A Study to Investigate the Safety and Efficacy of Elsubrutinib and Upadacitinib Given Alone or in Combination in Participants With Moderately to Severely Active Systemic Lupus Erythematosus (SLE)

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Systemic Lupus Erythematosus (SLE)

Intervention / Treatment
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* Drug: Elsubrutinib
* Drug: Placebo for elsubrutinib
* Drug: Upadacitinib
* Drug: Placebo for upadacitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant has clinical diagnosis of Systemic Lupus Erythematosus (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 SLICC classification criteria, including at least 1 clinical criterion and 1 immunologic criterion. At Screening, must have at least one of the following: antinuclear antibody (ANA)+ (titer ≥ 1:80) anti-dsDNA+ anti-Smith+ SLEDAI-2K (SLE Disease Activity Index) ≥ 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 participant has rash and Principal Investigator (PI) considers it to be attributable to SLE, participant must consent to skin photograph collection for adjudication. Score must be re-confirmed at the Baseline visit. Physician's Global Assessment (PhGA) ≥ 1 during screening period. Must be on background treatment, 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 methotrexate (MTX) (≤ 20 mg). No combinations of the above with immunomodulators other than prednisone (or equivalents) and antimalarials. Exclusion Criteria: - Participant using intravenous (IV) or intramuscular (IM) corticosteroids greater than or equal to a 40 mg prednisone-equivalent bolus within 30 days of planned randomization.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Elsubrutinib placebo/upadacitinib placebo<br>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 | Drug: Placebo for elsubrutinib<br>* Capsule; Oral<br>Drug: Placebo for upadacitinib<br>* Film-coated tablet; Oral<br>|
| Experimental: ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg)<br>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 | Drug: Elsubrutinib<br>* Capsule; Oral<br>* Other names: ABBV-105;Drug: Upadacitinib<br>* Film-coated tablet; Oral<br>* Other names: RINVOQ;|
| Experimental: Elsubrutinib placebo/upadacitinib 30 mg<br>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 | Drug: Placebo for elsubrutinib<br>* Capsule; Oral<br>Drug: Upadacitinib<br>* Film-coated tablet; Oral<br>* Other names: RINVOQ;|
| Experimental: ABBV-599 Low Dose (Elsubrutinib 60 mg/upadacitinib 15 mg)<br>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 | Drug: Elsubrutinib<br>* Capsule; Oral<br>* Other names: ABBV-105;Drug: Upadacitinib<br>* Film-coated tablet; Oral<br>* Other names: RINVOQ;|
| Experimental: Elsubrutinib 60 mg/upadacitinib placebo<br>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 | Drug: Elsubrutinib<br>* Capsule; Oral<br>* Other names: ABBV-105;Drug: Placebo for upadacitinib<br>* Film-coated tablet; Oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving 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 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 British Isles Lupus Assessment Group (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). A letter score is 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. | Baseline, Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving SLE Responder Index (SRI)-4 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 British Isles Lupus Assessment Group (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). A letter score is 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. | Baseline, Week 24 | 
| Percentage of Participants Achieving British Isles Lupus Assessment Group (BILAG) Based Combined Lupus Assessment (BICLA) Response at Week 24 | BICLA is a composite responder index. Achievement of BICLA response is defined as improvement in all initial A and B BILAG scores, with no more than one new BILAG B score without worsening of the overall condition (no worsening in Physician's Global Assessment [PhGA], < 0.3 point increase) and no worsening of the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score. | Baseline, Week 24 | 
| Percentage of Participants Achieving Lupus Low Disease Activity State (LLDAS) at Week 24 | LLDAS is a state of low disease activity based on Systemic Lupus Erythematosus Disease Activity Index 2000 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). | Baseline, Week 24 | 
| Change From Baseline in Daily Prednisone Dose at Week 24 | Participants' current use of steroid therapy was assessed at each study visit, and the amount of daily prednisone was documented. | From Baseline to Week 24 | 
| Number of Flares Per Patient-year by Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Flare Index Through Week 24 | The SELENA SLEDAI flare index defines mild/moderate or severe SLE flares using the SLEDAI score, definitions of worsening signs and symptoms, treatment changes, and Physician's Global Assessment of Disease Activity. | From Baseline to Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Systemic Lupus Erythematosus (SLE), ABBV-105, Upadacitinib, ABBV-599, Elsubrutinib