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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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03682705
Recruitment Status : Completed
First Posted : September 25, 2018
Results First Posted : May 3, 2021
Last Update Posted : May 3, 2021
Sponsor:
Information provided by (Responsible Party):
AbbVie

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Rheumatoid Arthritis (RA) Drug: Elsubrutinib Drug: Upadacitinib Drug: Placebo for elsubrutinib Drug: Placebo for upadacitinib Phase 2

Detailed Description:
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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 242 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : October 8, 2018
Actual Primary Completion Date : March 26, 2020
Actual Study Completion Date : March 26, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Placebo Comparator: ELS placebo/UPA placebo
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
Placebo capsule for elsubrutinib will be administered orally.

Drug: Placebo for upadacitinib
Placebo tablet for upadacitinib will be administered orally.

Experimental: UPA 15 mg/ELS 60 mg
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
Elsubrutinib capsule will be administered orally.
Other Name: ABBV-105

Drug: Upadacitinib
Upadacitinib tablet will be administered orally.
Other Name: ABT-494

Experimental: ELS 60 mg/UPA placebo
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
Elsubrutinib capsule will be administered orally.
Other Name: ABBV-105

Drug: Placebo for upadacitinib
Placebo tablet for upadacitinib will be administered orally.

Experimental: ELS 20 mg/UPA placebo
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
Elsubrutinib capsule will be administered orally.
Other Name: ABBV-105

Drug: Placebo for upadacitinib
Placebo tablet for upadacitinib will be administered orally.

Experimental: ELS 5 mg/UPA placebo
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
Elsubrutinib capsule will be administered orally.
Other Name: ABBV-105

Drug: Placebo for upadacitinib
Placebo tablet for upadacitinib will be administered orally.

Experimental: UPA 15 mg/ELS placebo
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
Upadacitinib tablet will be administered orally.
Other Name: ABT-494

Drug: Placebo for elsubrutinib
Placebo capsule for elsubrutinib will be administered orally.




Primary Outcome Measures :
  1. Change From Baseline in Disease Activity Score 28 C-reactive Protein [DAS28-CRP]) at Week 12 [ Time Frame: Baseline, 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.


Secondary Outcome Measures :
  1. Change From Baseline in Clinical Disease Activity Index (CDAI) [ Time Frame: Baseline, Week 2, Week 4, Week 8, and Week 12 ]
    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.

  2. Change From Baseline in Simplified Disease Activity Index (SDAI) [ Time Frame: Baseline, Week 2, Week 4, Week 8, and Week 12 ]
    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.

  3. Percentage of Participants Achieving Clinical Remission (CR) Based on Disease Activity Score 28 C-reactive Protein [DAS28-CRP]) at Week 12 [ Time Frame: 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.

  4. Percentage of Participants Achieving Low Disease Activity (LDA) Based on Disease Activity Score 28 C-reactive Protein [DAS28-CRP]) at Week 12 [ Time Frame: 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.

  5. Percentage of Participants Achieving Low Disease Activity (LDA) Based on Clinical Disease Activity Index (CDAI) Criteria [ Time Frame: Week 2, Week 4, Week 8, and Week 12 ]
    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.

  6. Percentage of Participants Achieving Complete Remission (CR) Based on Clinical Disease Activity Index (CDAI) Criteria [ Time Frame: Week 2, Week 4, Week 8, and Week 12 ]
    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.

  7. Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response [ Time Frame: Baseline, Week 2, Week 4, Week 8, and Week 12 ]

    Participants who met the following 3 conditions for improvement from baseline were classified as meeting the American College of Rheumatology 20% response (ACR20) criteria:

    1. ≥ 20% improvement in 68-tender joint count
    2. ≥ 20% improvement in 66-swollen joint count and
    3. ≥ 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)

  8. Percentage of Participants With an American College of Rheumatology 50% (ACR50) Response [ Time Frame: Baseline, Week 2, Week 4, Week 8, and Week 12 ]

    Participants who met the following 3 conditions for improvement from baseline were classified as meeting the American College of Rheumatology 50% response (ACR50) criteria:

    1. ≥ 50% improvement in 68-tender joint count
    2. ≥ 50% improvement in 66-swollen joint count and
    3. ≥ 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)

  9. Percentage of Participants With an American College of Rheumatology 70% (ACR70) Response [ Time Frame: Baseline, Week 2, Week 4, Week 8, and Week 12 ]

    Participants who met the following 3 conditions for improvement from baseline were classified as meeting the American College of Rheumatology 70% response (ACR70) criteria:

    1. ≥ 70% improvement in 68-tender joint count
    2. ≥ 70% improvement in 66-swollen joint count and
    3. ≥ 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)

  10. Change From Baseline in Tender Joint Count 68 (TJC68) [ Time Frame: Baseline, Week 2, Week 4, Week 8, and Week 12 ]
    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.

  11. Change From Baseline in Swollen Joint Count 66 (SJC66) [ Time Frame: Baseline, Week 2, Week 4, Week 8, and Week 12 ]
    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.

  12. Change From Baseline in Participant's Assessment of Pain (Visual Analog Scale [VAS]) [ Time Frame: Baseline, Week 2, Week 4, Week 8, and Week 12 ]
    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.

  13. Change From Baseline in Patient's Global Assessment of Disease Activity (PGA) [ Time Frame: Baseline, Week 2, Week 4, Week 8, and Week 12 ]
    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.

  14. Change From Baseline in Physician's Global Assessment of Disease Activity (PhGA) [ Time Frame: Baseline, Week 2, Week 4, Week 8, and Week 12 ]
    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.

  15. Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) [ Time Frame: Baseline, Week 2, Week 4, Week 8, and Week 12 ]
    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.

  16. Change From Baseline in High-Sensitivity C-reactive Protein (hsCRP) [ Time Frame: Baseline, Week 2, Week 4, Week 8, and Week 12 ]
    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.

  17. Change From Baseline in Disease Activity Score 28 C-reactive Protein [DAS28-CRP]) [ Time Frame: Baseline, Week 2, Week 4, Week 8, and 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.

  18. Change From Baseline in Disease Activity Score 28 Erythrocyte Sedimentation Rate (DAS28- ESR) [ Time Frame: Baseline, Week 2, Week 4, Week 8, and Week 12 ]
    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.

  19. Change From Baseline in Morning Stiffness Severity [ Time Frame: Baseline, Week 2, Week 4, Week 8, and Week 12 ]
    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.

  20. Percentage of Participants Achieving Minimal Clinically Important Difference (MCID) in Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) [ Time Frame: Baseline, Week 2, Week 4, Week 8, and Week 12 ]
    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.

  21. Percentage of Participants Achieving American College of Rheumatology/European League Against Rheumatism (EULAR) Boolean Remission [ Time Frame: Baseline, Week 2, Week 4, Week 8, and Week 12 ]
    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).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03682705


Locations
Show Show 115 study locations
Sponsors and Collaborators
AbbVie
Investigators
Layout table for investigator information
Study Director: AbbVie Inc. AbbVie
  Study Documents (Full-Text)

Documents provided by AbbVie:
Study Protocol  [PDF] October 15, 2019
Statistical Analysis Plan  [PDF] January 23, 2020

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Responsible Party: AbbVie
ClinicalTrials.gov Identifier: NCT03682705    
Other Study ID Numbers: M16-063
2018-000666-10 ( EudraCT Number )
First Posted: September 25, 2018    Key Record Dates
Results First Posted: May 3, 2021
Last Update Posted: May 3, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual and trial-level data (analysis data sets), as well as other information (e.g., protocols and clinical study reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Time Frame: Data requests can be submitted at any time and the data will be accessible for 12 months, with possible extensions considered.
Access Criteria: Access to this clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). For more information on the process, or to submit a request, visit the following link.
URL: https://www.abbvie.com/our-science/clinical-trials/clinical-trials-data-and-information-sharing/data-and-information-sharing-with-qualified-researchers.html

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by AbbVie:
Elsubrutinib
ABBV-105
Upadacitinib
ABBV-599
Rheumatoid Arthritis
Additional relevant MeSH terms:
Layout table for MeSH terms
Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Upadacitinib
Janus Kinase Inhibitors
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antirheumatic Agents