assessment or due to early 
withdrawal from the study) as a non-responder for the visit. There are two 
exceptions which will be handled in the order below:
1) when a subject is a responder at both before and after the visit window, the 
subject will be categorized as a responder for the visit.
2) missing data due to COVID-19 infection or logistical restriction and not 
satisfying 1) will be handled by MI.
Of note, subjects will be counted as non-responders, thereafter, and will not be 
imputed using 1) or 2), on or after the intercurrent event as specified in Section 8.2.2.
●
Details on MI method are described below:
MI will be performed using observed data excluding data on or after 
intercurrent events specified in Section 8.2.2.  Markov Chain Monte Carlo 
(MCMC) will be first applied to augment data into monotonic missing pattern, 
where applicable, and PROC MI will be used to generate 30 datasets using the 
regression method. If the binary endpoints are derived from the continuous 
variables, PROC MI will be applied to the continuous variables. The variables 
to be included in the imputation model are: treatment group, randomization 
stratification factors (baseline corticosteroid dose above 10 mg prednisone-
equivalent (≤10 mg or > 10 mg), screening SLEDAI-2K (< 10 or ≥10), 
baseline interferon score (high or low or not applicable), baseline 
immunosuppressant (yes or no)), gender, pooled race (White, Black, Asian, or 
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Europe, or Asian), age, baseline BMI, and if applicable, baseline measurement 
and post-baseline measurements at each visit up to the end of the analysis 
period. The random seed for MCMC and the random seed for PROC MI are 
specified in Appendix E. The imputed post-baseline measurements will be 
rounded to the same precision as the observed data before the determination of 
responder status. Prior to applying CMH model, subjects will be characterized 
as responders or non-responders based on MI imputed values if missing due to 
Covid-19, otherwise subjects will be considered as non-responder for missing
due to other reasons in the NRI-C approach. Using the CMH model adjusted 
by randomization stratification factors, the endpoints will be analyzed using 
each of the 30 imputed datasets. SAS PROC MIANALYZE will be used to 
generate the final inferences of the risk difference using Rubin's rule. The rules 
of handling intercurrent events, as specified in Section 8.2.2, will be applied 
before and after applying MI for efficacy assessments.
Mixed-Effect Model Repeated Measurements (MMRM)
MMRM analysis will be conducted using a mixed-effect model including observed 
measurements at all visits for continuous variables.  Data collected on or after initiation of 
rescue treatment or after initiation or dose escalation of SLE-related corticosteroid as 
defined in Section 8.2.2 will not be included. The mixed model includes the categorical 
fixed effects of treatment, visit and treatment-by-visit interaction, randomization 
stratification factors, and the continuous fixed covariate of baseline measurement.  An 
unstructured variance covariance matrix will be used.  The parameter estimations are
based on the assumption of data being missing at random and using the method of 
restricted maximum likelihood (REML).
As Observed (AO)
AO analysis will not impute values for missing evaluations, and thus a subject who does 
not have an evaluation on a scheduled visit will be excluded from the AO analysis for that 
visit.  Regardless of premature discontinuation of study drug or initiation of rescue 
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Section 8.2.2, all observed data will be used in the analysis. As observed analysis may be 
used for both categorical variables and continuous variables for sensitivity analysis.
Multiple Imputation (MI)
As a sensitivity analysis, MI will be utilized for the primary endpoint. Data collected on 
or after the occurrence of intercurrent events defined in Section 8.2.2 will be considered 
as non-responder. When a subject is a responder at both before and after the visit 
window, the subject will be categorized as a responder for the visit. Otherwise, subjects 
who have no available measurements will be handled by multiple imputations. Details on 
MI can be found in NRI-C approach.
Observed Case (OC)
The OC analysis will not impute values for missing evaluations and, thus, a subject who 
does not have an evaluation on a scheduled visit will be excluded from OC analysis for 
that visit.  In addition, the OC analysis will not use values on or after the occurrence of 
intercurrent events defined in Section 8.2.2.
Censoring
For the time-to-event endpoint, i.e., time to flare, missing data will be considered as 
censored at the last available time for the information.
8.4
Primary Efficacy Endpoint and Analyses
8.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint is the composite of SRI-4 and steroid dose ≤ 10 mg 
prednisone equivalent QD at Week 24.
8.4.2
Main Analysis of Primary Efficacy Endpoint(s)
The attributes of the estimand corresponding to the primary efficacy endpoint are 
summarized in Table 1.


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Table 1.
Summary of the Estimand Attributes of the Primary Efficacy 
Endpoint(s)
Estimand 
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling of 
Intercurrent 
Events
Statistical 
Summary
Primary

Elsubrutinib 60 mg 
QD and 
upadacitinib 30 mg 
QD

Elsubrutinib 60 mg 
QD and 
upadacitinib 15 mg 
QD

Elsubrutinib 60 mg 
QD and 
upadacitinib placebo 
QD

Elsubrutinib placebo 
QD and 
upadacitinib 30 mg 
QD 

Elsubrutinib placebo 
QD and 
upadacitinib placebo 
QD
Achievement 
of SRI-4 and 
steroid dose 
≤ 10 mg 
prednisone 
equivalent 
once a day 
(QD) at 
Week 24.
FAS
 
 
 
 
 
 
 
Difference in
the percentage
of subjects
achieving SRI-
4 and steroid 
dose ≤ 10 mg 
prednisone 
equivalent once 
a day (QD)
between 
treatment 
groups.
The primary analysis of the primary endpoint will be conducted on FAS based on 
randomized treatment groups (each active treatment group vs placebo) using NRI-C for 
missing data handling.  Point estimate and 95% CI using normal approximation will be 
provided for the response rate for each randomized treatment group.  The difference 
between the treatment groups in the primary efficacy endpoint will be assessed using the 
Cochran-Mantel-Haenszel (CMH) test and will be stratified by baseline corticosteroid 
dose above 10 mg prednisone-equivalent (≤10 mg or > 10 mg), screening SLEDAI-2K 
(< 10 or ≥10), baseline interferon score (high or low or not applicable), baseline 
immunosuppressant (azathioprine, tacrolimus, cyclosporine, methotrexate [MTX], 
mycophenolate) (yes or no). Baseline interferon score for patients in China will be 


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considered as not applicable. Point estimate, 95% CI and nominal p-value for the 
treatment comparison will be presented.
ABBV-599 treatment arms will be compared to the corresponding monotherapy treatment 
arms, in addition to comparison to placebo.  All comparisons or analyses are summarized 
below,
●
Each ABBV-599 vs placebo
●
Upadacitinib vs placebo
●
Elsubrutinib vs placebo
●
Each ABBV-599 vs Elsubrutinib
●
Each ABBV-599 vs upadacitinib
●
Elsubrutinib 60 mg QD and upadacitinib 30 mg QD vs Elsubrutinib 60 mg QD 
and upadacitinib 15 mg QD 
There will be no multiplicity adjustment for the multiple comparisons.
In the event the study is partially terminated, terminated groups will be removed from the 
comparisons above.
8.4.3
Sensitivity and Supplementary Analyses of the Primary 
Efficacy Endpoint
The same CMH analysis will be repeated based on FAS:
●
Using AO data handling without any imputation as additional analysis.
●
Using MI approach as additional analysis.
8.5
Secondary Efficacy Endpoints and Analyses
8.5.1
Secondary Efficacy Endpoints
The secondary efficacy endpoints are defined in Section 3.2.


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8.5.2
Main Analyses of Secondary Efficacy Endpoints
The attributes of the estimands corresponding to the secondary efficacy endpoints are 
summarized in Table 2.


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Table 2.
Summary of the Estimand Attributes of the Secondary Efficacy 
Endpoints
Estimand 
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling of
Intercurrent 
Events
Statistical 
Summary*
Binary
Secondary 
Endpoint

Elsubrutinib 
60 mg QD and 
upadacitinib 
30 mg QD

Elsubrutinib 
60 mg QD and 
upadacitinib 
15 mg QD

Elsubrutinib 
60 mg QD and 
upadacitinib 
placebo QD

Elsubrutinib 
placebo QD and 
upadacitinib 
30 mg QD 

Elsubrutinib 
placebo QD and 
upadacitinib 
placebo QD
Achievement of 
SRI-4 at Week 24.
Achievement of 
BILAG-Based 
Combined Lupus 
Assessment 
(BICLA) response 
at Week 24.
Achievement of 
Lupus Low 
Disease Activity 
State (LLDAS) at 
Week 24.
FAS
 
 
 
 
 
 
Difference in
the percentage
of subjects
achieving 
each binary
secondary
endpoint
between 
groups.
Continuous 
Secondary 
Endpoint

Elsubrutinib 
60 mg QD and 
upadacitinib 
30 mg QD

Elsubrutinib 
60 mg QD and 
upadacitinib 
15 mg QD

Elsubrutinib 
60 mg QD and 
upadacitinib 
placebo QD

Elsubrutinib 
placebo QD and 
upadacitinib 
30 mg QD 

Elsubrutinib 
placebo QD and 
upadacitinib 
placebo QD
Steroid burden, 
assessed as change 
from Baseline at 
Week 24.
FAS
 
 
 
 
 
 
 
Difference in
the mean
change from
Baseline in
Continuous 
endpoint
between 
groups.


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Table 2.
Summary of the Estimand Attributes of the Secondary Efficacy 
Endpoints (Continued)
Estimand 
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling of
Intercurrent 
Events
Statistical 
Summary*
Count 
Secondary 
Endpoint

Elsubrutinib 
60 mg QD and 
upadacitinib 
30 mg QD

Elsubrutinib 
60 mg QD and 
upadacitinib 
15 mg QD

Elsubrutinib 
60 mg QD and 
upadacitinib 
placebo QD

Elsubrutinib 
placebo QD and 
upadacitinib 
30 mg QD 

Elsubrutinib
placebo QD and 
upadacitinib 
placebo QD
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 
(mild/moderate, 
severe, and any) 
per subject 
through Week 24 
and through 
Week 48.
FAS
 
 
 
 
 
Ratio in the 
mean
incidence 
rate of mild, 
moderate, or 
severe flares 
per patient-
year between 
groups.
*
Note: In the event the study is partially terminated, terminated groups will be removed from the comparison.
The binary secondary endpoints will be analyzed using the same approach as that for 
primary endpoint as specified in Section 8.4.2.  Specifically, CMH adjusting for 
randomization stratification factors will be used to construct the treatment difference, the 
associated 95% CI and p-value between treatment group comparison.  The NRI-C will be 
the primary approach for missing data handling in the analyses of binary secondary 
efficacy endpoints.
All continuous endpoints will be evaluated through the change from Baseline. For 
continuous endpoints with multiple post-Baseline visits, the treatment effect will be 
assessed through Mixed-effect Model Repeated Measures (MMRM) with treatment, visit 


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and treatment-by-visit interaction, randomization stratification factors, and the continuous 
fixed covariate of baseline measurement. An unstructured variance covariance matrix 
will be used.  For continuous endpoints with a single post-baseline visit, the treatment 
effect may be assessed through analysis of covariance (ANCOVA) with baseline value, 
treatment, and randomization stratification factors as covariates.  In addition, the 
descriptive statistics for continuous variables will be provided including sample size, 
mean, standard deviation, median, minimum and maximum.
For the count endpoint (e.g., number of flares by SLENAI SFI), negative binomial 
regression model will be used to assess treatment effect with treatment, and randomization 
stratification factors as covariates.
8.5.3
Sensitivity and Supplementary Analyses for Secondary 
Efficacy Endpoints
For all secondary endpoints, analyses using AO data will be performed as additional 
analyses based on FAS.
8.6
Additional Efficacy Analyses
For the annualized flare rate, a negative binomial regression model will be used with the 
response variable being the number of flares over the 24-week or 48-week treatment 
period using both OC and AO data. The model will include covariates of treatment group, 
and randomization stratification factors. The logarithm (to base e) of the follow-up time 
will be used as an offset variable in the model to adjust for subjects having different 
exposure times. The estimated treatment effect and the corresponding 95% CI, as well as 
the 2-sided p-value will be presented.
A summary of the annualized flare rate by descriptive statistics as well as a summary of 
the number and percentage of subjects with no flares, at least one flare, 1 flare, 2 flares, 
and 3 or more flares, respectively, will be presented by treatment group.
Time to event (time to first flare) is defined as number of days from the date of the first 
dose to the date of the first occurrence of an event. It is calculated as (date of first 


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occurrence of Event – date of the first dosing + 1). Subjects who discontinue from study 
prior to experiencing the event are censored at the time of discontinuation. Subjects who 
are not experiencing the event are censored at the date of last non-missing measurement 
of SELENA SFI. Data collected on or after the occurrence of intercurrent events as 
specified in Section 8.2.2 will be excluded.  Pairwise comparison between each treatment 
group and placebo will be performed by log-rank test and Cox proportional hazards 
regression analysis including treatment and baseline stratification factors as covariates.  
Same analysis will be performed using AO data as additional analysis.
All other efficacy endpoints specified in Section 3.3 will be analyzed based on FAS using 
the same approach as that for secondary endpoints as specified in Section 8.5.
8.7
Efficacy Subgroup Analyses
To evaluate the consistency of the efficacy over demographic and other baseline 
characteristics, subgroup analysis will be performed for the primary endpoint for the 
subgroups listed in Table 3 below. If any of the resulting subgroups except for age, sex 
and race has fewer than 5% of the Analysis Population, the subgroup analyses for that 
category will not be presented.
Point estimate and 95% CI for each treatment group as well as point estimate and 95% CI 
for treatment differences between treatment groups will be presented using the same 
analysis method as in the primary analysis. P-value for treatment and subgroup factor 
interaction using Breslow-Day test will also be provided. In addition:
●
A logistic regression with treatment group, subgroup, randomization 
stratification factors, and treatment by subgroup interaction as factors will be 
performed to evaluate the significance of the interaction between subgroup and 
treatment group.
●
A stepwise logistic regression with treatment group, all subgroup factors, 
randomization stratification factors will be performed to evaluate potential 
important subgroup factor(s).


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Table 3.
Subgroups
Subgroup Factor
Categories
Age at screening
18 – < 40 years old
40 – < 65 years old
≥ 65 years old
Sex
Male
Female
BMI
< 25
≥ 25
Race
White
Black
Asian
Other
Baseline corticosteroid dose
≤10 mg
> 10 mg
Screening SLEDAI-2K
< 10
≥10
Baseline immunosuppressant
Yes
No
Baseline interferon score
High
Low
NA
Region
North America/South America, Europe, Asia
9.0
Safety Analyses
9.1
General Considerations
Safety analyses will include reporting of adverse events, laboratory, and vital signs 
measurements.  Safety analyses will be carried out using the Safety Analysis Set for both 
continued and terminated groups except for mean change from baseline analysis of
laboratory and vital signs, which will be provided for continued groups only.
All summaries of adverse events will be provided using data through Week 24, through 
Week 48 and through Week 48 per 100 patient-years.


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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.
For the safety analyses, subjects are assigned to a treatment group based on the treatment 
actually received, regardless of the treatment randomized. A subject's actual treatment 
will be determined by the most frequent dose regimen received.
For the safety analyses, baseline is defined as the last measurement prior to the first dose 
of study drug.
Missing safety data will not be imputed.
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.
9.2.1
Treatment-Emergent Adverse Events
Treatment-emergent Adverse Events (TEAE) are defined as any AE that begins either on 
or after the first dose of study drug in M19-130 and within 30 days after the last dose 
administration of the study drug in M19-130.
Events where the onset date is the same as the study drug start date are assumed to be 
treatment-emergent.  If an incomplete onset date was collected for an adverse event, the 


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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
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 will be 
summarized for each treatment group:
●
Any treatment-emergent AEs.
●
Any COVID-19 related TEAEs.
●
Any treatment-emergent AEs related to study drug according to the 
investigator.
●
Any severe treatment-emergent AEs.
●
Any serious treatment-emergent AEs.
●
Any treatment-emergent AEs leading to discontinuation of study drug.
●
Any treatment-emergent AEs leading to death.
●
TEAEs of special interest (AESIs) (as defined in Appendix B).
●
All deaths.
○
Any COVID-19 related deaths.
○
Occurring <= 30 days after the last dose.
○
Occurring > 30 days after the last dose.
Additional AEs may be considered for tabulation/summary based on recommendations 
from Clinical and Safety as deemed appropriate.


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An overview of AEs will be presented based on data through Week 24 and Week 48. In 
addition, an overview of AEs through Week 48 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, including COVID-19 related TEAEs, will be 
summarized by SOC and PT; by maximum relationship to study drug as assessed by the 
investigator (e.g., reasonable possibility or no reasonable possibility) and SOC and PT; by 
maximum 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, TEAEs will be summarized by PT and sorted by decreasing frequency for the 
total active group.
TEAEs through Week 24, through Week 48 and through Week 48 per 100 patient-years of 
study exposure will be presented for the AE categories defined above.
9.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure
Exposure-adjusted AEs through Week 48 per 100 patient-years will be provided, where 
AEs per 100 patient-years of exposure are defined as the number of AEs divided by the 
total exposure in 100 patient-years, i.e.,
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. Note that one event per preferred 


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term per day per subject will be counted in the calculation of the number of AEs (i.e., a 
preferred term will not be counted twice on the same day for the same subject).
The TEAE through Week 48 per 100 patient-years will be provided for the following AE 
categories by SOC and PT:
●
Any treatment-emergent AEs.
●
Any COVID-19 related TEAEs.
●
Any severe treatment-emergent AEs.
●
Any serious treatment-emergent AEs.
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) through Week 24, through Week 48 and 
through Week 48 per 100 patient-years will be summarized by SOC and PT.  AESI will 
also be provided in listing format. It will be identified based on standardized or company 
MedDRA queries (SMQs or CMQs specified in Appendix B).
9.2.7
Adverse Events by "Reasonably Possibly Related"
Relationship
TEAEs and reasonably possibly related AEs through Week 24, through Week 48 and 
through Week 48 per 100 patient-years 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 subject will be counted in as 'related.'


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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 through Week 24, through Week 48 and 
through Week 48 per 100 patient-years occurring for more than 5% of the subjects in any 
of the treatment groups will be summarized by MedDRA PT in decreasing frequency 
separately.
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.
For the analysis of laboratory data, values observed up to 30 days after the last dose of 
study drug will be included.
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.


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For continued groups, 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.  The change from baseline mean, standard error, and 95% 
confidence interval will be presented for the mean change from baseline within each 
treatment group and difference between treatment groups.
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.'
For selected laboratory variables including hemoglobin, neutrophils, lymphocytes, 
platelets, leukocytes, creatinine, ALT, AST, bilirubin, CPK, 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 treatment group for both short-
term and long-term analyses:
●
ALT ≥ 3 × ULN
●
ALT ≥ 5 × ULN
●
ALT ≥ 10 × ULN
●
ALT ≥ 20 × ULN
●
AST ≥ 3 × ULN


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●
AST ≥ 5 × ULN
●
AST ≥ 10 × ULN
●
AST ≥ 20 × ULN
●
TBL ≥ 2 × ULN
●
Alkaline phosphatase ≥ 1.5 × ULN
●
ALT and/or AST > 3 × ULN and TBL > 1.5 × ULN
●
ALT and/or AST > 3 × ULN and TBL > 2 × ULN
A listing of possible Hy's Law cases, defined as those who meet all of the following
conditions at any post-baseline visit will be provided: ALT > 3 × ULN or 
AST > 3 × ULN and Total Bilirubin ≥2 × ULN.
9.4
Analysis of Vital Signs
Vital sign measurements of systolic and diastolic blood pressure, pulse rate, body 
temperature, and weight will be summarized.
For the analysis of vital sign data, values observed up to 30 days after the last dose of 
study drug will be included.
Each vital sign variable will be summarized for all time points (starting with Baseline)
with the number of non-missing observations, mean and standard deviation, median, 
minimum and maximum.
For continued groups, mean change from baseline to each applicable post-baseline visit 
will be summarized for each vital sign variable, with the number of observations, baseline 
mean, and visit mean. The change from baseline mean, standard error, and 95% 
confidence interval will be presented for the mean change from baseline within each 
treatment group and difference between treatment groups.
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 


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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 2, 4, 8, 12, 16, 20, 24 and 48.  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
Data Monitoring Committee
An unblinded internal data monitoring committee (DMC) has been established to ensure 
the overall integrity and conduct of the study.  DMC reviews will be conducted quarterly.  
In addition to the unblinded internal DMC, a multi-disciplinary internal Safety Review 
team will also conduct regular reviews in a blinded fashion during the study and at study 
completion.  AbbVie will also conduct regular systematic reviews of emerging safety data 
from all clinical studies with elsubrutinib, upadacitinib and ABBV-599 
(elsubrutinib/upadacitinib) combination.
A separate DMC charter describes the roles and responsibilities of the DMC members, 
frequency of data reviews, relevant data to be assessed, and general operations.
Since there are no efficacy analyses for early stopping, no alpha adjustment is needed.


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11.2
Interim Analysis
An unblinded interim analysis will be performed after the first 50% of the subjects 
complete Week 24 visit or withdraw from the study by an independent team at AbbVie 
that does not include members of the blinded M19-130 Study team.  The objective of the 
interim analysis is to reassess the treatment regimens in the rollover Study M20-186.  The 
Interim Analysis results will be reviewed by an Internal Executive Review Committee 
(IERC) following a separate IERC charter and one or more treatment groups may be 
terminated.  The IERC members are not involved in the study but have the depth of 
technical knowledge and experience to make decisions based on Interim Analysis results.
An interim unblinding plan will be developed separately describing the analysis to be 
presented to the IERC and will include execution logistics, unblinded analysis team, and 
the data chain of custody to protect the integrity of the clinical study.
11.2.1
Interim Analysis Population
Efficacy Analysis Population
●
Full Analysis Set for Interim Analysis (FAS_IA): all randomized subjects with 
at least one dose of study drug before the cutoff date (20JUN2021). Subjects 
will be analyzed as randomized.
○
FAS_IA50 Subset: the subset of FAS_IA which includes the first 50% of 
planned randomized subjects.
Safety Analysis Population
●
Safety Analysis Set for Interim Analysis (SA_IA) includes same subjects as 
FAS_IA. Subjects will be analyzed as treated.
○
SA_IA50 Subset includes same subjects as FAS_IA50 Subset. Subjects 
will be analyzed as treated.


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Analysis of efficacy endpoints and summaries of baseline demographics and disease 
characteristics will be based on the FAS_IA50 Subset for primary analysis and on the 
FAS_IA for additional supportive analysis.
Safety analysis will be performed based on the SA_IA for primary analysis and on the 
SA_IA50 Subset for additional supportive analysis.
Cutoff dates for all efficacy and safety analysis are as follows:
●
For subjects in FAS_IA50 Subset or SA_IA50 Subset, the cutoff date is 
7JUL2021.
●
For the rest of subjects, the cutoff date is 20JUN2021.
This interim analysis will also include PK and Biomarker data. PK analysis and 
communication plan will be provided separately by CPPM.
11.2.2
Subject Disposition, Demographics and Disease 
Characteristics, and Treatment Compliance
The following summaries will be provided based on FAS_IA and FAS_IA50 Subset:
●
Subject disposition (randomized, took at least one dose, completed study drug 
at Week 24, completed study drug at Week 48, prematurely discontinued study 
drug, completed the 24 weeks study period, completed Week 48 Study Period, 
prematurely discontinued study, enrolled in LTE (M20-186)).
●
Demographics and Disease 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).


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○
Weight (kg).
○
Weight Categories (< 60 kg, ≥ 60 kg).
○
Height (cm).
○
Body Mass Index (BMI) (kg/m2).
○
BMI Category (BMI < 25 kg/m2, BMI ≥ 25 kg/m2).
○
Study drug duration and compliance.
11.2.3
Efficacy Analyses
Primary Endpoint
The primary efficacy endpoint (achieving SRI-4 and steroid dose ≤ 10 mg prednisone 
equivalent once a day (QD) at Week 24).  Will be analyzed according to the study SAP 
(Section 8.4) based on the FAS_IA50 Subset.
Additional analyses will also be performed for the primary endpoint at the interim 
analysis based on FAS_IA50 Subset:  for subjects who don't have Week 24 data, all 
available data will be used to impute Week 24 response using multiple imputation 
method.
Secondary and Additional Endpoints
The following secondary and additional endpoints will be included in the interim analysis:
●
Achievement of SRI-4 at all visits.
●
Achievement of BICLA response at all visits.
●
Achievement of ≥ 4-point decrease in SLEDAI-2K from Baseline at all visits.
●
Change from Baseline in SLEDAI-2K at all visits.
●
Change from Baseline in PhGA at all visits.
●
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 


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(mild/moderate, severe, and any) per subject through Week 24 and through 
Week 48.
●
Achievement of at least a 50% reduction from baseline in prednisone dose at all 
visits.
●
Achievement of SRI-4 and steroid dose ≤ 10 mg prednisone equivalent once a 
day (QD) at all visits starting from Week 8.
●
Steroid burden, assessed as change from Baseline at all visits.
●
Change from Baseline in Functional Assessment of Chronic Illness Therapy 
(FACIT)-Fatigue at all visits.
●
Change from Baseline in Pain Numerical Rating Scale (NRS) at all visits.
Analysis specified in Section 8.5 will be performed.
11.2.4
Safety Analyses
Safety Analysis specified in this SAP will be included in the interim analysis except 
summary of other baseline characteristics listed in Section 7.1:
The following safety results will be summarized in the interim analysis:
●
Overview of TEAEs (treatment emergent adverse events).
●
TEAEs by SOC (system organ class) and PT (preferred term).
●
Treatment-emergent SAEs (serious adverse events) by SOC and PT.
●
TEAEs leading to study drug discontinuation by SOC and PT.
●
TEAEs by SOC and PT and maximum relationship to study drug.
●
TEAEs by SOC and PT and maximum toxicity grade.
●
AESIs (adverse events of special interest) by SOC and PT.
●
Listing of Pre-treatment SAEs.
●
Listing of SAEs.
●
Listings of AESIs.
●
Listing of Aes leading to death.
●
Listing of Aes leading to study drug discontinuation.


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●
Analysis of mean change from baseline in laboratory and vital sign variables.
●
Summary of potentially clinically significant laboratory and vital sign 
variables.
●
Listings of potentially clinically significant laboratory and vital sign variables.
●
Shift tables for laboratory and vital sign variables.
12.0
Overall Type-I Error Control
All tests will be performed at two-sided statistical significance level of α= 0.1.  No 
multiplicity adjustment will be conducted.
13.0
Version History
Table 4.
SAP Version History Summary
Version
Date
Summary
1.0
12 Apr 2019
Original version
2.0
24 July 2021

Revise the SAP per the latest SAP template and to maintain 
consistency with the most recent protocol.

Add definitions of estimand for primary and secondary endpoints.

Clarified the MI method to handle missing data due to COVID-19 
and other reasons.

Update Hy's Law rules to be consistent with the most recent 
Upadacitinib PSSAP.

Add sections to include the planned interim analysis.
3.0
17 Dec 2021

Update SAP language to be consistent with Protocol Amendment 
Version 7.

Add one efficacy endpoint in Section 3.3

Update subgroup analysis for primary endpoint in Section 8.7.

Clarify how efficacy analysis and safety analysis will be performed 
for discontinued treatment groups and continued treatment groups if 
the study is partially terminated after the planned interim analysis,
4.0
26 July 2022

Update AESI searching criteria to be consistent with the most recent 
Upadacitinib PSSAP.

Add additional efficacy endpoints for exploratory purpose in 
Section 3.3.


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14.0
References
None


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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 (code 
80000189)
"Opportunistic Infection
excluding Tuberculosis and 
Herpes Zoster" 
Herpes Zoster
CMQ (code 
80000175)
"Herpes Zoster"
Active Tuberculosis
CMQ (code 
80000188)
"Active Tuberculosis"
Possible Malignancy
SMQ
Narrow
"Malignancies" 
Malignancy
SMQ
Narrow
"Malignant Tumours"
Non-Melanoma Skin Cancer (NMSC)
SMQ
Narrow
"Skin Malignant Tumours"
(SMQ 20000204)
removing Melanoma CMQ (code 
80000119)
Malignancies excluding NMSC
SMQ
Narrow
"Malignant Tumours" removing
NMSC output
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" 


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AESI
Type of 
MedDRA 
Query
Broad or 
Narrow 
Search
SMQ/CMQ Search Criteria
Neutropenia
CMQ
"Hematological Toxicity –
Neutropenia"
Lymphopenia
CMQ
"Hematological Toxicity –
Lymphopenia"
Renal dysfunction
SMQ
Narrow
"Acute Renal Failure"
Hepatic disorders
SMQ
Narrow
"Drug Related Hepatic 
Disorders" - Comprehensive 
Search SMQ 
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 Safety Endpoints
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


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Appendix D.
Attributes of the Estimand for Primary and Secondary Endpoints
Attributes of the Estimand
Population
Endpoint
Treatment
Intercurrent 
Events
Statistical 
Summary*
Primary
FAS
Achievement of 
SRI-4 and steroid 
dose ≤ 10 mg 
prednisone 
equivalent once a 
day (QD) at 
Week 24.
Elsubrutinib 60 mg QD 
and upadacitinib 30 mg 
QD
Elsubrutinib 60 mg QD 
and upadacitinib 15 mg 
QD
Elsubrutinib 60 mg QD 
and upadacitinib placebo 
QD
Elsubrutinib placebo QD 
and upadacitinib 30 mg 
QD 
Elsubrutinib placebo QD 
and upadacitinib placebo 
QD
 
 
 
 
 
 
 
 
Difference in
the percentage
of subjects
achieving SRI-
4 and steroid 
dose ≤ 10 mg 
prednisone 
equivalent 
once a day 
(QD) between 
groups.
Binary 
Secondary 
Endpoint
FAS
Achievement of 
SRI-4 at Week 24.
Achievement of 
BILAG-Based 
Combined Lupus 
Assessment 
(BICLA) response 
at Week 24.
Achievement of 
Lupus Low 
Disease Activity 
State (LLDAS) at 
Week 24.
Elsubrutinib 60 mg QD 
and upadacitinib 30 mg 
QD
Elsubrutinib 60 mg QD 
and upadacitinib 15 mg 
QD
Elsubrutinib 60 mg QD 
and upadacitinib placebo 
QD
Elsubrutinib placebo QD 
and upadacitinib 30 mg 
QD 
Elsubrutinib placebo QD 
and upadacitinib placebo 
QD
 
 
 
 
 
 
 
 
Difference in
the percentage
of subjects
achieving each
binary
secondary
endpoint 
between 
groups.


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Attributes of the Estimand
Population
Endpoint
Treatment
Intercurrent 
Events
Statistical 
Summary*
Continuous 
Secondary 
Endpoint
FAS
Steroid burden, 
assessed as change 
from Baseline at 
Week 24.
Elsubrutinib 60 mg QD 
and upadacitinib 30 mg 
QD
Elsubrutinib 60 mg QD 
and upadacitinib 15 mg 
QD
Elsubrutinib 60 mg QD 
and upadacitinib placebo 
QD
Elsubrutinib placebo QD 
and upadacitinib 30 mg 
QD 
Elsubrutinib placebo QD 
and upadacitinib placebo 
QD
 
 
 
 
 
 
 
Difference in
the mean
change from
Baseline in
Continuous 
endpoint 
between 
groups.
Count 
Secondary 
Endpoint
Number of mild,
moderate, or 
severe flares by 
Safety of 
Estrogens in 
Lupus 
Erythematosus 
National 
Assessment 
(SELENA) 
SLEDAI Flare 
Index (SFI), 
assessed by 
number and types 
of flare 
(mild/moderate, 
severe, and any)  
per subject 
through Week 24 
and through 
Week 48.
Elsubrutinib 60 mg QD 
and upadacitinib 30 mg 
QD
Elsubrutinib 60 mg QD 
and upadacitinib 15 mg 
QD
Elsubrutinib 60 mg QD 
and upadacitinib placebo 
QD
Elsubrutinib placebo QD 
and upadacitinib 30 mg 
QD 
Elsubrutinib placebo QD 
and upadacitinib placebo 
QD
 
 
 
 
 
 
 
 
 
Ratio in the 
mean 
incidence rate 
of mild, 
moderate, or 
severe flares 
per patient-
year between 
groups.
*
Note: In the event the study is partially terminated, terminated groups will be removed from the comparisons 
above.


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Appendix E.
Random Seeds
In case of non-convergence, the random seed will be updated by adding 100000 at each 
attempt until convergence of model happens.
Variables
Random Seed
MCMC Procedure
PROC MI
SLEDAI-2K Total Score*
20001
80001
PhGA*
20002
80002
TJC28*
20003
80003
SJC28*
20004
80004
CLASI*
20005
80005
FACIT-F
20006
80006
PtGA
20007
80007
Pain NRS
20008
80008
No new BILAG A or more than 
1 new BILAG B disease activity 
scores
20009
80009
*
This only applies when these variables are a component to derive a binary endpoint.