Systemic Lupus Erythematosus (SLE)
Conditions
Keywords
Systemic Lupus Erythematosus (SLE), ABBV-105, Upadacitinib, ABBV-599, Elsubrutinib
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.
Interventions
DRUGElsubrutinib
Capsule; Oral
Capsule; Oral
DRUGUpadacitinib
Film-coated tablet; Oral
Film-coated tablet; Oral
Sponsors
AbbVie
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving SLE Responder Index (SRI)-4 and Steroid Dose ≤ 10 mg Prednisone Equivalent Once a Day (QD) at Week 24 | Baseline, 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving SLE Responder Index (SRI)-4 at Week 24 | Baseline, 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. |
| Percentage of Participants Achieving British Isles Lupus Assessment Group (BILAG) Based Combined Lupus Assessment (BICLA) Response at Week 24 | Baseline, 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. |
| Percentage of Participants Achieving Lupus Low Disease Activity State (LLDAS) at Week 24 | Baseline, 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). |
| Change From Baseline in Daily Prednisone Dose at Week 24 | From Baseline to Week 24 | Participants' current use of steroid therapy was assessed at each study visit, and the amount of daily prednisone was documented. |
| Number of Flares Per Patient-year by Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Flare Index Through Week 24 | From Baseline to 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. |
Countries
Argentina, Australia, Bulgaria, Canada, China, Colombia, France, Germany, Hungary, Italy, Japan, Mexico, Netherlands, New Zealand, Poland, Puerto Rico, South Korea, Spain, Taiwan, United Kingdom, United States
Participant flow
Pre-assignment details
Full Analysis Set: all randomized participants who received at least 1 dose of study drug
Participants by arm
| Arm | Count |
|---|---|
| Elsubrutinib Placebo/Upadacitinib Placebo 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 | 75 |
| ABBV-599 High Dose (Elsubrutinib 60 mg/Upadacitinib 30 mg) 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 | 68 |
| Elsubrutinib Placebo/Upadacitinib 30 mg 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 | 62 |
| ABBV-599 Low Dose (Elsubrutinib 60 mg/Upadacitinib 15 mg) 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 | 69 |
| Elsubrutinib 60 mg/Upadacitinib Placebo 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 | 67 |
| Total | 341 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 5 | 3 | 5 | 6 |
| Overall Study | COVID-19 infection | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 2 | 2 | 2 | 0 | 1 |
| Overall Study | Other, not specified | 9 | 4 | 1 | 1 | 2 |
| Overall Study | Sponsor decision based on interim analysis data review | 0 | 0 | 0 | 33 | 24 |
| Overall Study | Withdrawal by Subject | 10 | 4 | 5 | 6 | 5 |
Baseline characteristics
| Characteristic | Elsubrutinib Placebo/Upadacitinib Placebo | ABBV-599 High Dose (Elsubrutinib 60 mg/Upadacitinib 30 mg) | Elsubrutinib Placebo/Upadacitinib 30 mg | ABBV-599 Low Dose (Elsubrutinib 60 mg/Upadacitinib 15 mg) | Elsubrutinib 60 mg/Upadacitinib Placebo | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 41.7 years STANDARD_DEVIATION 12.05 | 42.7 years STANDARD_DEVIATION 11.27 | 42.5 years STANDARD_DEVIATION 11.89 | 41.4 years STANDARD_DEVIATION 11.85 | 42.0 years STANDARD_DEVIATION 11.84 | 42.1 years STANDARD_DEVIATION 11.73 |
| Daily dose of corticosteroid | 7.937 mg/day STANDARD_DEVIATION 7.127 | 6.743 mg/day STANDARD_DEVIATION 6.3736 | 6.242 mg/day STANDARD_DEVIATION 6.092 | 6.891 mg/day STANDARD_DEVIATION 6.1056 | 6.291 mg/day STANDARD_DEVIATION 6.1096 | 6.856 mg/day STANDARD_DEVIATION 6.3885 |
| Physician's Global Assessment (PhGA) score | 1.75 units on a scale STANDARD_DEVIATION 0.44 | 1.80 units on a scale STANDARD_DEVIATION 0.417 | 1.70 units on a scale STANDARD_DEVIATION 0.438 | 1.77 units on a scale STANDARD_DEVIATION 0.422 | 1.77 units on a scale STANDARD_DEVIATION 0.392 | 1.76 units on a scale STANDARD_DEVIATION 0.421 |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 3 Participants | 0 Participants | 1 Participants | 4 Participants | 11 Participants |
| Race (NIH/OMB) Asian | 23 Participants | 14 Participants | 13 Participants | 13 Participants | 9 Participants | 72 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 4 Participants | 9 Participants | 8 Participants | 6 Participants | 31 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 2 Participants | 6 Participants | 2 Participants | 4 Participants | 16 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 43 Participants | 45 Participants | 34 Participants | 45 Participants | 44 Participants | 211 Participants |
| Sex: Female, Male Female | 75 Participants | 62 Participants | 57 Participants | 63 Participants | 62 Participants | 319 Participants |
| Sex: Female, Male Male | 0 Participants | 6 Participants | 5 Participants | 6 Participants | 5 Participants | 22 Participants |
| Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score | 9.1 units on a scale STANDARD_DEVIATION 3.88 | 8.9 units on a scale STANDARD_DEVIATION 2.75 | 9.0 units on a scale STANDARD_DEVIATION 2.75 | 8.8 units on a scale STANDARD_DEVIATION 2.86 | 9.2 units on a scale STANDARD_DEVIATION 3.18 | 9.0 units on a scale STANDARD_DEVIATION 3.12 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 75 | 2 / 68 | 0 / 62 | 0 / 69 | 2 / 67 |
| other Total, other adverse events | 39 / 75 | 38 / 68 | 35 / 62 | 28 / 69 | 36 / 67 |
| serious Total, serious adverse events | 13 / 75 | 7 / 68 | 13 / 62 | 9 / 69 | 7 / 67 |
Outcome results
Primary
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.
Time frame: Baseline, Week 24
Population: Full Analysis Set: all randomized participants who received at least 1 dose of study drug; non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C). When 50% of planned participants had completed Week 24 or withdrawn from the study, the ABBV-599 Low Dose and elsubrutinib 60 mg treatment groups were terminated as these groups did not meet projected efficacy. Per protocol, terminated groups were removed from the efficacy analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Elsubrutinib Placebo/Upadacitinib Placebo | Percentage of Participants Achieving SLE Responder Index (SRI)-4 and Steroid Dose ≤ 10 mg Prednisone Equivalent Once a Day (QD) at Week 24 | 37.3 percentage of participants |
| ABBV-599 High Dose (Elsubrutinib 60 mg/Upadacitinib 30 mg) | Percentage of Participants Achieving SLE Responder Index (SRI)-4 and Steroid Dose ≤ 10 mg Prednisone Equivalent Once a Day (QD) at Week 24 | 48.5 percentage of participants |
| Elsubrutinib Placebo/Upadacitinib 30 mg | Percentage of Participants Achieving SLE Responder Index (SRI)-4 and Steroid Dose ≤ 10 mg Prednisone Equivalent Once a Day (QD) at Week 24 | 54.8 percentage of participants |
Comparison: ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg) vs elsubrutinib placebo/upadacitinib placebo~The difference between the groups was assessed using the Cochran-Mantel-Haenszel (CMH) test, 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 NA), baseline immunosuppressant (azathioprine, tacrolimus, cyclosporine, methotrexate \[MTX\], mycophenolate) (yes or no).p-value: =0.08195% CI: [-1.6, 27.1]Cochran-Mantel-Haenszel
Comparison: Elsubrutinib placebo/upadacitinib 30 mg vs elsubrutinib placebo/upadacitinib placebo~The difference between the groups was assessed using the Cochran-Mantel-Haenszel (CMH) test, 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 NA), baseline immunosuppressant (azathioprine, tacrolimus, cyclosporine, methotrexate \[MTX\], mycophenolate) (yes or no).p-value: =0.02895% CI: [1.8, 31.9]Cochran-Mantel-Haenszel
Comparison: ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg) vs elsubrutinib placebo/upadacitinib 30 mg~The difference between the groups was assessed using the Cochran-Mantel-Haenszel (CMH) test, 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 NA), baseline immunosuppressant (azathioprine, tacrolimus, cyclosporine, methotrexate \[MTX\], mycophenolate) (yes or no).p-value: =0.56695% CI: [-20.8, 11.4]Cochran-Mantel-Haenszel
Secondary
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.
Time frame: From Baseline to Week 24
Population: Full Analysis Set: all randomized participants who received at least 1 dose of study drug with available data; Mixed-Effect Model Repeat Measurement was used. When 50% of planned participants had completed Week 24 or withdrawn from the study, the ABBV-599 Low Dose and elsubrutinib 60 mg treatment groups were terminated as these groups did not meet projected efficacy. Per protocol, terminated groups were removed from the efficacy analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Elsubrutinib Placebo/Upadacitinib Placebo | Change From Baseline in Daily Prednisone Dose at Week 24 | -0.65 mg |
| ABBV-599 High Dose (Elsubrutinib 60 mg/Upadacitinib 30 mg) | Change From Baseline in Daily Prednisone Dose at Week 24 | -0.45 mg |
| Elsubrutinib Placebo/Upadacitinib 30 mg | Change From Baseline in Daily Prednisone Dose at Week 24 | -0.62 mg |
Comparison: ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg) vs elsubrutinib placebo/upadacitinib placebo~The Mixed-Effect Model Repeat Measurement model included fixed effects of Tx, visit and Tx-by-visit interaction, stratification factors (Baseline corticosteroid dose \> 10 mg prednisone-equivalent (≤ 10 mg or \>10 mg), screening SLEDAI-2K (\<10 or ≥ 10), baseline interferon score (high/low/NA, baseline immunosuppressant (yes/no)), and continuous fixed covariates of measurements at Baseline.p-value: =0.7195% CI: [-0.84, 1.23]Mixed-effect model repeat measurement
Comparison: Elsubrutinib placebo/upadacitinib 30 mg vs elsubrutinib placebo/upadacitinib placebo~The Mixed-Effect Model Repeat Measurement model included fixed effects of Tx, visit and Tx-by-visit interaction, stratification factors (Baseline corticosteroid dose \> 10 mg prednisone-equivalent (≤ 10 mg or \>10 mg), screening SLEDAI-2K (\<10 or ≥ 10), baseline interferon score (high/low/NA, baseline immunosuppressant (yes/no)), and continuous fixed covariates of measurements at Baseline.p-value: =0.96395% CI: [-1.05, 1.1]Mixed-effect model repeat measurement
Comparison: ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg) vs elsubrutinib placebo/upadacitinib 30 mg~The Mixed-Effect Model Repeat Measurement model included fixed effects of Tx, visit and Tx-by-visit interaction, stratification factors (Baseline corticosteroid dose \> 10 mg prednisone-equivalent (≤ 10 mg or \>10 mg), screening SLEDAI-2K (\<10 or ≥ 10), baseline interferon score (high/low/NA, baseline immunosuppressant (yes/no)), and continuous fixed covariates of measurements at Baseline.p-value: =0.75495% CI: [-0.9, 1.25]Mixed-effect model repeat measurement
Secondary
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.
Time frame: From Baseline to Week 24
Population: Full Analysis Set: all randomized participants who received at least 1 dose of study drug with available data; data as observed. When 50% of planned participants had completed Week 24 or withdrawn from the study, the ABBV-599 Low Dose and elsubrutinib 60 mg treatment groups were terminated as these groups did not meet projected efficacy. Per protocol, terminated groups were removed from the efficacy analyses.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Elsubrutinib Placebo/Upadacitinib Placebo | Number of Flares Per Patient-year by Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Flare Index Through Week 24 | Severe | 0.36 Events per patient-year |
| Elsubrutinib Placebo/Upadacitinib Placebo | Number of Flares Per Patient-year by Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Flare Index Through Week 24 | Mild/Moderate | 2.45 Events per patient-year |
| Elsubrutinib Placebo/Upadacitinib Placebo | Number of Flares Per Patient-year by Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Flare Index Through Week 24 | Overall | 2.81 Events per patient-year |
| ABBV-599 High Dose (Elsubrutinib 60 mg/Upadacitinib 30 mg) | Number of Flares Per Patient-year by Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Flare Index Through Week 24 | Severe | 0.26 Events per patient-year |
| ABBV-599 High Dose (Elsubrutinib 60 mg/Upadacitinib 30 mg) | Number of Flares Per Patient-year by Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Flare Index Through Week 24 | Mild/Moderate | 1.39 Events per patient-year |
| ABBV-599 High Dose (Elsubrutinib 60 mg/Upadacitinib 30 mg) | Number of Flares Per Patient-year by Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Flare Index Through Week 24 | Overall | 1.65 Events per patient-year |
| Elsubrutinib Placebo/Upadacitinib 30 mg | Number of Flares Per Patient-year by Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Flare Index Through Week 24 | Mild/Moderate | 1.76 Events per patient-year |
| Elsubrutinib Placebo/Upadacitinib 30 mg | Number of Flares Per Patient-year by Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Flare Index Through Week 24 | Overall | 1.87 Events per patient-year |
| Elsubrutinib Placebo/Upadacitinib 30 mg | Number of Flares Per Patient-year by Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Flare Index Through Week 24 | Severe | 0.10 Events per patient-year |
Comparison: Mild/Moderate~ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg) vs elsubrutinib placebo/upadacitinib 30 mg~A negative binomial regression model was used to assess treatment effect with treatment, visit, and stratification factors as covariates.p-value: =0.25295% CI: [-1.01, 0.27]Binomial regression
Comparison: Mild/Moderate~ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg) vs Elsubrutinib placebo/upadacitinib placebo~A negative binomial regression model was used to assess treatment effect with treatment, visit, and stratification factors as covariates.p-value: =0.00295% CI: [-1.74, -0.39]Binomial regression
Comparison: Mild/Moderate~Elsubrutinib placebo/upadacitinib 30 mg vs elsubrutinib placebo/upadacitinib placebo~A negative binomial regression model was used to assess treatment effect with treatment, visit, and stratification factors as covariates.p-value: =0.05995% CI: [-1.41, 0.03]Binomial regression
Comparison: Severe~ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg) vs elsubrutinib placebo/upadacitinib placebo~A negative binomial regression model was used to assess treatment effect with treatment, visit, and stratification factors as covariates.p-value: =0.46795% CI: [-0.37, 0.17]Binomial regression
Comparison: Severe~Elsubrutinib placebo/upadacitinib 30 mg vs elsubrutinib placebo/upadacitinib placebo~A negative binomial regression model was used to assess treatment effect with treatment, visit, and stratification factors as covariates.p-value: =0.03395% CI: [-0.49, -0.02]Binomial regression
Comparison: Severe~ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg) vs elsubrutinib placebo/upadacitinib 30 mg~A negative binomial regression model was used to assess treatment effect with treatment, visit, and stratification factors as covariates.p-value: =0.15695% CI: [-0.06, 0.37]Binomial regression
Comparison: Overall~ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg) vs elsubrutinib placebo/upadacitinib placebo~A negative binomial regression model was used to assess treatment effect with treatment, visit, and stratification factors as covariates.p-value: =0.00295% CI: [-1.89, -0.44]Binomial regression
Comparison: Overall~Elsubrutinib placebo/upadacitinib 30 mg vs elsubrutinib placebo/upadacitinib placebo~A negative binomial regression model was used to assess treatment effect with treatment, visit, and stratification factors as covariates.p-value: =0.01495% CI: [-1.7, -0.19]Binomial regression
Comparison: Overall~ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg) vs elsubrutinib placebo/upadacitinib 30 mg~A negative binomial regression model was used to assess treatment effect with treatment, visit, and stratification factors as covariates.p-value: =0.52695% CI: [-0.89, 0.46]Binomial regression
Secondary
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.
Time frame: Baseline, Week 24
Population: Full Analysis Set: all randomized participants who received at least 1 dose of study drug; non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C). When 50% of planned participants had completed Week 24 or withdrawn from the study, the ABBV-599 Low Dose and elsubrutinib 60 mg treatment groups were terminated as these groups did not meet projected efficacy. Per protocol, terminated groups were removed from the efficacy analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Elsubrutinib Placebo/Upadacitinib Placebo | Percentage of Participants Achieving British Isles Lupus Assessment Group (BILAG) Based Combined Lupus Assessment (BICLA) Response at Week 24 | 42.7 percentage of participants |
| ABBV-599 High Dose (Elsubrutinib 60 mg/Upadacitinib 30 mg) | Percentage of Participants Achieving British Isles Lupus Assessment Group (BILAG) Based Combined Lupus Assessment (BICLA) Response at Week 24 | 54.4 percentage of participants |
| Elsubrutinib Placebo/Upadacitinib 30 mg | Percentage of Participants Achieving British Isles Lupus Assessment Group (BILAG) Based Combined Lupus Assessment (BICLA) Response at Week 24 | 58.1 percentage of participants |
Comparison: ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg) vs elsubrutinib placebo/upadacitinib placebo~The difference between the groups was assessed using the Cochran-Mantel-Haenszel (CMH) test, 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 NA), baseline immunosuppressant (azathioprine, tacrolimus, cyclosporine, methotrexate \[MTX\], mycophenolate) (yes or no).p-value: =0.04995% CI: [0, 29.4]Cochran-Mantel-Haenszel
Comparison: Elsubrutinib placebo/upadacitinib 30 mg vs elsubrutinib placebo/upadacitinib placebo~The difference between the groups was assessed using the Cochran-Mantel-Haenszel (CMH) test, 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 NA), baseline immunosuppressant (azathioprine, tacrolimus, cyclosporine, methotrexate \[MTX\], mycophenolate) (yes or no).p-value: =0.09195% CI: [-2.2, 30.1]Cochran-Mantel-Haenszel
Comparison: ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg) vs Elsubrutinib placebo/upadacitinib 30 mg~The difference between the groups was assessed using the Cochran-Mantel-Haenszel (CMH) test, 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 NA), baseline immunosuppressant (azathioprine, tacrolimus, cyclosporine, methotrexate \[MTX\], mycophenolate) (yes or no).p-value: =0.44795% CI: [-22.5, 9.9]Cochran-Mantel-Haenszel
Secondary
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).
Time frame: Baseline, Week 24
Population: Full Analysis Set: all randomized participants who received at least 1 dose of study drug; non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C). When 50% of planned participants had completed Week 24 or withdrawn from the study, the ABBV-599 Low Dose and elsubrutinib 60 mg treatment groups were terminated as these groups did not meet projected efficacy. Per protocol, terminated groups were removed from the efficacy analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Elsubrutinib Placebo/Upadacitinib Placebo | Percentage of Participants Achieving Lupus Low Disease Activity State (LLDAS) at Week 24 | 13.3 percentage of participants |
| ABBV-599 High Dose (Elsubrutinib 60 mg/Upadacitinib 30 mg) | Percentage of Participants Achieving Lupus Low Disease Activity State (LLDAS) at Week 24 | 30.9 percentage of participants |
| Elsubrutinib Placebo/Upadacitinib 30 mg | Percentage of Participants Achieving Lupus Low Disease Activity State (LLDAS) at Week 24 | 45.2 percentage of participants |
Comparison: ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg) vs elsubrutinib placebo/upadacitinib placebo~The difference between the groups was assessed using the Cochran-Mantel-Haenszel (CMH) test, 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 NA), baseline immunosuppressant (azathioprine, tacrolimus, cyclosporine, methotrexate \[MTX\], mycophenolate) (yes or no).p-value: =0.00795% CI: [4.5, 28.9]Cochran-Mantel-Haenszel
Comparison: Elsubrutinib placebo/upadacitinib 30 mg vs elsubrutinib placebo/upadacitinib placebop-value: <0.00195% CI: [18.1, 44]Cochran-Mantel-Haenszel
Comparison: ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg) vs elsubrutinib placebo/upadacitinib 30 mg~The difference between the groups was assessed using the Cochran-Mantel-Haenszel (CMH) test, 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 NA), baseline immunosuppressant (azathioprine, tacrolimus, cyclosporine, methotrexate \[MTX\], mycophenolate) (yes or no).p-value: =0.06895% CI: [-28.4, 1]Cochran-Mantel-Haenszel
Secondary
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.
Time frame: Baseline, Week 24
Population: Full Analysis Set: all randomized participants who received at least 1 dose of study drug; non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C). When 50% of planned participants had completed Week 24 or withdrawn from the study, the ABBV-599 Low Dose and elsubrutinib 60 mg treatment groups were terminated as these groups did not meet projected efficacy. Per protocol, terminated groups were removed from the efficacy analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Elsubrutinib Placebo/Upadacitinib Placebo | Percentage of Participants Achieving SLE Responder Index (SRI)-4 at Week 24 | 38.7 percentage of participants |
| ABBV-599 High Dose (Elsubrutinib 60 mg/Upadacitinib 30 mg) | Percentage of Participants Achieving SLE Responder Index (SRI)-4 at Week 24 | 54.4 percentage of participants |
| Elsubrutinib Placebo/Upadacitinib 30 mg | Percentage of Participants Achieving SLE Responder Index (SRI)-4 at Week 24 | 56.5 percentage of participants |
Comparison: ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg) vs elsubrutinib placebo/upadacitinib placebo~The difference between the groups was assessed using the Cochran-Mantel-Haenszel (CMH) test, 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 NA), baseline immunosuppressant (azathioprine, tacrolimus, cyclosporine, methotrexate \[MTX\], mycophenolate) (yes or no).p-value: =0.01395% CI: [3.9, 32.6]Cochran-Mantel-Haenszel
Comparison: Elsubrutinib placebo/upadacitinib 30 mg vs elsubrutinib placebo/upadacitinib placebo~The difference between the groups was assessed using the Cochran-Mantel-Haenszel (CMH) test, 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 NA), baseline immunosuppressant (azathioprine, tacrolimus, cyclosporine, methotrexate \[MTX\], mycophenolate) (yes or no).p-value: =0.01895% CI: [3, 33.2]Cochran-Mantel-Haenszel
Comparison: ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg) vs elsubrutinib placebo/upadacitinib 30 mg~The difference between the groups was assessed using the Cochran-Mantel-Haenszel (CMH) test, 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 NA), baseline immunosuppressant (azathioprine, tacrolimus, cyclosporine, methotrexate \[MTX\], mycophenolate) (yes or no).p-value: =0.88295% CI: [-17.6, 15.2]Cochran-Mantel-Haenszel