December 12, 2011
In April 2011, the FDA approved Rituximab (anti-CD20; Genentech) for use in granulomatosis and microscopic polyangiitis based on results from the ITN RAVE study. Before the Rituximab label extension, the standard of care for this disease was cyclophosphamide, a potent immunosuppressant that although effective is very toxic when used long-term. The RAVE study was able to successfully compare a potentially safer biologic therapy for a rare and challenging disease against the long-accepted standard of care treatment. Designing such a study required creative approaches which are described in the November 2011 publication in the Open Arthritis Journal, “Design of the Rituximab in ANCA-Associated Vasculitis (RAVE) Trial” (Specks et al.). In this paper, the authors “illuminate the unique challenges involved in comparing a new treatment approach against an entrenched standard of care.”
There were a number of difficulties designing a pivotal trial in a severe orphan disease. Patients with such diseases generally cannot go without active treatment, making the gold-standard placebo-controlled study unethical. This situation applies to ANCA-associated vasculitis (AAV) which can be fatal if untreated. To address this issue, the investigators designed a double-blind, double-dummy study where patients in the treatment arm received rituximab plus a cyclophosphamide placebo, and those in the standard therapy arm received cyclophosphamide plus a rituximab placebo. To provide proper equipoise, patients who experienced severe disease flares were crossed over to the opposite treatment arm.
Because cyclophosphamide is accepted in the community as effective at achieving remission for AAV, a superior outcome would have been difficult to achieve due to sample size limitations with a small patient population. Additionally, cyclophosphamide is not actually FDA-approved for this disease (nor was any therapy at the time), and there is a lack of randomized, controlled data demonstrating its effects in AAV. To overcome this unique situation the investigators were able to use historical data on untreated patients to predict superiority of rituximab over a would-be placebo arm. The RAVE study utilized a non-inferiority study design and successfully demonstrated that rituximab is as effective as cyclophosphamide for remission induction.
Designing a successful label-enabling trial for such a challenging disease with no approved therapy is a testament to the innovative and creative efforts of the Principal Investigators, John Stone, MD and Ulrich Specks, MD, and the RAVE-ITN Research Group. The RAVE trial utilized novel approaches to address study design issues and “represents a paradigm for designing a pivotal trial in an orphan disease indication” (Specks et al.).
The Open Arthritis Journal is an open-source publication and the paper can be found here.
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