Evaluation of the Safety and Efficacy of Avacopan, a C5a Receptor Inhibitor, in Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis Treated Concomitantly With Rituximab or Cyclophosphamide/Azathioprine: Protocol for a Randomized, Double-Blind, Active-Controlled, Phase 3 Trial

Peter A Merkel, David R Jayne, Chao Wang, Jan Hillson, Pirow Bekker, Peter A Merkel, David R Jayne, Chao Wang, Jan Hillson, Pirow Bekker

Abstract

Background: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a serious, often life-threatening disease. In new-onset disease or a relapse, the standard treatment is immunosuppressive therapy with glucocorticoids; these therapies are associated with substantial short- and long-term toxicity. Complement component 5a (C5a) binding to C5a receptor (C5aR) may play a central role in the pathogenesis of ANCA-associated vasculitis. Avacopan is a novel, orally bioavailable, and highly selective antagonist of human C5aR. Avacopan does not interfere with the production of C5b or the membrane attack complex (ie, terminal complement complex) and does not block C5a binding to a second receptor, C5L2 (also called C5aR2), shown to be protective in antimyeloperoxidase glomerulonephritis. This trial will evaluate if avacopan replaces the need for chronic glucocorticoids in the treatment of ANCA-associated vasculitis.

Objective: The aim of this study is to determine the proportions of patients in remission at week 26 and with sustained remission at week 52, defined as Birmingham Vasculitis Activity Score=0, and not taking glucocorticoids within the 4 weeks before week 26 and week 52, respectively.

Methods: The Avacopan Development in Vasculitis to Obtain Corticosteroid elimination and Therapeutic Efficacy study is a randomized, double-blind, active-comparator (prednisone), 2-arm study evaluating the safety and efficacy of avacopan versus prednisone, administered in combination with other immunosuppressive therapy. Eligible subjects will have active disease requiring induction of remission. Subjects are stratified based on the type of immunosuppressive therapy, ANCA subtype, and new or relapsing disease. Target sample size is 300 patients, enrolled at over 200 sites globally. All authors and local ethics committees approved the study design. All patients will provide informed consent.

Results: Enrollment of patients was completed in Q4 2018. Topline results are anticipated to be published by Q3 2020.

Conclusions: Results will be released irrespective of whether the findings are positive or negative.

Trial registration: ClinicalTrials.gov NCT02994927; https://ichgcp.net/clinical-trials-registry/NCT02994927.

International registered report identifier (irrid): DERR1-10.2196/16664.

Keywords: ADVOCATE; ANCA-associated vasculitis; C5a receptor; avacopan.

Conflict of interest statement

Conflicts of Interest: PM has received research grants and/or consulting fees from AbbVie, AstraZeneca, Biogen, Boeringher-Ingelheim, Bristol-Myers Squibb, Celgene, ChemoCentryx, Genentech/Roche, GlaxoSmithKline, InflaRx, Insmed, Janssen, Kiniksa, and Sanofi; DJ has received research grants and consulting fees from ChemoCentryx, Roche/Genentech, and GlaxoSmithKline; CW has been a paid consultant of ChemoCentryx; PB and JH have been employees, consultants, and shareholders of ChemoCentryx.

©Peter A Merkel, David R Jayne, Chao Wang, Jan Hillson, Pirow Bekker. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 07.04.2020.

Figures

Figure 1
Figure 1
Avacopan Development in Vasculitis to Obtain Corticosteroid Elimination and Therapeutic Efficacy trial design. AZA: azathioprine; BVAS: Birmingham Vasculitis Activity Score; CYC: cyclophosphamide; GC: glucocorticoids; IV: intravenous; MPO: myeloperoxidase; PR3: proteinase 3; RTX: rituximab.

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