A Study to Investigate the Safety and Efficacy of ABBV-105 Alone or in Combination With Upadacitinib (ABBV-599 Combination) in Participants With Active Rheumatoid Arthritis

Study Overview
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Brief Summary
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This was a phase 2 study to evaluate the safety and efficacy of elsubrutinib (ELS) and ABBV-599 (ELS plus upadacitinib [UPA]) vs placebo on a background of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) for the treatment of signs and symptoms of rheumatoid arthritis (RA) at 12 weeks in biological disease-modifying anti-rheumatic drugs (bDMARD)-inadequate response (bDMARD-IR) or bDMARD-intolerant participants with moderately to severely active RA and to define optimal dose for further development.

Detailed Description
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This was a 12-week, randomized, double-blind, parallel-group, Phase 2, dose exploratory, multicenter study. Participants who met eligibility criteria were randomized in a 3:2:2:2:2:1 ratio to 1 of 6 treatment groups: ABBV-599 [UPA 15 mg/ELS 60 mg]); ELS 60 mg/UPA placebo; ELS 20 mg/UPA placebo; ELS 5 mg/UPA placebo; UPA 15 mg/ELS placebo; and ELS placebo/UPA placebo. The study included a 35-day maximum screening period and a 12-week treatment period with 30-day follow-up.

Official Title
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Rheumatoid Arthritis: A Phase 2 Study to Investigate the Safety and Efficacy of ABBV-105 Given Alone or in Combination With Upadacitinib (ABBV-599 Combination) With a Background of Conventional Synthetic DMARDs in Subjects With Active Rheumatoid Arthritis With Inadequate Response or Intolerance to Biologic DMARDs

Conditions
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Rheumatoid Arthritis (RA)

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of rheumatoid arthritis (RA) for ≥ 3 months based on the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for RA Participant meets the following minimum disease activity criteria: ≥ 6 swollen joints (based on 66 joint counts) and ≥ 6 tender joints (based on 68 joint counts) at Screening and Baseline Visits High-sensitivity C-reactive protein (hsCRP) ≥ 3 mg/L (central lab) at Screening Visit Participants must have been treated for ≥ 3 months with ≥ 1 biologic disease-modifying anti-rheumatic drug (bDMARD) therapy but continue to exhibit active RA or had to discontinue due to intolerability or toxicity, irrespective of treatment duration Participants must have been receiving conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) therapy ≥ 3 months and on a stable dose for ≥ 4 weeks prior to the first dose of study drug Participants must have discontinued all bDMARDs prior to the first dose of study drug Exclusion Criteria: - Participant has prior exposure to any Janus Kinase (JAK) inhibitor for greater than 2 weeks (including but not limited to upadacitinib, tofacitinib, baricitinib, and filgotinib). A washout period of ≥ 30 days is required for any JAK inhibitor prior to the first dose of study drug.

Ages Eligible for Study
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Minimum Age: 18 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: ELS placebo/UPA placebo<br>Placebo capsule for elsubrutinib once a day by mouth for 12 weeks; placebo film-coated tablet for upadacitinib once a day by mouth for 12 weeks | Drug: Placebo for elsubrutinib<br>* Placebo capsule for elsubrutinib will be administered orally.<br>Drug: Placebo for upadacitinib<br>* Placebo tablet for upadacitinib will be administered orally.<br>|
| Experimental: UPA 15 mg/ELS 60 mg<br>15 mg film-coated upadacitinib tablet once a day by mouth for 12 weeks; 60 mg elsubrutinib capsule once a day by mouth for 12 weeks | Drug: Elsubrutinib<br>* Elsubrutinib capsule will be administered orally.<br>* Other names: ABBV-105;Drug: Upadacitinib<br>* Upadacitinib tablet will be administered orally.<br>* Other names: ABT-494;|
| Experimental: ELS 60 mg/UPA placebo<br>60 mg elsubrutinib capsule once a day by mouth for 12 weeks; placebo film-coated tablet for upadacitinib once a day by mouth for 12 weeks | Drug: Elsubrutinib<br>* Elsubrutinib capsule will be administered orally.<br>* Other names: ABBV-105;Drug: Placebo for upadacitinib<br>* Placebo tablet for upadacitinib will be administered orally.<br>|
| Experimental: ELS 20 mg/UPA placebo<br>20 mg elsubrutinib capsule once a day by mouth for 12 weeks; placebo film-coated tablet for upadacitinib once a day by mouth for 12 weeks | Drug: Elsubrutinib<br>* Elsubrutinib capsule will be administered orally.<br>* Other names: ABBV-105;Drug: Placebo for upadacitinib<br>* Placebo tablet for upadacitinib will be administered orally.<br>|
| Experimental: ELS 5 mg/UPA placebo<br>5 mg elsubrutinib capsule once a day by mouth for 12 weeks; placebo film-coated tablet for upadacitinib once a day by mouth for 12 weeks | Drug: Elsubrutinib<br>* Elsubrutinib capsule will be administered orally.<br>* Other names: ABBV-105;Drug: Placebo for upadacitinib<br>* Placebo tablet for upadacitinib will be administered orally.<br>|
| Experimental: UPA 15 mg/ELS placebo<br>15 mg film-coated upadacitinib tablet once a day by mouth for 12 weeks; placebo capsule for elsubrutinib once a day by mouth for 12 weeks | Drug: Upadacitinib<br>* Upadacitinib tablet will be administered orally.<br>* Other names: ABT-494;Drug: Placebo for elsubrutinib<br>* Placebo capsule for elsubrutinib will be administered orally.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Disease Activity Score 28 C-reactive Protein [DAS28-CRP]) at Week 12 | The DAS28-CRP is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100 mm), and high-sensitivity C-reactive protein (hsCRP; in mg/L). Scores on the DAS28-CRP range from 0 to approximately 10, where higher scores indicate more disease activity. A negative change from baseline indicates improvement in disease activity. | Baseline, Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Clinical Disease Activity Index (CDAI) | The CDAI is a composite index for assessing disease activity based on the summation of the total tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), patient global assessment of disease activity measured on a VAS from 0 to 10 cm, and physician global assessment of disease activity measured on a VAS from 0 to 10 cm. The total CDAI score ranges from 0 to 78 with higher scores indicating higher disease activity. A negative change from baseline indicates improvement in disease activity. | Baseline, Week 2, Week 4, Week 8, and Week 12 | 
| Change From Baseline in Simplified Disease Activity Index (SDAI) | The SDAI is a validated measure of rheumatoid arthritis disease activity. Twenty-eight tender joint counts, 28 swollen joint counts, global disease activity assessed by the participant on a visual analogue scale from 0 to 10 (cm), global disease activity assessed by an investigator on a visual analogue scale from 0 to 10 (cm), and serum levels of C-reactive protein (CRP; mg/dL) were included in the SDAI score. Scores on the SDAI range from 0 to 86.with higher scores indicating higher disease activity. A negative change from baseline indicates improvement in disease activity. | Baseline, Week 2, Week 4, Week 8, and Week 12 | 
| Percentage of Participants Achieving Clinical Remission (CR) Based on Disease Activity Score 28 C-reactive Protein [DAS28-CRP]) at Week 12 | The DAS28-CRP is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100 mm), and high-sensitivity C-reactive protein (hsCRP; in mg/L). Scores on the DAS28-CRP range from 0 to approximately 10, where higher scores indicate more disease activity. Clinical remission (CR) based on DAS28 (CRP) is defined as achieving a DAS28 (CRP) of less than 2.6. | At Week 12 | 
| Percentage of Participants Achieving Low Disease Activity (LDA) Based on Disease Activity Score 28 C-reactive Protein [DAS28-CRP]) at Week 12 | The DAS28-CRP is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100 mm), and high-sensitivity C-reactive protein (hsCRP; in mg/L). Scores on the DAS28-CRP range from 0 to approximately 10, where higher scores indicate more disease activity. Low Disease Activity (LDA) based on DAS28 (CRP) is defined as achieving a DAS28 (CRP) of less than or equal to 3.2. | At Week 12 | 
| Percentage of Participants Achieving Low Disease Activity (LDA) Based on Clinical Disease Activity Index (CDAI) Criteria | The CDAI is a composite index for assessing disease activity based on the summation of the total tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), patient global assessment of disease activity measured on a VAS from 0 to 10 cm, and physician global assessment of disease activity measured on a VAS from 0 to 10 cm. The total CDAI score ranges from 0 to 78 with higher scores indicating higher disease activity. Low Disease Activity (LDA) based on CDAI is defined as achieving a CDAI of less than or equal to 10. | Week 2, Week 4, Week 8, and Week 12 | 
| Percentage of Participants Achieving Complete Remission (CR) Based on Clinical Disease Activity Index (CDAI) Criteria | The CDAI is a composite index for assessing disease activity based on the summation of the total tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), patient global assessment of disease activity measured on a VAS from 0 to 10 cm, and physician global assessment of disease activity measured on a VAS from 0 to 10 cm. The total CDAI score ranges from 0 to 78 with higher scores indicating higher disease activity. Complete Remission (CR) based on CDAI is defined as achieving a CDAI of less than or equal to 2.8. | Week 2, Week 4, Week 8, and Week 12 | 
| Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response | Participants who met the following 3 conditions for improvement from baseline were classified as meeting the American College of Rheumatology 20% response (ACR20) criteria: ≥ 20% improvement in 68-tender joint count ≥ 20% improvement in 66-swollen joint count and ≥ 20% improvement in at least 3 of the 5 following parameters: Patient's Assessment of Pain (Visual Analog Scale [VAS]) Patient's Global Assessment of Disease Activity (PtGA) Physician's Global Assessment of Disease Activity (PhGA) Health Assessment Questionnaire Disability Index (HAQ-DI) High-sensitivity C-reactive protein (hsCRP) | Baseline, Week 2, Week 4, Week 8, and Week 12 | 
| Percentage of Participants With an American College of Rheumatology 50% (ACR50) Response | Participants who met the following 3 conditions for improvement from baseline were classified as meeting the American College of Rheumatology 50% response (ACR50) criteria: ≥ 50% improvement in 68-tender joint count ≥ 50% improvement in 66-swollen joint count and ≥ 50% improvement in at least 3 of the 5 following parameters: Patient's Assessment of Pain (Visual Analog Scale [VAS]) Patient's Global Assessment of Disease Activity (PtGA) Physician's Global Assessment of Disease Activity (PhGA) Health Assessment Questionnaire Disability Index (HAQ-DI) High-sensitivity C-reactive protein (hsCRP) | Baseline, Week 2, Week 4, Week 8, and Week 12 | 
| Percentage of Participants With an American College of Rheumatology 70% (ACR70) Response | Participants who met the following 3 conditions for improvement from baseline were classified as meeting the American College of Rheumatology 70% response (ACR70) criteria: ≥ 70% improvement in 68-tender joint count ≥ 70% improvement in 66-swollen joint count and ≥ 70% improvement in at least 3 of the 5 following parameters: Patient's Assessment of Pain (Visual Analog Scale [VAS]) Patient's Global Assessment of Disease Activity (PtGA) Physician's Global Assessment of Disease Activity (PhGA) Health Assessment Questionnaire Disability Index (HAQ-DI) High-sensitivity C-reactive protein (hsCRP) | Baseline, Week 2, Week 4, Week 8, and Week 12 | 
| Change From Baseline in Tender Joint Count 68 (TJC68) | Sixty-eight joints were assessed for tenderness by physical examination. Pain or tenderness of each joint was classified as present (1) or absent (0), for a total possible score of 0 (0 joints with tenderness) to 68 (worst possible score/68 joints with tenderness). Negative values indicate improvement from baseline. | Baseline, Week 2, Week 4, Week 8, and Week 12 | 
| Change From Baseline in Swollen Joint Count 66 (SJC66) | Sixty-six joints were assessed for swelling by physical examination. Swelling of each joint was classified as present (1) or absent (0), for a total possible score of 0 (0 joints with swelling) to 66 (worst possible score/66 joints with swelling). Negative values indicate improvement from baseline. | Baseline, Week 2, Week 4, Week 8, and Week 12 | 
| Change From Baseline in Participant's Assessment of Pain (Visual Analog Scale [VAS]) | Participants rated their pain on a visual analogue scale (VAS) of 0 to 100 (mm), with 0 representing no pain and 100 representing the worst possible pain. Negative values indicate improvement from baseline. | Baseline, Week 2, Week 4, Week 8, and Week 12 | 
| Change From Baseline in Patient's Global Assessment of Disease Activity (PGA) | Participants rated their disease activity for the past 24 hours using a Patient's Global Assessment of Disease Activity Global visual analogue scale (VAS). The range is 0 to 100 mm, with 0 representing no disease activity and 100 representing severe disease activity. Negative values indicate improvement from baseline. | Baseline, Week 2, Week 4, Week 8, and Week 12 | 
| Change From Baseline in Physician's Global Assessment of Disease Activity (PhGA) | The physician assessed a participant's disease activity at the time of the visit using a Physician's Global Assessment of Disease visual analogue scale (VAS). The range is 0 to 100 mm, with 0 representing no disease activity and 100 representing severe disease activity. Negative values indicate improvement from baseline. | Baseline, Week 2, Week 4, Week 8, and Week 12 | 
| Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) | The Health Assessment Questionnaire - Disability Index is a patient-reported questionnaire that measures the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and errands and chores) over the past week. Participants assessed their ability to do each task on a scale from 0 (without any difficulty) to 3 (unable to do). Scores were averaged to provide an overall score ranging from 0 to 3, where 0 represents no disability and 3 represents very severe, high-dependency disability. A negative change from baseline in the overall score indicates improvement. | Baseline, Week 2, Week 4, Week 8, and Week 12 | 
| Change From Baseline in High-Sensitivity C-reactive Protein (hsCRP) | C-reactive protein is a blood test marker for inflammation in the body, and levels rise in response to inflammation. A negative change from baseline in indicates improvement. | Baseline, Week 2, Week 4, Week 8, and Week 12 | 
| Change From Baseline in Disease Activity Score 28 C-reactive Protein [DAS28-CRP]) | The DAS28-CRP is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100 mm), and high-sensitivity C-reactive protein (hsCRP; in mg/L). Scores on the DAS28-CRP range from 0 to approximately 10, where higher scores indicate more disease activity. A negative change from baseline indicates improvement in disease activity. | Baseline, Week 2, Week 4, Week 8, and Week 12 | 
| Change From Baseline in Disease Activity Score 28 Erythrocyte Sedimentation Rate (DAS28- ESR) | The DAS28-ESR is a validated index of rheumatoid arthritis disease activity. Twenty-eight tender joint counts, 28 swollen joint counts, the erythrocyte sedimentation rate (ESR; mm/hour), and the participant's assessment of global disease activity (on a visual analog scale [VAS] from 0 to 100 mm) are included in the DAS28 -ESR score. Scores on the DAS28-ESR range from 0 to 10; higher scores indicate more disease activity. | Baseline, Week 2, Week 4, Week 8, and Week 12 | 
| Change From Baseline in Morning Stiffness Severity | Morning stiffness severity was assessed by a numeric rating-scale (NRS). Participants rated the severity of morning stiffness during the past week from 0 to 10 with 0 representing not severe and 10 very severe. Negative values indicate improvement from baseline. | Baseline, Week 2, Week 4, Week 8, and Week 12 | 
| Percentage of Participants Achieving Minimal Clinically Important Difference (MCID) in Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) | The Health Assessment Questionnaire - Disability Index is a patient-reported questionnaire that measures the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and errands and chores) over the past week. Participants assessed their ability to do each task on a scale from 0 (without any difficulty) to 3 (unable to do). Scores were averaged to provide an overall score ranging from 0 to 3, where 0 represents no disability and 3 represents very severe, high-dependency disability. The minimal clinically important difference (MCID) in HAQ-DI is defined as change from Baseline ≤ -0.22 for rheumatoid arthritis. | Baseline, Week 2, Week 4, Week 8, and Week 12 | 
| Percentage of Participants Achieving American College of Rheumatology/European League Against Rheumatism (EULAR) Boolean Remission | The EULAR Boolean-based definition of remission is as follows: at any time point, a participant must satisfy all of the following: tender joint count ≤1, swollen joint count ≤1, C-reactive protein ≤1 mg/dl and Patient Global Assessment (PGA) ≤1 (on a 0-10 scale). | Baseline, Week 2, Week 4, Week 8, and Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Elsubrutinib, ABBV-105, Upadacitinib, ABBV-599, Rheumatoid Arthritis