A Dose Response Study of E6011 in Participants With Rheumatoid Arthritis Inadequately Responding to Methotrexate

The ACR20 response was defined as if the following 3 criteria (ACR components) were met: Greater than or equal to (>=) 20 percent (%) reduction from baseline in the tender joint count (TJC) in 68 joints (TJC68); >=20% reduction from baseline in the swollen joint count (SJC) in 66 joints (SJC66); >=20% reduction from baseline in at least 3 of the following 5 assessments: Physician's Global Assessment of Disease Activity (visual analog scale [VAS]) , Participant's Global Assessment of Disease Activity (VAS), Participant's Assessment of Pain (VAS), Health Assessment Questionnaire disability index (HAQ-DI), and C-reactive protein (CRP).

The ACR20 response was defined as if the following 3 criteria (ACR components) were met: >=20% reduction from baseline in the TJC in 68 joints (TJC68); >=20% reduction from baseline in the SJC in 66 joints (SJC66); >=20% reduction from baseline in at least 3 of the following 5 assessments: Physician's Global Assessment of Disease Activity (VAS), Participant's Global Assessment of Disease Activity (VAS), Participant's Assessment of Pain (VAS), HAQ-DI, and CRP.

The ACR50 response was defined as if the following 3 criteria (ACR components) were met: >=50% reduction from baseline in the TJC in 68 joints (TJC68); >=50% reduction from baseline in the SJC in 66 joints (SJC66); >=50% reduction from baseline in at least 3 of the following 5 assessments: Physician's Global Assessment of Disease Activity (VAS), Participant's Global Assessment of Disease Activity (VAS), Participant's Assessment of Pain (VAS), HAQ-DI, and CRP.

The ACR70 response was defined as if the following 3 criteria (ACR components) were met: >=70% reduction from baseline in the TJC in 68 joints (TJC68); >=70% reduction from baseline in the SJC in 66 joints (SJC66); >=70% reduction from baseline in at least 3 of the following 5 assessments: Physician's Global Assessment of Disease Activity (VAS), Participant's Global Assessment of Disease Activity (VAS), Participant's Assessment of Pain (VAS), HAQ-DI, and CRP.

A total of 68 joints were examined for tenderness by applying pressure to the joint line or by moving joints through their respective ranges of motion. Joints were examined for tenderness by applying pressure to the joint line or by moving joints through their respective ranges of motion. Tender joints were marked with tick or cross in corresponding frames of the Assessment Sheet for Tender Joint Counts. Data reported for the Extension Phase from Baseline to Week 24, is the same data for the Treatment Phase, but excluding the participants who did not gave consent to participate in Extension Phase.

A total of 66 joints (minus 2 hip joints from evaluated tender joints) were examined for swollen joints. Swollen joints were marked with open circles in corresponding frames of the Assessment Sheet for Swollen Joint Counts. Data reported for the Extension Phase from Baseline to Week 24, is the same data for the Treatment Phase, but excluding the participants who did not gave consent to participate in Extension Phase.

Intensity and severity of pain associated with rheumatoid arthritis (RA) were indicated by the participant on a score sheet, Pain/disease activity assessments reported by the participant, by placing a mark on a 100 millimeter (mm) horizontal VAS. The scale ranged from 0-100 mm, where 0 indicated no disease activity (symptom free and no arthritis symptoms) and 100 represented maximum disease activity (maximum arthritis disease activity). Data reported for the Extension Phase from Baseline to Week 24, is the same data for the Treatment Phase, but excluding the participants who did not gave consent to participate in Extension Phase.

Participants were evaluated on their disease activity of RA, and entered the result on the score sheet, disease activity assessments reported by the participant, by placing a mark on a 100 mm horizontal VAS. The scale ranged from 0-100 mm, where 0 indicated no disease activity (symptom free and no arthritis symptoms) and 100 represented maximum disease activity (maximum arthritis disease activity). Data reported for the Extension Phase from Baseline to Week 24, is the same data for the Treatment Phase, but excluding the participants who did not gave consent to participate in Extension Phase.

The Physician's Global Assessment of Disease Activity was recorded using the 100 mm horizontal VAS. Physician rated participant's RA disease activity on a scale ranged from 0-100 mm, where 0 indicated no disease activity (no arthritis) and 100 represented maximum disease activity (maximum arthritis). Data reported for the Extension Phase from Baseline to Week 24, is the same data for the Treatment Phase, but excluding the participants who did not gave consent to participate in Extension Phase.

The degree of disability was self-evaluated by the participant using the HAQ-DI. The assessment was made based on the activities capable without any aids or devices. The 20-question instrument assessed the degree of difficulty a person had in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living). Responses in each functional area were scored from 0, indicated no difficulty, to 3, indicated inability to perform a task in that area. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range: 0-3 where 0 = least difficulty and 3 = extreme difficulty. Data reported for the Extension Phase from Baseline to Week 24, is the same data for the Treatment Phase, but excluding the participants who did not gave consent to participate in Extension Phase.

CRP of each participants was measured as a part of blood biochemical tests. Data reported for the Extension Phase from Baseline to Week 24, is the same data for the Treatment Phase, but excluding the participants who did not gave consent to participate in Extension Phase.

ESR were a type of blood test. An ESR was used to monitor the arthritis condition. Data reported for the Extension Phase from Baseline to Week 24, is the same data for the Treatment Phase, but excluding the participants who did not gave consent to participate in Extension Phase.

The DAS28 index was a composite score of weighted components including tender joint counts of 28, swollen joint counts of 28, participant global assessment of disease activity score, and ESR value. Total score ranged between 0-10. A DAS28-ESR score of 5.1 or above = high disease activity, a value between 3.2 and 5.1 = moderate disease activity and value between 2.6 and 3.2 = low disease activity, value <2.6 = disease remission. A positive change in score indicates worsening, and a negative change indicates improvement. Data reported for the Extension Phase from Baseline to Week 24, is the same data for the Treatment Phase, but excluding the participants who did not gave consent to participate in Extension Phase.

The DAS28 index was a composite score of weighted components including tender joint counts of 28, swollen joint counts of 28, participant global assessment of disease activity score, and CRP value. Total score ranged between 0-10. A DAS28-CRP score of 5.1 or above = high disease activity, a value between 3.2 and 5.1 = moderate disease activity and value between 2.6 and 3.2 = low disease activity, value <2.6 = disease remission. A positive change in score indicates worsening, and a negative change indicates improvement. Data reported for the Extension Phase from Baseline to Week 24, is the same data for the Treatment Phase, but excluding the participants who did not gave consent to participate in Extension Phase.

The SDAI was calculated from tender joint counts of 28, swollen joint counts of 28, participant's global assessment of disease activity, physician global assessment of disease activity score, and CRP value. Total score ranged between 0-86. SDAI score of 26 or above = high disease activity, a value between 11 and 26 = moderate disease activity and value less than or equal to (<=) 11 = low disease activity, value <=33 = disease remission. Higher scores indicated higher disease activity. Data reported for the Extension Phase from Baseline to Week 24, is the same data for the Treatment Phase, but excluding the participants who did not gave consent to participate in Extension Phase.

The CDAI was calculated from tender joint counts of 28, swollen joint counts of 28, participant's global assessment of disease activity, physician global assessment of disease activity score, and CRP value. Total score ranged between 0-76. CDAI score of 22 or above = high disease activity, a value between 10 and 22 = moderate disease activity and value less than or equal to <=10 = low disease activity, value <=2.8 = disease remission. Higher scores indicated higher disease activity. Data reported for the Extension Phase from Baseline to Week 24, is the same data for the Treatment Phase, but excluding the participants who did not gave consent to participate in Extension Phase.

The Disease Activity Score Based on 28-joints Count based EULAR response criteria were used to measure individual response as none, good, and moderate, depending on the extent of change from baseline and the level of disease activity reached. Good responders: change from baseline >1.2 with DAS28 <=3.2; moderate responders: change from baseline >1.2 with DAS28 >3.2 to <=5.1 or change from baseline >0.6 to <=1.2 with DAS28 <=5.1; non-responders: change from baseline <=0.6 or change from baseline >0.6 and <=1.2 with DAS28 >5.1. Data reported for the Extension Phase from Week 2 to Week 24, is the same data for the Treatment Phase, but excluding the participants who did not gave consent to participate in Extension Phase.

The Disease Activity Score Based on 28-joints Count based EULAR response criteria were used to measure individual response as none, good, and moderate, depending on the extent of change from baseline and the level of disease activity reached. Good responders: change from baseline >1.2 with DAS28 <=3.2; moderate responders: change from baseline >1.2 with DAS28 >3.2 to <=5.1 or change from baseline >0.6 to <=1.2 with DAS28 <=5.1; non-responders: change from baseline <=0.6 or change from baseline >0.6 and <=1.2 with DAS28 >5.1. Data reported for the Extension Phase from Week 2 to Week 24, is the same data for the Treatment Phase, but excluding the participants who did not gave consent to participate in Extension Phase.

The SDAI was calculated from tender joint counts of 28, swollen joint counts of 28, participant's global assessment of disease activity, physician global assessment of disease activity score, and CRP value. Total score ranged between 0-86. SDAI score of 26 or above = high disease activity, a value between 11 and 26 = moderate disease activity and value <=11 = low disease activity. Higher scores indicated higher disease activity. SDAI Remission was defined as SDAI score <=3.3. Data reported for the Extension Phase from Week 2 to Week 24, is the same data for the Treatment Phase, but excluding the participants who did not gave consent to participate in Extension Phase.

The CDAI was calculated from tender joint counts of 28, swollen joint counts of 28, participant's global assessment of disease activity, physician global assessment of disease activity score, and CRP value. Total score ranged between 0-76. CDAI score of 22 or above = high disease activity, a value between 10 and 22 = moderate disease activity and value less than or equal to <=10 = low disease activity. Higher scores indicated higher disease activity. CDAI Remission was defined as CDAI score <=2.8. Data reported for the Extension Phase from Week 2 to Week 24, is the same data for the Treatment Phase, but excluding the participants who did not gave consent to participate in Extension Phase.

Boolean remission criteria was defined as: tender joint count 68 <=1; swollen joint count 68 <=1; CRP <=1 mg/dL; and disease activity assessments VAS (mm) by participants <=1. Data reported for the Extension Phase from Week 2 to Week 24, is the same data for the Treatment Phase, but excluding the participants who did not gave consent to participate in Extension Phase.

The mTSS was a measure of change in joint health. X-rays of hands, wrists, and feet (including distal interphalangeal joints) were obtained. Totals for hands and feet for erosion scores (range 0 to 320) and joint space narrowing scores (range 0 to 208) were calculated and added to obtain the mTSS (range = 0 [normal] to 528 [maximal disease]). An increase in mTSS from Baseline represents disease progression and/or joint worsening; no progression was defined as a change of <=0.5. Data reported for the Extension Phase from Baseline and Week 24, is the same data for the Treatment Phase, but excluding the participants who did not gave consent to participate in Extension Phase.