Phase IIB Dose Ranging Study in Subjects With Moderate to Severe Rheumatoid Arthritis

Study Overview
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Brief Summary
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The primary purpose of this study is to identify an appropriate dose of study medication.

Official Title
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A Phase IIb, Randomized, Multi-Center, Double-Blind, Dose-Ranging Study to Evaluate the Efficacy and Safety of Clazakizumab in Subjects With Moderate to Severe Active Rheumatoid Arthritis Who Have Experienced an Inadequate Response to TNF Inhibitors

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Clazakizumab
* Drug: Placebo (Matching with Clazakizumab)


Participation Criteria
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Eligibility Criteria
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For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria: Diagnosis of active Rheumatoid Arthritis (RA) by standard criteria (American Rheumatism association (ARA) [1987] or American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) [2010]) at least 16 weeks prior to screening ACR global functional status class of 1 to 3 Documented evidence of inadequate response tumor necrosis factor (TNF) inhibitors All subjects must have been receiving treatment with a minimum dose of 15 mg per week of Methotrexate for at least 12 weeks and at a stable dose for 28 days prior to screening. A dose as low as 10 mg Methotrexate is permitted if 15 mg could not be reached, due to toxicity. In Japan, Korea and Taiwan, a minimum dose of 7.5 mg per week is permitted. Additional treatment with Hydroxychloroquine or Chloroquine is permitted, if it is at a dose approved for the treatment of RA and the dose has been stable for at least 28 days prior to screening Minimum of 6 swollen and 6 tender joints on a 66/68 joint count at screening and at baseline (Day 1) Elevated High-sensitivity (hs) CRP and/or ESR Exclusion Criteria: Active serious infection History of or active tuberculosis (TB) Elevated liver function tests (LFTs)

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 |
| --- | --- |
| Experimental: Arm 1: Clazakizumab (Dose # A) (Double-Blind)<br>Clazakizumab Dose # A injection by subcutaneous for 12 weeks + background Methotrexate | Drug: Clazakizumab<br> <br> * Other names: BMS-945429;|
| Experimental: Arm 2: Clazakizumab (Dose # B) (Double-Blind)<br>Clazakizumab Dose # B injection by subcutaneous for 12 weeks + background Methotrexate | Drug: Clazakizumab<br> <br> * Other names: BMS-945429;|
| Experimental: Arm 3: Clazakizumab (Dose # C) (Double-Blind)<br>Clazakizumab Dose # C injection by subcutaneous for 12 weeks + background Methotrexate | Drug: Clazakizumab<br> <br> * Other names: BMS-945429;|
| Experimental: Arm 4: Placebo matching with Clazakizumab (Double-Blind)<br>Clazakizumab Dose # D injection by subcutaneous for 12 weeks + background Methotrexate | Drug: Placebo (Matching with Clazakizumab)<br> <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 in 28 Joints - C-reactive Protein (DAS28-CRP) at Week 12 | DAS28-CRP describes severity of rheumatoid arthritis. The components of the joint count assessment are shoulder, elbow, wrist, metacarpophalangeal joints 1 through 5, proximal interphalangeal joints 1 through 5, and the knee joints on the right and left sides, whereby the number of affected joints, tender and swollen, respectively, are counted. The formula used to calculate the score is: DAS28-CRP=0.56 \times \sqrt{TEN28} + 0.28 \times \sqrt{SW28} + 0.36 \times \ln(CRP+1) + 0.014 \times SA+0.96 with: TEN28: number of joints with tenderness upon touching SW28: number of swollen joints CRP: C-reactive Protein SA: subjective assessment of disease activity by the patient during the preceding 7 days on a scale between 0 and 100 (0:no activity, 100: highest activity possible). DAS-CRP score range is 0.49 to 9.07 A DAS-CRP value >5.1 corresponds to a high disease activity A DAS-28 reduction by 0.6 represents a moderate improvement. A reduction >1.2 represents a major improvement | Baseline and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| American College of Rheumatology (ACR) 20/50/70 Response Rates | The ACR20/50/70 is a composite measure defined as both improvement of 20%, 50% or 70% in the number of tender and number of swollen joints, and a 20%, 50% or 70% improvement in three of the following five criteria: patient global assessment, physician global assessment, functional ability measure [most often Health Assessment Questionnaire (HAQ)], visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein (CRP). | At week 12 | 
| Change From Baseline in Clinical Disease Activity Index (CDAI) Score at Week 12 | CDAI is a composite index for assessing disease activity. CDAI is based on the simple summation of the count of swollen joint count (SCJ) (0-28) and tender joint count (TJC) (0-28) along with patient global assessment (0-10) Scale and physician global assessment (0-10) for estimating disease activity where 10 means maximal activity. The CDAI has a range from 0 to 76. CDAI <= 2.8 = Remission CDAI > 2.8 and <= 10 = Low Disease Activity CDAI > 10 and <= 22 = Moderate Disease Activity CDAI > 22 = High Disease Activity | Baseline and week 12 | 
| Change From Baseline in Simplified Disease Activity Index (SDAI) at Week 12 | SDAI is a composite index for assessing disease activity. CDAI is based on the simple summation of the count of swollen joint count (0-28) and tender joint count (0-28) along with patient global assessment (0-10) Scale and physician global assessment (0-10) for estimating disease activity where 10 means maximal activity and C-reactive protein (0-10). The SDAI has a range from 0 to 86. 0.0 - 3.3 = Remission 3.4 - 11.0 = Low Activity 11.1 - 26.0 = Moderate Activity 26.1 - 86.0 = High Activity | Baseline and week 12 | 
| Boolean Remission at Week 12 | Boolean-based definition: At any time point, a patient must satisfy all of the following: TJC ≤1 (0-28) SJC ≤1 (0-28) CRP ≤1 mg/dl Patient Global Assessment ≤1 (on a 0-10 scale) | At week 12 | 
| Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score at Week 12 | Patients report the amount of difficulty they have in performing 8 categories. Each category is scored on a scale ranging from 0 (performed without any difficulty) to 3 (cannot be done at all). The HAQ-DI is then calculated by summing the scores and dividing by the number of categories answered. Total score is between 0-3.0. Increasing scores indicate worse functioning with 0 indicating no functional impairment and 3 indicating complete impairment. The HAQ-DI cannot be calculated if the subject does not have scores for at least 6 categories. A response was defined as a subject with a reduction from baseline in HAQ-DI of at least 0.22. | Baseline and Week 12 | 
| Percent of Participants With a DAS28-Erythrocyte Sedimentation Rate (ESR) <2.6 | DAS28- ESR = Disease Activity Scores 28 based on erythrocyte sedimentation rate. A DAS28-ESR below 2.6 is interpreted as remission. | At week 12 | 
| Percent of Participants With a DAS28-C Reactive Protein (CRP) <2.6 | DAS28-CRP = Disease Activity Scores 28 based on C Reactive Protein. A DAS28-CRP below 2.6 is interpreted as remission. | At week 12 |