A Study Investigating the Efficacy and Safety of ABT-494 Given With Methotrexate in Subjects With Rheumatoid Arthritis Who Failed Anti-Tumor Necrosis Factor (TNF) Biologic Therapy

Study Overview
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Brief Summary
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The primary objective is to compare the safety and efficacy of multiple doses of ABT-494 versus placebo in moderately to severely active RA subjects on stable background MTX therapy with inadequate response or intolerance to anti-TNF biologic therapy.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study to Investigate the Safety and Efficacy of ABT-494 Given With Methotrexate (MTX) in Subjects With Moderately to Severely Active Rheumatoid Arthritis (RA) Who Have Had an Inadequate Response or Intolerance to Anti-TNF Biologic Therapy

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: ABT-494
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosed with rheumatoid arthritis (RA) based on either the 1987-revised American College of Rheumatology (ACR) classification criteria or the 2010 American College of Rheumatology/European League against Rheumatism (ACR/EULAR) criteria for ≥ 3 months. Subjects must have been receiving oral or parenteral methotrexate (MTX) therapy ≥ 3 months and on a stable prescription of 7.5 to 25 mg/week for at least 4 weeks prior to initiating the study drug. Subjects should also be on a stable dose of folic acid (or equivalent) for at least 4 weeks prior to initiating the study drug. Subjects should continue with their stable doses of MTX and folic acid throughout the study Subjects have been treated with 1 or more anti-tumor necrosis factor (TNF) biologics (no maximum cap) for ≥ 3 months but continue to exhibit active RA, or had to discontinue due to intolerability or toxicity. In addition, subjects with prior exposure to non-anti-TNF biologic(s) (no maximum cap) (e.g., abatacept, rituximab, anakinra, or tocilizumab) are allowed. Have active RA as defined by the following minimum disease activity criteria: ≥ 6 swollen joints (based on 66 joint counts) at Screening and Baseline, ≥ 6 tender joints (based on 68 joint counts) at Screening and Baseline, high sensitivity C reactive protein (hs-CRP) > Upper Limit of Normal (ULN) OR positive for both rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP) antibody. Exclusion Criteria: Prior exposure to Janus Activated Kinase (JAK) inhibitor (e.g. tofacitinib, baricitinib) Pregnant or breastfeeding female Ongoing or active infection.

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: Placebo BID<br>Placebo twice daily (BID) for 12 weeks. | Drug: Placebo<br>* Placebo for ABT-494 capsule administered orally twice daily (BID).<br>|
| Experimental: ABT-494 3 mg BID<br>ABT-494 3 mg twice daily (BID) for 12 weeks. | Drug: ABT-494<br>* ABT-494 capsule administered orally twice daily (BID).<br>|
| Experimental: ABT-494 6 mg BID<br>ABT-494 6 mg twice daily (BID) for 12 weeks. | Drug: ABT-494<br>* ABT-494 capsule administered orally twice daily (BID).<br>|
| Experimental: ABT-494 12 mg BID<br>ABT-494 12 mg twice daily (BID) for 12 weeks. | Drug: ABT-494<br>* ABT-494 capsule administered orally twice daily (BID).<br>|
| Experimental: ABT-494 18 mg BID<br>ABT-494 18 mg twice daily (BID) for 12 weeks. | Drug: ABT-494<br>* ABT-494 capsule administered orally twice daily (BID).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Achieving American College of Rheumatology 20% (ACR20) Response at Week 12 | Response defined as at least 20% reduction (improvement) compared with baseline in tender joint count (TJC68), swollen joint count (SJC66), and at least 3 of the 5 remaining ACR core set measures: patient's assessment of pain, patient's global assessment of disease activity (PtGA); physician's global assessment of disease activity (PGA), Health Assessment Questionnaire - Disability Index (HAQ-DI), and high-sensitivity C-reactive protein (hs CRP). Last observation carried forward (LOCF) was used for missing data. | Baseline (Week 0) and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Achieving American College of Rheumatology 50% (ACR50) Response at Week 12 | Response defined as at least 50% reduction (improvement) compared with baseline in tender joint count (TJC68), swollen joint count (SJC66), and at least 3 of the 5 remaining ACR core set measures: patient's assessment of pain, PtGA; PGA, HAQ-DI, and hs CRP. LOCF was used. | Baseline (Week 0) and Week 12 | 
| Number of Subjects Achieving American College of Rheumatology 70% (ACR70) Response at Week 12 | Response defined as at least 70% reduction (improvement) compared with baseline in tender joint count (TJC68), swollen joint count (SJC66), and at least 3 of the 5 remaining ACR core set measures: patient's assessment of pain, PtGA; PGA, HAQ-DI, and hs CRP. LOCF was used. | Baseline (Week 0) and Week 12 | 
| Number of Subjects Achieving Low Disease Activity (LDA) Based on Disease Activity Score (DAS28) or Clinical Remission (CR) Based on (DAS28) at Week 12 | LDA is defined as DAS28 from 2.6 to < 3.2 at Week 12. CR is defined as DAS28 (CRP) < 2.6 at Week 12. The DAS28 is a validated index of rheumatoid arthritis disease activity. Twenty-eight tender joint counts, 28 swollen joint counts, hs CRP, and general health are included in the DAS28 score. Scores on the DAS28 range from 0 to 10. A DAS28 score >5.1 indicates high disease activity, a DAS28 score <3.2 indicates low disease activity, and a DAS28 score <2.6 indicates clinical remission. LOCF was used. | Baseline (Week 0) and Week 12 | 
| Number of Subjects Achieving CR Based on DAS28 at Week 12 | The DAS28 is a validated index of rheumatoid arthritis disease activity. Twenty-eight tender joint counts, 28 swollen joint counts, hs CRP, and general health are included in the DAS28 score. Scores on the DAS28 range from 0 to 10. A DAS28 score >5.1 indicates high disease activity, a DAS28 score <3.2 indicates low disease activity, and a DAS28 score <2.6 indicates clinical remission. LOCF was used. | Baseline (Week 0) and Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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anti-inflammatory agents, Joint Diseases, Arthritis, Musculoskeletal Disease, antirheumatic agents