A Study of Tocilizumab in Combination With DMARD Therapy in Patients With Active Rheumatoid Arthritis.

Study Overview
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Brief Summary
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This 2 arm study will compare the safety and efficacy, with regard to reduction of signs and symptoms, of tocilizumab versus placebo, both in combination with DMARDs, in patients with active rheumatoid arthritis who currently have an inadequate response to DMARD therapy. Patients will be randomized 2:1 to receive tocilizumab 8mg/kg iv or placebo iv every 4 weeks, in conjunction with stable DMARD therapy. The anticipated time on study treatment is 3-12 months, and the target sample size is 100-500 individuals.

Official Title
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A Randomized, Double Blind Study of Safety and Reduction in Signs and Symptoms During Treatment With Tocilizumab Versus Placebo, in Combination With DMARD Therapy, in Patients With Active Rheumatoid Arthritis and Inadequate Response to Current DMARD Therapy

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: tocilizumab [RoActemra/Actemra]
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: adult patients, 18-70 years of age; rheumatoid arthritis for >= 6 months; receiving permitted DMARDs, at a stable dose, for >= 8 weeks prior to baseline; current inadequate clinical response to DMARDs. Exclusion Criteria: major surgery, including joint surgery, within 8 weeks before entering study, or planned major surgery within 6 months following randomization; rheumatic autoimmune disease or inflammatory joint disease other than rheumatoid arthritis; unsuccessful treatment with an anti-TNF agent; previous treatment with tocilizumab.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: 1<br> | Drug: tocilizumab [RoActemra/Actemra]<br>* 8mg/kg iv every 4 weeks for 24 weeks<br>|
| Placebo Comparator: 2<br> | Drug: Placebo<br>* iv every 4 weeks for 24 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With an American College of Rheumatology (ACR)20 Response at Week 24 | To achieve an ACR20 response required at least a 20% improvement, compared with baseline, in both (tender joints count)TJC and (swollen joints count) SJC, as well as in 3 out of 5 additional ACR core set variables: physician's global assessment of disease activity, participant's global assessment of disease activity, participant's assessment of pain, health assessment questionnaire disease index (HAQ-DI) and C-reactive protein (CRP). CRP was used primarily for the calculation of the ACR response; if missing, Erythrocyte Sedimentation Rate (ESR) was substituted. ITT sensitivity analysis was carried out using an alternative imputation method (last observation carried forward [LOCF]). | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With ACR50 and ACR70 Responses at Week 24 | To achieve an ACR50 or ACR 70 response required at least a 50% or 70% improvement, compared with baseline in both TJC and SJC, as well as in 3 out of 5 additional ACR core set variables: physician's global assessment of disease activity, participant's global assessment of disease activity, participant's assessment of pain, HAQ-DI and CRP. CRP was used primarily for the calculation of the ACR response; if missing, ESR was substituted. | Week 24 | 
| Number of Participants Who Received Escape Therapy | Participants who did not achieve a 20% improvement from baseline in both SJC and TJC at week 16 could, if requested and deemed necessary by the investigator, receive escape therapy, comprising adjustment of the background DMARD dose and/or treatment with a different traditional DMARD. | 24 Weeks | 
| Change in Tender and Swollen Joint Counts From Baseline to Week 24 | 68 joints were assessed for tenderness and joints were classified as tender/not tender giving a total possible tender joint count score of 0 to 68. 66 joints were assessed for swelling and joints were classified as swollen/not swollen giving a total possible swollen joint count score of 0 to 66. | Baseline and Week 24 | 
| Change in Participant's Global Assessment of Disease Activity From Baseline to Week 24 | The participant's global assessment of disease activity is assessed on a 0 to 100 mm horizontal visual analogue scale (VAS) by the participant. The left-hand extreme of the line equals 0 mm, and is described as no disease activity (symptom-free and no arthritis symptoms) and the right-hand extreme equals 100 mm, as maximum disease activity (maximum arthritis disease activity). A negative change from Baseline indicated improvement. | Baseline and Week 24 | 
| Change in Physician's Global Assessment of Disease Activity From Baseline to Week 24 | The physician's global assessment of disease activity is assessed on a 0 to 100 mm horizontal VAS by the physician. The left-hand extreme of the line equals 0 mm, and is described as no disease activity (symptom-free and no arthritis symptoms) and the right-hand extreme equals 100 mm as maximum disease activity (maximum arthritis disease activity). | Baseline and Week 24 | 
| Change in Participant's Global Assessment of Pain From Baseline to Week 24 | The participants assessed their pain on a 0 to 100 mm VAS. The left-hand extreme of the line equals 0 mm, and is described as no pain and the right-hand extreme equals 100 mm as unbearable pain. A negative change indicated improvement. | Baseline and Week 24 | 
| Change in C-Reactive Protein From Baseline to Week 24 | The serum concentration of CRP an acute phase inflammatory marker, is measured in milligrams/deciliter (mg/dL). A reduction in the level is considered an improvement. | Baseline and Week 24 | 
| Change in ESR From Baseline to Week 24 | The ESR was measured in mm/hour. A reduction in the level is considered an improvement. | Baseline and Week 24 | 
| Percentage of Participants With Low Disease Activity and in Clinical Remission | DAS28 calculated from the number of swollen joints and tender joints using the 28-joint count, ESR and global health assessment (participant rated global assessment of disease activity using 10-mm VAS); DAS28 score ranged from 0 to 10, where higher scores correspond to greater disease activity. DAS28 less than or equal to (≤3.2) = low disease activity, DAS28 greater than (>)3.2 to 5.1 = moderate to high disease activity. | Baseline and Weeks 2, 4, 8, 12, 16, 20 and 24 | 
| Change From Baseline to Week 24 in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Score | FACIT-F is a 13-item questionnaire. Patients scored each item on a 5-point scale: 0 (Not at all) to 4 (Very much). The larger the participant's response to the questions (with the exception of 2 negatively stated), the greater the fatigue. For all questions, except for the 2 negatively stated ones, the code was reversed and a new score was calculated as (4 minus the participant's response). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worse score) to 52 (better score). A higher score reflects an improvement in health status. | Baseline and Week 24 | 
| Mean Rheumatoid Factor at Baseline and Week 24 | Rheumatoid factor (RF) is a disease characteristic and more than 85% of the participants studied were positive for the factor. These data are from patients who were RF positive. RF level was reported in international units/milliliter (IU/mL). A positive RF= >15 IU/mL. | Baseline and 24 Weeks | 
| Change in Hemoglobin From Baseline to Week 24 | Levels of hemoglobin were determined in grams/liter (g/L)as a measure of anemia in participants | Baseline and 24 Weeks | 
| Change in Health Assessment Questionnaire - Disease Index (HAQ-DI) From Baseline to Week 24 | HAQ-DI is a self-completed participant questionnaire specific for RA. It consists of 20 questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip; common daily activities. Each domain has at least 2 component questions. There are 4 possible responses for each component 0=without any difficulty 1=with some difficulty 2=with much difficulty 3=unable to do. The HAQ-DI is the sum of the scores, divided by the number of domains that have a score (in range 6-8) for a total possible score minimum/maximum 0 (best) to 3 (worst). A negative change from baseline indicated improvement. | Baseline and 24 Weeks | 
| Percentage of Participants With ACR20 Response by First Week of Onset | ACR 20 responses are summarized by first onset as a percentage of the total number of responders at week 24. The number of participants first achieving an ACR20 response at each time point is represented by treatment arm as a proportion of the total number of participants that had an ACR20 response at Week 24 using n as the denominator. | Weeks 2, 4, 8, 12, 16, 20, and 24 | 
| Time to First Low Disease Activity | Time to Low disease activity was calculated as the number of days from the first dose of drug administration to the date of first achievement of DAS28≤3.2. | Weeks 2, 4, 8, 12, 16, 20, and 24 | 
| Time to First Remission | Time to first Remission was calculated as the number of days from the date of first dose of study drug administration to the date of first achievement of DAS<2.6 | Weeks 2, 4, 8, 12, 16, 20, and 24 |