Efficacy and Safety Study of BMS-986142 in Patients With Moderate to Severe Rheumatoid Arthritis

Study Overview
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Brief Summary
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The purpose of this study is to determine whether the study drug, BMS-986142, is safe and effective in treating moderate to severe rheumatoid arthritis in subjects with an inadequate response to methotrexate or methotrexate and up to 2 tumour necrosis factor (TNF) Inhibitors. Patients who qualify will be randomized to either one of 3 doses of BMS-986142 or placebo in 1:1:1 randomization for 12 weeks. Disease activity and safety will be assessed over the course of the study.

Official Title
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Phase 2, Randomized, Multi-Center, Double-Blind, Dose-Ranging, Placebo Controlled, Adaptive Design Study to Evaluate the Efficacy and Safety/Pharmacokinetics of BMS-986142 in Subjects With Moderate to Severe Rheumatoid Arthritis With an Inadequate Response to Methotrexate With or Without TNF Inhibitors

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: BMS-986142
* Drug: Placebo
* Drug: Methotrexate


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: Male and female age 18 and above Diagnosed with active rheumatoid arthritis (RA) by standard criteria at least 16 weeks before screening, have functional ACR class I-III Have an inadequate response to methotrexate In addition to an inadequate response to methotrexate have an inadequate response or intolerance to 1 but not more than 2 TNF inhibitors Have a minimum of 6 swollen and 6 tender joints (from 66/68 joint count) Have hsCRP of ≥ 0.8 mg/dL (8mg/L) [by central laboratory values] or an ESR ≥ 28 mm/hr Willing to use effective birth control for the entire length of the study Exclusion Criteria: Diagnosed with juvenile Rheumatoid Arthritis Have been treated with other biologic treatment than a TNF inhibitor Active systemic bacterial, viral or fungal infection or evidence of prior or current Hepatitis B or C infection or HIV infection, latent bacterial, viral or fungal infections Have been treated with Intramuscular or Intra-articular glucocorticosteroids within 4 weeks of randomization Taking Oral steroids at dose above 10 mg/day of prednisone (or prednisone equivalents) Have other autoimmune disease other than RA like lupus, multiple sclerosis Have significant concurrent medical condition at the time of screening or baseline visit

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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<br>Placebo + Methotrexate dose as specified | Drug: Placebo<br>* Placebo of BMS-986142 specific dose on specific days<br>Drug: Methotrexate<br>* Methotrexate specific dose on specific days<br>|
| Experimental: Dose Level 1<br>BMS-986142 at dose level 1+ Methotrexate as specified | Drug: BMS-986142<br>* BMS986142 specific dose on specific days<br>Drug: Methotrexate<br>* Methotrexate specific dose on specific days<br>|
| Experimental: Dose Level 2<br>BMS-986142 at dose level 2 + Methotrexate as specified | Drug: BMS-986142<br>* BMS986142 specific dose on specific days<br>Drug: Methotrexate<br>* Methotrexate specific dose on specific days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response at Week 12 | ACR responses are assessed with a composite rating scale of the American College of Rheumatology that includes 7 variables: tender joint count (TJC); swollen joint count (SJC); levels of an acute phase reactant C-reactive Protein levels (CRP); participant's assessment of pain; participant's global assessment of disease activity; physician's global assessment of disease activity; participant's assessment of physical function by health assessment questionnaire disability index (HAQ-DI). ACR20 is defined as achieving at least 20% improvement in both TJC and SJC, and at least 20% improvement in at least 3 of the 5 other assessments of the ACR. Percentage of Participants achieving ACR20 = (number of participants with measure/event of interest)/(number of particpants in the analysis)*100 | Week 12 | 
| Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response at Week 12 | ACR responses are assessed with a composite rating scale of the American College of Rheumatology that includes 7 variables: TJC; SJC; levels of an acute phase reactant (CRP level); participant's assessment of pain; participant's global assessment of disease activity; physician's global assessment of disease activity; participant's assessment of physical function by HAQ--DI. ACR70 is defined as achieving at least 70% improvement in both TJC and SJC, and at least 70% improvement in at least 3 of the 5 other assessments of the ACR. Percentage of Participants achieving ACR70 = (number of participants with measure/event of interest)/(number of particpants in the analysis)*100 | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving American College of Rheumatology 20% Response Over Time From Baseline to Week 12 | ACR responses are assessed with a composite rating scale of the American College of Rheumatology that includes 7 variables: tender joint count (TJC); swollen joint count (SJC); levels of an acute phase reactant C-reactive Protein levels (CRP); participant's assessment of pain; participant's global assessment of disease activity; physician's global assessment of disease activity; participant's assessment of physical function by health assessment questionnaire disability index (HAQ-DI). ACR20 is defined as achieving at least 20% improvement in both TJC and SJC, and at least 20% improvement in at least 3 of the 5 other assessments of the ACR. Percentage of Participants achieving ACR20 = (number of participants with measure/event of interest)/(number of particpants in the analysis)*100 | Baseline, Day 15, Day 29, Day 57, Day 85 | 
| Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response Over Time From Baseline to Week 12 | ACR responses are assessed with a composite rating scale of the American College of Rheumatology that includes 7 variables: TJC; SJC; levels of an acute phase reactant (CRP level); participant's assessment of pain; participant's global assessment of disease activity; physician's global assessment of disease activity; participant's assessment of physical function by HAQ--DI. ACR70 is defined as achieving at least 50% improvement in both TJC and SJC, and at least 50% improvement in at least 3 of the 5 other assessments of the ACR. Percentage of Participants achieving ACR50 = (number of participants with measure/event of interest)/(number of particpants in the analysis)*100 | Baseline, Day 15, Day 29, Day 57, Day 85 | 
| Percentage of Participants Achieving American College of Rheumatology 70% Response Over Time From Baseline to Week 12 | ACR responses are assessed with a composite rating scale of the American College of Rheumatology that includes 7 variables: TJC; SJC; levels of an acute phase reactant (CRP level); participant's assessment of pain; participant's global assessment of disease activity; physician's global assessment of disease activity; participant's assessment of physical function by HAQ--DI. ACR70 is defined as achieving at least 70% improvement in both TJC and SJC, and at least 70% improvement in at least 3 of the 5 other assessments of the ACR. Percentage of Participants achieving ACR70 = (number of participants with measure/event of interest)/(number of particpants in the analysis)*100 | Baseline, Day 15, Day 29, Day 57, Day 85 | 
| Percentage of Participants Achieving < 2.6 Response in Disease Activity Score for 28 Joints -C-Reactive Protein (DAS28--CRP) Score at Week 12 | DAS28 is a composite score that includes 4 variables: TJC (based on 28 joints); SJC (based on 28 joints); General health (GH) assessment by the participant assessed from the ACR rheumatoid arthritis (RA) core set questionnaire (participant global assessment) in 100 mm visual analog scale (VAS). Marker of inflammation assessed by the high sensitivity C-reactive protein (hs-CRP) in mg/L. The DAS28 score provides a number indicating the current disease activity of the RA. DAS28 total score ranges from 2-10. A DAS28 score above 5.1 means high disease activity, whereas a DAS28 score below 3.2 indicates low disease activity and a DAS28 score below 2.6 means disease remission. | Week 12 | 
| Percentage of Participants Achieving < 2.6 Response in Disease Activity Score for 28 Joints Erythrocyte Sedimentation Rate (DAS28--ESR) Score at Week 12 | DAS28-ESR is a composite score that includes 4 variables: TJC (based on 28 joints); SJC (based on 28 joints); General health (GH) assessment by the participant assessed from the ACR RA core set questionnaire (participant global assessment) in 100 mm VAS; Marker of inflammation assessed by ESR in mm/hr. The DAS28-ESR score provides a number indicating the current disease activity of the RA. DAS28-ESR total score ranges from 2-10. A DAS28-ESR score above 5.1 means high disease activity, DAS28-ESR score below 3.2 indicates low disease activity and DAS28-ESR score below 2.6 means disease remission. | Week 12 | 
| Percentage of Participants Achieving <= 2.8 Response in Clinical Disease Activity Index (CDAI) Score at Week 12 | CDAI is a composite index constructed to measure clinical remission in RA that does not include a laboratory test, and is a numerical summation of 4 components: TJC (28 joints), SJC (28 joints), Participant's Global Assessment of Disease Activity VAS (in cm), and Physician's Global Assessment of Disease VAS (in cm). Total scores ranges from 0 to 76 with a negative change in CDAI score indicating an improvement in disease activity and a positive change in score indicating a worsening of disease activity. | Week 12 | 
| Percentage of Participants Achieving <= 3.3 Response in Simple Disease Activity Index (SDAI) Score at Week 12 | The SDAI is the numerical sum of five outcome parameters: TJC and SJC based on a 28-joint assessment, patient global assessment (PtGA) and physician global assessment (PGA) assessed on a VAS scale ranging from 0 to 10 cm, where higher scores indicate greater affection due to disease activity, and CRP measured in terms of milligram per deciliter (mg/dL). SDAI total score ranges from 0 to 86. SDAI <= 3.3 indicates disease remission, > 3.4 to 11 indicates low disease activity, >11 to 26 indicates moderate disease activity, and >26 indicates high disease activity. | Week 12 | 
| Percentage of Participants Achieving Boolean Remission Criteria at Week 12 | Boolean remission criteria was defined as: tender joint count28 <= 1; swollen joint count28 <= 1; physician's global assessment <= 1; and CRP <= 1 mg/deciliter. | Week 12 | 
| Change From Baseline in DAS28-CRP Score Over Time up to Week 12 | DAS28 is a composite score that includes 4 variables: TJC (based on 28 joints); SJC (based on 28 joints); General health (GH) assessment by the participant assessed from the ACR rheumatoid arthritis (RA) core set questionnaire (participant global assessment) in 100 mm visual analog scale (VAS). Marker of inflammation assessed by the high sensitivity C-reactive protein (hs-CRP) in mg/L. The DAS28 score provides a number indicating the current disease activity of the RA. DAS28 total score ranges from 2-10. A DAS28 score above 5.1 means high disease activity, whereas a DAS28 score below 3.2 indicates low disease activity and a DAS28 score below 2.6 means disease remission. | Baseline, Day 85 (Week 12) | 
| Change From Baseline in DAS28-ESR Score Over Time up to Week 12 | DAS28-ESR is a composite score that includes 4 variables: TJC (based on 28 joints); SJC (based on 28 joints); General health (GH) assessment by the participant assessed from the ACR RA core set questionnaire (participant global assessment) in 100 mm VAS; Marker of inflammation assessed by ESR in mm/hr. The DAS28-ESR score provides a number indicating the current disease activity of the RA. DAS28-ESR total score ranges from 2-10. A DAS28-ESR score above 5.1 means high disease activity, DAS28-ESR score below 3.2 indicates low disease activity and DAS28-ESR score below 2.6 means disease remission. | Baseline, Week 12 | 
| Change From Baseline in CDAI Score Over Time up to Week 12 | CDAI is a composite index constructed to measure clinical remission in RA that does not include a laboratory test, and is a numerical summation of 4 components: TJC (28 joints), SJC (28 joints), Participant's Global Assessment of Disease Activity VAS (in cm), and Physician's Global Assessment of Disease VAS (in cm). Total scores ranges from 0 to 76 with a negative change in CDAI score indicating an improvement in disease activity and a positive change in score indicating a worsening of disease activity. | Baseline, Week 12 | 
| Change From Baseline in SDAI Score Over Time up to Week 12 | The SDAI is the numerical sum of five outcome parameters: TJC and SJC based on a 28-joint assessment, PtGA and PGA assessed on a VAS scale ranging from 0 to 10 cm, where higher scores indicate greater affection due to disease activity, and CRP measured in terms of mg/dL. SDAI total score ranges from 0 to 86. SDAI <= 3.3 indicates disease remission, > 3.4 to 11 indicates low disease activity, >11 to 26 indicates moderate disease activity, and >26 indicates high disease activity. | Baseline, Week 12 | 
| Number of Participants With Adverse Events (AEs), and Serious AEs (SAEs) | An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. An SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death, initial or prolonged inpatient hospitalization, life-threatening experience (immediate risk of dying), persistent or significant disability/incapacity, or a congenital anomaly, or a medically important event. | Up to 30 days after treatment discontinuation | 
| Trough Observed Plasma Concentration (Ctrough) of BMS-986142 | Ctrough was defined as trough observed plasma concentration. | Week 4, 8, and 12 | 
| Mean Change From Baseline in Rheumatoid Arthritis Magnetic Resonance Imaging Scoring System (RAMRIS) Scores for Synovitis at Week 4 and 12 | Synovitis is assessed in 3 wrist regions (A. the distal radioulnar joint; B. the radiocarpal joint; C. the intercarpal and carpometacarpophalangeal, CMC, joints) and in each MCP joint. For each wrist region, possible score ranges from 0-3, with 0=normal, 1=mild, 2=moderate, and 3=severe damage. The total synovitis score per wrist=the sum of the individual scores for the 3 wrist regions. Minimum score per wrist ranges from 0, indicating no damage, to 9 (score of 3*3 wrist regions), indicating most severe damage. A negative change from baseline indicates improvement. | Week 4 and Week 12 | 
| Mean Change From Baseline in Rheumatoid Arthritis Magnetic Resonance Imaging Scoring System (RAMRIS) Scores for Osteitis at Week 4 and 12 | Osteitis was assessed at a total of 23 anatomic locations: 15 in 1 wrist and 8 in the hand of the same side. Each site is scored in 1.0 increments from 0 to 3, indicating involvement of original articular bone. The total score for the hands/wrists is the sum of the individual scores for each location. Thus the maximum score achievable per hand/wrist is 23 (total number of anatomic locations) * 3 (maximum per joint)=69. Minimum score=0, indicating normal. Increasing score=greater severity. A negative change from baseline indicates improvement. | Week 4, and Week 12 | 
| Mean Change From Baseline in Rheumatoid Arthritis Magnetic Resonance Imaging Scoring System (RAMRIS) Scores for Bone Erosion at Week 4 and 12 | Bone erosion assessed at a total of 23 anatomic locations: 15 in 1 wrist and 8 in the hand of the same side. Each site is scored in 1.0 increments from 0 (no damage) to 10 (severe damage) according to erosion of the original articular bone (each unit=10% loss of articular bone). The total erosion score for the hands/wrists is the sum of the individual scores for each location. Thus the maximum score achievable per hand/wrist is 230. Increasing score=greater severity.A negative change from baseline indicates improvement. | Week 4 and Week 12 | 
| Mean Change From Baseline in Rheumatoid Arthritis Magnetic Resonance Imaging Scoring System (RAMRIS) Scores for Cartilage Loss at Week 4 and 12 | Cartilage loss was assessed by MRI. Scans of 25 joints were read and scored for each participant by assessors. Scores for each location ranged 0-4 on a 9-point scale, with 0= no cartilage loss and 4= complete cartilage loss. Total score was the sum of the 25 individual scores and ranged 0-100 with 0= no cartilage loss and 100= most severe cartilage loss. A negative change from baseline indicates improvement. | Week 4, and Week12 |