A Study of RoActemra/Actemra (Tocilizumab) in Patients With Active Rheumatoid Arthritis Who Have an Inadequate Response to Current Non-Biologic and/or Biologic DMARDS

Study Overview
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Brief Summary
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This single arm, open-label study will evaluate the efficacy and safety of RoActemra/Actemra (tocilizumab) in patients with active, moderate to severe rheumatoid arthritis who have an inadequate response to non-biologic and/or biologic disease-modifying antirheumatic drugs (DMARDs). Patients will receive intravenous RoActemra/Actemra at a dose of 8 mg/kg every 4 weeks. Anticipated time on study treatment is 96 weeks.

Official Title
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An Open-Label Study to Evaluate the Efficacy and Safety Of Tocilizumab in Patients With Active Rheumatoid Arthritis Who Have an Inadequate Response to Current Non-biologic DMARDs and/or Biologic DMARDs

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: Adult patients, >/=18 years of age Active moderate to severe rheumatoid arthritis Inadequate response to >/=3 DMARDs (non-biologic and/or biologic) Current treatment at stable dose for >/=8 weeks Etanercept discontinued >/=2 weeks, Anakinra >/=1 week, Infliximab, Adalimumab, Abatacept, Golimumab, Certolizumab >/=4 weeks, prior to baseline visit. Patients have discontinued MabThera/Rituxan or Ocrelizumab >/=16 weeks, and must have proven B-cell repletion Exclusion Criteria: Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months following baseline Rheumatic autoimmune disease other than RA Functional class IV (American College of Rheumatology Classification) Prior history or current inflammatory joint disease other than RA Oral corticosteroids at a dose of >10 mg/day prednisone equivalent Positive hepatitis B surface antigen (HBsAg) and / or total hepatitis B core antibodies (HBcAb) or hepatitis C virus (HCV) antibody Current or history of recurrent bacterial, viral, fungal or mycobaterial infection History of or currently active primary or secondary immunodeficiency

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: Single Arm<br> | Drug: tocilizumab [RoActemra/Actemra]<br>* 8 mg/kg intravenously, every 4 weeks for 96 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Score at Week 24 in Intent-to-treat (ITT) Population | The FACIT-Fatigue score was calculated according to a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function. 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. 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 (worst score) to 52 (best score). | Baseline, Week 24 | 
| Change From Baseline in FACIT Fatigue Score at Week 48 in ITT Population | The FACIT-Fatigue score was calculated according to a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function. 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. 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 (worst score) to 52 (best score). | Baseline, Week 48 | 
| Change From Baseline in FACIT Fatigue Score at Week 72 in ITT Population | The FACIT-Fatigue score was calculated according to a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function. 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. 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 (worst score) to 52 (best score). | Baseline, Week 72 | 
| Change From Baseline in FACIT Fatigue Score at Week 96 in ITT Population | The FACIT-Fatigue score was calculated according to a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function. 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. 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 (worst score) to 52 (best score). | Baseline, Week 96 | 
| Change From Baseline in FACIT Fatigue Score at Week 24 in Per Protocol (PP) Population | The FACIT-Fatigue score was calculated according to a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function. 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. 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 (worst score) to 52 (best score). | Baseline, Week 24 | 
| Change From Baseline in FACIT Fatigue Score at Week 48 in PP Population | The FACIT-Fatigue score was calculated according to a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function. 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. 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 (worst score) to 52 (best score). | Baseline, Week 48 | 
| Change From Baseline in FACIT Fatigue Score at Week 72 in PP Population | The FACIT-Fatigue score was calculated according to a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function. 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. 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 (worst score) to 52 (best score). | Baseline, Week 72 | 
| Change From Baseline in FACIT Fatigue Score at Week 96 in PP Population | The FACIT-Fatigue score was calculated according to a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function. 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. 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 (worst score) to 52 (best score). | Baseline, Week 96 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Bone Mineral Density (BMD) in Lumbar Spine, Total Hip and Femoral Neck Regions at End of Study | BMD was measured by dual energy X-ray absorptiometry (DXA) and T-scores (a standard deviation [SD] compared with the peak BMD value of an adult aged from 20 to 30 years) were calculated. Osteopenia was defined by a T-score between -1 and -2.5 SD and osteoporosis as a T-score below -2.5 SD, according to the World Health Organization (WHO) guidelines. T-scores for L1-L4 lumbar spine, total spine, total hip (left), and femoral neck (left) were calculated. | Baseline, End of the study (up to Week 100) | 
| Number of Participants Achieving Remission According to Disease Activity Score 28 (DAS28) at Weeks 24, 48, 72, and 96 | Remission was defined as DAS28 score less than (<) 2.6. The DAS28 score was a measure of the participant's disease activity calculated using the tender joint count (TJC) [28 joints], swollen joint count (SJC) [28 joints], patient's global assessment of disease activity (visual analog scale [VAS]: 0=no disease activity to 100=maximum disease activity) and the erythrocyte sedimentation rate (ESR) for a total possible score of 0 to approximately 10. In case of missing ESR value, C-Reactive Protein (CRP) was used to calculate DAS28. Higher scores represented higher disease activity. | Weeks 24, 48, 72 and 96 | 
| Percentage of Participants Achieving Remission According to DAS28 at Weeks 24, 48, 72, and 96 | Remission was defined as DAS28 score <2.6. The DAS28 score was a measure of the participant's disease activity calculated using the TJC [28 joints], SJC [28 joints], patient's global assessment of disease activity (VAS: 0=no disease activity to 100=maximum disease activity) and the ESR for a total possible score of 0 to approximately 10. In case of missing ESR value, CRP was used to calculate DAS28. Higher scores represented higher disease activity. | Weeks 24, 48, 72 and 96 | 
| Percentage of Participants With DAS28 Good or Moderate European League Against Rheumatism (EULAR) Response at Weeks 24, 48, 72 and 96 | The DAS28 score was a measure of the participant's disease activity calculated using the TJC [28 joints], SJC [28 joints], patient's global assessment of disease activity (VAS: 0=no disease activity to 100=maximum disease activity) and the ESR for a total possible score of 0 to approximately 10. In case of missing ESR value, CRP was used to calculate DAS28. Higher scores represented higher disease activity. EULAR Good response: DAS28 ≤3.2 and a change from Baseline <-1.2. EULAR Moderate response: DAS28 greater than (>) 3.2 to less than or equal to (≤) 5.1 or a change from Baseline <-0.6 to greater than or equal to (≥) -1.2. | Weeks 24, 48, 72 and 96 | 
| Percentage of Participants Achieving Remission and Low Disease Activity According to Simplified Disease Activity Index (SDAI) at Weeks 24, 48, 72, and 96 | SDAI was calculated by a simple numerical sum of tender and swollen joint count (based on a 28-joint assessment), patient and physician global assessment of disease activity (VAS 0-10 centimeter [cm]), and level of CRP. SDAI total score 0-86; higher scores = greater effect due to disease activity. Remission was defined as SDAI score ≤3.3. Low disease activity was defined as SDAI score ≤11.0. | Weeks 24, 48, 72 and 96 | 
| Percentage of Participants Achieving Remission and Low Disease Activity According to Clinical Disease Activity Index (CDAI) at Weeks 24, 48, 72, and 96 | CDAI was calculated by a simple numerical sum of tender and swollen joint count (based on 28-joint assessment) and the patient and physician global disease assessment (VAS 0-10 cm). CDAI total score 0-76; higher scores = greater effect due to disease activity. Remission was defined as CDAI score ≤2.8. Low disease activity was defined as CDAI score ≤10.0. | Weeks 24, 48, 72 and 96 | 
| Change From Baseline in TJC At Weeks 24, 48, 72, and 96 | 68 joints are assessed for tenderness and joints are classified as tender/not tender giving a total possible tender joint count score of 0 to 68. A negative change from baseline indicated improvement. | Baseline; Weeks 24, 48, 72 and 96 | 
| Change From Baseline in SJC At Weeks 24, 48, 72, and 96 | 66 joints were assessed for swelling and joints are classified as swollen/not swollen giving a total possible swollen joint count score of 0 to 66. A negative change from baseline indicated improvement. | Baseline; Weeks 24, 48, 72 and 96 | 
| Percentage of Participants Achieving American College of Rheumatology (ACR) 20, ACR50 and ACR70 Response at Weeks 24, 48, 72, and 96 | ACR20 response: ≥20% improvement in TJC; ≥20% improvement in SJC; and ≥20% improvement in at least 3 of 5 remaining ACR core measures: Patient Assessment of Pain; Patient Global Assessment of Disease Activity (PtGA); Physician Global Assessment of Disease Activity (PGA); self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ-DI]); and either CRP or ESR. ACR50 response required ≥50% improvement in the above criteria and ACR70 response required ≥70% improvement in the above criteria. | Weeks 24, 48, 72 and 96 | 
| Change From Baseline in Hemoglobin at Weeks 20, 44, 72 and 96 |  | Baseline; Weeks 20, 44, 72 and 96 | 
| C-reactive Protein Level |  | Baseline; Weeks 8, 16, 24, 36 48, 72 and 96 | 
| Erythrocyte Sedimentation Rate |  | Baseline; Weeks 8, 16, 24, 36 48, 72 and 96 | 
| Participant Assessment of Pain (VAS) | The mean score of pain as assessed by participants using a 100-mm horizontal VAS, where the left endpoint (0) indicated No pain, and the right endpoint (100) indicated Unbearable pain. Higher score indicated higher pain. | Baseline; Weeks 8, 16, 24, 36 48, 72 and 96 | 
| Change From Baseline in Health Assessment Questionnaire (HAQ) at Weeks 24, 48, 72, and 96 | HAQ: 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. | Baseline; Weeks 24, 48, 72 and 96 |