Proof-of-Concept Study With BMS-817399 to Treat Moderate to Severe Rheumatoid Arthritis

Study Overview
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Brief Summary
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The purpose of this study is to assess whether BMS-817399 in combination with Methotrexate is effective in treating moderate to severe rheumatoid arthritis.

Official Title
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A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of BMS-817399 in Adults With Active, Moderate to Severe Rheumatoid Arthritis and Inadequate Response to Methotrexate

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Placebo
* Drug: BMS-817399
* Drug: BMS-817399


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects, 18 years of age or older, with rheumatoid arthritis (RA) for at least 6 months prior to screening Subjects must have a tender joint count of at least 6 (28 joint count), swollen joint count of at least 6 (28 joint count) at screening. All subjects must have clinical evidence of synovitis in one hand/wrist at screening Serum C-reactive protein (hsCRP) above upper limits of normal at screening Subjects must have been treated with and tolerated Methotrexate (MTX) therapy at a weekly oral or parenteral dose ≥ 10 mg for ≥ 4 months prior to screening. Dose must be stable, with no change in route of administration, for ≥ 6 weeks prior to randomization. A MTX weekly dose as low as 7.5 mg is permitted if intolerance to doses ≥10 mg has been documented in the subject's medical history Subjects must be receiving folic acid, folinic acid, or leucovorin supplementation at a stable dose for at least 4 weeks prior to randomization Subjects who were previously treated with up to two tumor necrosis factor α (TNF-α) inhibitors If taking antimalarials (e.g. hydroxychloroquine or chloroquine), subject must have been on a stable dose for ≥ 4 months prior to randomization If taking non-steroidal anti-inflammatory drugs (NSAIDs), subjects must have been on stable doses for ≥ 2 weeks prior to randomization If taking oral corticosteroids, daily doses must be ≤ 10 mg/day of prednisone or equivalent and stable for ≥ 4 weeks before randomization Subject is willing to participate to the study and has signed the informed consent prior to undergoing any screening procedures Women of childbearing potential (WOCBP) and men must agree to use at least two acceptable methods to avoid pregnancy for the entire study period and until 60 days (for women) and 90 days (for men) after the last dose of BMS-817399. WOCBP must have a negative urine pregnancy test at screening, randomization and at scheduled visits throughout the study Exclusion Criteria: Arthritis onset prior to 16 years of age or subjects with documented juvenile RA Subjects who are bed- or wheelchair-bound Subjects with other autoimmune diseases or arthritis syndromes Women who are pregnant, breastfeeding or with a positive pregnancy test at screening or prior to randomization Subjects who have any condition that could impact upon the absorption of study drug (i.e., gastric stapling, duodenal surgery, malabsorption syndrome) Subjects with a history of, or a concurrent severe, progressive, or uncontrolled disease (other than RA) that in the opinion of the investigator might place the subject at unacceptable risk for participation in this study Subjects who have present or previous (last 5 years) malignancies, except history of cured squamous or basal skin cell carcinoma or cured breast or cervical cancer Subjects at risk for tuberculosis (TB) or with evidence of TB clinical history, chest X rays or tuberculin skin test Subjects with evidence of active or latent bacterial or viral infections (including human immunodeficiency virus); Positive blood screen for hepatitis B surface antigen or hepatitis C antibody Subjects with any serious bacterial infection within the last 2 months, unless treated and resolved with antibiotics Subjects who have clinically significant drug or alcohol abuse or known cirrhosis including alcoholic cirrhosis If a subject has received any of the following treatments, the indicated washout period prior to randomization must be followed: Oral or injectable azathioprine, gold, D-Penicillamine, cyclosporine, anakinra, etanercept, parenteral or intra-articular corticosteroids: 30 days Leflunomide: 6 months unless an active washout with Cholestyramine has been performed Mycophenolate mofetil, cyclophosphamide, tacrolimus or other immunosuppressant: 3 months Adalimumab, Infliximab, Golimumab, Certolizumab pegol, Abatacept or Tocilizumab: 60 days Rituximab or any B-cell depleting agent: 1 year Use CYP3A4 inhibitors or inducers during the study Subjects with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 1.5x upper limit of normal (ULN), total bilirubin ≥ 1.4x ULN, estimated glomerular filtration rate (GFR) < 50 mL/min/1.73m2, hemoglobin < 10.0 g/dL, white blood cell count < 3,500/mm3, absolute neutrophil count < 1,700/mm3 or platelets < 125,000/mm3

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: Arm 1: Placebo<br> | Drug: Placebo<br>* Tablets, Oral, 0 mg, twice daily, 12 weeks<br>|
| Experimental: Arm 2: BMS-817399 (200 mg)<br> | Drug: BMS-817399<br>* Tablets, Oral, 200 mg, twice daily, 12 weeks<br>|
| Experimental: Arm 3: BMS-817399 (400 mg)<br> | Drug: BMS-817399<br>* Tablets, Oral, 400mg, twice daily, 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Activity Score using 28 joint count and C Reactive Protein (DAS28-CRP) change from baseline of BMS-817399 versus placebo |  | Baseline and at 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety assessments will be based on adverse event reports and the results of vital sign measurements, electrocardiogram, physical examinations, and clinical laboratory tests |  | 16 weeks | 
| Proportion of subjects achieving 20% American College of Rheumatology (ACR) response in each treatment group |  | Day 15 | 
| Proportion of subjects achieving 20% ACR response in each treatment group |  | Day 29 | 
| Proportion of subjects achieving 20% ACR response in each treatment group |  | Day 57 | 
| Proportion of subjects achieving 20% ACR response in each treatment group |  | Day 85 | 
| Proportion of subjects achieving 50% ACR response in each treatment group |  | Day 15 | 
| Proportion of subjects achieving 50% ACR response in each treatment group |  | Day 29 | 
| Proportion of subjects achieving 50% ACR response in each treatment group |  | Day 57 | 
| Proportion of subjects achieving 50% ACR response in each treatment group |  | Day 85 | 
| Proportion of subjects achieving 70% ACR response in each treatment group |  | Day 15 | 
| Proportion of subjects achieving 70% ACR response in each treatment group |  | Day 29 | 
| Proportion of subjects achieving 70% ACR response in each treatment group |  | Day 57 | 
| Proportion of subjects achieving 70% ACR response in each treatment group |  | Day 85 | 
| Percent change from baseline in disability index of the Health Assessment Questionnaire (HAQ-DI) |  | Baseline and Day 15 | 
| Percent change from baseline in disability index of the Health Assessment Questionnaire (HAQ-DI) |  | Baseline and Day 29 | 
| Percent change from baseline in disability index of the Health Assessment Questionnaire (HAQ-DI) |  | Baseline and Day 57 | 
| Percent change from baseline in disability index of the Health Assessment Questionnaire (HAQ-DI) |  | Baseline and Day 85 | 
| To assess the minimum observed concentration (Cmin) of BMS-817399 |  | Day 15, Day 29, Day 57 and Day 85 |