An Exploratory Study of Tocilizumab in Patients With Active Rheumatoid Arthritis (RA) and an Inadequate Response to Current Non-Biologic DMARDs and/or Anti-TNF Therapy.

Study Overview
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Brief Summary
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This open-label, single arm study will investigate the safety, tolerability and efficacy of tocilizumab monotherapy, or combination therapy with non-biologic disease modifying antirheumatic drugs (DMARDs), in patients with severe active RA. Patients will receive tocilizumab 8mg/kg iv as a 60 minute infusion every 4 weeks for a total of 6 infusions. The anticipated time on study treatment is 3-12 months, and the target sample size is >500 individuals.

Official Title
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International Multi-Center Open Label Study to Evaluate the Safety, Tolerability and Efficacy of Tocilizumab in Patients With Active Rheumatoid Arthritis on Background Non-biologic DMARDs Who Have An Inadequate Response to Current Non-Biologic DMARD or Anti-TNF Therapy.

Conditions
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Rheumatoid Arthritis

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: male and non-pregnant or nursing female patients >=18 years of age; body weight <=150kg; moderate to severe active RA (DAS28 >=3.2) of >=6 months duration; on >=1 non-biologic DMARDs at a stable dose for a period of >= 8 weeks prior to start of treatment; inadequate clinical response to a stable dose of non-biologic DMARD or anti-TNF therapy; if receiving oral corticosteroids, the dose must have been stable for at least 25 of 28 days prior to start of treatment. Exclusion Criteria: major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months following enrollment; rheumatic autoimmune disease other than RA; prior history of, or current inflammatory joint disease other than RA; functional class IV as defined by the ACR Classification of Functional Status in RA.

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: tocilizumab [RoActemra/Actemra]<br>* 8mg/kg iv (60 minute infusion)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Adverse Events (AEs): Overall Summary | Percentage of participants with AEs, serious AEs (SAEs), related AEs, related SAEs, severe AEs, with AEs leading to withdrawal or dose modification, with infection, serious infection, infusion reactions, infusion reactions during an infusion, infusion reactions within 24 hours of an infusion, major adverse cardiac event (MACE), or death. | Weeks 4, 8, 12, 16, 20, and 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved Low Disease Activity or Remission Based on Disease Activity Score Based on 28-Joints Count (DAS28) by Visit | DAS28 calculated from the number of swollen joints and tender joints using the 28 joints count, the erythrocyte sedimentation rate (ESR) (millimeters per hour [mm/hr]) and Patient's Global Assessment of Disease Activity (participant-rated arthritis activity assessment) with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity. Low disease activity was defined as DAS28 less than or equal to (≤)3.2 and remission was defined as DAS28 less than (<)2.6. | Baseline, Weeks 4, 8, 12, 16, 20, and 24 | 
| Time to Low Disease Activity or Remission Based on DAS28 - Number of Participants With an Event | DAS28 calculated from the number of swollen joints and tender joints using the 28 joints count, the ESR (mm/hr) and Patient's Global Assessment of Disease Activity (participant-rated arthritis activity assessment) with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity. Low disease activity was defined as DAS28 ≤3.2 and remission was defined as DAS28 <2.6. | Baseline, Weeks 4, 8, 12, 16, 20, and 24 | 
| Time to Low Disease Activity and Remission Based on DAS28 Score - Time to Event | The time to low disease activity or remission was calculated as the number of days from study Day 1 to the first occurrence of low disease activity or remission. Participants who did not achieve low disease activity on or before Week 24 or who withdrew from the study prior to achieving low disease activity were considered censored. DAS28 calculated from the number of swollen joints and tender joints using the 28 joints count, the ESR (mm/hr) and Patient's Global Assessment of Disease Activity (participant-rated arthritis activity assessment) with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity. Low disease activity defined as DAS28 ≤3.2 and remission defined as DAS28 <2.6. | Baseline,Weeks 4, 8, 12, 16, 20, and 24 | 
| Percentage of Participants Achieving a Response by European League Against Rheumatism (EULAR) Response Category and Visit | DAS28-based EULAR response criteria were used to measure individual response as none, good, and moderate, depending on the extent of change from baseline and the level of disease activity reached. Good responders: change from baseline >1.2 with DAS28 ≤3.2; moderate responders: change from baseline >1.2 with DAS28 >3.2 to ≤5.1 or change from baseline >0.6 to =<1.2 with DAS28 ≤5.1; non-responders: change from baseline ≤0.6 or change from baseline >0.6 and ≤1.2 with DAS28 >5.1. If the EULAR response could not be determined, it was set to 'No response'. | Weeks 4, 8, 12, 16, 20, and 24 | 
| DAS28 Scores by Visit | DAS28 calculated from the number of swollen joints and tender joints using the 28 joints count, the ESR (mm/hr) and Patient's Global Assessment of Disease Activity (participant-rated arthritis activity assessment) with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity. A negative change from baseline indicates improvement. | Baseline, Weeks 4, 8, 12, 16, 20, and 24 | 
| Percentage of Participants Achieving an American College of Rheumatology 20 Percent (%), 50%, 70%, or 90% Improvement (ACR20/ACR50/ACR70/ACR90) by Visit | ACR20, ACR50, ACR70, and ACR90 are defined as ≥20%, ≥50%, ≥70%, or ≥90% improvement, respectively, in: swollen joint count (SJC; 66 joints) and tender joint count (TJC; 68 joints) and ≥20%, ≥50%, ≥70%, or ≥90% improvement, respectively, in 3 of following 5 assessments: Patient's Global Assessment of Pain (visual analog scale [VAS]); Patient's Global Assessment of Disease Activity (VAS); Investigator/Physician's Global Assessment of Disease Activity (VAS); participant's assessment of disability measured by the Health Assessment Questionnaire Disability Index (HAQ-DI); or acute phase reactant (ESR or C-reactive protein [CRP]). Participants who did not have the required data to assess ACR status at a given visit were classified as non-responders. | Weeks 4, 8, 12, 16, 20, and 24 | 
| Time to Achieve ACR20, ACR50, ACR70 and ACR90 Response - Number of Participants With an Event | ACR20, ACR50, ACR70, and ACR90 are defined as ≥20%, ≥50%, ≥70%, or ≥90% improvement, respectively, in: swollen joint count (SJC; 66 joints) and tender joint count (TJC; 68 joints) and ≥20%, ≥50%, ≥70%, or ≥90% improvement, respectively, in 3 of following 5 assessments: Patient's Global Assessment of Pain (VAS); Patient's Global Assessment of Disease Activity (VAS); Investigator/Physician's Global Assessment of Disease Activity (VAS); participant's assessment of disability measured by the HAQ-DI; or acute phase reactant (ESR or CRP). | Weeks 4, 8, 12, 16, 20, and 24 | 
| Time to Achieve ACR20, ACR50, ACR70 and ACR90 Response | ACR20, ACR50, ACR70, and ACR90 are defined as ≥20%, ≥50%, ≥70%, or ≥90% improvement, respectively, in: swollen joint count (SJC; 66 joints) and tender joint count (TJC; 68 joints) and ≥20%, ≥50%, ≥70%, or ≥90% improvement, respectively, in 3 of following 5 assessments: Patient's Global Assessment of Pain (VAS); Patient's Global Assessment of Disease Activity (VAS); Investigator/Physician's Global Assessment of Disease Activity (VAS); participant's assessment of disability measured by the HAQ-DI; or acute phase reactant (ESR or CRP). Time to ACR response was calculated as the number of days from day 1 of study to the date of first achievement of ACR response. Data represent median time for responders only. | Weeks 4, 8, 12, 16, 20, and 24 | 
| Swollen Joint Count by Visit | Number of swollen joints was determined by examination of 66 joints and identifying when swelling was present. The number of swollen joints was recorded on the joint assessment form at each visit, no swelling = 0, swelling =1; total was calculated by adding all the joints for a maximum score of 66. A negative change from baseline indicates improvement. | Baseline, Weeks 4, 8, 12, 16, 20, and 24 | 
| Tender Joint Count by Visit | Number of tender joints was determined by examining 68 joints and identified the joints that were painful under pressure or to passive motion. The number of tender joints was recorded on the joint assessment form at each visit, no tenderness = 0, tenderness = 1; total was calculated by adding all the joints for a maximum score of 68. A negative change from baseline indicates improvement. | Baseline, Weeks 4, 8, 12, 16, 20, and 24 | 
| Patient's Global Assessment of Disease Activity by Visit | The participant's global assessment of disease activity is assessed on a 0 to 100 mm horizontal VAS by the participant. The left-hand extreme of the line=0 mm, and is described as no disease activity (symptom-free and no arthritis symptoms) and the right-hand extreme=100 mm, as maximum disease activity (maximum arthritis disease activity). The line was marked by the participant and the distance from the left edge was recorded. A negative change from baseline indicated improvement. | Baseline, Weeks 4, 8, 12, 16, 20, and 24 | 
| Physician's Global Assessment of Disease Activity by Visit | 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=0 mm, and is described as no disease activity (symptom-free and no arthritis symptoms) and the right-hand extreme=100 mm as maximum disease activity (maximum arthritis disease activity). The physician marked the line and the distance from the left edge was recorded. A negative change from baseline indicated improvement. | Baseline, Weeks 4, 8, 12, 16, 20, and 24 | 
| Patient's Global Assessment of Pain by Visit | The participants assessed their pain using a 0 to 100 mm horizontal VAS. The left-hand extreme of the line=0 mm, and is described as no pain and the right-hand extreme=100 mm as unbearable pain. The participant marked the line and the distance from the left edge was recorded. A negative change from baseline indicated improvement. | Baseline, Weeks 4, 8, 12, 16, 20, and 24 | 
| C-Reactive Protein by Visit | The test for CRP (mg per deciliter [mg/dL]) is a laboratory measurement for evaluation of an acute phase reactant of inflammation through the use of an ultrasensitive assay. A decrease in the level of CRP indicates reduction in inflammation and therefore improvement. | Baseline, Weeks 4, 8, 12, 16, 20, and 24 | 
| Erythrocyte Sedimentation Rate by Visit | ESR (mm/hr) is a blood test used to monitor therapy in inflammatory diseases such as rheumatoid arthritis (RA) and reflects acute phase reactant levels. Active disease in RA is defined by an ESR greater than 30 mm/hr. Change from baseline is computed as the value at each week minus the baseline value. A negative value in change from baseline indicates an improvement. | Baseline, Weeks 4, 8, 12, 16, 20, and 24 | 
| HAQ-DI Scores by Visit | HAQ-DI includes 20 questions concerning participant's activities of daily life, grouped in 8 scales of 2 to 3 questions for each activity. To respond to each question, a four-level response (score of 0 to 3 points), with higher scores showing larger functional limitations, was chosen. Scoring was as follows with respect to performance of participant's everyday activities: 0 (equals)=without difficulties; 1=with some difficulties; 2=with great difficulties; and 3=unable to perform these actions at all. Minimum score was 0, maximum score was 3. | Baseline, Weeks 4, 8, 12, 16, 20, and 24 | 
| Short Form-36 (SF-36) Physical Functioning Domain Scores by Visit | The SF-36 covers 8 health dimensions including 4 physical subscales (physical function, role-physical, bodily pain, and general health) and 4 mental subscales (vitality, social function, role-emotional, and mental health). The scores range from a minimum of 0 to a maximum of 100, with a higher score indicating better quality of life. Improvements of >3 points were considered clinically meaningful. | Baseline, Weeks 4, 8, 12, 16, 20, and 24 | 
| Percentage of Participants With HAQ-DI Clinical Remission and Clinically Meaningful Improvement By Visit | The HAQ-DI scale ranges from 0 to 3, where higher scores represent higher disease activity. A score of <0.5 represents clinical remission. A participant achieves a clinically meaningful improvement in HAQ-DI if they had a reduction from baseline of ≥0.22. | Baseline, Weeks 4, 8, 12, 16, 20, and 24 | 
| Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) Score by Visit | FACIT-Fatigue is a 13-item questionnaire; participants 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 participant's fatigue. 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 the participant's health status. | Baseline, Weeks 4, 8, 12, 16, 20, and 24 |