Clinical Trial Result Information

Title of Study:
A randomized, placebo-controlled, double-blind, mulitcenter study to evaluate the safety and efficacy of rituximab in combination with methotrexate in patients with active rheumatoid arthritis who have had an inadequate response to anti-TNF therapies.

Fast Facts:

Protocol number:	WA17042
Sponsor:	Roche Products Ltd; IDEC Pharmaceuticals Corporation.
Company division:	Pharmaceutical
Product name:	MabThera/Rituxan
Generic name:	rituximab
Phase of development:	III
Therapeutic area, approved indication:	Rheumatoid arthritis
Date of report:	7/27/2005

Clinical study summary:
This was a randomized, placebo-controlled, double-blind, parallel group study to evaluate the effect of MabThera (rituximab) + methotrexate (MXT) versus MTX alone in patients with active rheumatoid arthritis who had experienced an inadequate response to previous treatment with an anti-TNF therapy. Patients were randomized to receive MabThera 1000mg iv or placebo; all patients received weekly MTX.

Study center(s) :
114 centers in Belgium, Canada, France, Germany, Ireland, Israel, Italy, Netherlands, Norway, UK and USA.

Objectives:
To determine the efficacy and safety of MabThera when used in combination with methotrexate (MTX) in patients with active rheumatoid arthritis who have had an inadequate response to one or more anti-TNF therapies; to explore the pharmacokinetics and pharmacodynamics of MabThera in this patient population (e.g. extent of duration of B cell depletion and effects on immunoglobulins and rheumatoid factor).

Methodology:
Patients were randomized to receive MabThera 1000mg iv or placebo iv on days 1 and 15; all patients also received concomitant MTX (10-25 mg/week po or parenterally) together with a corticosteroid regimen, and weekly folate. The primary endpoint (ACR20 response) was determined at week 24; after the week 24 visit, patients were followed every 2 months for up to 18 months.

Number of patients (planned/analyzed):
500 patients planned; 520 patients enrolled.

Diagnosis and main criteria for inclusion:
Adult patients with RA for at least 6 months who had experienced an inadequate response to previous treatment with an anti-TNF therapy (etanercept, infliximab or adalimumab), and who had received MTX at a dose of 10-25 mg/week (p.o. or parenteral) for at least 12 weeks, with the last 4 weeks prior to screening at a stable dose.

Test product, dose and mode of administration or test procedure:
MabThera/Rituxan (rituximab): intravenous infusions of 1000 mg given on days 1 and 15 (total dose 2000 mg).

Duration of treatment:
2 infusions, on Days 1 and 15.

Reference therapy, dose and mode of administration or reference procedure:
Matching placebo: intravenous infusions given on days 1 and 15.

All patients received weekly MTX (po or parenteral) at a dose of 10-25 mg/week.

All patients also received a corticosteroid regimen consisting of methylprednisolone, 100 mg i.v. administered 30 minutes prior to both infusions of MabThera/placebo, and prednisone, 60 mg p.o. on days 2-7, 30 mg p.o. on days 8-14, returning to baseline dose by day 16. In addition, all patients received folate (5 mg/week) given as either a single dose or as divided daily doses and continued to receive any background corticosteroid (≤10 mg/day prednisone or equivalent) throughout the study, including days 1-15.

Criteria for evaluation (efficacy, safety):
Efficacy: Primary: Proportion of patients with an ACR20 response at week 24. Secondary: Proportion of patients with ACR50 and ACR70 responses at week 24; change in mean disease activity score (DAS28) from baseline to week 24; categorical DAS28 responders (EULAR response) at week 24; changes from baseline in the individual ACR core set parameters. Pharmacokinetics: Cfirst, Csecond (concentration 1h after first/second infusion) and t½ of rituximab. Pharmacodynamics: Lymphocyte subsets, comprising B cells (CD19) and T cells (CD3, CD4 and CD8); total rheumatoid factor (RF) and RF Ig isotypes; immunoglobulins – IgG, IgA and IgM isotypes and levels of individual IgG , IgA and IgM isotypes; human anti-chimeric antibodies (HACA); Complement C3 and C4; anti-nuclear antibodies (ANA); antibody titers. Safety: Adverse events, standard hematology and biochemistry, urinalysis.

Statistical methods:
The primary analysis was a test of the difference in proportions of patients with an ACR20 response at week 24 between the placebo + MTX and MabThera + MTX groups using a Cochran-Mantel-Haenszel (CMH) analysis, stratifying by rheumatoid factor and region. As supporting analyses, the ACR20 response rates were summarized descriptively and analyzed using logistic regression, including treatment group and stratification factor in the model. The secondary endpoints of ACR50 and ACR70 responses were analyzed using the same statistical methodology as described for the primary endpoint. Changes in DAS28 were assessed using an ANOVA model with baseline DAS28, RF, region and treatment as terms in the model. Categorical DAS28 responders (EULAR response) were assessed using a CMH test stratified for RF and region. Changes from baseline in the individual ACR core set were summarized by descriptive statistics. In addition, the difference between the MabThera + MTX group and the placebo + MTX group was assessed using ANOVA models with baseline parameter of interest, RF and region as terms in the model.

Summary (efficacy, safety, other results):
Efficacy: Analysis of the primary efficacy parameter showed that a significantly higher proportion of patients achieved an ACR20 response at week 24 following treatment with MabThera in combination with MTX than with MTX monotherapy (51% vs. 18%, 95% CI for the difference in proportions [0.26, 0.41], p < 0.0001). Similar results were obtained for all robustness and sensitivity analyses of the primary parameter. The proportion of patients achieving ACR50 and ACR70 responses at week 24 were also significantly higher for MabThera + MTX patients than for those who received placebo + MTX (ACR50: 27% vs. 5%, p < 0.0001, ACR70: 12% vs. 1%, p < 0.0001). A clear benefit of MabThera therapy was further demonstrated by a significantly greater reduction in DAS28 (-27.6% vs. -5.7%, p < 0.0001) and an increase in the proportions of patients achieving a good or moderate EULAR response (65% vs. 22%, p < 0.0001) in the MabThera + MTX group compared to the placebo + MTX group. Consistent with these findings, treatment with MabThera resulted in a statistically significant improvement from baseline in all of the ACR core set parameters compared to treatment with placebo (p < 0.005). Fifty-one percent of patients in the MabThera + MTX group showed an improvement in HAQ-DI at week 24 compared to 20% of patients in the placebo + MTX group.
Logistic regression analysis showed that the odds of achieving an ACR20 response at week 24 were 5 times higher for patients in the MabThera + MTX group than for patients in the placebo + MTX group (odds ratio 5.03, p < 0.001). Overall, 66% of patients in the MabThera + MTX group had a positive ACRn score at week 24, indicating that their disease symptoms had improved since the start of the study, compared to 32% of patients in the placebo + MTX group.
Pharmacokinetics: The pharmacokinetics of MabThera in this patient population were comparable with those seen in other MabThera studies in RA patients. No correlations between rituximab concentrations and changes from baseline in CD19+ B-cell counts, total RF, ACRn and DAS28 at week 24 were observed.
Pharmacodynamics: Treatment with MabThera resulted in rapid and sustained peripheral B-cell depletion. Mean peripheral T cell counts remained stable, with the exception of a transient decrease post-infusion (on days 1 and 15). Mean concentrations of immunoglobulin were slightly reduced in the placebo + MTX group at week 24 compared with baseline, with larger decreases in mean concentrations observed in the MabThera + MTX group. However, immunoglobulin concentrations generally remained within normal levels in patients in both groups throughout the 24 week study period. Positive HACA titers were recorded in 13 MabThera-treated patients at week 24, all of whom were HACA negative at baseline. While all these patients showed complete peripheral CD19+ B-cell depletion (to ≤ 1 cell/μL) following MabThera administration (2 x 1000 mg), most showed signs of B cell recovery at week 24. There did not appear to be a direct correlation between HACA titer, peripheral B-cell count and ACR response at week 24 for these patients. Antibody titers to mumps, rubella, varicella, tetanus toxoid, influenza, and S. pneumoniae remained stable during the study.
Safety: In general, the incidence of adverse events in >=5% of patients was similar for both groups during the 24 week study period. Worsening of RA was the most common adverse event during the study, reported twice as frequently in patients who received placebo + MTX (42%) than in patients treated with MabThera + MTX (21%).
A higher proportion of patients in the MabThera + MTX group (23%) than in the placebo + MTX group (18%) experienced adverse events considered to be acute infusion reactions during or within 24 hours of the first infusion. These included rashes, itching, throat or laryngeal discomfort, nausea and diarrhea. Five patients in the MabThera + MTX group withdrew from the study prematurely due to acute infusion-related reactions. Fewer infusion-related adverse events were recorded during or within 24 hours of the second MabThera +MTX (8%) or placebo + MTX (11%) infusions.
The overall incidence of infections was higher in the MabThera + MTX group (41%) than the placebo + MTX group (38%). However, there was very little difference between the two treatment groups in the infection rate per 100 patient years (154.61 for placebo + MTX patients vs. 138.2 for MabThera + MTX patients). The most common infections in both groups affected the upper respiratory tract (including upper respiratory tract infections, nasopharyngitis, sinusitis, and rhinitis). Patients treated with MabThera + MTX experienced an average of 5.2 clinically significant infections (ie serious adverse events or requiring i.v. antibiotics) per 100 patient years, compared to an average of 3.65 for patients receiving placebo + MTX.
The overall incidence of serious adverse events was comparable between the two treatment groups (10% in the placebo + MTX group and 7% in the MabThera + MTX group). No deaths were recorded during the 2 week double-blind study period.
The most frequent newly occurring laboratory abnormality was lymphopenia, which occurred at a higher incidence in patients treated with MabThera + MTX (56%) than in patients who received placebo + MTX (34%). In the majority of patients, lymphopenia occurred immediately post-infusion, and cell numbers subsequently recovered.
Overall, the safety profile observed in this study was consistent with the known safety profile of MabThera.

Conclusions:
An induction regimen of two 1000 mg infusions of MabThera in the first 2 weeks of therapy, in combination with MTX, significantly improved disease activity over 24 weeks in this population of RA patients who had experienced an inadequate response to anti-TNF therapies. Statistically significant differences from continued MTX monotherapy were observed for all clinical parameters (ACR response and components, DAS28, EULAR). The pharmacokinetics of MabThera were comparable with those seen in other MabThera studies in RA patients. MabThera treatment resulted in an immediate and complete peripheral B-cell depletion that was maintained over the 24 week primary study period in the majority of patients. The drug was well tolerated and the adverse event profile was consistent with the known safety profile of MabThera; adverse events occurring at a higher incidence in the MabThera group were generally associated with acute infusion-related reactions. Overall, MabThera in combination with methotrexate demonstrated an acceptable benefit/risk profile over 24 weeks following first treatment in this RA patient population with a high unmet medical need

Publications (references, if available):
Cohen S, Emery P, Greenwald M et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy. Arthritis and Rheumatism 2006; 54 (9): 2793-2806.

Click here for the protocol registry listing of this trial.