A Study of RoActemra/Actemra (Tocilizumab) in Combination With Methotrexate Versus RoActemra/Actemra Monotherapy in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate

Study Overview
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Brief Summary
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This randomized, double-blind, parallel-group study will evaluate the efficacy and safety of RoActemra/Actemra (tocilizumab) in combination with methotrexate versus RoActemra/Actemra monotherapy in patients with rheumatoid arthritis and an inadequate response to methotrexate. All patients will receive RoActemra/Actemra 8 mg/kg intravenously (iv) every 4 weeks plus oral methotrexate for 16 weeks. Patients achieving low disease activity at Week 16 will be randomized to receive a further 12 weeks of RoActemra/Actemra treatment plus either methotrexate or placebo. Anticipated time on study treatment is 28 weeks.

Official Title
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A Multi-center Study of the Safety and Effect on Disease Activity of Tocilizumab (TCZ) in Combination With MTX Versus Tocilizumab Monotherapy in Patients With Rheumatoid Arthritis, With Inadequate Response to MTX (Defined as DAS 28 > 3,2)

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: methotrexate
* Drug: methotrexate
* Drug: placebo
* Drug: tocilizumab [RoActemra/Actemra]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients, >/= 18 years of age Active moderate to severe rheumatoid arthritis (DAS28 >/= 3.2) at baseline Currently receiving methotrexate for at least 12 weeks, at a stable oral dose of at least 15 mg/week for at least 6 weeks prior to treatment (Day 1) Body weight < 150 kg Oral corticoids must have been at stable dose for at least 25 out of 28 days prior to baseline; maximum dose 10 mg/day Exclusion Criteria: Pregnant or nursing women Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months after baseline Rheumatic autoimmune disease other than RA Functional class IV as defined by the American College of Rheumatology (ACR) Classification of Functional Status in Rheumatoid Arthritis Prior history of or current inflammatory joint disease other than RA Treatment with a biologic agent at any time prior to baseline Treatment with traditional DMARDs other than methotrexate within 1 month (for leflunomide 3 months) prior to baseline Intraarticular or parenteral corticosteroids within 6 weeks prior to baseline Previous treatment with RoActemra/Actemra History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies Known active current or history of recurrent infection History of or currently active primary or secondary immunodeficiency Active tuberculosis requiring treatment within the previous 3 years Positive for HIV infection

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br> | Drug: methotrexate<br>* orally, Week 1 - 16<br>Drug: methotrexate<br>* orally, Week 17-28<br>Drug: tocilizumab [RoActemra/Actemra]<br>* 8 mg/kg iv every 4 weeks, 28 weeks<br>|
| Active Comparator: B<br> | Drug: methotrexate<br>* orally, Week 1 - 16<br>Drug: placebo<br>* methotrexate placebo orally, Week 17-28<br>Drug: tocilizumab [RoActemra/Actemra]<br>* 8 mg/kg iv every 4 weeks, 28 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Disease Activity Score Based on 28-Joint Count (DAS28) From Week 16 to Week 28 | The DAS28 is a combined index for measuring disease activity in rheumatoid arthritis (RA). The index includes swollen (range 0-28) and tender (range 0-28) joint counts, acute phase response (erythrocyte sedimentation rate [ESR] in millimeters per hour [mm/hr]), and general health status (participant global assessment of disease activity using visual analog scale [VAS], range 1-100 mm). DAS28, which uses a 28-joint count, is derived from the original DAS, which includes a 44-swollen joint count. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity. | Baseline, Week 16, and Week 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With DAS28 Score Less Than (<) 2.6 at Week 28 | The DAS28 is a combined index for measuring disease activity in RA. The index includes swollen (range 0-28) and tender (range 0-28) joint counts, acute phase response (ESR in mm/hr), and general health status (participant global assessment of disease activity using VAS, range 1-100 mm). DAS28, which uses a 28-joint count, is derived from the original DAS, which includes a 44-swollen joint count. The DAS28 scale ranges from 0 to 10, where higher scores indicate worsening. DAS28 <2.6 equals (=) remission. | Week 28 | 
| Percentage of Participants With Clinical Disease Activity Index (CDAI) <2.8 at Week 28 | CDAI is the sum of tender and swollen joint count based on 28 joints and the participant and physician global disease assessment (VAS 0-10 centimeters [cm]). CDAI total score 0-76; higher scores = greater affect due to disease activity. CDAI <2.8 = clinical remission. | Week 28 | 
| Percentage of Participants With Simplified Disease Activity Index (SDAI) <3.3 at Week 28 | SDAI is calculated by a simple numerical sum of tender and swollen joint count (based on a 28-joint assessment), participant and physician global assessment of disease activity (VAS 0-10 cm), and level of C-reactive protein in milligram per deciliter (mg/dL). SDAI total score 0-86; higher scores = greater affect due to disease activity. SDAI <3.3 = clinical remission. | 28 weeks | 
| Change in the Health Assessment Questionnaire Disability Index (HAQ-DI) From Week 16 to Week 28 | HAQ-DI: participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week. Each item scored on 4-point scale from 0 to 3: 0 = no difficulty; 1 = some difficulty; 2 = much difficulty; 3 = unable to do. 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. | Week 16 and Week 28 | 
| Change in the Quality of Life Questionnaire (Short Form-12 [SF-12]) From Week 16 to Week 28 in Mental Health | Quality of life questionnaire (SF-12) scores were computed using the scores of 12 questions and ranged from 0 to 100, where a 0 score indicated the lowest level of health measured by the scales and 100 indicated the highest level of health. A negative change from baseline indicated decline in health and higher scores indicated improvement in health. | Week 16 and Week 28 | 
| Change in the Quality of Life Questionnaire (SF-12) From Week 16 to Week 28 in Physical Health | Quality of life questionnaire (SF-12) scores were computed using the scores of 12 questions and ranged from 0 to 100, where a 0 score indicated the lowest level of health measured by the scales and 100 indicated the highest level of health. A negative change from baseline indicated a worsening of quality of life. | Week 16 and Week 28 | 
| Change From Week 16 to Week 28 in Global Assessment of Disease Activity as Assessed With the Visual Analogue Scale (VAS) Performed by Participant | Participants were asked to rate their global assessment of disease activity on a scale ranging from 0=very good to 100=very bad. The scale was represented by a line with 0 at the left edge and 100 at the right edge. The participant was asked to mark the line corresponding to the assessment of their disease activity. The distance from the left edge was measured in mm. | Week 16 and Week 28 | 
| Change From Week 16 to Week 28 in Global Assessment of Disease Activity Assessed Using the VAS Performed by the Investigator | Participants were asked to rate their global assessment of disease activity on a scale ranging from 0=very good to 100=very bad. The scale was represented by a line with 0 at the left edge and 100 at the right edge. The participant was asked to mark the line corresponding to the assessment of their disease activity. The distance from the left edge was measured in mm. | Week 16 and Week 28 |