TY - JOUR
T1 - Design of the Rituximab in ANCA-Associated Vasculitis (RAVE) Trial
AU - Specks, Ulrich
AU - Merkel, Peter A.
AU - Hoffman, Gary S.
AU - Langford, Carol A.
AU - Spiera, Robert
AU - Seo, Phil
AU - Kallenberg, Cees G.M.
AU - St Clair, E. William
AU - Ding, Linna
AU - Webber, Lisa
AU - Mokhtarani, Masoud
AU - Tchao, Nadia K.
AU - Sayre, Peter
AU - Seyfert-Margolis, Vicky
AU - Ikle, David
AU - Brunetta, Paul P.
AU - Zhang, David
AU - Sejismundo, Lourdes
AU - Mueller, Mark
AU - Stone, John H.
PY - 2011
Y1 - 2011
N2 - 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, active controlled, 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 inten tion-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, pa tients were required to achieve and maintain disease remissions, complete the prednisone taper, and remain on no immu nosuppressive 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.
AB - 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, active controlled, 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 inten tion-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, pa tients were required to achieve and maintain disease remissions, complete the prednisone taper, and remain on no immu nosuppressive 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.
KW - Antineutrophil cytoplasmic antibody (ANCA)
KW - B cell depletion
KW - Controlled trial
KW - Granulomatosis with polyangiitis
KW - Immune tolerance
KW - Microscopic polyangiitis
KW - Non-inferiority trial
KW - Randomized
KW - Rituximab
KW - Vasculitis
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U2 - 10.2174/1876539401104010001
DO - 10.2174/1876539401104010001
M3 - Article
AN - SCOPUS:82755165229
SN - 1876-5394
VL - 4
SP - 1
EP - 18
JO - Open Arthritis Journal
JF - Open Arthritis Journal
IS - 1
ER -