A Study of MabThera (Rituximab) in Combination With Methotrexate in Patients With Rheumatoid Arthritis Who Have Had an Inadequate Response to Anti-TNF Therapies.

Study Overview
=================
Brief Summary
-----------------
This single arm study will evaluate the efficacy and safety of MabThera in combination with methotrexate in patients with rheumatoid arthritis who have had an inadequate response to one or more anti-TNF therapies. Patients will receive MabThera 1000mg i.v. on days 1 and 15, and methotrexate (10-25mg/week p.o. or parenteral), together with methylprednisolone 100mg i.v. prior to infusion of MabThera. After week 24, eligible patients may receive re-treatment. The anticipated time on study treatment is 3-12 months, and the target sample size is <100 individuals.

Official Title
-----------------
An Open-label Study to Evaluate the Effect of MabThera in Combination With Methotrexate on Treatment Response in Patients With Active Rheumatoid Arthritis Who Have Had an Inadequate Response to Anti-TNF Therapies

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

Intervention / Treatment
-----------------
* Drug: rituximab
* Drug: Methotrexate
* Drug: Corticosteroid or NSAID
* Dietary Supplement: Folate


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: adult patients, 18-80 years of age; rheumatoid arthritis for >=6 months; receiving outpatient treatment; an inadequate response to at least one anti-TNF therapy; stable methotrexate for >=12 weeks. Exclusion Criteria: other rheumatic autoimmune disease or inflammatory joint disease; previous treatment with MabThera; concurrent treatment with any DMARD (apart from methotrexate), anti-TNF alpha therapy, or other biologic agent.

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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rituximab, Methotrexate<br>Participants received rituximab 1000 milligrams (mg), intravenously (IV), on Day 1 and Day 15. Participants also received methylprednisolone 100 mg, IV, 30 minutes before the infusion of rituximab. Participants also received methotrexate (MTX) 10 to 25 milligrams per week (mg/week), orally (PO) or parenterally, and folate greater than or equal to (≥) 5 mg/week, PO, folate greater than or equal to (≥) 5 mg/week, PO, either as a single dose or as divided daily doses from Day 1 through Week 24. Participants also received prednisone less than or equal to (≤) 10 milligrams per day (mg/day), PO, OR equivalent corticosteroid, OR non-steroidal anti-inflammatory drugs (NSAIDs), PO, from Day 1 through Week 24. Eligible participants who completed the first 24-week course were entered into a second course. | Drug: rituximab<br>* 1000 mg i.v. on Days 1 and 15<br>* Other names: Rituxan;Drug: Methotrexate<br>* 10 to 25 mg/week p.o. or parenteral from Day 1 through Week 24<br>Drug: Corticosteroid or NSAID<br>* ≤10 mg/day prednisone p.o., or equivalent corticosteroid, or NSAIDs p.o. from Day 1 through Week 24<br>Dietary Supplement: Folate<br>* ≥5 mg/week, once daily or b.i.d. from Day 1 through Week 24<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With An American College of Rheumatology 20 Percent (%) Improvement Criteria (ACR20) Response at Week 24 | ACR20 response: ≥20% improvement in tender joint count; ≥20% improvement in swollen joint count; and ≥20% improvement in at least 3 of 5 remaining ACR core measures: Patient Assessment of Pain; Patient Global Assessment of Disease Activity (PtGA); Physician Global Assessment of Disease Activity (PGA); self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ-DI]); and either C-Reactive Protein (CRP) or erythrocyte sedimentation rate (ESR). | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With An American College of Rheumatology 50% Improvement Criteria (ACR50) Response at Week 24 | ACR50 response: ≥50% improvement in tender joint count; ≥50% improvement in swollen joint count; and ≥50% improvement in at least 3 of 5 remaining ACR core measures: Patient Assessment of Pain; PtGA; PGA; self-assessed disability (HAQ-DI); and either CRP or ESR. | Week 24 | 
| Percentage of Participants With An American College of Rheumatology 70% Improvement Criteria (ACR70) Response at Week 24 | ACR70 response: ≥70% improvement in tender joint count; ≥70% improvement in swollen joint count; and ≥70% improvement in at least 3 of 5 remaining ACR core measures: Patient Assessment of Pain; PtGA; PGA; self-assessed disability (HAQ-DI); and either CRP or ESR. | Week 24 | 
| Disease Activity Score Based on 28-Joint Count (DAS-28) | DAS28 was calculated from the number of swollen joints and tender joints using the 28 joints count, the ESR (millimeters per hour [mm/hr]) and PtGA of disease activity with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity. DAS28 ≤3.2 equals (=) low disease activity, DAS28 greater than (>)3.2 to 5.1 = moderate to high disease activity. | Baseline and Week 24 | 
| Percentage of Participants With Change in DAS-28 From BL to Week 24 of ≥1.2 | DAS28 was calculated from the number of swollen joints and tender joints using the 28 joints count, the ESR (mm/hr) and PtGA of disease activity with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity. | Baseline, Week 24 | 
| Percentage of Participants With DAS Response by European League Against Rheumatism (EULAR) Category at Week 24 | The percentage of participants categorized as good, moderate, or nonresponders according to the EULAR response criteria at Week 24. Participants were categorized as good responders if the intensity of their symptoms was in the low disease activity (DAS28 less than [<]3.2) category after treatment, and their symptoms significantly decreased to >1.2. Participants were categorized as moderate responders if the intensity of their symptoms was in the moderate or high disease activity (DAS28 >3.2) category after treatment, and the symptoms significantly decreased to >1.2; or if the intensity of their symptoms was in the low or moderate disease activity (DAS28 <5.1) category, and the DAS28 score changed more than 0.6 or 1.2 or less. Participants were categorized as non-responders if they did not fall into the good or moderate categories. | Week 24 | 
| Swollen Join Count (SJC) | Number of swollen joints was determined by examination of 66 joints (as assessed through pressing and palpating during the physical examination) and identifying when swelling was present. The number of swollen joints was recorded on the joint assessment form at each visit as swollen or not swollen. | Baseline, Weeks 24 and 48 | 
| Tender Joint Count (TJC) | Number of tender joints was determined by examination of 68 joints (as assessed through pressing and palpating during the physical examination) and identifying when swelling was present. The number of tender joints was recorded on the joint assessment form at each visit as either tender or not tender. | Baseline, Weeks 24 and 48 | 
| Patient Global Assessment of Disease Activity (VAS) | The mean score of the symptoms of rheumatoid arthritis (RA) at Week 0 (baseline) and the change from Week 0 to Weeks 24 and 48 as assessed by participants using a 100 mm horizontal VAS, where the left endpoint indicated No disease activity (no symptom, or no symptom of RA), and the right endpoint indicated Maximum disease activity (maximum RA activity). A negative change from Baseline indicated improvement. | Baseline, Weeks 24 and 48 | 
| Physician Global Assessment of Disease Activity (VAS) | The mean score of the symptoms of RA at Week 0 and the change from Week 0 (baseline) to Weeks 24 and 48 as assessed by investigators using a 100-mm horizontal VAS, where the left endpoint indicated No disease activity (no symptom, or no symptom of RA), and the right endpoint indicated Maximum disease activity (maximum RA activity). A negative change from Baseline indicated improvement. | Baseline, Weeks 24 and 48 | 
| Patient Assessment of Pain (VAS) | The mean score of pain at Week 0 (baseline) and the change from Week 0 to Weeks 24 and 48 as assessed by participants using a 100-mm horizontal VAS, where the left endpoint indicated No pain, and the right endpoint indicated Unbearable pain. A negative change indicated improvement. | Baseline, Weeks 24 and 48 | 
| C-reactive Protein (CRP) Level | The mean level of CRP in milligrams per liter (mg/L), an acute phase reactant, at Week 0 and the change from Week 0 to Weeks 24 and 48. | Baseline, Weeks 24 and 48 | 
| Erythrocyte Sedimentation Rate (ESR) | The mean level of ESR (in mm/hr), an acute phase reactant, at Week 0 and the change from Week 0 to Weeks 24 and 48. | Baseline, Weeks 24 and 48 | 
| HAQ-DI Score | 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. | Baseline, Weeks 24 and 48 | 
| Physical Function as Assessed by Short Form 36 (SF-36) | 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). | Screening, Weeks 24 and 48 | 
| SF-36 Mental Component Scores | 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). | Screening, Weeks 24 and 48 | 
| Modified Total Sharp-Genant Score (mTSS) | Posterior-anterior (PA) radiograph of each hand and anterior-posterior (AP) radiograph of each foot were taken separately and assessed according to Genant's method as modified from Sharp's method. The Sharp-Genant score=total of the erosion score and the joint space narrowing (JSN) score of all the hands and feet. Erosion Score: 14 locations in each hand and wrist and 6 joints in the foot were evaluated for erosion using an 8-point scale where 0=Normal to 3.5=very severe erosion. JSN Score:13 locations in each hand and wrist and 6 joints in the foot were evaluated for joint narrowing score using a 9-point scale where 0=Normal to 4.0=definite ankylosis (stiffness or fixation of a joint). Maximum total erosion score in hands=100 and in feet=42; maximum scores for JSN in the hands=100 and in feet=48. Maximum modified Sharp score achievable is 290. A lower number change from Baseline indicated a better score. Change in scores was calculated as change=final score minus initial score. | Screening and Weeks 24 and 48 | 
| Modified Sharp Radiographic Erosion Score (ES) | Erosion Score: A total of 14 locations in each hand and wrist and 6 joints in the foot were evaluated for erosion using an 8-point scale where 0=Normal to 3.5=very severe erosion. Maximum total erosion score in the hands was 100 and in the feet was 42, for a maximum overall score of 142. Total erosion score was for both hands and feet. | Screening, Weeks 24 and 48 | 
| Modified Sharp Radiographic Joint Space Narrowing Score (JSN) | JSN Score: A total of 13 locations in each hand and wrist and 6 joints in the foot were evaluated for joint narrowing score using a 9-point scale where 0=Normal to 4.0=definite ankylosis (stiffness or fixation of a joint). Maximum total scores for JSN in the hands was 100 and in the feet was 48, for a maximum overall score of 148. Total JSN was for both hands and feet. | Screening, Weeks 24 and 48 |