Rheumatoid Arthritis Clinical Trial
Official title:
Addition of Rituximab to Leflunomide in Patients With Active Rheumatoid Arthritis - a Multicenter Randomised Double-blind Clinical Trial
Combination of rituximab (RTX) with several different chemotherapeutic regimes has proven synergistic effects in patients with either lymphoma or autoimmune diseases. First data of uncontrolled trials with the combination of RTX and leflunomide (LEF) are available.
Rituximab provides lasting improvement in the signs and symptoms of rheumatoid arthritis
(RA) after two infusions per treatment course in tumor necrosis factor (TNF) inhibitor
inadequate responder (IR) patients. Importantly, MabThera® has been shown to inhibit
radiographic progression in this highly pre-treated patient population. Rituximab is
licensed for adult patients with severe active RA in combination with methotrexate after
inadequate response to previous treatment, including TNF alpha- Inhibitors.
In daily practice the combination with methotrexate is often limited to side effects or
contraindications to Methotrexate (MTX). Therefore there is an unmet medical need for
evidence for the combination of RTX with other Disease modifying anti-rheumatic drugs
(DMARDs)than MTX.
Leflunomide is a DMARD that selectively inhibits de novo pyrimidine synthesis by blocking
the enzyme dihydro-orotate dehydrogenase, thereby preventing DNA synthesis. The efficacy and
safety of leflunomide in patients with active RA have been demonstrated in three phase III
studies. Leflunomide was shown to be better than placebo and at least as effective as
methotrexate in improving individual signs and symptoms of RA; these responses were seen as
early as 4 weeks and were maintained for up to 2 years. Leflunomide was also effective in
slowing disease progression as assessed by radiographic analysis of joint damage, and in
improving functional activity as measured by the Stanford Health Assessment Questionnaire
Disease Activity Index. An open label extension study of patients treated with leflunomide
demonstrated that these improvements are maintained for up to 5 years in a subset of
patients, with no new or unexpected adverse events emerging compared with the initial phase
III studies.
In Europe leflunomide is often used in daily clinical practice as an alterative to MTX in
patients with active RA.
Recently published data of a small open label trial (Vital et al. 2008) and data of a German
non-interventional study (NIS) (Wendler et al. 2009) demonstrated the effectiveness of the
addition of RTX to leflunomide in patients with active RA. The proportion of patients
achieving EULAR (European League against Rheumatism) moderate to good response was 61% for
RTX alone, 65 % for RTX plus MTX and 79% for RTX plus leflunomide in the German NIS. In the
Leeds study of Vital et al.
33% of the patients achieved ACR (American College of Rheumatology)50 response (ACR 20: 68%,
ACR 70: 20%) despite multiple pre-treatments, including patients with inadequate response to
three TNF-Inhibitors.
The low rate of serious adverse drug reactions in the different groups of the German NIS
demonstrated the safety of the combination of RTX and leflunomide (n=90) (1.6 / 1.1 / 0,5%
for RTX+MTX / RTX+LEF / RTX Mono, 5.1 / 6,7 / 3,8% experienced infusion reactions)
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment
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