A Study of Rituximab (MabThera®/Rituxan®) in Patients With Rheumatoid Arthritis and Inadequate Response to Methotrexate

Study Overview
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Brief Summary
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This 3 arm study assessed the efficacy of rituximab (MabThera®/Rituxan®) in the prevention of progression of structural joint damage in participants with active rheumatoid arthritis who had an inadequate clinical response to methotrexate. Participants were randomized to receive rituximab 500 mg intravenously (iv), rituximab 1000 mg iv, or placebo iv on days 1 and 15 every 24 weeks in the main study; all participants received concomitant methotrexate at a stable dose of 12.5-25 mg/week throughout the study. Further courses of rituximab were provided to eligible participants. Structural joint damage was assessed by magnetic resonance imaging (MRI) at baseline and at intervals during the study.

Detailed Description
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There were 3 phases in the study: A 52 week long main study, a study extension phase, and a 48 week long safety follow-up phase. The first course of treatment with placebo or rituximab was initiated on Day 1 of the 52 week long main study. A second course of treatment was initiated after Week 24, if the participant met eligibility criteria. After Week 52, eligible participants received further treatment courses at intervals ≥ 6 months in the study extension phase. No treatments were administered in the safety follow-up phase. Participants had to meet the following eligibility criteria to receive rituximab in the study extension phase. Minimum of 24 weeks had passed since the first infusion of the last course of study medication. C-reactive protein-based Disease Activity Score 28 (DAS28-CRP) ≥ 2.6. Absolute neutrophil count not below 1.5 x 103/μL. Patient had not developed contraindications for receiving rituximab, such as: Any new or uncontrolled concomitant disease such as, but not limited to, cardiovascular disease, nervous system, pulmonary, renal, hepatic, endocrine or gastrointestinal disorders. Primary or secondary immunodeficiency (history of, or currently active), including known history of HIV infection. Known active infection of any kind (excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization, or treatment with iv anti-infectives within 4 weeks prior to infusion or completion of oral anti-infectives within 2 weeks prior to infusion. Patient was not pregnant or breast feeding. Patients who entered the study and were found to be hepatitis B surface antigen (HBsAg) negative, hepatitis B core antibody (HBcAb) positive, were to be negative for hepatitis B viral DNA (< 29 IU/mL) and were to have aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN) results within the last 12 weeks.

Official Title
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A Randomized, Placebo Controlled, Multicenter Clinical Study Investigating Efficacy of Rituximab in the Inhibition of Joint Structural Damage Assessed by Magnetic Resonance Imaging in Patients With Rheumatoid Arthritis and Inadequate Response to Methotrexate

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Biological: Rituximab
* Drug: Placebo
* Drug: Methylprednisolone
* Drug: Methotrexate
* Drug: Folic acid or folate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients, 18-80 years of age. Active rheumatoid arthritis for ≥ 3 months and ≤ 10 years. Evidence of erosive disease and/or clinical synovitis in a signal joint. Inadequate response to 12.5-25 mg/week methotrexate for ≥ 12 weeks. Exclusion Criteria: Rheumatic autoimmune disease or inflammatory joint disease other than rheumatoid arthritis. - Any surgical procedure within 12 weeks prior to baseline. Previous treatment with a biologic agent or with a B cell modulating or cell depleting therapy.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rituximab 500 mg<br>Participants received rituximab 500 mg iv on Day 1 and Day 15 of the main study. Participants received a second course of treatment on Day 1 and Day 15 after Week 24 of the main study, if they met eligibility criteria (see the Detailed Description). Participants received further treatment courses on Day 1 and Day 15 at intervals of ≥ 6 months after Week 52 in the study extension phase, if they met eligibility criteria (see the Detailed Description). Throughout the study, participants received methylprednisolone 100 mg iv prior to infusion of the investigational drug, methotrexate 7.5 to 25 mg/week orally or parenterally, and folic acid or folate ≥ 5 mg/week orally. | Biological: Rituximab<br>* Rituximab was supplied as a sterile liquid for iv administration.<br>* Other names: Rituxan®;Drug: Methylprednisolone<br> <br> Drug: Methotrexate<br> <br> Drug: Folic acid or folate<br> <br> |
| Experimental: Rituximab 1000 mg<br>Participants received rituximab 1000 mg iv on Day 1 and Day 15 of the main study. Participants received a second course of treatment on Day 1 and Day 15 after Week 24 of the main study, if they met eligibility criteria (see the Detailed Description). Participants received further treatment courses on Day 1 and Day 15 at intervals of ≥ 6 months after Week 52 in the study extension phase, if they met eligibility criteria (see the Detailed Description). Throughout the study, participants received methylprednisolone 100 mg iv prior to infusion of the investigational drug, methotrexate 7.5 to 25 mg/week orally or parenterally, and folic acid or folate ≥ 5 mg/week orally. | Biological: Rituximab<br>* Rituximab was supplied as a sterile liquid for iv administration.<br>* Other names: Rituxan®;Drug: Methylprednisolone<br> <br> Drug: Methotrexate<br> <br> Drug: Folic acid or folate<br> <br> |
| Placebo Comparator: Placebo<br>Participants received placebo intravenously (iv) on Day 1 and Day 15 of the main study. Participants received a second course of treatment on Day 1 and Day 15 after Week 24 of the main study, if they met eligibility criteria (see the Detailed Description). Participants were switched to receive rituximab 1000 mg iv on Day 1 and Day 15 at intervals of ≥ 6 months after Week 52 in the study extension phase, if they met eligibility criteria (see the Detailed Description). Throughout the study, participants received methylprednisolone 100 mg iv prior to infusion of the investigational drug, methotrexate 7.5 to 25 mg/week orally or parenterally, and folic acid or folate ≥ 5 mg/week orally. | Drug: Placebo<br>* Placebo was supplied as a sterile liquid in single-use vials for iv administration.<br>Drug: Methylprednisolone<br> <br> Drug: Methotrexate<br> <br> Drug: Folic acid or folate<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Magnetic Resonance Imaging (MRI) Erosion Score From Baseline to Week 24 | The erosion score was determined according to the Outcome Measures in Rheumatology (OMERACT) rheumatoid arthritis MRI scoring (RAMRIS) system in magnetic resonance images with and without gadolinium of 15 anatomical locations in each wrist and 10 locations in each hand in the hand and wrist with the most arthritic activity. If there was no difference in disease activity between the hands, the dominant hand was used. Images were assessed by 2 experienced blinded musculoskeletal radiologists. Each location was scored in 0.5 increments from 0 to 10 with each integer unit increment representing a 10% loss of articular bone using the following scale. 0.0=normal, no erosion; 0.5=1-5% erosion; 1.0=6-10% erosion; 1.5=11-15% erosion; 2.0=16-20% erosion; etc, up to 10.0=96-100% erosion. The individual scores were summed and normalized to a range of 0 to 100 with a higher score indicating more erosion. A negative change score indicates improvement. | Baseline to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Magnetic Resonance Imaging (MRI) Erosion Score From Baseline to Weeks 12 and 52 | The erosion score was determined according to the Outcome Measures in Rheumatology (OMERACT) rheumatoid arthritis MRI scoring (RAMRIS) system in magnetic resonance images with and without gadolinium of 15 anatomical locations in each wrist and 10 locations in each hand in the hand and wrist with the most arthritic activity. If there was no difference in disease activity between the hands, the dominant hand was used. Images were assessed by 2 experienced blinded musculoskeletal radiologists. Each location was scored in 0.5 increments from 0 to 10 with each integer unit increment representing a 10% loss of articular bone using the following scale. 0.0=normal, no erosion; 0.5=1-5% erosion; 1.0=6-10% erosion; 1.5=11-15% erosion; 2.0=16-20% erosion; etc, up to 10.0=96-100% erosion. The individual scores were summed and normalized to a range of 0 to 100 with a higher score indicating more erosion. A negative change score indicates improvement. | Baseline to Week 52 | 
| Change in Magnetic Resonance Imaging (MRI) Synovitis Score From Baseline to Weeks 12, 24, and Week 52 | The synovitis score was determined according to the Outcome Measures in Rheumatology (OMERACT) rheumatoid arthritis MRI scoring (RAMRIS) system in magnetic resonance images of 3 wrist regions and 5 metacarpophalangeal joints in the hand and wrist with the most arthritic activity. If there was no difference in disease activity between the hands, the dominant hand was used. Images were assessed by 2 experienced blinded musculoskeletal radiologists. Each location was scored in 0.5 increments from 0 to 3 with each integer unit increment representing a 33% enhancement of the maximum volume of enhancing tissue in the synovial compartment using the following scale: 0.0=normal, no synovitis; 0.5=1-17% estimated volume of enhancement; 1.0=18-33%; 1.5=34-50%; 2.0=51-67%; 2.5=68-83%; 3.0=84-100% estimated volume of enhancement. The individual scores were summed and normalized to a range of 0 to 100 with a higher score indicating more synovitis. A negative change score indicates improvement. | Baseline to Week 52 | 
| Change in Magnetic Resonance Imaging (MRI) Osteitis Score From Baseline to Weeks 12, 24, and Week 52 | The osteitis score was determined according to the Outcome Measures in Rheumatology (OMERACT) rheumatoid arthritis MRI scoring (RAMRIS) system in magnetic resonance images of 15 anatomical locations in each wrist and 10 locations in each hand in the hand and wrist with the most arthritic activity. If there was no difference in disease activity between the hands, the dominant hand was used. Each location was scored in 0.5 increments from 0 to 3 with each integer unit increment representing a 33% increase in the volume of the peripheral 1 cm of original (eroded + residual) articular bone using the following scale: 0.0=normal, no osteitis; 0.5=1-17% involvement of original articular bone; 1.0=18-33%; 1.5=34-50%; 2.0=51-67%; 2.5=68-83%; 3.0=84-100% involvement of original articular bone. The individual scores were summed and normalized to a range of 0 to 100 with a higher score indicating more synovitis. A negative change score indicates improvement. | Baseline to Week 52 | 
| Percentage of Participants With no Newly Eroded Joints at Weeks 24 and 52 | No newly eroded joints was defined as no new erosions in joints which were scored 0 at baseline. The erosion score was determined according to the Outcome Measures in Rheumatology (OMERACT) rheumatoid arthritis MRI scoring (RAMRIS) system in magnetic resonance images with and without gadolinium of 15 anatomical locations in each wrist and 10 locations in each hand in the hand and wrist with the most arthritic activity. If there was no difference in disease activity between the hands, the dominant hand was used. Images were assessed by 2 experienced blinded musculoskeletal radiologists. Each location was scored in 0.5 increments from 0 to 10 with each integer unit increment representing a 10% loss of articular bone using the following scale. 0.0=normal, no erosion; 0.5=1-5% erosion; 1.0=6-10% erosion; 1.5=11-15% erosion; 2.0=16-20% erosion; etc, up to 10.0=96-100% erosion. | Baseline to Week 52 | 
| Percentage of Participants With no Progression/no Worsening in Bone Erosion at Weeks 24 and 52 | There were 2 definitions of no progression/no worsening in bone erosion. A participant met the criterion for definition 1 when there was a change in the magnetic resonance imaging erosion score ≤ 0. A participant met the criteria for definition 2 when there was either (1) no change from Baseline in the MRI erosion score, (2) an increase in erosion score and the size of the increase in score was smaller than the smallest detectable change, or (3) a drop in the erosion score. The erosion score was determined according to the Outcome Measures in Rheumatology (OMERACT) rheumatoid arthritis MRI scoring (RAMRIS) system in magnetic resonance images with and without gadolinium of 15 anatomical locations in each wrist and 10 locations in each hand in the hand and wrist with the most arthritic activity. If there was no difference in disease activity between the hands, the dominant hand was used. Images were assessed by 2 experienced blinded musculoskeletal radiologists. | Baseline to Week 52 | 
| Percentage of Participants With Improvement in Synovitis at Weeks 24 and 52 | There were 2 definitions of improvement in synovitis. A participant met the criterion for definition 1 when there was a drop in the magnetic resonance imaging synovitis score from Baseline > 0.5. A participant met the criterion for definition 2 when there was a drop in the magnetic resonance imaging synovitis score from Baseline > than the smallest detectable change. The synovitis score was determined according to the Outcome Measures in Rheumatology (OMERACT) rheumatoid arthritis MRI (RAMRIS) scoring system in magnetic resonance images with and without gadolinium of 15 anatomical locations in each wrist and 10 locations in each hand in the hand and wrist with the most arthritic activity. If there was no difference in disease activity between the hands, the dominant hand was used. Images were assessed by 2 experienced blinded musculoskeletal radiologists. | Baseline to Week 52 | 
| Percentage of Participants With Improvement in Osteitis at Weeks 24 and 52 | There were 2 definitions of improvement in osteitis. A participant met the criterion for definition 1 when there was a drop in the magnetic resonance imaging osteitis score from Baseline > 0.5. A participant met the criterion for definition 2 when there was a drop in the magnetic resonance imaging osteitis score from Baseline > than the smallest detectable change. The osteitis score was determined according to the Outcome Measures in Rheumatology (OMERACT) rheumatoid arthritis MRI (RAMRIS) scoring system in magnetic resonance images with and without gadolinium of 15 anatomical locations in each wrist and 10 locations in each hand in the hand and wrist with the most arthritic activity. If there was no difference in disease activity between the hands, the dominant hand was used. Images were assessed by 2 experienced blinded musculoskeletal radiologists. | Baseline to Week 52 | 
| Change From Baseline in the Disease Activity Score 28 (DAS28) at Weeks 24 and 52 | The DAS28 is a combined index for measuring disease activity in rheumatic arthritis (RA) and includes swollen and tender joint counts, C-reactive protein level (CRP), and general health (GH) status. The index is calculated with the following formula: DAS28 = (0.56 × √(TJC28)) + (0.28 × √(SJC28)) + (0.7 × log(CRO)) + (0.014 × GH), where TJC28 = tender joint count and SJC28 = swollen joint count, each on 28 joints, GH = a participant'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]). The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity. A negative change score indicates improvement. | Baseline to Week 52 | 
| Percentage of Participants With European League Against Rheumatism (EULAR) Good, Moderate, or no Response at Weeks 24 and 52 | Change of the DAS28 score from Baseline was used to determine the EULAR responses. 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. DAS28=(0.56×√(TJC28))+(0.28×√(SJC28))+(0.7×log(CRP))+(0.014×GH), where TJC28=tender joint count (JC) and SJC28=swollen JC (28 joints), GH=a participant's global assessment of disease activity in the previous 24 hours on a 100 mm visual analog scale (left end=no disease activity, right end=maximum disease activity), and CRP=C-reactive protein level. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity. | Baseline to Week 52 | 
| Percentage of Participants With Low Disease Activity (Disease Activity Score 28 [DAS28] ≤ 3.2) at Weeks 24 and 52 | The percentage of participants who had low rheumatic arthritis disease activity at Weeks 24 and 52, as measured by a DAS28 score ≤ 3.2, is reported. DAS28 is calculated with the following formula: DAS28 = (0.56 × √(TJC28)) + (0.28 × √(SJC28)) + (0.7 × log(CRO)) + (0.014 × GH), where TJC28 = tender joint count and SJC28 = swollen joint count, each on 28 joints, GH = a participant'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]), and CRP = C-reactive protein level. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity. | Baseline to Week 52 | 
| Percentage of Participants in Remission Response (Disease Activity Score 28 [DAS28] < 2.6) at Weeks 24 and 52 | The percentage of participants in remission of their rheumatic arthritis at Weeks 24 and 52, as measured by a DAS28 score < 2.6, is reported. DAS28 is calculated with the following formula: DAS28 = (0.56 × √(TJC28)) + (0.28 × √(SJC28)) + (0.7 × log(CRO)) + (0.014 × GH), where TJC28 = tender joint count and SJC28 = swollen joint count, each on 28 joints, GH = a participant'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]), and CRP = C-reactive protein level. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity. | Baseline to Week 52 | 
| Percentage of Participants With an Improvement of at Least 20%, 50%, or 70% in the American College of Rheumatology (ACR) Score (ACR20/50/70) From Baseline at Weeks 24 and 52 | Improvement must be seen in tender and swollen joint counts (28 assessed joints; Joints were evaluated and classified as swollen or not swollen and tender or not tender based on pressure and joint manipulation upon physical examination) and in at least 3 | Baseline to Week 52 | 
| Percentage of Participants Achieving a Major Clinical Response at Week 52 | A major clinical response was defined as an improvement of at least 70% in the American College of Rheumatology score from Baseline at Week 52. Improvement must be seen in tender and swollen joint counts (28 assessed joints) and in at least 3 of the following 5 parameters: Separate participant and physician assessments of participant disease activity in the previous 24 hours on a visual analog scale (VAS, the extreme left end of the line no disease activity [symptom-free and no arthritis symptoms] and the extreme right end maximum disease activity); participant assessment of pain in previous the 24 hours on a VAS (extreme left end of the line no pain and the extreme 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 C reactive protein level. | Baseline to Week 52 | 
| Correlation of Magnetic Resonance Imaging Assessments and Clinical Outcome Measures | Correlation coefficients of magnetic resonance imaging erosion, synovitis, and osteitis scores and clinical outcome measures of swollen joint count (SJC), tender joint count (TJC), C-reactive protein level (CRP), erythrocyte sedimentation rate (ESR), a participant's global assessment of disease activity in the previous 24 hours on a 100 mm visual analog scale (GH), Disease Activity Score 28-C-reactive protein (DAS28-CRP), and Disease Activity Score 28-erythrocyte sedimentation rate (DAS28-ESR) are reported. Not all of these variables were specified as primary or secondary Outcome Measures in the study protocol and were not individually analyzed. | Baseline to Week 52 | 
| Change From Baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Weeks 24 and 52 | The HAQ-DI assesses how well the patient is able to perform 8 activities: Dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. The patient answers 20 questions with 1 of 4 responses with the past week as the time frame: 0=without difficulty, 1=with some difficulty, 2=with much difficulty, and 3=unable to do. The highest score for any question in a category determines the category score. The total score ranges from 0 (no disability) to 3 (completely disabled). A negative change score indicates improvement. | Baseline to Week 52 | 
| Adverse Events (AEs), Laboratory Parameters, C-reactive Protein, ESR. |  | Throughout study |