Clinical Trial Result Information

Title of Study:
A randomized, multifactorial, double-blind, parallel-group, dose-ranging study of the efficacy and safety of rituximab (MabThera/Rituxan) in combination with methotrexate in patients with active rheumatoid arthritis.

Fast Facts:

Protocol number:	WA17043
Sponsor:	Roche Products Ltd; Genentech Inc.
Company division:	Pharmaceutical
Product name:	MabThera/Rituxan
Generic name:	rituximab
Phase of development:	II
Therapeutic area, approved indication:	Rheumatoid arthritis
Date of report:	7/1/2005

Clinical study summary:
This randomized, double-blind, double-dummy, controlled, multifactorial study evaluated nine different treatment regimens in a 3 x 3 configuration, comprising three different dose levels of MabThera (rituximab) (including placebo) and three different corticosteroid regimens (including placebo), along with methotrexate (MTX), and folate. Approximately 40 RF-positive patients were enrolled into each of the nine possible combinations. In addition, 20 RF-negative patients were studied in each of four different treatment regimens: rituximab placebo plus placebo corticosteroid and high-dose rituximab with the three differing corticosteroid regimens (none, peri-infusional and peri-infusional plus oral).
See below for individual treatment regimens.

A Placebo Placebo MTX	B Placebo Corticosteroids iv MTX	C Placebo Corticosteroids iv + po MTX
D Low dose MabThera Placebo MTX	E Low dose MabThera Corticosteroids iv MTX	F Low dose MabThera Corticosteroids iv + po MTX
G High dose MabThera Placebo MTX	H High dose MabThera Corticosteroids iv MTX	I High dose MabThera Corticosteroids iv + po MTX

Study center(s) :
95 centers in Australia, Brazil, Canada, Czech Republic, Finland, Germany, Italy, Mexico, New Zealand, Poland, Spain, Sweden, UK and USA

Objectives:
(1) To determine the appropriate treatment regimen (including dose and concomitant use of corticosteroids) of MabThera in combination with MTX in patients with rheumatoid arthritis (RA) who had failed previous disease modifying anti-rheumatic drug (DMARD) therapy and currently had inadequate clinical response to MTX. (2) To explore the pharmacokinetics and pharmacodynamics of MabThera in this patient population (eg, extent and duration of B-cell depletion and effects on immunoglobulins and rheumatoid factor [RF]).

Methodology:
Patients were randomized to one of 9 treatment regimens comprising 3 different doses of MabThera (including placebo) and 3 different corticosteroid regimens (including placebo), together with a weekly regimen of MTX and folate. The primary endpoint (ACR20 response) was determined at week 24. After week 24, all patients received 18 months of follow-up for an overall study duration of 24 months.

Number of patients (planned/analyzed):
Planned: 440 patients. Actual: 465 patients were randomized and treated in this study.

Diagnosis and main criteria for inclusion:
Adult (≥18 years) patients with active RA, who had previously failed one to five DMARDs/biologics (other than MTX) and who currently had an inadequate response to MTX.

Test product, dose and mode of administration or test procedure:
MabThera/Rituxan (rituximab) (0.5g or 1g) was administered by iv infusion.

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

Reference therapy, dose and mode of administration or reference procedure:
Placebo was administered by iv infusion on days 1 and 15. All patients received weekly MTX (po or parenterally) at a dose of 10-25mg/week, and weekly folate. In addition, all patients continued to receive background corticosteroid throughout days 1-15. Three different regimens of corticosteroids were studied: no additional corticosteroid, peri-infusional methylprednisolone 2x100mg IV, or iv methyl prednisolone and prednisone 60mg/day on days 2-7 followed by 30mg/day on days 8-14.

Criteria for evaluation (efficacy, safety):
Efficacy: Primary: The proportion of RF-positive patients with an ACR20 response at week 24. Secondary (in RF-positive patients): (1) Proportion of patients with ACR50 and 70 responses at week 24. (2)Proportion of patients with an ACR20 response in the peri-infusional corticosteroid treatment arms versus the placebo corticosteroid treatment arms. (3) Proportion of patients with an ACR20 response in the peri-infusional plus oral corticosteroid treatment arms versus the placebo corticosteroid arms. (4) Change in disease activity score (DAS28-4 [ESR]. (5) Proportion of patients with DAS responses [EULAR]). (6) Changes from baseline in the ACR core set. (7) Changes from baseline in SF-36.

Pharmacodynamics: B cell and T cell counts, quantitative Ig and RF levels, human anti-chimeric antibodies (HACA), antibody titers.

Pharmacokinetics: C_max, T_max, t_1/2.

Safety: Adverse events (AEs), standard hematology and biochemistry, urinalysis.

Statistical methods:
The primary analysis tested for an association between ACR20 response at week 24 and MabThera treatment while controlling for corticosteroid usage and region in RF-positive patients using a logistic regression model. The main effects were MabThera treatment, corticosteroid usage and region. The secondary endpoints of ACR50 and ACR70 response rates were analyzed using the same statistical methodology as described for the primary endpoint. Changes in DAS28 were summarized descriptively. Additionally, changes from baseline in DAS28 at week 24 between the pooled treatment groups were tested using an ANOVA model with baseline DAS28, pooled MabThera and corticosteroid treatment groups and region in the model. The difference in EULAR response rates between treatment groups was tested using logistic regression with MabThera dose, corticosteroid use and region as main effects in the model. Changes in baseline in the individual ACR core set were summarized descriptively. The change from baseline in SF-36 physical and mental health summary scores, and the eight domain scores were summarized using descriptive statistics.

Summary (efficacy, safety, other results):
Efficacy: More patients in the MabThera treatment groups achieved an ACR20 response at week 24 compared with patients who received MabThera placebo, and this difference was highly statistically significant (the proportion of ACR20 responders for the 2 x 0.5g MabThera group was 55%, odds ratio of 3.43, p<0.0001 and for the 2 x 1g MabThera group the proportion of responders was 54%, odds ratio of 3.17, p<0.0001, compared with 28% patients in the MabThera placebo group who achieved an ACR response). Corticosteroid regimen did not have a statistically significant impact on the proportion of ACR20 responders at week 24 in this study. However, the receipt of corticosteroid appeared to alter the early response rate in all treatment arms, resulting in more patients achieving an ACR20 response by week 4 than in treatment arms not given corticosteroid. There was no statistically significant difference in proportions of ACR20 responders between the high-dose (2 x 1g) and the lower dose (2 x 0.5g) MabThera groups. Secondary endpoints in RF-positive patients (ACR50, ACR70, DAS28 and EULAR) reflected the observations seen with the primary endpoint.

Pharmacodynamics: MabThera treatment (2 x 0.5g and 2 x 1g) 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 RF concentrations decreased during the study in the MabThera groups, whereas mean RF concentrations increased over the course of the study in the MabThera placebo groups. Antibody titers to mumps, rubella, Varicella, tetanus toxoid, influenza, and S. pneumoniae remained stable during the study. HACA were present at week 24 in five patients in the 2 x 0.5g MabThera group and five patients in the 2 x 1g MabThera group, without significant adverse events.

Pharmacokinetics: Serum concentration data demonstrated a dose-response on increasing the dose from 2 x 0.5g to 2 x 1g. There was a clinically insignificant difference in the pharmacokinetics of MabThera when administered alone and co-administered with either peri-infusional corticosteroids or peri-infusional plus oral corticosteroids.

Safety: The overall incidence of AEs in each treatment group was higher in the MabThera groups than in the MabThera placebo group (81% and 85% of patients experienced AEs in the 2 x 0.5g and 2 x 1g MabThera groups, respectively, compared with 70% of patients in the MabThera placebo group). Worsening of RA was the most common adverse event during the study, reported by 30% of patients in the MabThera placebo group, 17% in the 2 x 0.5g group and 14% in the 2 x 1g MabThera group. Headache, nausea, upper respiratory tract infections and nasopharyngitis were also reported by >5% of patients in all groups. The majority of events were mild to moderate in intensity.
Most adverse reactions to MabThera occurred in association with the first infusion. Acute infusion reactions occurred in 23% of patients receiving the first 0.5g MabThera infusion and 32% of patients receiving their first infusion of 1g MabThera compared with 17% of MabThera placebo-treated patients; pre-infusion premedication with IV corticosteroids reduced both the incidence and severity of these events. In the treatment arms that did not receive corticosteroid, 32% of patients who received 0.5g MabThera and 37% of patients who received 1g MabThera experienced an acute infusion reaction compared with 19% and 29% in the 2 x 0.5g and 2 x 1g MabThera arms, respectively, that did receive corticosteroid. Two patients had infusion-associated events that were reported as serious AEs – drug hypersensitivity (one patient in the 2 x 0.5g MabThera plus CS placebo arm) and generalized edema (one patient in the 2 x 1g MabThera plus CS placebo arm). The number of patients experiencing acute infusion reactions following the second course was substantively lower; 10% of patients in the MabThera placebo group, 6% in the 2 x 0.5g MabThera group and 8% of patients in the 2 x 1g MabThera group were affected following the second infusion.
The incidence of infections was higher in the MabThera groups (35% in both active dose groups) than in the MabThera placebo group (28% of patients). Serious infections (requiring hospitalization or use of an IV antibiotic) were uncommon, and occurred in two patients in the MabThera placebo group (pneumonia and respiratory tract infection) and five patients in the 2 x 1g MabThera group (epiglottitis, bronchitis, two episodes of pyelonephritis and urosepsis).
Serious AEs were reported by 3% of patients in the MabThera placebo group, 7% in the 2 x 0.5g MabThera group and 7% in the 2 x 1g MabThera group. One patient died during the study of a cerebral infarction, which was not considered to be related to the study medication. Serious cardiac events were reported in two patients with underlying cardiovascular disorders in the 2 x 0.5g MabThera group. In total, eight patients (3%) were withdrawn due to AEs, all in the MabThera groups; five of these were infusion-related events.

Conclusions:
Both doses of MabThera significantly improved disease activity, as measured by ACR20, ACR50 and ACR70, compared with methotrexate alone. There were no statistically significant differences in efficacy between the 2 x 1g and 2 x 0.5g MabThera groups during the 24 week study period. Both doses of MabThera resulted in a near-complete depletion of peripheral CD19 cells that was maintained for up to 24 weeks. In this study, the corticosteroid regimen (peri-infusional plus oral, peri-infusional alone or placebo) had no significant effect on efficacy. MabThera was generally well-tolerated in this study and the adverse event profile was consistent with the known safety profile of MabThera, with the majority of events being associated with infusions. Infusion-related reactions were reduced by using peri-infusional corticosteroids. Serum concentration of rituximab exhibited linear kinetics. There was no clinically significant difference in pharmacokinetics between the treatment arms that received corticosteroids compared with the treatment arms that did not receive corticosteroids. Mean immunoglobulin concentrations decreased slightly from baseline to week 24 in patients who received MabThera, but remained within the normal range. MabThera treatment reduced mean RF concentrations, whereas RF concentrations increased in placebo-treated patients.

Publications (references, if available):
Emery P, Fleischmann R, Filipowicz-Sosnowska A et al. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment. Arthritis and Rheumatism 2006; 54 (5): 1390-1400

Click here for the protocol registry listing of this trial.