A Study of RoActemra/Actemra (Tocilizumab) With or Without Methotrexate in Patients With Mild to Moderate Rheumatoid Arthritis With an Inadequate Response to Methotrexate

Study Overview
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Brief Summary
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This multicenter study with a randomized, double-blind, parallel-group phase will evaluate the safety and efficacy of RoActemra/Actemra (tocilizumab) in combination with methotrexate versus RoActemra/Actemra monotherapy in patients with mild to moderate rheumatoid arthritis, with an inadequate response to methotrexate. Patients will receive RoActemra/Actemra 8 mg/kg intravenously every 4 weeks plus oral methotrexate 15-25 mg weekly for 12 weeks. Patients with a good/moderate EULAR response will then be randomized to receive either RoActemra/Actemra plus methotrexate or RoActemra/Actemra plus placebo for the following 12 weeks. Anticipated time on study treatment is 6 months.

Official Title
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A Multi-center Study of the Safety and Effect on Disease Activity of Tocilizumab (TCZ) in Combination With Methotrexate (MTX) Versus Tocilizumab Monotherapy in Patients With Mild to Moderate Rheumatoid Arthritis, With Inadequate Response to MTX (Defined as DAS 28 < 4,5 and >2,6)

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 Rheumatoid arthritis of >/= 1 year duration Mild to moderate disease activity at screening (DAS 28 </= 4.5 and >2.6) On methotrexate treatment for at least 12 weeks, at stable oral dose of (10)15 mg to 25 mg/week for at least 6 weeks prior to Day 1 Body weight </= 150 kg Oral corticosteroids must have been at stable dose (maximum 10 mg/day) for at least 25 out of 28 days prior to baseline Exclusion Criteria: 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 rheumatoid arthritis Functional class IV American College of Rheumatology (ACR) Classification Prior history of or current inflammatory joint disease other than rheumatoid arthritis 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 tocilizumab Pregnant or lactating women Uncontrolled disease states, such as asthma, psoriasis or inflammatory bowel disease where flares are commonly treated with oral or parenteral corticosteroids Known active current or history of recurrent bacterial, viral, fungal, mycobacterial or other infections History of or currently active primary or secondary immunodeficiency Evidence of active malignant disease, malignancies diagnosed within the previous 5 years 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 |
| --- | --- |
| Active Comparator: A Methotrexate<br> | Drug: methotrexate<br>* 15-25 mg orally weekly, Weeks 1-12<br>Drug: methotrexate<br>* 15-25 mg orally weekly, Weeks 13-24<br>Drug: tocilizumab [RoActemra/Actemra]<br>* 8 mg/kg iv every 4 weeks, 24 weeks<br>|
| Experimental: B Methotrexate Placebo<br> | Drug: methotrexate<br>* 15-25 mg orally weekly, Weeks 1-12<br>Drug: placebo<br>* methotrexate placebo orally weekly, Weeks 13-24<br>Drug: tocilizumab [RoActemra/Actemra]<br>* 8 mg/kg iv every 4 weeks, 24 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Week 12 (Randomization) to Week 24 in DAS28 | The DAS28 is a combined index for measuring disease activity in rheumatoid arthritis (RA). The index includes swollen joint counts (SJC) and tender joint counts (TJC), both scored 0-28 (higher scores indicate higher disease activity), as well as acute phase response (APR) determined as erythrocyte sedimentation rate (ESR), and general health (GH), both scored 1-100 (higher scores indicate higher disease activity). DAS28 was calculated according to the following formula: DAS28 equals (=) [0.56 multiplied by (*) the square root (√) of TJC] plus (+) [0.28 * √ of SJC] + (0.70 * the natural logarithm (ln) ESR in millimeters per hour (mm/h)] + [0.014 * GH in mm visual analogue assessment (VAS)]. A negative change from randomization indicated improvement. | Weeks 12 and 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With DAS28 Remission at Week 24 | The DAS28 is a combined index for measuring disease activity in RA. The index includes SJC and TJC, both scored 0-28 (higher scores indicate higher disease activity, as well as APR determined as ESR, and GH, both scored 1-100 (higher scores indicate higher disease activity). DAS28 was calculated according to the following formula: DAS28 = 0.56 * √ of TJC + 0.28 * √ of SJC + 0.70 * ln ESR mm/hr + 0.014 * GH in mm VAS. DAS28 < 2.6 = remission. | Week 24 | 
| vPercentage of Participants With Clinical Disease Activity Index (CDAI) Remission at Week 24 | The CDAI is a combined index for measuring disease activity in RA. CDAI is the sum of TJC and SJC, both scored 0-28 (higher scores indicate higher disease activity), as well as patient global assessment (PGA) and evaluator global assessment (EGA) of disease activity, both scored 0 to 10 centimeter (cm) as assessed by VAS. CDAI was calculated according to the following formula: CDAI = SJC + TJC + PGA + EGA. CDAI < 2.8 = remission. | Week 24 | 
| Percentage of Participants With Simplified Disease Activity Index (SDAI) Remission at Week 24 | The SDAI is a combined index for measuring disease activity in RA. SDAI is the sum of TJC and SJC, both scored 0-28 (higher scores indicate higher disease activity), PGA and EGA of disease activity, both scored 0 to 10 cm as assessed by VAS, and C-reactive protein level (CRP) in milligrams per deciliter (mg/dL) where normal < 1 mg/dL. CDAI was calculated according to the following formula: SDAI = TJC + SJC + PGA + EGA + CRP. SDAI < 3.3 = remission. | Week 24 | 
| Percentage of Participants With Rheumatoid Arthritis Disease Activity Index-5 (RADAI-5) Remission at Week 24 | The RADAI-5 is a combined index for measuring disease activity in RA. RADAI-5 is comprised of the following 5 questions: how active was your arthritis the last 6 months? (0 = completely inactive to 10 = extremely active); how active is your arthritis today with respect to joint tenderness and swelling? (0 = completely inactive to 10 = extremely active); how severe is your arthritis pain today? (0 = no pain to 10 = unbearable pain); how would you describe your general health today? (0 = very good to 10 = very bad); and did you experience joint (hand) stiffness on awakening yesterday morning? If yes, how long did this stiffness last? (0 = no stiffness to 10 = stiffness the whole day). RADAI was calculated according to the following formula: [question (Q) 1 + Q2 + Q3 + Q4 + Q5]/5. RADAI-5 from 0-1.4 = remission. | Week 24 | 
| Change From Week 12 (Randomization) to Week 24 in Health Assessment Questionnaire - Disability Index (HAQ-DI) Score | HAQ-DI scores were obtained by scoring participants' responses to a 20-item questionnaire. HAQ-DQ evaluated 8 domains of health: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and common daily activities from a range of 0 (without any difficulty) to 3 (unable to do). The sum of scores was divided by the number of domains for a total score of 0 (best) to 3 (worst). A negative change from randomization indicated improvement. | Weeks 12 and 24 | 
| Change From Week 12 (Randomization) to Week 24 in Short Form-36 Health Survey (SF-36) Score | SF-36 scores were obtained by scoring participants' responses to a 36-item questionnaire. SF-36 evaluated 8 aspects of functional health and well being: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, mental health from a range of 1 (better) to 5 (worst). The score for each section was an average of the individual question scores, which were scaled 0-100 (100=highest level of functioning). These 8 aspects were summarized as physical and mental component scores. A negative change from randomization indicated improvement. | Weeks 12 and 24 | 
| Change From Week 12 (Randomization) to Week 24 in Visual Analog Scales (VAS) Scores | VAS scores were obtained by scoring participants' disease activity as assessed on a 0-100 millimeter (mm) horizontal visual scale. The left-hand extreme of the line = 0 mm (no disease activity = symptom-free and no arthritis symptoms), and the right-hand extreme of the line = 100 mm (maximum disease activity). A negative change from randomization indicated improvement. | Weeks 12 and 24 | 
| Participant Satisfaction With Treatment as Assessed by Treatment Satisfaction Questionnaire for Medication (TSQM) Score | TSQM scores were obtained by scoring participants' responses to a 14-item questionnaire. TSQM evaluated 4 aspects of treatment satisfaction: effectiveness, side effects, convenience, and global satisfaction from a range of 0 to 100 percent (%), with 100% being the best possible result. | Week 24 |