A Study for Patients With Rheumatoid Arthritis on Methotrexate (MTX) With an Inadequate Response to TNFα Inhibitor Therapy

ACR50 Responder Index is a composite of clinical, laboratory, and functional measures in rheumatoid arthritis. ACR50 Responder is defined as a participant with greater than 50% improvement from baseline in both tender and swollen joint counts and in at least 3 of the following 5 criteria: physician global assessment, patient global assessment, functional ability measure (Health Assessment Questionnaire-Disability Index which measures participants' perceived degree of difficulty when performing various daily activities), visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein.

Time frame: 16 weeks

Population: Non-responder imputation/last observation carried forward (NRI/LOCF); intention to treat (ITT) population defined as participants who were randomized, received at least one dose of study drug, and had at least one post-baseline ACR50 assessment. Two participants from sites with good clinical practice \[GCP\] violations are excluded.

Disease Activity Score (modified to include the 28 joint count \[DAS28\]) consists of a composite score of the following variables: tender joint count (TJC28), swollen joint count (SJC28), C-reactive protein (CRP), and participant global assessment of their disease activity (patient global VAS). It is calculated by using the following formula:DAS28-CRP=0.56 times the square root of(28TJC)+0.28 times the square root of(28SJC)+0.36\*natural log (ln)(CRP+1)+0.014\*patient global VAS+0.96. Scores ranged from 1.0-9.4, where lower scores indicated less disease activity, and remission was DAS28-CRP \<2.6. A decrease in DAS28-CRP indicated an improvement in participant's condition.

Time frame: Baseline, 16 weeks

Population: Intention to treat (ITT) population defined as participants who were randomized, received at least one dose of study drug, and had at least one post-baseline DAS28 assessment; last observation carried forward (LOCF). Two participants from sites with good clinical practice \[GCP\] violations are excluded.

The FACIT Fatigue Score is a brief patient-reported measure of fatigue and consists of 13 items. Scores range from 0 to 52, with higher scores indicating less fatigue.

Time frame: Baseline, 16 weeks

Population: Intention to treat (ITT) population defined as participants who were randomized, received at least one dose of study drug, and had at least one post-baseline FACIT assessment; last observation carried forward (LOCF). Two participants from sites with good clinical practice \[GCP\] violations are excluded.

The HAQ-DI questionnaire scores the participant's self-perception on the degree of difficulty when dressing and grooming, arising, eating, walking, hygiene, reach, grip, and performing other daily activities (0=without any difficulty, 1=with some difficulty, 2=with much difficulty, and 3=unable to do). The scores for each of the functional areas, which have a range from 0 to 3, are averaged to calculate the functional disability index. Higher scores are associated with greater disability.

Time frame: Baseline, 16 weeks

Population: Intention to treat (ITT) population defined as participants who were randomized, received at least one dose of study drug, and had at least one post-baseline HAQ-DI assessment; last observation carried forward (LOCF). Two participants from sites with good clinical practice \[GCP\] violations are excluded.

Self-reported questionnaire of 36 questions in 8 domains (physical functioning, social functioning, bodily pain, vitality, mental health, role-physical, role-emotional, general health). Each domain is scored by summing individual items and transforming scores into a 0-100 scale (higher scores=better health status/function). The mental and physical component summaries are based on the 8 domains. Component scores are transformed scores representing a mean (50) and standard deviation (10) in the general United States (US) population. Scores \> or \<50 are above or below the average US population.

Time frame: Baseline, 16 weeks

Population: Intention to treat (ITT) population defined as participants who were randomized, received at least one dose of study drug, and had at least one post-baseline SF-36 assessment; last observation carried forward (LOCF). Two participants from sites with good clinical practice \[GCP\] violations are excluded.

Participant's assessment of their current arthritis disease activity using a visual analog scale (VAS), which ranged from 0 to 100 millimeters, where 0 indicated no arthritis activity and 100 indicated extremely active arthritis.

Time frame: Baseline, 16 weeks

Population: Intention to treat (ITT) population defined as participants who were randomized, received at least one dose of study drug, and had at least one post-baseline disease activity assessment; last observation carried forward (LOCF). Two participants from sites with good clinical practice \[GCP\] violations are excluded.

Participant's assessment of joint pain using a visual analog scale (VAS), which ranged from 0 to 100 millimeters, where 0 indicated no pain and 100 indicated worst possible pain.

Time frame: Baseline, 16 weeks

Population: Intention to treat (ITT) population defined as participants who were randomized, received at least one dose of study drug, and had at least one post-baseline joint pain assessment; last observation carried forward (LOCF). Two participants from sites with good clinical practice \[GCP\] violations are excluded.

Physician's global assessment of arthritis disease activity using a visual analog scale (VAS) which ranged from 0 to 100 millimeters, where 0 indicates no arthritis activity and 100 indicates extremely active arthritis.

Time frame: Baseline, 16 weeks

Population: Intention to treat (ITT) population defined as participants who were randomized, received at least one dose of study drug, and had at least one post-baseline physician's disease activity assessment; last observation carried forward (LOCF). Two participants from sites with good clinical practice \[GCP\] violations are excluded.

The number of swollen joints is determined by examination of 28 joints (14 on each side) which include: the 2 shoulders, the 2 elbows, the 2 wrists, the 10 metacarpophalangeal joints, the 2 interphalangeal joints of the thumb, the 8 proximal interphalangeal joints, and the 2 knees. The joints are assessed and classified as swollen or not swollen.

Time frame: Baseline, 16 weeks

Population: Intention to treat (ITT) population defined as participants who were randomized, received at least one dose of study drug, and had at least one post-baseline swollen joint assessment; last observation carried forward (LOCF). Two participants from sites with good clinical practice \[GCP\] violations are excluded.

The number of tender and painful joints is determined by examination of 28 joints (14 on each side) which include: the 2 shoulders, the 2 elbows, the 2 wrists, the 10 metacarpophalangeal joints, the 2 interphalangeal joints of the thumb, the 8 proximal interphalangeal joints, and the 2 knees. The joints are assessed and classified as tender or not tender.

Time frame: Baseline, 16 weeks

Population: Intention to treat (ITT) population defined as participants who were randomized, received at least one dose of study drug, and had at least one post-baseline tender joint assessment; last observation carried forward (LOCF). Two participants from sites with good clinical practice \[GCP\] violations are excluded.

Serious adverse events and other non-serious adverse events are located in the Reported Adverse Event section.

Time frame: Baseline up to 68 weeks

Population: Safety population defined as all participants who were randomized and received at least one dose of study drug.

EULAR28 categorizes clinical response based upon improvement since baseline in Disease Activity Score modified to include the 28 joint count (DAS28) and post-baseline DAS28. DAS28 consists of a composite score of the following variables: tender joint count (TJC28), swollen joint count (SJC28), C-reactive protein (CRP), and participant global assessment of their disease activity (patient global VAS). EULAR28 categories include: No Response (improvement in DAS28 of less than or equal to 0.6 units or post-baseline DAS28 score greater than 5.1 with improvement by less than or equal to 1.2 units), Moderate Response (post-baseline DAS28 score less than or equal to 5.1 with improvement by more than 0.6 units but no greater than 1.2 units or post-baseline DAS28 score greater than 3.2 with improvement by more than 1.2 units), and Good Response (post-baseline DAS28 score less than or equal to 3.2 with improvement by more than 1.2 units).

Time frame: 16 weeks

Population: Intention to treat (ITT) population defined as participants who were randomized, received at least one dose of study drug, and had at least one post-baseline EULAR28 assessment; last observation carried forward (LOCF). Two participants from sites with good clinical practice \[GCP\] violations are excluded.

ACR20 Responder Index is a composite of clinical, laboratory, and functional measures in rheumatoid arthritis. An ACR20 Responder is defined as a participant with at least 20% improvement from baseline in both tender and swollen joint counts and in at least 3 of the following 5 criteria: physician global assessment, patient global assessment, functional ability measure (Health Assessment Questionnaire-Disability Index which measures participants' perceived degree of difficulty when performing various daily activities), visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein.

Time frame: 16 weeks

Population: Non-responder imputation (NRI)/last observation carried forward; intention to treat (ITT) population defined as participants who were randomized, received at least one dose of study drug, and had at least one post-baseline ACR20 assessment. Two participants from sites with good clinical practice \[GCP\] violations are excluded.

ACR70 Responder Index is a composite of clinical, laboratory, and functional measures in rheumatoid arthritis. An ACR70 Responder is defined as a participant with at least 70% improvement from baseline in both tender and swollen joint counts and in at least 3 of the following 5 criteria: physician global assessment, patient global assessment, functional ability measure (Health Assessment Questionnaire-Disability Index which measures participants' perceived degree of difficulty when performing various daily activities), visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein.

Time frame: 16 weeks

Population: Non-responder imputation (NRI)/last observation carried forward; intention to treat (ITT) population defined as participants who were randomized, received at least one dose of study drug, and had at least one post-baseline ACR70 assessment. Two participants from sites with good clinical practice \[GCP\] violations are excluded.

Time frame: Baseline, 16 weeks

Population: Intention to treat (ITT) population defined as participants who were randomized, received at least one dose of study drug, and had at least one post-baseline CRP assessment; last observation carried forward (LOCF). Two participants from sites with good clinical practice \[GCP\] violations are excluded.

B-lymphocyte antigen CD20 or CD20 is an activated-glycosylated phosphoprotein expressed on the surface of all mature B-cells. For this endpoint, total B cell counts (CD20+CD3- cells) are represented by number of cells per microliter. The reference range for the absolute counts is 43-602 cells per microliter.

Time frame: Baseline, 16 weeks

Population: Intention to treat (ITT) population defined as participants who were randomized, received at least one dose of study drug, and had at least one post-baseline CD20 assessment; last observation carried forward (LOCF). Two participants from sites with good clinical practice \[GCP\] violations are excluded.

Serum immunoglobulin measured by Immunoglobulin A (IgA), Immunoglobulin G (IgG), and Immunoglobulin M (IgM) levels.

Time frame: Baseline, 16 weeks

Population: Intention to treat (ITT) population defined as participants who were randomized, received at least one dose of study drug, and had at least one post-baseline serum immunoglobulin assessment; last observation carried forward (LOCF). Two participants from sites with good clinical practice \[GCP\] violations are excluded.

B-lymphocyte antigen CD20 or CD20 is an activated-glycosylated phosphoprotein expressed on the surface of all mature B-cells. For this outcome, total B cells (CD20+CD3- cells) are expressed as the relative percent of lymphocytes. There is no reference range provided for this parameter by the performing laboratory.

Time frame: Baseline, 16 weeks

Population: Intention to treat (ITT) population defined as participants who were randomized, received at least one dose of study drug, and had at least one post-baseline CD20 assessment; last observation carried forward (LOCF). Two participants from sites with good clinical practice \[GCP\] violations are excluded.

C-trough is defined as the concentration of LY at the end of the dosing interval at steady state. Mean C-trough value was obtained by conducting a simulation consisting of 1000 participants. The simulated data were then used to determine the noncompartmental PK parameters for each regimen. Mean and standard deviation of the Ctrough values were calculated for each dose group based on simulated data.

Time frame: Pre-dose, Day 1 through Week 24

Population: All randomized participants with evaluable PK C-trough data.

T-half life (t1/2, tau) is defined as the apparent steady state elimination within the dosing interval. T-half life was obtained by conducting a simulation consisting of 1000 participants using the study drug regimens (30 and 80 mg, intravenous infusion over 30 minutes, once every 3 weeks). The simulated data were then used to determine the noncompartmental PK parameters for each regimen. Mean and standard deviation of the t-half life values were calculated for each dose group based on simulated data.

Time frame: Pre-dose, Day 1 through Week 24

Population: All randomized participants with evaluable PK t-half life data.