A Study to Assess Efficacy With Respect to Clinical Improvement in Disease Activity and Safety of Tocilizumab in Patients Wtih Active Rheumatoid Arthritis.

Study Overview
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Brief Summary
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This single arm study will assess the effectiveness of tocilizumab in combination with traditional DMARDs with regard to the clinical improvement in disease activity (achievement of LDAS) after 24 weeks' treatment in patients with active rheumatoid arthritis (RA) who have had an inadequate response to current traditional DMARD and/or anti-TNF therapy. Patients will receive tocilizumab 8mg/kg iv every 4 weeks, in addition to ongoing DMARDs at the stable pre-entry dose prescribed by the physician, for a total of 6 infusions during the regular treatment period and a further 6 infusions during an optional extension phase. The anticipated time on study treatment is 6 to 12 months, and the target sample size is <500 individuals.

Official Title
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Effectiveness After Four and Twentyfour Weeks and Safety of Tocilizumab in Patients With Active RA

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Tocilizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: adult patients, >=18 years of age; rheumatoid arthritis of >=6 months duration diagnosed according to the revised 1987 ACR criteria; DAS28 of >3.2; At screening either ESR >=28 mm/h or CRP >=1 mg/dL; Having received permitted DMARDs, 1 or more; current DMARD therapy must have been at a stable dose for at least 8 weeks prior to baseline. Exclusion Criteria: major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months following screening; functional class IV as identified by the ACR classification of functional status in RA; rheumatoid autoimmune disease other than RA; prior history of or current inflammatory joint disease other than 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tocilizumab<br> | Drug: Tocilizumab<br>* 8mg/kg iv every 4 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Low Disease Activity Score at Week 24 | Low Disease Activity Score (LDAS) is defined as Disease Activity score less than or equal to (≤ ) 3.2. Disease activity score 28 (DAS28) was 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 100-mm Visual analog scale [VAS]); DAS28 score ranged from 0 to 10, where higher scores correspond to greater disease activity. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Changes in DAS28 From Baseline | 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 100-mm VAS); DAS28 score ranged from 0 to 10, where higher scores correspond to greater disease activity. DAS28 ≤3.2 = low disease activity, DAS28 greater than (>)3.2 to 5.1 = moderate to high disease activity. | Weeks 1, 2, 4, 8, 12, 16, 20 and 24 | 
| Percentage of Participants With a Response at Week 24 by European League Against Rheumatism (EULAR) Category | The 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. | Week 24 | 
| Percentage of Participants With a DAS28 Response at Weeks 4 and 24 | DAS28 calculated from the number of swollen joints and painful joints using the 28-joint count, the ESR and participant's global assessment (PGA) of disease activity (participant rated arthritis activity assessment using VAS) with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity. DAS28 ≤3.2 = low disease activity, DAS28 <2.6 = remission and a clinically significant (CS) reduction was defined as ≥1.2. | Weeks 4 and 24 | 
| Percentage of Participants With an American College of Rheumatology 20%, 50%, or 70% (ACR20/ACR50/ACR70) Response | ACR20/50/70 response: ≥20%, 50%, or 70% improvement, respectively, in swollen and tender joint count; and ≥20% improvement 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 Health Assessment Questionnaire [HAQ-DI]); and C-Reactive Protein (CRP). | Weeks 1, 2, 4, 8, 12, 16, 20 and 24 | 
| Change From Baseline in Swollen and Tender Joint Counts at Week 24 | Swollen joint count: 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. Tender joint counts: 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. | Week 24 | 
| Change From Baseline in the Levels of C-Reactive Protein at Week 24 | The serum concentration of CRP is measured in mg/L. A reduction in the level was considered an improvement. | Week 24 | 
| Change From Baseline in Participant's Global Assessment of Pain (VAS) at Week 24 | Participant's global assessment of pain was assessed using a 100-mm horizontal VAS (0 to 100 mm) with 0=pain absent and 100=unbearable pain. Participants responded by placing a mark on the line to indicate their current level of pain. | Week 24 | 
| Change From Baseline in Participant and Physician Assessment of Global Disease Activity (VAS) at Week 24 | Participant's global assessment of disease activity was an overall assessment of their current disease activity on a 100-mm horizontal VAS scale (left-hand extreme: no disease activity; right-hand extreme: maximum disease activity). Physician's global assessment of disease activity was measured as participant's current disease activity on a 100-mm horizontal VAS scale (left hand extreme: no disease activity; right-hand extreme: maximum disease activity). | Week 24 | 
| Change From Baseline in Clinical Disease Activity Index (CDAI) Score | CDAI was calculated according to the following formula: CDAI = Number of swollen joints (plus) + Number of tender joints + VAS disease activity participant assessment + VAS disease activity investigator assessment. The maximum score was 334 (66 joints + 68 joints + 100 mm + 100 mm); higher scores indicated higher disease activity. | Weeks 1, 2, 4, 8, 12, 16, 20 and 24 | 
| Change From Baseline in HAQ-DI at Week 24 | HAQ-DI: 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. | Week 24 | 
| Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Week 24 | FACIT-F 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. 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 the participant's health status. | Week 24 | 
| Change From Baseline in Short Form-36 (SF-36) Score at Week 24 | SF-36 is a standardized survey evaluating 8 aspects of functional health and well being: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, mental health. The score for a section is an average of the individual question scores, which are scaled 0-100 (100=highest level of functioning). Absolute change was defined as the change from baseline to Week 24. | Week 24 | 
| Participant's Global Assessment of Pain as Assessed by Patient Take Home Form (PTHF) | Participant's were asked to state the worst level of pain felt in the past 24 hours using a 100-mm horizontal VAS (0 to 100 mm) with 0=no pain and 100=unbearable pain. Participants responded by placing a mark on the line to indicate their level of pain. Participants were asked to document their response during the first 4 treatment weeks at approximately the same time every day. | Baseline and Weeks 1, 2, and 4 | 
| Duration of Morning Stiffness as Assessed Using PTHF | Duration of morning stiffness: participants were asked 'how long did your morning stiffness last from the time you woke up yesterday' and the response was provided in minutes and hours. Participants were asked to document their response during the first 4 treatment weeks at approximately the same time every day. | Baseline, Weeks 1, 2, and 4 | 
| Participant Assessment of Fatigue/Tiredness as Assessed Using PTHF | Participants were asked to assess their overall level of fatigue/tiredness during the previous 24 hours using a 100-mm horizontal VAS with 0=none and 100=very severe. Participants responded by placing a mark on the line to indicate their current level of fatigue. Participants were asked to document their response during the first 4 treatment weeks at approximately the same time every day. | Baseline and Weeks 1, 2 and 4 | 
| Treatment Satisfaction Questionnaire for Medication (TSQM) Score | The TSQM is a general measure of participants treatment satisfaction and consists of 14 questions that result in 4 subscales: effectiveness, side-effects, convenience and global satisfaction. All subscale scores range from 0 to 100%, with 100% being the best possible result. | Week 24 | 
| Changes in Hemoglobin | Hemoglobin levels were determined as a hematology parameter to measure changes in disease related anemia. | Baseline, Weeks 1, 2, 4 and 24 | 
| Changes in C-Reactive Protein | CRP is an acute phase inflammatory marker used as a measure of inflammation. A reduction in CRP is considered to be an improvement. | Baseline, Weeks 1, 2 ,4 and 24 | 
| Changes in Erythrocyte Sedimentation Rate (ESR) | ESR is an inflammation marker used to determine acute phase response. | Baseline, Weeks 1, 2, 4 and 24 | 
| Percentage of Participants Withdrawing From Study Treatment Because of Insufficient Therapeutic Response | Participants who withdrew from study drug due to other reasons were not taken into account. | Weeks 1, 2, 4, 8, 12, 16, 20 and 24 |