A Study of Retreatment With MabThera (Rituximab) in Combination With Methotrexate in Patients With Rheumatoid Arthritis (RA)

Study Overview
=================
Brief Summary
-----------------
This study will evaluate the efficacy and safety of various treatment and retreatment regimens of MabThera. All patients will receive concomitant methotrexate, 10-25mg once weekly either orally or parenterally. The anticipated time on study treatment is 2+ years, and the target sample size is 100-500 individuals.

Official Title
-----------------
A Randomized, Double-blind Study to Evaluate the Effect of Various Re-treatment Regimens of MabThera in Combination With Methotrexate on Treatment Response in Rheumatoid Arthritis Patients With an Inadequate Response to Methotrexate.

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

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: adult patients >=18 years of age; RA for >=6 months; receiving outpatient treatment; inadequate response to methotrexate, having received and tolerated it for >=12 weeks, with a stable dose for >=4 weeks. Exclusion Criteria: rheumatic autoimmune disease other than RA, or significant systemic involvement secondary to RA; inflammatory joint disease other than RA, or other systemic autoimmune disorder; diagnosis of juvenile arthritis, or RA before the age of 16; previous treatment with >1 biologic agent, any cell-depleting therapies, or concurrent treatment with any biologic agent or DMARD other than methotrexate.

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

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: rituximab [MabThera/Rituxan]<br>* 500mg iv in days 1 and 15, and 500mg iv on days 168 and 182<br>|
| Experimental: 2<br> | Drug: rituximab [MabThera/Rituxan]<br>* 500mg iv on days 1 and 15, and 1000mg iv on days 168 and 182<br>|
| Experimental: 3<br> | Drug: rituximab [MabThera/Rituxan]<br>* 1000mg iv on days 1 and 15 and 1000mg iv (or placebo in UK)on days 168 and 182<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Response as Determined by American College of Rheumatology (ACR) 20% Improvement (ACR20) | ACR20 defined as overall score of ≥20 in ACR number (ACRn) calculation. Overall score defined as lowest percent improvement from baseline (BL) of following 3 measures: tender joint count (TJC; 68 joints), swollen joint count (SJC: 66 joints), and the 3rd lowest improvement achieved by at least 3 of 5 remaining ACR core parameters: physician's global assessment of disease activity, participant's global assessment of disease activity, participant's assessment of pain (visual analog assessment [VAS]), Health Assessment Questionnaire (HAQ), and C-Reactive Protein (CRP). If CRP missing, erythrocyte sedimentation rate (ESR) was used. In order for improvements in the ACRn score to be expressed as a positive result, rather than the negative changes that improvements represent, the final ACRn results were multiplied by negative 1. Last observation carried forward (LOCF) for TJC/SJC, HAQ, CRP/ESR, VAS. If change in CRP incalculable, change in ESR used. ACR20 set to Non-Responder if ACRn missing | Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With ACR 50% Improvement Criteria (ACR50) Response at Week 48 | ACR50 was defined as an overall score of 50 in the ACRn calculation. Overall score defined as lowest percent improvement from BL of following 3 measures: TJC (68 joints), SJC (66 joints), and the 3rd lowest improvement achieved by at least 3 of 5 remaining ACR core parameters: physician's global assessment of disease activity, participant's global assessment of disease activity, participant's assessment of pain (VAS), HAQ, and CRP. If CRP missing, ESR was used. In order for improvements in the ACRn score to be expressed as a positive result, rather than the negative changes that improvements represent, the final ACRn results were multiplied by negative 1. LOCF for TJC/SJC, HAQ, CRP/ESR, VAS. If change in CRP incalculable, change in ESR used. ACR50 set to Non-Responder if ACRn missing. | Week 48 | 
| Percentage of Participants With a ACR 70% Improvement Criteria (ACR70) Response at Week 48 | ACR70 was defined as an overall score of 70 in the ACRn calculation. The Overall score defined as lowest percent improvement from BL of following 3 measures: TJC (68 joints), SJC (66 joints), and the 3rd lowest improvement achieved by at least 3 of 5 remaining ACR core parameters: physician's global assessment of disease activity, participant's global assessment of disease activity, participant's assessment of pain (VAS), HAQ, and CRP. If CRP missing, ESR was used. In order for improvements in the ACRn score to be expressed as a positive result, rather than the negative changes that improvements represent, the final ACRn results were multiplied by negative 1. LOCF for TJC/SJC, HAQ, CRP/ESR, VAS. If change in CRP incalculable, change in ESR used. ACR70 set to Non-Responder if ACRn missing. | Week 48 | 
| Disease Activity Score Based on 28-Joint Count and Erythrocyte Sedimentation Rate (DAS28-ESR): Adjusted Mean Change From BL at Week 48 | DAS28 was calculated according to the following formula: DAS28 equals (=) [0.56 multiplied by (*) the square root (√) of TJC] plus (+) [0.28 * √ of SJC] + (0.70 * the natural logarithm (ln) ESR in millimeters per hour (mm/h)] + [0.014 * participant's global assessment of disease activity (GH)]. DAS28-ESR ≥ 5.1 = high disease activity, DAS28-ESR less than or equal to (≤) 3.2 = low disease activity, DAS28-ESR less than (<) 2.6 = remission. | BL, Week 48 | 
| Percentage of Participants With a Response at Week 48 by European League Against Rheumatism (EULAR) Category | EULAR responses were categorized according to DAS28-ESR score. DAS28-ESR ≤ 3.2 at Week 48 and a change from BL to Week 48 < -1.2 = good response, DAS28-ESR ≤ 3.2 or greater than (>) 3.2 and ≤ 5.1 at Week 48 and a change from BL to Week 48 < -0.6 and ≥ -1.2 = moderate response, DAS28-ESR > 3.2 and ≤ 5.1 at Week 48 and a change from BL to Week 48 < -1.2 = moderate response, DAS28-ESR > 5.1 at Week 48 and a change from BL to Week 48 < -1.2 = moderate response, DAS28-ESR ≤ 3.2 or > 3.2 and ≤ 5.1 at Week 48 and a change from BL to Week 48 ≥ -0.6 = no response, DAS28-ESR > 5.1 at Week 48 and a change from BL to Week 48 < -0.6 and ≥ -1.2 or ≥ -0.6 = no response. | Week 48 | 
| Change in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Score From BL at Week 48 | FACIT-F scores were obtained from a 13 question self-administered participant questionnaire designed to measure the degree of fatigue experienced by participants in the previous 7 days. Participants responded to the questions using a value between 0 and 4, where 0 indicated not at all and 4 indicated very much. 11 of the 13 questions were negatively stated; indicating the higher the score of the participant's response, the greater their fatigue. These questions were calculated as 4 minus the participants' response, so that a higher score indicated an improvement in health. The scores for the 2 positively stated questions were not changed. The participants' responses were summed to result in an overall score, which are scored 0 to 52 (52 = highest level of functioning). A positive change from BL indicated improvement. | BL, Week 48 | 
| Short-Form 36 Health Survey (SF-36) Score | SF-36 scores were obtained by scoring participants' responses to a 36 item questionnaire. SF-36 evaluated 8 aspects of functional health and well being: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, mental health from a range of 1 (better) to 5 (worst). The score for each section was an average of the individual question scores, which were scaled 0-100 (100=highest level of functioning). These 8 aspects were summarized as physical and mental component scores. | BL, Week (Wk) 24 and 48 | 
| Change in SF-36 Score From BL | SF-36 scores were obtained by scoring participants' responses to a 36 item questionnaire. SF-36 evaluated 8 aspects of functional health and well being: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, mental health from a range of 1 (better) to 5 (worst). The score for each section was an average of the individual question scores, which were scaled 0-100 (100=highest level of functioning). These 8 aspects were summarized as physical and mental component scores. | BL, Weeks 24 and 48 | 
| Maximum Observed Serum Concentrations Following the 1st Infusion of Rituximab (Cfirst) in the 1st and 2nd Courses of Treatment in Micrograms Per mL (µg/mL) | Cfirst values were estimated from rituximab serum concentrations by non-compartmental methods using the software WinNonlin Enterprise Version 5.2. | Days 1 and 15 (before infusion and 30 minutes following infusion) and Weeks 4, 8, 16, 24, 26, 28, 32, 40, and 48 or early withdrawal and at Weeks 24 and 48 of safety follow-up (1 year period following the completion of study treatment). | 
| Maximum Observed Serum Concentrations Following the 2nd Infusion of Rituximab (Csecond) in the 1st and 2nd Courses of Treatment in µg/mL | Csecond values were estimated from rituximab serum concentrations by non-compartmental methods using the software WinNonlin Enterprise Version 5.2. | Days 1 and 15 (before infusion and 30 minutes following infusion) and Weeks 4, 8, 16, 24, 26, 28, 32, 40, and 48 or early withdrawal and at Weeks 24 and 48 of safety follow-up (1 year period following the completion of study treatment). | 
| Terminal Elimination Half-Life (t1/2) in the 1st and 2nd Courses of Treatment in Days | t1/2 values were estimated from rituximab serum concentrations by non-compartmental methods using the software WinNonlin Enterprise Version 5.2. | Days 1 and 15 (before infusion and 30 minutes following infusion) and Weeks 4, 8, 16, 24, 26, 28, 32, 40, and 48 or early withdrawal and at Weeks 24 and 48 of safety follow-up (1 year period following the completion of study treatment). | 
| Peripheral Cluster of Differentiation (CD) 19 Positive (+) B Cell Count at BL in Cells Per Microliter (Cells/µL) | Surface expression of CD19 was assessed by fluorescence-activated cell sorting (FACS) analysis as a marker of absolute B lymphocyte count. | BL | 
| Percentage of Participants With Peripheral CD19+ B Cell Counts Above BL or the Lower Limit of Normal (LLN) | Surface expression of CD19 was assessed by FACS analysis as a marker of absolute B lymphocyte count. The LLN was defined as < 80 cells/µL. | BL, Days 1 and 15, Weeks 4, 8, 16, 24, 28, 32, 40, and 48 | 
| Peripheral CD20+ B Cell Count in Cells/µL | Surface expression of CD20 was assessed by FACS analysis as a marker of mature and memory B lymphocyte count. | BL, Day 15, Weeks 4, 8, 16, 24, 28, 32, 40, and 48 | 
| Peripheral CD22+ B Cell Count in Cells/µL | Surface expression of CD22 was assessed by FACS analysis as a marker of mature lymphocyte count. | BL, Day 15, Weeks 4, 8, 16, 24, 28, 32, 40, and 48 | 
| Peripheral CD19+CD27+ B Cell Count in Cells/µL | Simultaneous surface expression of CD19 and CD27 was assessed by FACS analysis as a marker of memory B lymphocyte count. | BL, Day 15, Weeks 4, 8, 16, 24, 28, 32, 40, and 48 | 
| Peripheral CD19+CD27 Negative (-) B Cell Count in Cells/µL | Surface expression of CD19 in the absence of CD27 expression was assessed by FACS analysis as a marker of naive B lymphocyte count. | BL, Day 15, Weeks 4, 8, 16, 24, 28, 32, 40, and 48 | 
| Peripheral CD3+ T Cell Count in Cells/µL | Surface expression of CD3 was assessed by FACS analysis as a marker of absolute T lymphocyte count. The normal range of CD3+ T cells was defined as 723-2737 cells/µL. | BL, Day 15, Weeks 4, 8, 16, 24, 28, 32, 40, and 48 | 
| Change From BL in Peripheral CD3+ T Cell Count | Surface expression of CD3 was assessed by FACS analysis as a marker of absolute T lymphocyte count. The normal range of CD3+ T cells was defined as 723-2737 cells/µL. | BL, Day 15, Weeks 4, 8, 16, 24, 28, 32, 40, and 48 | 
| Peripheral CD4+ T Cell Count in Cells/µL | Surface expression of CD4 was assessed by FACS analysis as a marker of T helper cell count. The normal range of CD4+ T cells was defined as 404-1612 cells/µL. | BL, Day 15, Weeks 4, 8, 16, 24, 28, 32, 40, and 48 | 
| Change From BL in Peripheral CD4+ T Cell Count | Surface expression of CD4 was assessed by FACS analysis as a marker of T helper cell count. The normal range of CD4+ T cells was defined as 404-1612 cells/µL. | BL, Day 15, Weeks 4, 8, 16, 24, 28, 32, 40, and 48 | 
| Peripheral CD8+ T Cell Count in Cells/µL | Surface expression of CD8 was assessed by FACS analysis as a marker of cytotoxic T lymphocyte count. The normal range of CD8+ T cells was defined as 220-1129 cells/µL. | BL, Day 15, Weeks 4, 8, 16, 24, 28, 32, 40, and 48 | 
| Change From BL in Peripheral CD8+ Cell Count | Surface expression of CD8 was assessed by FACS analysis as a marker of cytotoxic T lymphocyte count. The normal range of CD8+ T cells was defined as 220-1129 cells/µL. | BL, Day 15, Weeks 4, 8, 16, 24, 28, 32, 40, and 48 | 
| Peripheral CD16+56+ Natural Killer (NK) Cell Count in Cells/µL | Simultaneous surface expression of CD16 and CD56 was assessed by FACS analysis as a marker of NK cell count. | BL, Day 15, Weeks 4, 8, 16, 24, 28, 32, 40, and 48 | 
| Change From BL in Peripheral CD16+56+ Cell Count | Simultaneous surface expression of CD16 and CD56 was assessed by FACS analysis as a marker of NK cell count. | BL, Day 15, Weeks 4, 8, 16, 24, 28, 32, 40, and 48 | 
| Percentage of Participants With Total Immunoglobin (Ig), IgA, IgG, and IgM Results Below the LLN | The LLNs for total Ig, IgA, IgG, and IgM were defined as 6.75 grams per liter (g/L), 0.70 g/L, 65 g/L, and 0.40 g/L, respectively. | BL, Weeks 24 and 48 | 
| Percentage of Participants Who Were Rheumatoid Factor (RF) - Seronegative | Percentage of participants who were RF seropositive at BL who became RF seronegative over the course of the study. RF seropositive status was defined as RF ≥ 20 international units (IU) per mL. RF seronegative status was defined as RF < 20 IU/mL. | BL, Weeks 8, 24, and 48 | 
| Anti-Cyclic Citrullinated Peptide (CCP) Antibody Titers at BL in Units Per mL (U/mL) |  | BL | 
| Change From BL in Anti-CCP Antibody Titers in U/mL |  | Weeks 8, 24, and 48 | 
| Percentage of Participants With Complement Component 3 (C3) Protein Level ≤ LLN | The LLN for C3 protein was defined as <0.9 grams per liter (g/L). | BL, Day 15, Weeks 4, 8, 16, 24, 28, 32, 40, and 48 | 
| Change From BL in Complement C3 Protein Level in g/L | The LLN of C3 protein was defined as <0.9 g/L. | BL, Day 15, Weeks 4, 8, 16, 24, 28, 32, 40, and 48 | 
| Change From BL in Activated Complement Component 3a (C3a) Protein Level in g/L |  | BL, Day 15, Weeks 4, 8, 16, 24, 28, 32, 40, and 48 | 
| Percentage of Participants With Complement Component 4 (C4) Protein Level ≤ LLN | The LLN of C4 protein was defined as < 0.1 g/L. | BL, Day 15, Weeks 4, 8, 16, 24, 28, 32, 40, and 48 | 
| Change From BL in Complement C4 Protein Level in g/L |  | BL, Day 15, Weeks 4, 8, 16, 24, 28, 32, 40, and 48 | 
| Change From BL in Activated Complement Component 4a (C4a) Protein Level in g/L |  | BL, Day 15, Weeks 4, 8, 16, 24, 28, 32, 40, and 48 | 
| Percentage of Participants With Positive Human Anti-Chimeric Antibody (HACA) Titers | A participant was defined as being HACA positive if the HACA serum level was ≥ 5 relative units (RU) per mL and the physician comment read that participant was immunodepletable with rituximab. | BL, Weeks 24 and 48 | 
| Percentage of Participants With a Change From BL by Category in Anti-Nuclear Antibodies (ANA) Titers | ANA titers were obtained by the following serum dilution schema: negative = negative, borderline = 1 diluted to (:) 40 or 1:80, and positive ≥ 1:160. The change categories were defined for the change from BL to Weeks 24 and 48 according to this schema. Negative to borderline was defined as any change from negative to borderline as no dilution is given for negative results. Negative to positive was defined as at least a two-fold positive change in dilution from BL. Borderline to negative was defined as any change from borderline to negative as no dilution is given for negative results. Borderline to positive was defined as at least a two-fold positive change in dilution from BL. Positive to borderline was defined as at least a two-fold negative change in dilution from BL. Positive to negative was defined as at least a two-fold negative change in dilution from BL. Unchanged was defined as any difference in dilution less than two-fold. | BL, Weeks 24 and 48 | 
| Percentage of Participants With Positive Recall Antigen Antibody Titers | A positive titer result to recall antigens was defined as a serum antibody level equal to or above the following protective levels: tetanus toxoid ≥ 0.1 IU/mL, influenza A > 12 U/mL, influenza B > 12 U/mL, and streptococcus (S.) pneumococcus ≥ 1.0 mg/L. | BL, Weeks 24 and 48 |