A Study of the Efficacy and Safety of Re-treatments With Rituximab in Patients With Active Rheumatoid Arthritis Who Have Had an Inadequate Response to Anti-tnfa Therapies

Study Overview
=================
Brief Summary
-----------------
This study will assess the long-term safety and efficacy of repeating treatment with MabThera, in combination with methotrexate and steroids, in patients who were previously randomized into MabThera study WA17042. The anticipated time on study treatment is until Mabthera is available on the local market and the target sample size is 100-500 individuals.

Official Title
-----------------
An Open Label Study of the Efficacy and Safety of Re-treatments With Rituximab (MabThera/Rituxan) in Patients With Active Rheumatoid Arthritis Who Have Had an Inadequate Response to Anti-TNFa Therapies

Conditions
-----------------
Rheumatoid Arthritis

Intervention / Treatment
-----------------
* Drug: methotrexate
* Drug: rituximab [MabThera/Rituxan]


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: adult patients 18-80 years of age with active RA; patients who participated in MabThera study WA17042, and completed to at least the Week 24 visit; eligible for re-treatment, based on clinical symptoms; patients of reproductive potential must be using reliable contraceptive methods. Exclusion Criteria: patients who participated in MabThera study WA17042 but withdrew into the safety follow-up; current treatment with any other disease-modifying antirheumatic drug (apart from methotrexate), or any anti-TNFalfa, anti-IL1, or other biologic therapies; development of any new contraindications to receiving MabThera; women who are pregnant or breast-feeding.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MabThera/Rituxan<br> | Drug: methotrexate<br>* a 10-25 mg stable dose given orally or parenterally throughout study<br>Drug: rituximab [MabThera/Rituxan]<br>* 1 g given by intravenous infusion on Days 1 and 15 of each treatment course<br>* Other names: MabThera/Rituxan;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With an American College of Rheumatology 20 (ACR20) Response | A patient had an ACR20 response if there was at least a 20% improvement, ie, reduction from Baseline, in tender and swollen joint counts (28 assessed joints) and in at least 3 of the following 5 parameters: Separate patient and physician assessments of patient disease activity in the previous 24 hours on a visual analog scale (VAS, left end=no disease activity [symptom-free and no arthritis symptoms], right end=maximum disease activity; patient assessment of pain in previous 24 hours on a VAS (left end=no pain and right end=unbearable pain); Health Assessment Questionnaire-Disability Index (20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do); and acute-phase reactant (either C-reactive protein or erythrocyte sedimentation rate). The ACR20 response was compared to Baseline in the precursor study WA17042. The first retreatment may have occurred in the precursor study WA17042. | Baseline to the end of the retreatment period (up to 7 years, 6 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Disease Activity Score 28 (DAS28) | The DAS28 is an index for measuring disease activity in rheumatic arthritis and includes swollen and tender joint counts, erythrocyte sedimentation rate (ESR), and general health (GH) status. The index is calculated with the following formula: DAS28 = (0.56 × √(TJC28)) + (0.28 × √(SJC28)) + (0.7 × log(ESR)) + (0.014 × GH), where TJC28 = tender joint count and SJC28 = swollen joint count, each on 28 joints. GH = a patient's global assessment of disease activity in the previous 24 hours on a 100 mm visual analog scale (left end = no disease activity [symptom-free and no arthritis symptoms], right end = maximum disease activity [maximum arthritis disease activity]). When ESR equaled 0 mm/hr, it was set to 1 mm/hr. The DAS28 scale ranges from 0 to 10, where a higher score represents higher disease activity. A negative change score indicates improvement. The first retreatment may have occurred in the precursor study WA17042. | Baseline to the end of the retreatment period (up to 7 years, 6 months) | 
| Percentage of Participants With DAS28 Low Disease Activity and DAS28 Remission | The DAS28 is an index for measuring disease activity in rheumatic arthritis and includes swollen and tender joint counts, erythrocyte sedimentation rate (ESR), and general health (GH) status. The index is calculated with the following formula: DAS28 = (0.56 × √(TJC28)) + (0.28 × √(SJC28)) + (0.7 × log(ESR)) + (0.014 × GH), where TJC28 = tender joint count and SJC28 = swollen joint count, each on 28 joints. GH = a patient's global assessment of disease activity in the previous 24 hours on a 100 mm visual analog scale (left end = no disease activity [symptom-free and no arthritis symptoms], right end = maximum disease activity [maximum arthritis disease activity]). When ESR equaled 0 mm/hr, it was set to 1 mm/hr. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity. Low disease activity was defined as a DAS28 score ≤ 3.2. DAS28 remission was defined as a DAS28 score < 2.6. The first retreatment may have occurred in the precursor study WA17042. | Baseline to the end of the retreatment period (up to 7 years, 6 months) | 
| Percentage of Participants With Good, Moderate, or no European League Against Rheumatism (EULAR) Responses | Change of the Disease Activity Score 28 score from baseline was used to determine EULAR responses of good, moderate, or no response. For a post-baseline score ≤ 3.2, a change from baseline of < -1.2 was a good response, < -0.6 to ≥ -1.2 was a moderate response, and ≥ -0.6 was no response. For a post-baseline score > 3.2 to ≤ 5.1, a change from baseline of < -0.6 was a moderate response and ≥ -0.6 was no response. For a post-baseline score > 5.1, a change from baseline < -1.2 was a moderate response and ≥ -1.2 was no response. A good response could not be achieved for post-baseline scores > 3.2. The first retreatment may have occurred in the precursor study WA17042. | Baseline to the end of the retreatment period (up to 7 years, 6 months) | 
| Change From Baseline in the American College of Rheumatology n (ACRn) Response | The ACRn response was defined as each participant's least favorable percentage change from Baseline in 3 measures, tender joint count, swollen joint count (28 assessed joints), and improvement score achieved in at least 3 of the 5 remaining ACR parameters: Separate patient and physician assessments of patient disease activity in the previous 24 hours on a visual analog scale (VAS, left end=no disease activity, right end=maximum disease activity; patient assessment of pain in previous 24 hours on a VAS (left end=no pain, right end=unbearable pain); Health Assessment Questionnaire-Disability Index (20 questions, 8 components, 0=without difficulty to 3=unable to do); and acute-phase reactant (either C-reactive protein or erythrocyte sedimentation rate). A higher change percentage indicates greater improvement from Baseline. The ACRn response was compared to Baseline in the precursor study WA17042. The first retreatment may have occurred in the precursor study WA17042. | Baseline to the end of the retreatment period (up to 7 years, 6 months) | 
| Change From Baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) Score | The HAQ-DI is a questionnaire specific for rheumatoid arthritis and consists of 20 questions referring to 8 domains: Dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. Participants completed the questionnaire by answering the 20 questions on a scale of 0 (without difficulty) to 3 (unable to do). The total score ranges from 0 (no disability) to 3 (completely disabled). A negative change score indicates improvement. | Baseline to the end of the retreatment period (up to 7 years, 6 months) | 
| Change From Baseline in the Physical and Mental Component Scores of the Short Form 36 (SF-36) Health Survey | The SF-36 Health Survey uses patient-reported symptoms on 8 subscales to assess health-related quality of life (HRQoL). The Physical Component Summary (PCS) score summarizes the subscales Physical Functioning, Role-Physical, Bodily Pain, and General Health. The Mental Component Summary (MCS) score summarizes the subscales Vitality, Social Functioning, Role-Emotional, and Mental Health. Each score was scaled from 0 to 100 with a higher score indicating better HRQoL. A positive change score indicates an improvement in HRQoL. | Baseline to the end of the retreatment period (up to 7 years, 6 months) | 
| Change From Baseline in the Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Score | The FACIT-F is a 13-item participant self-reporting questionnaire that assesses fatigue over the previous 7 days by scoring each item on a 5-point scale (0=Not at all, 1=A little bit, 2=Somewhat, 3=Quite a bit, 4=Very much). An overall FACIT-F score was obtained by summing the scores of all 13 items. The overall score ranged from 0 to 52. A lower score indicates less fatigue. A negative change score indicates improvement. | Baseline to the end of the retreatment period (up to 7 years, 6 months) | 
| Percentage of Participants With no Radiographic Progression From Baseline to Year 5 | Radiographic progression was defined as a change of ≤ 0 in the total Genant-modified Sharp score. The Genant-modified Sharp scoring system assesses structural damage due to rheumatoid arthritis in radiographs. A score for erosions of 0-3.5 (8 gradations) is assigned for 14 joints in each hand and wrist, and 6 joints in each foot. Joint space narrowing scores of 0-4 (9 gradations) are assigned to 13 joints in each hand and 6 joints in each foot. The maximum erosion score is 40 x 3.5 = 140. The maximum joint space narrowing score is 38 x 4.0 = 152. Both the erosion and joint space narrowing scores are normalized to 145 and are added together for a maximum total Genant-modified Sharp score of 290; the minimum score is 0. A higher score indicates more damage. Data is reported for 2 groups. | Baseline to Year 5 | 
| Change From Baseline in the Total Genant-modified Sharp Score at Year 5 | The Genant-modified Sharp scoring system assesses structural damage due to rheumatoid arthritis in radiographs. A score for erosions of 0-3.5 (8 gradations) is assigned for 14 joints in each hand and wrist, and 6 joints in each foot. Joint space narrowing scores of 0-4 (9 gradations) are assigned to 13 joints in each hand and 6 joints in each foot. The maximum erosion score is 40 x 3.5 = 140. The maximum joint space narrowing score is 38 x 4.0 = 152. Both the erosion and joint space narrowing scores are normalized to 145 and are added together for a maximum total Genant-modified Sharp score of 290; the minimum score is 0. A higher score indicates more damage. A negative change score indicates improvement. Data is reported for 2 groups. | Baseline to Year 5 | 
| Change From Baseline in the Genant-modified Sharp Erosion Score at Year 5 | The Genant-modified Sharp scoring system assesses structural damage due to rheumatoid arthritis in radiographs. A score for erosions of 0-3.5 (8 gradations) is assigned for 14 joints in each hand and wrist, and 6 joints in each foot. The maximum erosion score is 40 x 3.5 = 140 which is normalized to 145. The minimum score is 0 and the maximum score is 145. A higher score indicates more damage. A negative change score indicates improvement. Data is reported for 2 groups. | Baseline to Year 5 | 
| Change From Baseline in the Genant-modified Sharp Joint Space Narrowing Score at Year 5 | The Genant-modified Sharp scoring system assesses structural damage due to rheumatoid arthritis in radiographs. A score joint space narrowing of 0-4 (9 gradations) is assigned to 13 joints in each hand and 6 joints in each foot. The maximum joint space narrowing score is 38 x 4.0 = 152 which is normalized to a score of 145. The minimum score is 0 and the maximum score is 145. A higher score indicates more damage. A negative change score indicates improvement. Data is reported for 2 groups. | Baseline to Year 5 | 
| Change From Baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Year 5 | The HAQ-DI is a questionnaire specific for rheumatoid arthritis and consists of 20 questions referring to 8 domains: Dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. Participants completed the questionnaire by answering the 20 questions on a scale of 0 (without difficulty) to 3 (unable to do). The total score ranges from 0 (no disability) to 3 (completely disabled). A negative change score indicates improvement. Data is reported for 2 groups. | Baseline to Year 5 |