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

Ulrich Specks, Peter A. Merkel, Gary S. Hoffman, Carol A. Langford, Robert Spiera, Philip Seo, Cees G M Kallenberg, E. William St Clair, Linna Ding, Lisa Webber, Masoud Mokhtarani, Nadia K. Tchao, Peter Sayre, Vicky Seyfert-Margolis, David Ikle, Paul P. Brunetta, David Zhang, Lourdes Sejismundo, Mark Mueller, John H. Stone

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1-18
Number of pages18
JournalOpen Arthritis Journal
Volume4
Issue number1
StatePublished - 2011
Externally publishedYes

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Antineutrophil Cytoplasmic Antibodies
Vasculitis
Glucocorticoids
Prednisone
Cyclophosphamide
Remission Induction
Standard of Care
Rare Diseases
Therapeutics
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Microscopic Polyangiitis
Myeloblastin
Immune Tolerance
Granulomatosis with Polyangiitis
Biological Factors
Random Allocation
Peroxidase
Rituximab
B-Lymphocytes
Cell Count

Keywords

  • Antineutrophil cytoplasmic antibody (ANCA)
  • B cell depletion
  • Controlled trial
  • Granulomatosis with polyangiitis
  • Immune tolerance
  • Microscopic polyangiitis
  • Non-inferiority trial
  • Randomized
  • Rituximab
  • Vasculitis

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology

Cite this

Specks, U., Merkel, P. A., Hoffman, G. S., Langford, C. A., Spiera, R., Seo, P., ... Stone, J. H. (2011). Design of the Rituximab in ANCA-Associated Vasculitis (RAVE) Trial. Open Arthritis Journal, 4(1), 1-18.

Design of the Rituximab in ANCA-Associated Vasculitis (RAVE) Trial. / Specks, Ulrich; Merkel, Peter A.; Hoffman, Gary S.; Langford, Carol A.; Spiera, Robert; Seo, Philip; Kallenberg, Cees G M; St Clair, E. William; Ding, Linna; Webber, Lisa; Mokhtarani, Masoud; Tchao, Nadia K.; Sayre, Peter; Seyfert-Margolis, Vicky; Ikle, David; Brunetta, Paul P.; Zhang, David; Sejismundo, Lourdes; Mueller, Mark; Stone, John H.

In: Open Arthritis Journal, Vol. 4, No. 1, 2011, p. 1-18.

Research output: Contribution to journalArticle

Specks, U, Merkel, PA, Hoffman, GS, Langford, CA, Spiera, R, Seo, P, Kallenberg, CGM, St Clair, EW, Ding, L, Webber, L, Mokhtarani, M, Tchao, NK, Sayre, P, Seyfert-Margolis, V, Ikle, D, Brunetta, PP, Zhang, D, Sejismundo, L, Mueller, M & Stone, JH 2011, 'Design of the Rituximab in ANCA-Associated Vasculitis (RAVE) Trial', Open Arthritis Journal, vol. 4, no. 1, pp. 1-18.
Specks U, Merkel PA, Hoffman GS, Langford CA, Spiera R, Seo P et al. Design of the Rituximab in ANCA-Associated Vasculitis (RAVE) Trial. Open Arthritis Journal. 2011;4(1):1-18.
Specks, Ulrich ; Merkel, Peter A. ; Hoffman, Gary S. ; Langford, Carol A. ; Spiera, Robert ; Seo, Philip ; Kallenberg, Cees G M ; St Clair, E. William ; Ding, Linna ; Webber, Lisa ; Mokhtarani, Masoud ; Tchao, Nadia K. ; Sayre, Peter ; Seyfert-Margolis, Vicky ; Ikle, David ; Brunetta, Paul P. ; Zhang, David ; Sejismundo, Lourdes ; Mueller, Mark ; Stone, John H. / Design of the Rituximab in ANCA-Associated Vasculitis (RAVE) Trial. In: Open Arthritis Journal. 2011 ; Vol. 4, No. 1. pp. 1-18.
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AU - Specks, Ulrich

AU - Merkel, Peter A.

AU - Hoffman, Gary S.

AU - Langford, Carol A.

AU - Spiera, Robert

AU - Seo, Philip

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.

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KW - Granulomatosis with polyangiitis

KW - Immune tolerance

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KW - Non-inferiority trial

KW - Randomized

KW - Rituximab

KW - Vasculitis

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