A Phase 2 Study of E6011 in Subjects With Rheumatoid Arthritis Inadequately Responding to Biologics

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. Data for the Core Treatment Phase from Week 0-10 is reported according to the participant's re-randomization in four arms at Week 12. Data reported for the Extension Phase from Week 2 to Week 24, is the same data for the Core Treatment Phase, but excluding the participants who received at least 1 dose of study drug after Week 24 and had at least 1 postdose primary efficacy measurement after Week 24 to Week 72.

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. Data for the Core Treatment Phase from Week 0-10 is reported according to the participant's re-randomization in four arms at Week 12. Data reported for the Extension Phase from Week 2 to Week 24, is the same data for the Core Treatment Phase, but excluding the participants who received at least 1 dose of study drug after Week 24 and had at least 1 postdose primary efficacy measurement after Week 24 to Week 72.

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. Data for the Core Treatment Phase from Week 0-10 is reported according to the participant's re-randomization in four arms at Week 12. Data reported for the Extension Phase from Week 2 to Week 24, is the same data for the Core Treatment Phase, but excluding the participants who received at least 1 dose of study drug after Week 24 and had at least 1 postdose primary efficacy measurement after Week 24 to Week 72.

A total of 28 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 for the Core Treatment Phase from Week 0-10 is reported according to the participant's re-randomization in four arms at Week 12. Data reported for the Extension Phase from Baseline to Week 24, is the same data for the Core Treatment Phase, but excluding the participants who received at least 1 dose of study drug after Week 24 and had at least 1 postdose primary efficacy measurement after Week 24 to Week 72.

A total of 28 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 for the Core Treatment Phase from Week 0-10 is reported according to the participant's re-randomization in four arms at Week 12. Data reported for the Extension Phase from Baseline to Week 24, is the same data for the Core Treatment Phase, but excluding the participants who received at least 1 dose of study drug after Week 24 and had at least 1 postdose primary efficacy measurement after Week 24 to Week 72.

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. Pain 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 for the Core Treatment Phase from Week 0-10 is reported according to the participant's re-randomization in four arms at Week 12. Data reported for the Extension Phase from Baseline to Week 24, is the same data for the Core Treatment Phase, but excluding the participants who received at least 1 dose of study drug after Week 24 and had at least 1 postdose primary efficacy measurement after Week 24 to Week 72.

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 for the Core Treatment Phase from Week 0-10 is reported according to the participant's re-randomization in four arms at Week 12. Data reported for the Extension Phase from Baseline to Week 24, is the same data for the Core Treatment Phase, but excluding the participants who received at least 1 dose of study drug after Week 24 and had at least 1 postdose primary efficacy measurement after Week 24 to Week 72.

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 for the Core Treatment Phase from Week 0-10 is reported according to the participant's re-randomization in four arms at Week 12. Data reported for the Extension Phase from Baseline to Week 24, is the same data for the Core Treatment Phase, but excluding the participants who received at least 1 dose of study drug after Week 24 and had at least 1 postdose primary efficacy measurement after Week 24 to Week 72.

Degree of disability was self-evaluated by participant using HAQ-DI.Assessment was made based on activities capable without any aids/devices.20-question instrument assessed degree of difficulty 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 task in that area).Overall score computed as: sum of domain scores and divided by number of domains answered.Total possible score range:0-3 where 0=least difficulty and 3=extreme difficulty.Data for Core Treatment Phase from Week 0-10 is reported according to participant re-randomization in 4 arms at Week 12.Data reported for Extension Phase from Baseline to Week 24,is same data for Core Treatment Phase,but excluding participants who received at least 1 dose of drug and had at least 1 postdose primary efficacy measurement after Week 24-72.

CRP of each participants was measured as a part of blood biochemical tests. A normal CRP value is less than (<) 10 milligram per deciliter (mg/dL). A test result showing a CRP level greater than 10 mg/dL is a sign of chronic disease. Data for the Core Treatment Phase from Week 0-10 is reported according to the participant's re-randomization in four arms at Week 12. Data reported for the Extension Phase from Baseline to Week 24, is the same data for the Core Treatment Phase, but excluding the participants who received at least 1 dose of study drug after Week 24 and had at least 1 postdose primary efficacy measurement after Week 24 to Week 72.

ESR were a type of blood test. An ESR was used to monitor the arthritis condition. Data for the Core Treatment Phase from Week 0-10 is reported according to the participant's re-randomization in four arms at Week 12. Data reported for the Extension Phase from Baseline to Week 24, is the same data for the Core Treatment Phase, but excluding the participants who received at least 1 dose of study drug after Week 24 and had at least 1 postdose primary efficacy measurement after Week 24 to Week 72.

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 greater than (>) 3.2 and less than or equal to (<=) 5.1=moderate disease activity and value <=3.2=low disease activity, value <2.6=disease remission. A positive change in score indicates worsening, and a negative change indicates improvement. Data for the Core Treatment Phase from Week 0-10 is reported according to the participant's re-randomization in four arms at Week 12. Data reported for the Extension Phase from Baseline to Week 24, is the same data for the Core Treatment Phase, but excluding the participants who received at least 1 dose of study drug after Week 24 and had at least 1 postdose primary efficacy measurement after Week 24 to Week 72.

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 4.1 or above=high disease activity, a value >2.7 and <=4.1=moderate disease activity and a value <=2.7=low disease activity, value <2.3=disease remission. A positive change in score indicates worsening, and a negative change indicates improvement. Data for the Core Treatment Phase from Week 0-10 is reported according to the participant's re-randomization in four arms at Week 12. Data reported for the Extension Phase from Baseline to Week 24, is the same data for the Core Treatment Phase, but excluding the participants who received at least 1 dose of study drug after Week 24 and had at least 1 postdose primary efficacy measurement after Week 24 to Week 72.

The SDAI was calculated from tender joint counts of 28 (score range as 0-28), swollen joint counts of 28 (score range as 0-28), participant's global assessment of disease activity (score range as 0-10), physician global assessment of disease activity score (score range as 0-10), and CRP value (score range as 0-10). Total score ranged between 0-86. SDAI score of 26 or above=high disease activity, a value >11 and <=26=moderate disease activity and value <=11=low disease activity, value <=3.3=disease remission. Higher scores indicated higher disease activity. Data for the Core Treatment Phase from Week 0-10 is reported according to the participant's re-randomization in four arms at Week 12. Data reported for the Extension Phase from Baseline to Week 24, is the same data for the Core Treatment Phase, but excluding the participants who received at least 1 dose of study drug after Week 24 and had at least 1 postdose primary efficacy measurement after Week 24 to Week 72.

The CDAI was calculated from tender joint counts of 28 (score range as 0-28), swollen joint counts of 28 (score range as 0-28), participant's global assessment of disease activity (score range as 0-10) and physician global assessment of disease activity (score range as 0-10). Total score ranged between 0-76. CDAI score of 22 or above=high disease activity, a value >10 and <=22=moderate disease activity, a value <=10=low disease activity, and a value <=2.8=disease remission. Higher scores indicated higher disease activity. Data for the Core Treatment Phase from Week 0-10 is reported according to the participant's re-randomization in four arms at Week 12. Data reported for the Extension Phase from Baseline to Week 24, is the same data for the Core Treatment Phase, but excluding the participants who received at least 1 dose of study drug after Week 24 and had at least 1 postdose primary efficacy measurement after Week 24 to Week 72.

The Disease Activity Score Based on 28-joints Count-ESR 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 for the Core Treatment Phase from Week 0-10 is reported according to the participant's re-randomization in four arms at Week 12. Data reported for the Extension Phase from Week 2 to Week 24, is the same data for the Core Treatment Phase, but excluding the participants who received at least 1 dose of study drug after Week 24 and had at least 1 postdose primary efficacy measurement after Week 24 to Week 72.

The Disease Activity Score Based on 28-joints Count-CRP 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 for the Core Treatment Phase from Week 0-10 is reported according to the participant's re-randomization in four arms at Week 12. Data reported for the Extension Phase from Week 2 to Week 24, is the same data for the Core Treatment Phase, but excluding the participants who received at least 1 dose of study drug after Week 24 and had at least 1 postdose primary efficacy measurement after Week 24 to Week 72.

The SDAI was calculated from tender joint counts of 28 (score range as 0-28), swollen joint counts of 28 (score range as 0-28), participant's global assessment of disease activity (score range as 0-10), physician global assessment of disease activity score (score range as 0-10), and CRP value (score range as 0-10). Total score ranged between 0-86. SDAI score of 86 or above=high disease activity, a value >11 and <=26=moderate disease activity, a value >=3.4 and <=11=low disease activity. Higher scores indicated higher disease activity. SDAI Remission was defined as SDAI score <=3.3. Data for Core Treatment Phase from Week 0-10 is reported according to participant's re-randomization in four arms at Week 12. Data reported for Extension Phase from Week 2 to Week 24, is same data for Core Treatment Phase, but excluding participants who received at least 1 dose of study drug after Week 24 and had at least 1 postdose primary efficacy measurement after Week 24 to Week 72.

The CDAI was calculated from tender joint counts of 28 (score range as 0-28), swollen joint counts of 28 (score range as 0-28), participant's global assessment of disease activity (score range as 0-10), and physician global assessment of disease activity score (score range as 0-10). Total score ranged between 0-76. CDAI score of 76 or above=high disease activity, a value >10 and <=22=moderate disease activity, a value >2.9 and <=10=low disease activity. Higher scores indicated higher disease activity. CDAI Remission was defined as CDAI score <=2.8. Data for the Core Treatment Phase from Week 0-10 is reported according to the participant's re-randomization in four arms at Week 12. Data reported for the Extension Phase from Week 2 to Week 24, is the same data for the Core Treatment Phase, but excluding the participants who received at least 1 dose of study drug after Week 24 and had at least 1 postdose primary efficacy measurement after Week 24 to Week 72.

Boolean remission criteria was defined as: tender joint count 68 <=1; swollen joint count 66 <=1; CRP <=1 mg/dL; and disease activity assessments VAS (mm) by participants <=10. Data for the Core Treatment Phase from Week 0-10 is reported according to the participant's re-randomization in four arms at Week 12. Data reported for the Extension Phase from Week 2 to Week 24, is the same data for the Core Treatment Phase, but excluding the participants who received at least 1 dose of study drug after Week 24 and had at least 1 postdose primary efficacy measurement after Week 24 to Week 72.