Design of the Rituximab in ANCA-Associated Vasculitis (RAVE) Trial

Granulomatosis with polyangiitis (formerly Wegener's) (GPA) and microscopic polyangiitis (MPA) share many clinical and pathological features, including antineutrophil cytoplasmic antibodies (ANCA) directed against either proteinase 3 (PR3) or myeloperoxidase (MPO).These two "ANCA-associated" vasculitides (AAV) are associated with a high mortality in untreated patients, substantial morbidity from standard therapies, and a significant risk of disease relapse.The Rituximab in ANCA-Associated Vasculitis (RAVE) trial is a randomized, double-blind, double-dummy, activecontrolled, non-inferiority trial of a new approach to the induction of remission.The RAVE trial represents the first challenge of a biologic agent to CYC as the standard of care for remission induction in AAV.The primary outcome analysis, reported in 2010, compared conventional therapy (the combination of cyclophosphamide (CYC) and glucocorticoids) to the combination of rituximab (RTX) and glucocorticoids.Longer term outcomes to 18 months and beyond have not been reported.The trial aimed to determine if the combination of RTX plus glucocorticoids was non-inferior to the combination of CYC and glucocorticoids.To test this hypothesis, eight clinical centers planned to enroll 200 patients.The randomization was stratified by center and by ANCA subtype.Patients were assigned randomly to each treatment arm in an allocation ratio of 1:1.The primary outcome had two components: 1) the ability of the assigned regimen to induce disease remission by month 6; and, 2) successful discontinuation of prednisone by month 6.All primary analyses were performed on an intention-to-treat basis.A major secondary outcome of interest was the restoration of immune tolerance, defined as disease quiescence and the absence of ANCA following the reconstitution of normal B cell numbers.To meet this definition, patients were required to achieve and maintain disease remissions, complete the prednisone taper, and remain on no immunosuppressive medications after discontinuing prednisone.Patients were followed for 18 months after the final patient was enrolled to evaluate the impact of the two treatment regimens on tolerance restoration.In this paper, we describe the development and design of the RAVE trial as a pivotal trial in an orphan disease indication.We illuminate the unique challenges involved in comparing a new treatment approach against an entrenched standard of care in a double-blind, double-dummy trial of a biologic for the treatment of a rare disease.