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

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

Time frame: Week 12

Population: Analysis was performed on efficacy population which excluded participants who were randomized to a treatment arm and discontinued based on the interim analysis (IA).

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

Time frame: Week 12

Population: Analysis was performed on efficacy population which excluded participants who were randomized to a treatment arm and discontinued based on the interim analysis (IA)

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.

Time frame: Baseline, Week 12

Population: Analysis was performed on efficacy population which excluded participants who were randomized to a treatment arm and discontinued based on the interim analysis (IA). Here 'N' signifies number of participants analyzed who were evaluable for this outcome measure.

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.

Time frame: Baseline, Day 85 (Week 12)

Population: Analysis was performed on efficacy population which excluded participants who were randomized to a treatment arm and discontinued based on the interim analysis (IA). Here 'N' signifies number of participants analyzed who were evaluable for this outcome measure.

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.

Time frame: Baseline, Week 12

Population: Analysis was performed on efficacy population which excluded participants who were randomized to a treatment arm and discontinued based on the interim analysis (IA). Here 'N' signifies number of participants analyzed who were evaluable for this outcome measure.

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.

Time frame: Baseline, Week 12

Population: Analysis was performed on efficacy population which excluded participants who were randomized to a treatment arm and discontinued based on the interim analysis (IA). Here 'N' signifies number of participants analyzed who were evaluable for this outcome measure.

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.

Time frame: Week 4 and Week 12

Population: Analysis was performed on efficacy population which excluded participants who were randomized to a treatment arm and discontinued based on the interim analysis (IA). Here number analyzed = number of randomized and treated participants with non-missing value at each time point

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.

Time frame: Week 4, and Week12

Population: Analysis was performed on efficacy population which excluded participants who were randomized to a treatment arm and discontinued based on the interim analysis (IA). Here number analyzed = number of randomized and treated participants with non-missing value at each time point

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.

Time frame: Week 4, and Week 12

Population: Analysis was performed on efficacy population which excluded participants who were randomized to a treatment arm and discontinued based on the interim analysis (IA). Here number analyzed = number of randomized and treated participants with non-missing value at each time point

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.

Time frame: Week 4 and Week 12

Population: Analysis was performed on efficacy population which excluded participants who were randomized to a treatment arm and discontinued based on the interim analysis (IA). Here number analyzed = number of randomized and treated participants with non-missing value at each time point

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.

Time frame: Up to 30 days after treatment discontinuation

Population: All treated participants.

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.

Time frame: Week 12

Population: Analysis was performed on efficacy population which excluded participants who were randomized to a treatment arm and discontinued based on the interim analysis (IA)

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.

Time frame: Week 12

Population: Analysis was performed on efficacy population which excluded participants who were randomized to a treatment arm and discontinued based on the interim analysis (IA)

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.

Time frame: Week 12

Population: Analysis was performed on efficacy population which excluded participants who were randomized to a treatment arm and discontinued based on the interim analysis (IA)

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.

Time frame: Week 12

Population: Analysis was performed on efficacy population which excluded participants who were randomized to a treatment arm and discontinued based on the interim analysis (IA)

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

Time frame: Baseline, Day 15, Day 29, Day 57, Day 85

Population: Analysis was performed on efficacy population which excluded participants who were randomized to a treatment arm and discontinued based on the interim analysis (IA)

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

Time frame: Baseline, Day 15, Day 29, Day 57, Day 85

Population: Analysis was performed on efficacy population which excluded participants who were randomized to a treatment arm and discontinued based on the interim analysis (IA)

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

Time frame: Baseline, Day 15, Day 29, Day 57, Day 85

Population: Analysis was performed on efficacy population which excluded participants who were randomized to a treatment arm and discontinued based on the interim analysis (IA)

Boolean remission criteria was defined as: tender joint count28 \<= 1; swollen joint count28 \<= 1; physician's global assessment \<= 1; and CRP \<= 1 mg/deciliter.

Time frame: Week 12

Population: Analysis was performed on efficacy population which excluded participants who were randomized to a treatment arm and discontinued based on the interim analysis (IA)

Ctrough was defined as trough observed plasma concentration.

Time frame: Week 4, 8, and 12

Population: Analysis was performed on pharmacokinetic population which included all participants who received BMS-986142 and had any available concentration-time data.