A Study of the Impact of Methotrexate (MTX) Discontinuation on the Efficacy of Subcutaneous (SC) Tocilizumab (TCZ) With MTX

Study Overview
=================
Brief Summary
-----------------
This randomized, multicenter, double-blind, parallel group study will evaluate the impact of MTX discontinuation on the efficacy of SC TCZ in participants with moderate to severe active rheumatoid arthritis who have an inadequate response to current MTX therapy. Participants will initiate treatment with TCZ weekly or every 2 weeks along with MTX at a stable dose orally in an open-label manner for 24 weeks. Participants with a disease activity score based on 28 joints (DAS28) less than or equal to (</=) 3.2 at Week 24, will be randomized to either continue receiving a stable dose of MTX or to switch to matching placebo up to Week 52. Participants without a DAS28 score </=3.2 at Week 24, will continue the same treatment in a non-randomized open-label manner up to Week 52.

Official Title
-----------------
A Randomized, Double-Blind Trial Assessing the Impact of Methotrexate Discontinuation on the Efficacy of Subcutaneous Tocilizumab With Methotrexate Therapy

Conditions
-----------------
Rheumatoid Arthritis

Intervention / Treatment
-----------------
* Drug: Tocilizumab (TCZ)
* Drug: Methotrexate (MTX)
* Drug: Placebo (PBO)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Body weight </=150 kg Active moderate to severe rheumatoid arthritis (DAS28 >/=4.4) according to the revised 1987 ACR criteria at screening and baseline (prior to treatment on Day 1) Currently receiving oral MTX for at least 24 weeks and on a stable oral dose of at least 15 mg/week for at least 6 weeks prior to treatment (Day 1), with the following exception: a stable dose of at least 10 mg/week is allowed for participants with a body weight <50 kg or calculated glomerular filtration rate (or creatinine clearance) <60 milliliters per minute (mL/min) History of parenteral (SC or intramuscular [IM]) MTX is allowed, but not within 6 weeks prior to treatment (Day 1). Participants must not have a documented, clinically significant intolerance to oral MTX and must be receiving oral MTX at a dose of 15 mg/week for at least 6 weeks prior to treatment (Day 1) Participants who have received one prior anti-tumor necrosis factor (TNF) must have discontinued etanercept, infliximab, certolizumab, adalimumab, or golimumab for at least 6 months prior to screening Oral corticosteroids must have been </=10 mg/day prednisone (or equivalent) and stable for at least 25 out of 28 days prior to treatment (Day 1) Participants receiving treatment on an outpatient basis Exclusion Criteria: Documented medical history of significant intolerance to oral MTX >/=15 mg/week Participants receiving other (non-MTX) disease modifying anti-rheumatic drugs (DMARDs) within 8 weeks of screening Previous treatment with abatacept, rituximab, tofacitinib, or anakinra Treatment with parenteral corticosteroids within 4 weeks prior to treatment Previous treatment with cell-depleting therapies or alkylating agents Previous treatment with TCZ Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery during the study Rheumatic autoimmune disease other than rheumatoid arthritis Non-rheumatic active autoimmune diseases (for example, inflammatory bowel diseases, psoriasis, multiple sclerosis) Prior history of or current inflammatory joint disease other than rheumatoid arthritis Functional Class IV according to the revised (1987) ACR criteria for rheumatoid arthritis History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies Evidence of significant uncontrolled concomitant diseases; uncontrolled disease states where flares are commonly treated with oral or parenteral corticosteroids Active current or history of recurrent infection, or any major episode of infection requiring hospitalization or treatment with intravenous antibiotics within 4 weeks prior to screening or oral antibiotics within 2 weeks prior to screening Active tuberculosis requiring treatment within the previous 3 years History of or currently active primary or secondary immunodeficiency Pregnant or breast-feeding women Positive for hepatitis B or hepatitis C infection For potential MRI substudy participants: the presence of any metal-containing device or object in the body

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Non-Randomized Participants (TCZ + MTX)<br>All participants will receive initial treatment with open-label TCZ + MTX. Participants who complete 24-week treatment with open-label TCZ + MTX and did not achieve a DAS28 score </=3.2 at Week 24, will continue receiving TCZ + MTX in open label manner up to Week 52. | Drug: Tocilizumab (TCZ)<br>* TCZ will be administered at a dose of 162 milligrams (mg) via SC injection weekly (if body weight is greater than or equal to [>/=] 100 kilograms [kg]) or every 2 weeks (if body weight was less than [<] 100 kg).<br>* Other names: Actemra;Drug: Methotrexate (MTX)<br>* MTX will be administered at a stable dose (15 mg to 25 mg per week) orally.<br>|
| Experimental: Randomized Participants (TCZ + MTX)<br>Participants who complete the initial 24-week treatment with open-label TCZ + MTX and achieve a DAS28 score </=3.2 at Week 24, will be randomized to receive TCZ along with MTX up to Week 52. | Drug: Tocilizumab (TCZ)<br>* TCZ will be administered at a dose of 162 milligrams (mg) via SC injection weekly (if body weight is greater than or equal to [>/=] 100 kilograms [kg]) or every 2 weeks (if body weight was less than [<] 100 kg).<br>* Other names: Actemra;Drug: Methotrexate (MTX)<br>* MTX will be administered at a stable dose (15 mg to 25 mg per week) orally.<br>|
| Active Comparator: Randomized Participants (TCZ + PBO)<br>Participants who complete the initial 24-week treatment with open-label TCZ + MTX and achieve a DAS28 score </=3.2 at Week 24, will be randomized to receive TCZ along with MTX matched placebo (PBO) up to Week 52. | Drug: Tocilizumab (TCZ)<br>* TCZ will be administered at a dose of 162 milligrams (mg) via SC injection weekly (if body weight is greater than or equal to [>/=] 100 kilograms [kg]) or every 2 weeks (if body weight was less than [<] 100 kg).<br>* Other names: Actemra;Drug: Placebo (PBO)<br>* PBO matching to MTX will be administered orally.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Week 24 in Disease Activity Score Based on 28 Joints (DAS28) Score at Week 40 | The DAS28 was derived from assessments of erythrocyte sedimentation rate (ESR) measured in millimeters per hour (mm/h), tender joint count on 28 joints (TJC28), swollen joint count on 28 joints (SJC28), and Patient's Global Assessment of disease activity according to 100--millimeter (mm) Visual Analog Scale (VAS). DAS28 score was calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. DAS28 score could range from 0 to 10, where higher score represented higher disease activity. The change from Week 24 to Week 40 was averaged among all participants, where negative changes indicated an improvement in disease activity. | Week 24, Week 40 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving 20% Improvement in American College of Rheumatology (ACR20) Response | The ACR20 response at any time was defined as >/=20% improvement compared to baseline in TJC (assessed on 68 joints) and SJC (assessed on 66 joints); and 20% improvement compared to baseline in 3 of the following 5 criteria, respectively: 1) Patient's global assessment of disease activity according to 100-mm VAS, 2) Physician's global assessment of disease activity according to 100-mm VAS, 3) participant's global assessment of pain according to 100-mm VAS, 4) Participant's assessment of functional ability via a Health Assessment Questionnaire-Disability Index (HAQ-DI), and 5) Acute phase reactant (ESR in mm/h or C-Reactive Protein [CRP] in milligrams per deciliter [mg/dL]). | Weeks 24, 40, and 52 | 
| Percentage of Participants Achieving 50% Improvement in American College of Rheumatology (ACR50) Response | The ACR50 response at any time was defined as >/=50% improvement compared to baseline in TJC (assessed on 68 joints) and SJC (assessed on 66 joints); and 50% improvement compared to baseline in 3 of the following 5 criteria, respectively: 1) Patient's global assessment of disease activity according to 100-mm VAS, 2) Physician's global assessment of disease activity according to 100-mm VAS, 3) participant's global assessment of pain according to 100-mm VAS, 4) Participant's assessment of functional ability via HAQ-DI, and 5) Acute phase reactant (ESR in mm/h or CRP in mg/dL). | Weeks 24, 40, and 52 | 
| Percentage of Participants Achieving 70% Improvement in American College of Rheumatology (ACR70) Response | The ACR70 response at any time was defined as >/=70% improvement compared to baseline in TJC (assessed on 68 joints) and SJC (assessed on 66 joints); and 70% improvement compared to baseline in 3 of the following 5 criteria, respectively: 1) Patient's global assessment of disease activity according to 100-mm VAS, 2) Physician's global assessment of disease activity according to 100-mm VAS, 3) participant's global assessment of pain according to 100-mm VAS, 4) Participant's assessment of functional ability via HAQ-DI, and 5) Acute phase reactant (ESR in mm/h or CRP in mg/dL). | Weeks 24, 40, and 52 | 
| Percentage of Participants With >/=1.2 Points Increase (Worsening) From Week 24 in DAS28 Score at Week 40 and 52 | The DAS28 was derived from assessments of ESR measured in mm/h, TJC28, SJC28, and Patient's global assessment of disease activity according to 100-mm VAS. DAS28 score was calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. DAS28- score could range from 0 to 10, where higher score represented higher disease activity. | Week 24, 40, and 52 | 
| Percentage of Participants With DAS28 Score <2.6 (DAS28 Remission) | The DAS28 was derived from assessments of ESR measured in mm/h, TJC28, SJC28, and Patient's global assessment of disease activity according to 100-mm VAS. DAS28 score was calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. DAS28 score could range from 0 to 10, where higher score represented higher disease activity. | Week 40, Week 52 | 
| Percentage of Participants With DAS28 Score </=3.2 (Low DAS28) | The DAS28 was derived from assessments of ESR measured in mm/h, TJC28, SJC28, and Patient's global assessment of disease activity according to 100-mm VAS. DAS28 score was calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. DAS28-ESR score could range from 0 to 10, where higher score represented higher disease activity. | Week 40, Week 52 | 
| Change From Week 24 in Bone Erosion Score at Week 40 for Participants in the Magnetic Resonance Imaging (MRI) Substudy | Bones from the wrist regions (carpal bones, distal radius, distal ulna, and metacarpal bases) and the metacarpophalangeal (MCP) joints (metacarpal heads and phalangeal bases) were assessed for erosion via MRI and scored separately based on the proportion of eroded bone compared to the 'assessed bone volume' judged from all available images. Scoring ranged from 0 (no erosion) to 10 (91-100%). Results were summed, resulting in scores from 0 to 80 for the wrist region, 0 to 150 for the MCP joints, and 0 to 230 on aggregate. A negative value for change from Week 24 in bone erosion score indicated an improvement. | Weeks 24, Week 40 | 
| Percentage of Participants With Anti-Therapeutic Antibodies (ATA) to TCZ | Percentage of participants with positive results for ATA against TCZ at Baseline and at any of the post-baseline assessment time-points was reported. Participants positive at any post-baseline time points were participants who had no positivity at baseline for the same assay. | Baseline, Post-baseline (assessed at Weeks 12, 24, 36, 52 and at follow up [Week 60]) | 
| Mean TCZ Serum Concentration |  | Baseline, Weeks 12, 24, 36, 52 and follow up (Week 60) | 
| Mean Soluble Interleukin-6 (IL-6) Receptor Concentration |  | Baseline, Weeks 12, 24, 36, 52 and follow up (Week 60) |