A Study of Tocilizumab Added to DMARDs in Patients With Moderate to Severe Rheumatoid Arthritis and an Inadequate Response to DMARDs.

Study Overview
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Brief Summary
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This open-label single arm study will evaluate the efficacy and safety of tocilizumab added to traditional disease-modifying antirheumatic drugs (DMARDs) in patients with moderate to severe active rheumatoid arthritis and an inadequate response to DMARDs. Patients will receive tocilizumab 8 mg/kg by intravenous infusion every 4 weeks for 24 weeks, in addition to their current non-biologic DMARDs at stable doses. Anticipated time on study treatment is 24 weeks, and the target sample size is 200.

Official Title
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Local Open-label Multicenter Study to Evaluate the Quality of Life in Patients With Moderate to Severe Active Rheumatoid Arthritis and an Inadequate Response to DMARDs When Adding Tocilizumab (TCZ)

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: tocilizumab [RoActemra/Actemra]
* Drug: DMARDs (disease-modifying antirheumatic drugs)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: adult patients, >/= 18 years of age moderate to severe active rheumatoid arthritis of >/=6 months duration inadequate clinical response to current non-biologic DMARDs current DMARDs must be at stable dose for 8 weeks prior to study entry oral corticosteroids (</=10mg/day prednisone or equivalent) and NSAIDs must be at stable dose for >/=4 weeks prior to screening Exclusion Criteria: rheumatic autoimmune disease other than RA history of or current inflammatory joint disease other than RA previous treatment with any biologic DMARD functional class IV as defined by the ACR classification intra-articular or parenteral corticosteroids within 6 weeks prior to screening

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>* 8 mg/kg iv every 4 weeks for 24 weeks<br>Drug: DMARDs (disease-modifying antirheumatic drugs)<br>* stable doses at investigator's prescription<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Health Assessment Questionnaire (HAQ) Score | HAQ 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. Withdrawal Visit is the final visit prior to the withdrawal of the subject from the study. | Weeks 0, 4, 8, 12, 16, 20, and 24 and Withdrawal Visit | 
| Percentage of Participants With an HAQ Score Decrease of 20 Percent (%), 50%, and 70% During Tocilizumab Treatment | HAQ 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=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. | Weeks 4, 8, 12, 16, 20, and 24 | 
| Change in HAQ Score at Week 24 | HAQ 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=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 and Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain Score as Assessed by Visual Analogue Scale (VAS) | Participant's global assessment of pain was assessed using a 100-millimeter (mm) horizontal VAS (0 to 100 mm) with 0=pain absent and 100=intolerable pain. Participants responded by placing a mark on the line to indicate their current level of pain. | Weeks 0, 4, 8, 12, 16, 20, and 24 | 
| European Quality of Life - 5 Dimensions (EQ-5D) Score | EQ-5D questionnaire assess 5 domains of quality of life including mobility, self-care, habitual daily activities, pain, discomfort, and anxiety/depression. Each of five domains was assessed by 3 levels depending on severity of a problem and scored using the following: 1=no disturbances, 2=moderate disturbances, 3=severe disturbances. Score is transformed and results in a total score range -0.594 to 1.000; higher score indicates a better health state. | Weeks 0, 4, 8, 12, 16, 20, and 24 | 
| Change in EQ-5D Score at Week 24 From Baseline | EQ-5D questionnaire assess 5 domains of quality of life including mobility, self-care, habitual daily activities, pain, discomfort, and anxiety/depression. Each of five domains was assessed by 3 levels depending on severity of a problem and scored using the following: 1=no disturbances, 2=moderate disturbances, 3=severe disturbances. Score is transformed and results in a total score range -0.594 to 1.000; higher score indicates a better health state. Minimum clinically significant change in EQ-5D corresponds to the parameter differences before and after treatment = 0.10. Graduations of assessment of the therapy efficacy by EQ-5D are: Difference (Δ) EQ-5D less than (<)0.10 points: none; 0.10 less than or equal to (≤)Δ EQ-5D ≤0.24: minimal effect; 0.24≤ Δ EQ-5D <0.31: satisfactory effect; Δ EQ-5D greater than or equal to (≥)0.31 points: pronounced effect. | Baseline and Week 24 | 
| General Health Score as Assessed by EQ-5D VAS | Participant-reported general health quality was assessed using an EQ-5D 100-mm horizontal VAS (0 to 100 mm) with 0=worst health state and 100=the best health state. The participants were asked to mark the line that corresponded to assessment of general health quality. | Weeks 0, 4, 8, 12, 16, 20, and 24 | 
| Percentage of Participants Achieving a Positive Response on Health Quality Assessment of EQ-5D | Participant-reported general health quality was assessed using an EQ-5D 100-mm horizontal VAS (0 to 100 mm) with 0=worst health state and 100=the best health state. The participants were asked to mark the line that corresponded to assessment of general health quality. Positive response was defined as an increase of EQ-5D score by 0.1 or more i.e. it is a clinically significant increase. | Weeks 0, 4, 8, 12, 16, 20, and 24 | 
| Change in General Health Assessed by VAS | Participant-reported general health quality was assessed using an EQ-5D 100-mm horizontal VAS (0 to 100 mm) with 0=worst health state and 100=the best health state. The participants were asked to mark the line that corresponded to assessment of general health quality. | Baseline and Week 24 | 
| Disease Activity Score Based on 28-Joint Count (DAS28) | DAS28 calculated from the number of swollen joints and tender joints using the 28-joint count, the erythrocyte sedimentation rate (ESR) (millimeters per hour [mm/hour]) 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. | Weeks 0, 4, 8, 12, 16, 20, and 24 | 
| Change in DAS28 Score From Baseline to Week 24 |  | Baseline and Week 24 | 
| Percentage of Patients With Varied Disease Activity Assessed Using DAS28 During Tocilizumab Treatment | DAS28 calculated from the number of swollen joints and tender joints using the 28-joint count, the ESR mm/hour, 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. Disease activity: 0=remission (DAS28 less than [<] 2.6), I=low (DAS28 less than or equal to [≤]2.6 to <3.2), II=moderate (DAS28=3.2 to 5.1), III=high (DAS28 greater than [>]5.1). | Weeks 0, 4, 8, 12, 16, 20, and 24 | 
| Percentage of Participants Achieving American College of Rheumatology 20% (ACR20), 50% (ACR50), and 70% (ACR70) Response | ACR20/50/70 response: ≥20%, ≥50%, or ≥70% improvement, respectively, in swollen/tender joint count (66 joints assessed for swelling and 68 joints assessed for tenderness) and in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the HAQ); and acute phase response: C-reactive protein (CRP) or ESR. | Weeks 0, 4, 8, 12, 16, 20, and 24 | 
| Percentage of Participants With European League Against Rheumatism (EULAR) Response Based on DAS28 | The DAS28-based EULAR response criteria were used to measure individual response as no effect, good effect, and moderate effect, depending on the extent of change from baseline and the level of disease activity reached. Good effect: change from baseline >1.2 with DAS28 score ≤3.2; moderate effect: change from baseline >1.2 with DAS28 score 3.2 to 5.1 or change from baseline >0.6 to <1.2 with DAS28 score <3.2; no effect: change from baseline ≤0.6 or change from baseline >0.6 and ≤1.2 with DAS28 score >5.1. | Weeks 4, 8, 12, 16, 20, and 24 | 
| C-Reactive Protein | CRP (milligrams/Liter) is a mediator of inflammation, acute phase protein. | Weeks 4, 8, 12, 16, 20, and 24 | 
| Erythrocyte Sedimentation Rate | ESR (mm/hr) is used to determine the acute phase response. | Weeks 4, 8, 12, 16, 20, and 24 |