Phase IIB Rheumatoid Arthritis Dose Ranging Study for BMS-945429 in Subjects Who Are Not Responding to Methotrexate

Study Overview
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Brief Summary
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The purpose of this study is to determine the effective dose of BMS-945429 in subjects with inadequate response to Methotrexate in the treatment of moderate to severe Rheumatoid Arthritis.

Official Title
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A Phase IIB , Randomized, Multi-Center, Double-Blind, Dose-Ranging, Placebo/Active Controlled Study to Evaluate the Efficacy and Safety of BMS-945429 Subcutaneous Injection With or Without Methotrexate in Subjects With Moderate to Severe Rheumatoid Arthritis With Inadequate Response to Methotrexate.

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: BMS-945429 Placebo
* Biological: BMS-945429
* Biological: BMS-945429
* Biological: BMS-945429
* Biological: BMS-945429
* Drug: Methotrexate
* Drug: Methotrexate
* Drug: Methotrexate Placebo
* Drug: Methotrexate
* Drug: Adalimumab Placebo
* Drug: Adalimumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inadequate response to Methotrexate Must have been taking Methotrexate for at least 3 months at a minimal weekly dose of at least 15 mg and stable dose for 4 weeks prior to randomization American College of Rheumatology (ACR) global function status class 1-3 Minimum of 6 swollen and 6 tender joints with evidence of synovitis in at least 1 hand or wrist High sensitivity C-reactive protein (hsCRP) ≥ 0.8 mg/dL Exclusion Criteria: Previously received or currently receiving concomitant biologic therapy

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<br>BMS-945429 Placebo/BMS-945429+Methotrexate+Adalimumab Placebo | Drug: BMS-945429 Placebo<br>* Injection, Subcutaneous, 0 mg, Every 4 weeks, Day 1 - Week 24 only<br>Biological: BMS-945429<br>* Injection, Subcutaneous, 200 mg, Every 4 weeks, Week 25 - Week 48<br>Drug: Methotrexate<br>* Tablets, Oral, 15 mg, Weekly, Day 1 - Week 24 only<br>Drug: Adalimumab Placebo<br>* Injection, Subcutaneous, 0 mg, Every 2 weeks, 48 weeks<br>|
| Experimental: Arm 2<br>BMS-945429 + Methotrexate + Adalimumab Placebo | Biological: BMS-945429<br>* Injection, Subcutaneous, 200 mg, Every 4 weeks, 48 weeks<br>Drug: Methotrexate<br>* Tablets, Oral, 15 mg, Weekly, 48 weeks<br>Drug: Adalimumab Placebo<br>* Injection, Subcutaneous, 0 mg, Every 2 weeks, 48 weeks<br>|
| Experimental: Arm 3<br>BMS-945429 + Methotrexate + Adalimumab Placebo | Biological: BMS-945429<br>* Injection, Subcutaneous, 100 mg, Every 4 weeks, 48 weeks<br>Drug: Methotrexate<br>* Tablets, Oral, 15 mg, Weekly, 48 weeks<br>Drug: Adalimumab Placebo<br>* Injection, Subcutaneous, 0 mg, Every 2 weeks, 48 weeks<br>|
| Experimental: Arm 4<br>BMS-945429 + Methotrexate + Adalimumab Placebo | Biological: BMS-945429<br>* Injection, Subcutaneous, 25 mg, Every 4 weeks, Day 1 - Week 24 only<br>Biological: BMS-945429<br>* Injection, Subcutaneous, 200 mg, Every 4 weeks, Week 25 - Week 48<br>Drug: Methotrexate<br>* Tablets, Oral, 15 mg, Weekly, 48 weeks<br>Drug: Adalimumab Placebo<br>* Injection, Subcutaneous, 0 mg, Every 2 weeks, 48 weeks<br>|
| Experimental: Arm 5<br>BMS-945429 + Methotrexate/Methotrexate Placebo + Adalimumab Placebo | Biological: BMS-945429<br>* Injection, Subcutaneous, 200 mg, Every 4 weeks, 48 weeks<br>Drug: Methotrexate Placebo<br>* Tablets, Oral, 0 mg, Weekly, Day 1 - Week 24 only<br>Drug: Methotrexate<br>* Tablets, Oral, 15 mg, Weekly, Week 25 - Week 48 only<br>Drug: Adalimumab Placebo<br>* Injection, Subcutaneous, 0 mg, Every 2 weeks, 48 weeks<br>|
| Experimental: Arm 6<br>BMS-945429 + Methotrexate/Methotrexate Placebo+Adalimumab Placebo | Biological: BMS-945429<br>* Injection, Subcutaneous, 100 mg, Every 4 weeks, 48 weeks<br>Drug: Methotrexate Placebo<br>* Tablets, Oral, 0 mg, Weekly, Day 1 - Week 24 only<br>Drug: Methotrexate<br>* Tablets, Oral, 15 mg, Weekly, Week 25 - Week 48 only<br>Drug: Adalimumab Placebo<br>* Injection, Subcutaneous, 0 mg, Every 2 weeks, 48 weeks<br>|
| Active Comparator: Arm 7<br>Adalimumab + Methotrexate | Drug: Methotrexate<br>* Tablets, Oral, 15 mg, Weekly, 48 weeks<br>Drug: Adalimumab<br>* Injection, Subcutaneous, 40 mg, Every 2 weeks, 48 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Participants Achieving an American College of Rheumatology (ACR) 20% Response Rate | 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 12 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Participants With ACR 20 Response | 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 24 weeks | 
| Percent of Participants Achieving ACR 50 Response Rate | 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 weeks 12 and 24 | 
| Percent of Participants Achieving ACR 70 Response Rate | 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 weeks 12 and 24 | 
| Mean Change From Baseline in Disease Activity as Measured by Disease Activity Score 28 C-reactive Protein (DAS28-CRP) | DAS28-CRP = Disease Activity Scores 28 based on C Reactive Protein. A DAS28-CRP below 2.6 is interpreted as remission. | Baseline, weeks 12 and 24 | 
| Percent of Participants With Remission by DAS28-CRP | DAS28-CRP = Disease Activity Scores 28 based on C Reactive Protein. A DAS28-CRP below 2.6 is interpreted as remission. | At weeks 12 and 24 | 
| Mean Change From Baseline in Clinical Disease Activity Index (CDAI) | 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, weeks 12 and 24 | 
| Percent of Participants With Remission by CDAI | 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 | At weeks 12 and 24 | 
| Mean Change From Baseline in Simplified Disease Activity Index (SDAI) | 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, weeks 12 and 24 | 
| Percent of Participants With Remission by SDAI | 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 | At weeks 12 and 24 | 
| Percent of Participants With Remission Rate by Boolean Definition | 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 weeks 12 and 24 | 
| Mean Change From Baseline in Health Assessment Questionnaire (HAQ) Disability Index | 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, weeks 12 and 24 | 
| Mean Change From Baseline in Short Form 36 (SF-36) as Measured by Physical and Mental Components | The SF-36 questionnaire consists of eight scales yielding two summary measures: physical and mental health. The physical health measure includes four scales of physical functioning (10 items), role-physical (4 items), bodily pain (2 items), and general health (5 items). The mental health measure is composed of vitality (4 items), social functioning (2 items), role-emotional (3 items), and mental health (5 items). To score the SF-36, scales are standardized with a scoring algorithm to obtain a score ranging from 0 to 100. Higher scores indicate better health status. | Baseline, weeks 12 and 24 | 
| Mean Change From Baseline in Fatigue Severity (VAS) Score | A 9-item questionnaire with questions related to how fatigue interferes with certain activities and rates its severity according to a self-report scale. The items are scored on a 7 point scale with 1 = strongly disagree and 7= strongly agree. The minimum score = 9 and maximum score possible = 63. Higher the score = greater fatigue severity. | Baseline, weeks 12 and 24 | 
| Mean Change From Baseline in Work Productivity and Activity Impairment Questionnaire (WPAI) Scores | The WPAI yeilds four types of scores: Absenteeism (work time missed) Presenteesism (impairment at work / reduced on-the-job effectiveness) Work productivty loss (overall work impairment / absenteeism plus presenteeism) Activity Impairment WPAI outcomes are expressed as impairment percentages with each subscale score ranging from 0-100. The subscale scores are added and averaged to produce a total WPAI score between 0-100. Higher scores indicate greater impairment and less productivity. | Baseline, weeks 12 and 24 | 
| Mean Change From Baseline in Radiographic (MRI) Progression of Synovitis, Osteitis (Bone Marrow Edema), Bone Erosion and Cartilage Loss (Joint-space Narrowing) |  | Baseline and week 12 | 
| Mean Change From Baseline in Radiographic (X-ray) Progression of Joint Damage as Measured by Modified Sharp/Van Der Heijde Total Score | The Sharp-van der Heijde total score ranges from 0-528. Scores for erosion range from 0 to 5 in the hands and 0 to 10 in the feet and reflect erosion size, with 0 defined as no erosion and 3 defined as a large erosion passing the midline of the joint. If there is > 1 erosion per joint, scores can be combined to give a maximum score of 5 per joint in the hands and 10 per joint in the feet (a maximum of 5 at each side of the joint). Joint space narrowing scores vary from 0 to 4 in both the hands and feet, with 0 being normal and 4 being the absence of joint space with evident ankylosis or subluxation. Gross osteolysis and pencil-in-cup change are scored separately and, if present, are assigned the maximum score for erosion and joint space narrowing for the same affected joint. Higher scores indicate increased joint damage. | Baseline and week 24 |