A Study of MabThera (Rituximab) in Patients With Rheumatoid Arthritis Who Have Failed on One Prior Anti-TNF Therapy (RESET)

Study Overview
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Brief Summary
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This study will evaluate the safety and effectiveness of MabThera (rituximab) in patients with active rheumatoid arthritis who are receiving methotrexate, and who have a previous or current inadequate response to one prior anti-TNF therapy. All patients will receive MabThera 1000 mg as an intravenous infusion on days 1 and 15. After the initial study phase of 24 weeks, eligible patients may receive one re-treatment with MabThera. The anticipated time on study treatment is 48 weeks.

Official Title
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Rituximab Phase IIIb Open-label, Multi-centre Assessment of Safety and Effectiveness in Patients With RA Following an Inadequate Response to One Prior Anti-TNF Inhibitor (RESET)

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients, 18-80 years of age Moderate to severe active rheumatoid arthritis Inadequate response to a single previous or current treatment with an anti-TNF agent Methotrexate for at least 12 weeks, at a stable dose over the past 4 weeks Exclusion Criteria: Previous treatment with MabThera Use of an anti-TNF agent within past 8 weeks (4 in the case of etanercept) Concurrent treatment with any Disease Modifying Anti-Rheumatic Drug (DMARD) other than methotrexate Active infection, or history of serious or chronic infection

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single arm<br> | Drug: rituximab<br>* 1000 mg intravenously on Days 1 and 15<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Adverse Events During the Initial Treatment Period - Overall Summary | Percentage of participants who reported an AE or serious AE (SAE), a drug-related AE, who had an acute infusion reaction, an AE leading to study drug discontinuation, with an infection or serious infection, or who died. | Days 1, 2, 15, and 16 and Week 48 of Initial treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Adverse Events During the Re-Treatment Period - Overall Summary | Percentage of participants who reported an AE or SAE, a drug-related AE, who had an acute infusion reaction, an AE leading to study drug discontinuation, with an infection or serious infection, or who died. | Days 1, 2, 15, and 16 and Week 48 of Re-treatment period | 
| Percentage of Participants Meeting American College of Rheumatology (ACR) Response Criteria During the Initial Treatment Period | ACR20/50/70, defined as ≥20 percent (%), 50%, or 70% improvement, respectively, compared to baseline in tender joint count (TJC) and swollen joint count (SJC), and 20%/50%/70% improvement in at least 3 of 5 additional ACR core set variables: Patient Assessment of Pain; Patient's Global Assessment of Disease Activity; Physician's Global Assessment of Disease Activity; Health Assessment Questionnaire - Disability Index (HAQ-DI); and an acute phase reactant (erythrocyte sedimentation rate [ESR] or C-Reactive Protein [CRP]). If CRP was missing or not done, then ESR was used. | Weeks 4, 12, 24, 36, and 48 of Initial treatment period | 
| Percentage of Participants With Complete Clinical Response Per ACR Criteria During the Initial Treatment Period | Complete clinical response was defined as having an ACR70 for at least 13 weeks. | Weeks 4, 12, 24, 36, and 48 of Initial treatment period | 
| Percentage of Participants Meeting ACR Response Criteria During the Re-treatment Period | ACR20/50/70, defined as ≥20%, 50%, or 70% improvement, respectively, compared to baseline in TJC and SJC, and 20%/50%/70% improvement in at least 3 of 5 additional ACR core set variables: Patient Assessment of Pain; Patient's Global Assessment of Disease Activity; Physician's Global Assessment of Disease Activity; HAQ-DI; and an acute phase reactant (ESR or CRP). If CRP was missing or not done, then ESR was used. | Weeks 12 and 24 of Re-treatment period | 
| Percentage of Participants With Complete Clinical Response Per ACR Criteria During the Re-Treatment Period | Complete clinical response was defined as having an ACR70 for at least 13 weeks. | Weeks 12 and 24 of Re-treatment period | 
| Percentage of Participants Meeting European League Against Rheumatism (EULAR) Response Criteria During the Initial Treatment Period | The EULAR response criteria were based on the assessment of disease activity using the DAS28. The EULAR response criteria included not only change in disease activity but current disease activity. To be classified as responders, participants had to have a significant change in DAS28 and a low current disease activity. There were 4 categories of EULAR response rates: good, moderate, good/moderate, and none. The DAS28 scoring used 4 core components: SJC, TJC, Patient's Global Assessment of Disease Activity, and ESR. The DAS28 has a continuous scale ranging from 0 to 9.4. The level of disease activity was interpreted as low (DAS28 score less than or equal to [≤]3.2), moderate (DAS28 score greater than [>]3.2 but ≤5.1), or high (DAS28 score >5.1). A DAS28 score <2.6 corresponded to a state of remission according to American Rheumatism Association criteria. | Weeks 4, 12, 24, 36, and 48 of Initial treatment period | 
| Percentage of Participants Meeting EULAR Response Criteria During the Re-Treatment Period | The EULAR response criteria were based on the assessment of disease activity using the DAS28. The EULAR response criteria included not only change in disease activity but current disease activity. To be classified as responders, participants had to have a significant change in DAS28 and a low current disease activity. There were 4 categories of EULAR response rates: good, moderate, good/moderate, and none. The DAS28 scoring used 4 core components: SJC, TJC, Patient's Global Assessment of Disease Activity, and ESR. The DAS28 has a continuous scale ranging from 0 to 9.4. The level of disease activity was interpreted as low (DAS28 score ≤3.2), moderate (DAS28 score >3.2 but ≤5.1), or high (DAS28 score >5.1). A DAS28 score <2.6 corresponded to a state of remission according to American Rheumatism Association criteria. | Weeks 12 and 24 of Re-treatment period | 
| Change From Baseline in DAS28 During the Initial Treatment Period | The DAS28 scoring used 4 core components: SJC, TJC, Patient's Global Assessment of Disease Activity, and ESR. The DAS28 has a continuous scale ranging from 0 to 9.4. The level of disease activity was interpreted as low (DAS28 score ≤3.2), moderate (DAS28 score >3.2 but ≤5.1), or high (DAS28 score >5.1). A DAS28 score <2.6 corresponded to a state of remission according to American Rheumatism Association criteria. A change of 1.2 units in DAS28 in an individual participant was considered a significant change. | Weeks 4, 12, 24, 36, and 48 of Initial treatment period | 
| Change From Baseline in DAS28 During the Re-Treatment Period | The DAS28 scoring used 4 core components: SJC, TJC, Patient Global Assessment of Disease Activity, and ESR. The DAS28 has a continuous scale ranging from 0 to 9.4. The level of disease activity was interpreted as low (DAS28 score ≤3.2), moderate (DAS28 score >3.2 but ≤5.1), or high (DAS28 score >5.1). A DAS28 score <2.6 corresponded to a state of remission according to American Rheumatism Association criteria. A change of 1.2 units in DAS28 in an individual participant was considered a significant change. | Weeks 12 and 24 of Re-treatment period | 
| Change From Baseline in SJC During the Initial Treatment Period | Joints assessed for swelling consisted of shoulders, elbows, wrists, interphalangeal (digit 1), distal interphalangeal joints (digits 2-5), proximal interphalangeal joints (digits 2-5), metacarpophalangeal joints (digits 1-5), and knees. | Weeks 4, 12, 24, 36, and 48 of Initial treatment period | 
| Change From Baseline in SJC During the Re-Treatment Period | Joints assessed for swelling consisted of shoulders, elbows, wrists, interphalangeal (digit 1), distal interphalangeal joints (digits 2-5), proximal interphalangeal joints (digits 2-5), metacarpophalangeal joints (digits 1-5), and knees. | Weeks 12 and 24 of Re-treatment period | 
| Change From Baseline in TJC During the Initial Treatment Period | Joints assessed for swelling consisted of shoulders, elbows, wrists, interphalangeal (digit 1), distal interphalangeal joints (digits 2-5), proximal interphalangeal joints (digits 2-5), metacarpophalangeal joints (digits 1-5), and knees. | Weeks 4, 12, 24, 36, and 48 of Initial treatment period | 
| Change From Baseline in TJC During the Re-Treatment Period | Joints assessed for swelling consisted of shoulders, elbows, wrists, interphalangeal (digit 1), distal interphalangeal joints (digits 2-5), proximal interphalangeal joints (digits 2-5), metacarpophalangeal joints (digits 1-5), and knees. | Weeks 12 and 24 of Re-treatment period | 
| Change From Baseline in Physician's Global Assessment of Disease Activity During the Initial Treatment Period | Physician Global Assessment of Disease Activity was measured using a 100-mm visual analog scale (VAS) where the extreme left end of the line was 0 = no disease activity and the extreme right end of the line was 100 = maximum disease activity. The physician marked the line and the distance from the left edge was measured in mm. | Weeks 4, 12, 24, 36, and 48 of Initial treatment period | 
| Change From Baseline in Physician's Global Assessment of Disease Activity During the Re-Treatment Period | Physician Global Assessment of Disease Activity was measured using a 100-mm VAS where the extreme left end of the line was 0 = no disease activity and the extreme right end of the line was 100 = maximum disease activity. The physician marked the line and the distance from the left edge was measured in mm. | Weeks 12 and 24 of Re-treatment period | 
| Change From Baseline in Patient Global Assessment of Disease Activity Score During the Initial Treatment Period | Patient Global Assessment of Disease Activity was measured using a 100-mm VAS where the extreme left end of the line was 0 = no disease activity and the extreme right end of the line was 100 = maximum disease activity. The participant was asked to marked the line and the distance from the left edge was measured in mm. | Weeks 4, 12, 24, 36, and 48 of Initial treatment period | 
| Change From Baseline in Patient Global Assessment of Disease Activity During the Re-Treatment Period | Patient Global Assessment of Disease Activity was measured using a 100-mm VAS where the extreme left end of the line was 0 = no disease activity and the extreme right end of the line was 100 = maximum disease activity. The participant was asked to marked the line and the distance from the left edge was measured in mm. | Weeks 12 and 24 of Re-treatment period and Week 4 after last maintenance | 
| Change From Baseline in Patient Global Assessment of Pain During the Initial Treatment Period | Patient Global Assessment of Pain was measured using a 100-mm VAS where the extreme left end of the line was 0 = no pain and the extreme right end of the line was 100 = unbearable pain. The participant was asked to mark the line and the distance from the left edge was measured in mm. | Weeks 4, 12, 24, 36, and 48 of Initial treatment period | 
| Change From Baseline in Patient Global Assessment of Pain During the Re-Treatment Period | Patient Global Assessment of Pain was measured using a 100-mm VAS where the extreme left end of the line was 0 = no pain and the extreme right end of the line was 100 = unbearable pain. The participant was asked to mark the line and the distance from the left edge was measured in mm. | Weeks 12 and 24 of Re-treatment period | 
| Change From Baseline HAQ-DI Score During the Initial Treatment Period | HAQ-DI: 20 questions, 8 categories of functioning: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and common usual activities. Participants report amount of difficulty in performing 2-3 specific subcategory items. Difficulty score is from 0 to 3 (0 = without any difficulty; 1 = with some difficulty; 2 = with much difficulty; and 3 = unable to do). The highest component score in each of the 8 categories determined the score for that category, unless aids, devices, and/or help from another person were required which = a score of 2 (unless already 2 or 3). The 8 category scores were averaged into overall HAQ-DI score ranging from 0 to 3 (0 to 1 = mild to moderate difficulty; 1 to 2 = moderate to severe disability; and 2 to 3 = severe to very severe disability). HAQ-DI not computed if > 2 categories were missing. | Weeks 4, 12, 24, 36, and 48 of Initial treatment period | 
| Change From Baseline HAQ-DI Score During the Re-Treatment Period | HAQ-DI: 20 questions, 8 categories of functioning: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and common usual activities. Participants report amount of difficulty in performing 2-3 specific subcategory items. Difficulty score is from 0 to 3 (0 = without any difficulty; 1 = with some difficulty; 2 = with much difficulty; and 3 = unable to do). The highest component score in each of the 8 categories determines the score for that category, unless aids, devices, and/or help from another person were required which = a score of 2 (unless already 2 or 3). The 8 category scores were averaged into overall HAQ-DI score ranging from 0 to 3 (0 to 1 = mild to moderate difficulty; 1 to 2 = moderate to severe disability; and 2 to 3 = severe to very severe disability). HAQ-DI not computed if >2 categories were missing. | Weeks 12 and 24 of Re-treatment period | 
| Change From Baseline in ESR During the Initial Treatment Period | ESR was measured in mm/hour and was used to determine the acute phase response. Lower ESR values indicate reduction in disease activity; normal reference range: 0-20 mm/hr. | Weeks 4, 12, 24, 36, and 48 of Initial treatment period | 
| Change From Baseline in ESR During the Re-Treatment Period | ESR was measured in mm/hour and was used to determine the acute phase response. Lower ESR values indicate reduction in disease activity; normal reference range: 0-20 mm/hr. | Weeks 12 and 24 of Re-treatment period | 
| Change From Baseline in CRP During the Initial Treatment Period | CRP levels were measured in milligrams/liter (mg/L) and were used to determine the acute phase response. A reduction in CRP levels is considered an improvement; normal reference range ≤10 mg/L. | Weeks 4, 12, 24, 36, and 48 of Initial treatment period | 
| Change From Baseline CRP During the Re-Treatment Period | CRP levels were measured in mg/L and were used to determine the acute phase response. A reduction in CRP levels is considered an improvement; normal reference range ≤10 mg/L. | Weeks 12 and 24 of Re-treatment period | 
| Percentage of Participants With Disease Remission According to DAS28 in the Initial Treatment Period | The DAS28 scoring used 4 core components: SJC, TJC, Patient's Global Assessment of Disease Activity, and ESR. The DAS28 has a continuous scale ranging from 0 to 9.4. The level of disease activity was interpreted as low (DAS28 score ≤3.2), moderate (DAS28 score >3.2 but ≤5.1), or high (DAS28 score >5.1). A DAS28 score ≤2.6 corresponded to a state of remission according to American Rheumatism Association criteria. | Weeks 4, 12, 24, 36, and 48 of Initial treatment period | 
| Percentage of Participants With Disease Remission According to DAS28 in the Re-Treatment Period | The DAS28 scoring used 4 core components: SJC, TJC, Patient's Global Assessment of Disease Activity, and ESR. The DAS28 has a continuous scale ranging from 0 to 9.4. The level of disease activity was interpreted as low (DAS28 score ≤3.2), moderate (DAS28 score >3.2 but ≤5.1), or high (DAS28 score >5.1). A DAS28 score ≤2.6 corresponded to a state of remission according to American Rheumatism Association criteria. | Weeks 12 and 24 of Re-treatment period | 
| Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Total Score During the Initial Treatment Period | Participant fatigue was evaluated using the FACIT-F scale, a 13-item questionnaire in which the participants were requested to score each item on a 5-point scale. The FACIT-F scores ranged from 0 to 52, with higher scores representing less fatigue. Score changes of 4 points or more were considered clinically meaningful. The total score was a summation of all 13 items, where 2 of the positive items (I have energy; I am able to do my usual activities) were reversed for scoring. | Weeks 4, 12, 24, 36, and 48 of Initial treatment period | 
| Change From Baseline in FACIT-F Total Score During the Re-Treatment Period | Participant fatigue was evaluated using the FACIT-F scale, a 13-item questionnaire in which the participants were requested to score each item on a 5-point scale. The FACIT-F scores ranged from 0 to 52, with higher scores representing less fatigue. Score changes of 4 points or more were considered clinically meaningful. The total score was a summation of all 13 items, where 2 of the positive items (I have energy; I am able to do my usual activities) were reversed for scoring. | Weeks 12 and 24 of Re-treatment period |