A Study of MabThera (Rituximab) in Patients With Rheumatoid Arthritis Who Have Had an Inadequate Response to a Single Anti-TNF Inhibitor

Study Overview
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Brief Summary
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This study will evaluate the efficacy and safety of MabThera in patients with active rheumatoid arthritis who have had an inadequate response to one prior anti-TNF alpha inhibitor. MabThera-naive patients will be stratified into 3 arms, according to previous inadequate response to a)etanercept, b)infliximab or c)adalimumab. Patients will be treated with MabThera (1g infusion) on day 1 and day 15, and will continue their basic methotrexate therapy. The anticipated time on study treatment is 2+ years, and the target sample size is 100-500 individuals.

Official Title
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An Open-label Study to Evaluate the Safety of MabThera, and Its Effect on Treatment Response, in Patients With Rheumatoid Arthritis Following Inadequate Response to a Single Anti-TNF Agent

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: rituximab [MabThera]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: adult patients, 18-75 years of age; rheumatoid arthritis for >=6 months; previous inadequate response to a single anti-TNF alpha inhibitor; methotrexate at a stable dose range 7.5-25 mg/week. Exclusion Criteria: other chronic inflammatory articular disease or systemic autoimmune disease; previous treatment with MabThera or intolerance to MabThera; corticosteroids>=10 mg/day prednisolone within last 2 weeks, or corticosteroids at unstable doses within last 2 weeks;

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: MabThera (Rituximab)<br> | Drug: rituximab [MabThera]<br>* 1 g was given by intravenous infusion on Days 1 and 15<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 24 in Disease Activity Score Based on 28-Joint Count (DAS28) | The DAS28 consists of swollen joint count (SJC) and tender joint count (TJC) measurements, the erythrocyte sedimentation rate (ESR) in millimeters per hour (mm/hr), and the Patient's Global Assessment of Disease Activity (participant-ated rheumatoid arthritis [RA] activity assessment) with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). DAS28 less than or equal to (≤)3.2 equals (=) low disease activity, DAS28 greater than (>)3.2 to 5.1 = moderate to high disease activity. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DAS28 Score | The DAS28 consists of SJC and TJC measurements, the ESR in mm/hr, and the Patient's Global Assessment of Disease Activity (participant-rated RA assessment) with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). DAS28 ≤3.2 = low disease activity, DAS28 >3.2 to 5.1 = moderate to high disease activity. | Screening and Weeks 8, 16, and 24 | 
| Percentage of Participants With European League Against Rheumatism (EULAR) Response of Good or Moderate | The DAS28-based EULAR response criteria were used to measure individual responses as none, good, and moderate, depending on the extent of change from baseline and the level of disease activity reached. Good responders experienced a change from baseline of >1.2 with a DAS28 score ≤3.2 and moderate responders experienced a change from baseline >1.2 with DAS28 >3.2 to ≤5.1 or a change from baseline >0.6 to ≤1.2 with a DAS28 score of ≤5.1. | Weeks 8, 16, and 24 | 
| Percentage of Participants With Low Disease Activity (DAS28 ≤3.2) at Week 24 | Percentage of participants with low disease activity defined as DAS28 ≤3.2 at follow-up Week 24. The DAS28 consists of SJC and TJC measurements, the ESR in mm/hr, and the 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). | Week 24 | 
| Percentage of Participants Achieving Remission (DAS28 <2.6) at Week 24 | Percentage of participants with remission defined as DAS28 <2.6 at follow-up Week 24. The DAS28 consists of SJC and TJC measurements, the ESR in mm/hr, and the 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). DAS28 ≤3.2 = low disease activity, DAS28 >3.2 to 5.1 = moderate to high disease activity. | Week 24 | 
| Percentage of Participants Achieving a Response By EULAR Category | Percentage of participants achieving a response by EULAR category, including 'moderate', 'good', or no response at follow-up Weeks 8, 16, and 24. 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 had a change from baseline >1.2 with a DAS28 score ≤ 3.2; moderate responders had a change from baseline >1.2 with a DAS28 score of >3.2 to ≤5.1 or a change from baseline >0.6 to ≤1.2 with a DAS28 score of ≤5.1; non-responders had a change from baseline ≤0.6 or change from baseline >0.6 and ≤1.2 with a DAS28 score of >5.1. | Weeks 8, 16, and 24 | 
| Health Assessment Questionnaire - Disability Index (HAQ-DI) Score | The HAQ-DI score consists of questions referring to 8 categories: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and common daily activities. For each of the categories, participants reported the amount of difficulty they had in performing 2 or 3 specific sub-category items. The standard disability score was calculated from the 8 categories by dividing the sum of the individual categories by the number of categories answered, yielding a score from 0 (without any difficulty) to 3 (unable to do). | Screening and Weeks 8, 16, and 24 | 
| Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Score | The FACIT fatigue scale is base on a 13-item questionnaire to assess the therapy-induced fatigue. Participants were requested to score each question on a scale ranging from 0 (best) to 4 (worst). The scoring system of the FACIT fatigue scale adds up to a total scale ranging from 0 (best) to 52 (worst). The assessment was originally developed for chronic illnesses and is now validated for patients with rheumatoid arthritis (RA). The questionnaire was provided in a German translation. | Screening and Weeks 8, 16, and 24 | 
| Short-Form 36 (SF-36) Physical Composite Scores (PCS) and Mental Composite Scores (MCS) | The SF-36 is a multi-purpose, short-form health survey with 36 questions. It yields an 8-scale profile of functional health and well-being scores (domains) as well as psychometrically based physical and mental health summary measures. The SF-36 taps 8 health concepts: physical functioning, bodily pain, physical role functioning, emotional role functioning, emotional well-being, social functioning, vitality, and general health perceptions. The 8 scales are further summarized to 2 distinct higher-ordered clusters: the physical and mental composite t-scores (PCS and MCS). The range for all 8 domains as well as for the composite t-scores is from 0 to 100 with 100 as best possible health status and 0 as worst health status. | Screening and Weeks 8, 16, and 24 | 
| SF-36 Domain Scores | The SF-36 is a multi-purpose, short-form health survey with 36 questions. It yields an 8-scale profile of functional health and well-being scores (domains) as well as psychometrically based physical and mental health summary measures. The SF-36 taps 8 health concepts: physical functioning, bodily pain, physical role functioning, emotional role functioning, emotional well-being, social functioning, vitality, and general health perceptions. The 8 scales are further summarized to two distinct higher-ordered clusters: the physical and mental composite t-scores (PCS and MCS). The range for all 8 domains as well as for the composite t-scores is from 0 to 100 with 100 as best possible health status and 0 as worst health status. | Screening and Weeks 8, 16, and 24 | 
| Percentage of Participants Achieving American College of Rheumatology (ACR) 20 Percent (%), 50% or 70% Response (ACR20/ACR50/ACR70) | ACR20/50/70 response: ≥20%, ≥50%, or ≥70% improvement, respectively, in tender or swollen joint counts and ≥20%, ≥50%, or ≥70% improvement, respectively, in 3 of the following 5 criteria: 1) Physician's Global Assessment of Disease Activity, 2) Patient's Global Assessment of Disease Activity, 3) Patient's Assessment of Pain, 4) participant assessment of functional disability via a HAQ-DI, and 5) C-reactive protein or ESR at each visit. | Weeks 8, 16, and 24 | 
| Swollen Joint Count (SJC) | The 28 joints to be assessed for tenderness and swelling were shoulder, elbow, wrist, metacarpophalangeal (MCP) joints 1-5, proximal interphalangeal (PIP) joints 1-5, and knee on both sides of the body. The sum of swollen joints, each, ranged from 0 to 28 with 0 as best possible health status and 28 as worst health status. | Screening and Weeks 8, 16, and 24 | 
| Tender Joint Count (TJC) | The 28 joints to be assessed for tenderness and swelling were shoulder, elbow, wrist, metacarpophalangeal (MCP) joints 1-5, proximal interphalangeal (PIP) joints 1-5, and knee on both sides of the body. The sum of tender joints ranged from 0 to 28 with 0 as best possible health status and 28 as worst health status. | Screening and Weeks 8, 16, and 24 | 
| Physician's Global Assessment of Disease Activity | Physicians assessed the disease (RA) activity on a 100 mm horizontal VAS. The left-hand extreme of the line (0 mm) was 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). | Screening and Weeks 8, 16, and 24 | 
| Patient's Assessment of Disease Activity | Participants were to assess the disease (RA) activity on a 100 mm horizontal VAS. The left-hand extreme of the line (0 mm) was 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). | Screening and Weeks 8, 16, and 24 | 
| Patient's Assessment of Pain | Participants were to assess their current level of pain on a 100 mm horizontal VAS. The left-hand extreme of the line (0 mm) was described as no pain and the right-hand (100 mm) as unbearable pain. | Screening and Weeks 8, 16, and 24 | 
| C-Reactive Protein (CRP) | Mean CRP as measured as an acute phase reactant by mg per deciliter (mg/dL) at screening, Days 1 and 15, and Weeks 8, 16, and 24. | Screening, Days 1 and 15, and Weeks 8, 16, and 24 | 
| Erythrocyte Sedimentation Rate (ESR) | Mean ESR, as an acute phase reactant, measured in mm/hr at screening, Days 1 and 15, and Weeks 8, 16, and 24. | Screening, Days 1 and 15, and Weeks 8, 16, and 24 | 
| Rheumatoid Factor (RF) | Mean RF as measured by international unit per milliliter (IU/mL) at screening and Weeks 8, 16, and 24. | Screening and Weeks 8, 16, and 24 |