A Pilot Study of MabThera (Rituximab) Evaluated by MRI in Patients With Rheumatoid Arthritis.

Study Overview
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Brief Summary
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This single arm study will measure the effect of MabThera in combination with methotrexate on the progression of synovitis, the extent of bone marrow edema, and the number of erosions in the wrist and hand of patients with rheumatoid arthritis, using a new MRI technique. Patients will receive MabThera 1000mg i.v. on days 1 and 15, in combination with a stable dosage of 10-25mg/week methotrexate throughout the duration of the study. Further courses of MabThera will be provided to eligible patients. MRI will be performed 1-2 weeks before treatment initiation, and repeated 1 and 6 months after the first MabThera infusion. The anticipated time on study treatment is 1-2 years, and the target sample size is <100 individuals.

Official Title
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Pilot Study to Evaluate the Effect of Mabthera in Combination With MTX in the Inhibition of Progression of Synovitis, Bone Marrow Edema, and Erosions Evaluated by Magnetic Resonance Imaging (MRI) in the Hand of Patients With Rheumatoid Arthritis.

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: rituximab [MabThera/Rituxan]
* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: adult patients, 18-75 years of age; rheumatoid arthritis for >=3 months and <=10 years; inadequate response to methotrexate (12.5-25mg/week) for >=3 months; evidence of erosive disease and/or clinical synovitis in a signal joint. Exclusion Criteria: autoimmune rheumatic diseases other than RA; surgical operations on bones/joints in 12 weeks prior to baseline visit; concomitant treatment with biologic agents; previous treatment with more than one biologic agent approved for RA, or with cell-depleting therapies.

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: 1<br> | Drug: rituximab [MabThera/Rituxan]<br>* 1000mg iv on days 1 and 15<br>Drug: Methotrexate<br>* 10-25mg/week<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) Rheumatoid Arthritis Magnetic Resonance Imaging Scoring System (RAMRIS) Synovitis Score | Extension and degree of synovitis in wrist according to RAMRIS score developed by OMERACT. Synovitis is an area in synovial compartment that shows above normal post-gadolinium enhancement of a thickness greater than width of normal synovium. Synovitis is assessed in 3 wrist regions (distal radioulnar joint; radiocarpal joint; intercarpal and carpometacarpal joints) and in each metacarpophalangeal (MCP) joint. 1st carpometacarpal joint and 1st MCP joint are not scored. Score 0 is normal, and 1-3 (mild, moderate, severe) are by thirds of the presumed maximum volume of enhancing tissue in the synovial compartment. Total synovitis score=the sum of the individual scores (3 wrist regions [range 0-9] or 4 MCP joints [range 0-12]) for an overall range of 0-21, where 0=no damage and maximum score [9, 12, or 21]=most severe damage. Change in synovitis = Follow-up synovitis score - baseline score. | Baseline, Week 4, and Week 24 | 
| OMERACT RAMRIS Bone Edema Score | Extension and degree of bone edema in the wrist according to the RAMRIS score developed by OMERACT. Bone edema is a lesion within the trabecular bone, with ill-defined margins and signal characteristics consistent with increased water content. Each bone (wrists: carpal bones, distal radius, distal ulna, metacarpal bases; MCP joints: metacarpal heads, phalangeal bases) is scored separately. The scale of 0-3 was based on the proportion of bone with edema, as follows: 0=no edema; 1=1 percent (%) to 33% of bone was edematous; 2 = 34%-66% of bone was edematous; and 3= 67%-100% of bone was edematous. Total bone edema score=sum of the individual scores for an overall range of 0-69, where 0=no edema and 69=most severe edema. Change in bone edema = follow-up bone edema score - baseline score. | Baseline, Weeks 4 and 24 | 
| OMERACT RAMRIS Erosion Score | MRI bone erosion measures a sharply marginated bone lesion, with correct juxta-articular localization and typical signal characteristics, which is visible in 2 planes with a cortical break seen in at least 1 plane. Each bone (wrists: carpal bones, distal radius, distal ulna, metacarpal bases; MCP joints: metacarpal heads, phalangeal bases) scored separately. Scale is 0-10 based on proportion of eroded bone compared to assessed bone volume (0=no erosion; 1=1%-10% of bone eroded; 2=11%-20%, etc). For long bones, assessed bone volume is from articular surface (or best estimated position if absent) to depth of 1 centimeter (cm); in carpal bones it is the whole bone. Total erosion score=sum of individual scores for an overall range of 0-230, where 0=no erosion and 230=most severe erosion. Change in erosion=Follow-up erosion score - baseline score. | Baseline, Week 4, and Week 24 | 
| Early Enhancement Rate (REE) | A low cost, low field dedicated extremity MRI unit was used, which is specifically designed for the examination of peripheral joints. In addition to the standard OMERACT-RAMRIS scoring system, additional data were elaborated by using dynamic MRI, i.e. Contrast-Enhanced Dynamic MRI (DCE-MRI). This method evaluates the diffusion of the contrast mean in a series of very short sequences thus providing a diffusion curve which is proportionate to the extent of inflammation in the synovial membrane. Numerical parameters used with this method are the slope in the initial phase (rate of early enhancement - REE) and its steady state condition (relative enhancement - RE). REE per second during the first 55 seconds was calculated according to the formula REE55 = (S55-S0)/(S0x55)x100%. The REE shows the slope of the curve of contrast uptake tangential to the α angle and is steeper if inflammation is higher. | Baseline, Weeks 4 and 24 | 
| Relative Enhancement (RE) Score | A low cost, low field dedicated extremity MRI unit was used, which is specifically designed for the examination of peripheral joints. In addition to the standard OMERACT-RAMRIS scoring system, additional data were elaborated by using dynamic MRI (DCE-MRI). This method evaluates the diffusion of the contrast mean in a series of very short sequences thus providing a diffusion curve which is proportionate to the extent of inflammation in the synovial membrane. Numerical parameters used with this method are the slope in the initial phase (REE) and its steady state condition (RE). | Baseline, Weeks 4 and 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ritchie Articular Index Scores | The Ritchie Articular Index is a graded assessment of tenderness in 26 joint regions. The sum of the grades of tenderness (0=not tender, 1=tender, 2=tender and causes wince, and 3 tender, causes wince and effort to withdraw) elicited by applying firm pressure over the joint margin of articular joints (such as shoulders, elbow, wrists, hips). The scores ranged from 0 (no tenderness) to 78 (most severe tenderness). | Baseline and Weeks 4, 12, and 24 | 
| Health Assessment Questionnaire - Disability Index (HAQ-DI) Score | The Stanford HAQ-DI is a participant-reported questionnaire specific for rheumatoid arthritis (RA). It consist of 20 items referring to eight component sets: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. Each item within a domain was scored on a 4-point Likert scale from 0 to 3: 0 = no difficulty; 1 = some difficulty; 2 = much difficulty; 3 = unable to do. The highest score reported by the participant for a domain determined the score for that domain. The overall disability index is 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 and Weeks 4, 12, and 24 | 
| Patient's Global Assessment of Pain | The participant's assessment of their current level of pain on a 0 to 100 millimeter (mm) horizontal VAS. The left-hand extreme of the line was described as no pain and the right-hand as unbearable pain. The participant was asked to mark the line corresponding to their current level of pain and the distance from the left edge was recorded. | Baseline and Weeks 4, 12, and 24 | 
| DAS28 Score | DAS28 calculated from the number of swollen joints and tender joints using the 28-joints count, the erythrocyte sedimentation rate (ESR) (millimeters per hour [mm/hr]) and 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. A DAS28 score of less than or equal to (≤) 3.2 = low disease activity, a DAS28 score of >3.2 to 5.1 = moderate to high disease activity. | Baseline and Weeks 4, 12, and 24 | 
| Erythrocyte Sedimentation Rate (ESR) | ESR was determined using the Westergren method. ESR measures how fast red blood cells (erythrocytes) fall to the bottom of a fine glass tube that is filled with the participant's blood. The higher the sedimentation rate the greater the inflammation. | Baseline and Weeks 4, 12, and 24 | 
| C-Reactive Protein (CRP) | CRP measured by milligrams per deciliter (mg/dL). High levels of CRP are indicators of active inflammation. | Baseline and Weeks 4, 12, and 24 | 
| Anti-Cyclic Citrullinated Peptide (Anti-CCP) Autoantibodies Count | Anti-CCP autoantibodies count measured by units per milliliter (U/mL). The anti-CCP autoantibodies bind antigenic determinants that contain the unusual amino acid citrulline. The anti-CCP antibody is a highly specific diagnostic test of RA (though with variable sensitivity) and a marker of joint damage with high prognostic significance. | Baseline and Weeks 4, 12, and 24 | 
| Rheumatoid Factor (RF) Immunoglobulin M (IgM) Concentrations | RF IgM concentrations measured by international units per milliliter (IU/mL). RF is an antibody reacting against the fragment, crystallizable (Fc) region of IgG. Quantitative measurements have shown a prognostic value in distinguishing between progressive and non-progressive disease in early RA, a correlation with radiologically determined joint damage, and relation with clinical improvement after disease-modifying anti-rheumatic treatment. | Baseline and Weeks 4, 12, and 24 | 
| Total Immunoglobulin (Ig) Concentrations | Total Ig concentrations as measured by milligrams per milliliter (mg/mL). | Baseline and Weeks 4, 12, and 24 | 
| Hematocrit Concentration (%) |  | Baseline and Weeks 4, 12, and 24 | 
| Percentage of Total B-lymphocytes | Concentration of all B-lymphocytes subtypes was assessed. | Baseline and Weeks 4, 12, and 24 | 
| Erosion Score - Right Hand | The erosion score per joint of the hands can range from 0 to 5. Erosions were scored 1 if they were discrete but clearly present, and 2 or 3 if they were larger, depending on the surface area of the joint involved. A score of 3 was given if the erosion was large and extended over the imaginary middle of the bone. A score of 5 was given if a complete collapse of the joint was present or if the full surface of the joint was affected. In each joint, individual erosions were summed up to a maximum of 5. The maximal erosion score for each hand was thus 80, considering the 16 areas for erosions per hand. | Baseline and Week 24 | 
| Erosion Score - Left Hand | The erosion score per joint of the hands can range from 0 to 5. Erosions were scored 1 if they were discrete but clearly present, and 2 or 3 if they were larger, depending on the surface area of the joint involved. A score of 3 was given if the erosion was large and extended over the imaginary middle of the bone. A score of 5 was given if a complete collapse of the joint was present or if the full surface of the joint was affected. In each joint, individual erosions were summed up to a maximum of 5. The maximal erosion score for each hand was thus 80, considering the 16 areas for erosions per hand. | Baseline and Week 24 | 
| Joint Space Narrowing - Right Hand | Joint space narrowing and joint subluxation or luxation are combined in a single score with a range of 0 to 4. A normal joint space was scored 0. A score of 2 was allowed to a focal narrowing of the joint or to a joint space not sufficiently narrowed to be scored 2. The score of 1 was not to be used when the reader was unsure whether there was joint space narrowing. A generalized narrowing leaving more than 50% of the original joint space present was scored 2. A generalized narrowing leaving less than 50% of the original joint space present was scored 3, and a subluxation of a joint was also scored 3. A bony ankylosis or a complete luxation of the joint was scored 4. A total of 13 joints were evaluated for narrowing and the scores were summed (13 times [x] 4 [maximum per joint]). Each sum was normalized to a scale of 0 (best possible outcome) to 100 (worst possible outcome). | Baseline and Week 24 | 
| Joint Space Narrowing - Left Hand | Joint space narrowing and joint subluxation or luxation are combined in a single score with a range of 0 to 4. A normal joint space was scored 0. A score of 2 was allowed to a focal narrowing of the joint or to a joint space not sufficiently narrowed to be scored 2. The score of 1 was not to be used when the reader was unsure whether there was joint space narrowing. A generalized narrowing leaving more than 50% of the original joint space present was scored 2. A generalized narrowing leaving less than 50% of the original joint space present was scored 3, and a subluxation of a joint was also scored 3. A bony ankylosis or a complete luxation of the joint was scored 4. A total of 13 joints were evaluated for narrowing and the scores were summed (13 x 4 [maximum per joint]). Each sum was normalized to a scale of 0 (best possible outcome) to 100 (worst possible outcome). | Baseline and Week 24 | 
| X-Rays: Right Hand Total Score | Right hand total scores as measured by X-rays examining erosion and joint space narrowing. Total score was calculated as the sum of the erosion score and the joint space narrowing score and scores ranged from 0 (best possible outcome) to 180 (worst possible outcome). | Baseline and Week 24 | 
| X-Rays: Left Hand Total Score | Left hand total scores as measured by X-rays examining erosion and joint space narrowing. Total score was calculated as the sum of the erosion score and the joint space narrowing score and ranged from 0 (best possible outcome) to 180 (worst possible outcome). | Baseline and Week 24 |