The Infliximab Rheumatoid Arthritis Methotrexate Tapering (iRAMT) Protocol

Rheumatoid arthritis (RA) is a chronic autoimmune disorder of unknown etiology that occurs in approximately one percent of the population. Current therapy for RA comprises non-steroidal anti-inflammatory drugs (NSAIDs) in early stages of the disease, ultimately giving way to oral glucocorticoids and the disease-modifying anti-rheumatic drugs (DMARDs) as the disease progressively worsens. Therapy with DMARDs (e.g., D-penicillamine, auranofin, hydroxychloroquine, azathioprine, methotrexate) is not ideal in that they generally have a slow onset of action (measured in months), variable levels of effectiveness, and dose-limiting toxicity. Methotrexate (MTX) has become the DMARD of choice of many rheumatologists because of its faster mode of action and better record of prolonged use. However, despite the use of high doses of MTX, many patients only experience partial relief of symptoms and still have features of active disease. The current product labeling provides for a range of infliximab doses. Four fixed maintenance dose regimens proved to be safe and efficacious in the Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT) trial. However, the efficacy of incremental dose titration in patients with RA who have not achieved or maintained a clinically important improvement from baseline status has not been established in a clinical trial setting. Additionally, whether MTX tapering is possible in those patients who have achieved a clinically important improvement from baseline status has not been demonstrated. The iRAMT trial utilizes a prescribed strategy for infliximab dose titration in the event that individuals do not achieve a 40% improvement in the combined swollen and tender joint count, or have a disease flare or recurrent worsening. The iRAMT trial defines a clinically important improvement as at least a 40% improvement from baseline. Once the 40% improvement is achieved, MTX tapering will be initiated as appropriate for the specific patient. The primary efficacy endpoint is the number (%) of patients on a maintenance dose of infliximab who achieve at least 40% improvement from baseline in the combined tender and swollen joint count and tolerate any reduction in MTX dose at Week 54. Hence, this trial will provide information regarding an infliximab dose titration strategy as well as a MTX tapering schedule in those patients responding to therapy. The iRAMT trial will examine, in a manner consistent with clinical practice, if a schedule of infliximab maintenance will allow for tapering of MTX to occur. Patients will receive Infliximab infusions at a minimum dose of 3 mg/kg at Weeks 0, 2, 6 and every 8 weeks thereafter until Week 46. During the study, the dose of infliximab may be increased by single 100-mg vials using a specified regimen up to a maximum of 10 mg/kg every 4 weeks.