Randomized Trial of C5a Receptor Inhibitor Avacopan in ANCA-Associated Vasculitis

Research output: Contribution to journalArticle

Authors

  • David R W Jayne
  • Annette N Bruchfeld
  • Lorraine Harper
  • Matthias Schaier
  • Michael C Venning
  • Patrick Hamilton
  • Volker Burst
  • Franziska Grundmann
  • Michel Jadoul
  • István Szombati
  • Vladimír Tesař
  • Mårten Segelmark
  • Antonia Potarca
  • Thomas J Schall
  • Pirow Bekker
  • CLEAR Study Group

Colleges, School and Institutes

External organisations

  • Department of Medicine, Addenbrooke's Hospital, Cambridge, United Kingdom; dj106@cam.ac.uk.
  • Department of Renal Medicine, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
  • Department of Nephrology, University of Birmingham Research Laboratories, Queen Elizabeth Hospital Birmingham, Edgbaston, Birmingham, United Kingdom.
  • Renal Centre, University of Heidelberg, Heidelberg, Germany.
  • Department of Renal Medicine, Manchester Royal Infirmary, Manchester, United Kingdom.
  • Department of Nephrology, Rheumatology, Diabetology and General Internal Medicine, Uniklinik Cologne, Cologne, Germany.
  • Service de Nephrologie, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
  • Budai Irgalmasrendi Korhaz, Budapest, Hungary.
  • Department of Nephrology, Charles University, Prague, Czech Republic.
  • Department of Nephrology, Linköping University, Linköping, Sweden; and.
  • ChemoCentryx, Inc., Mountain View, California.

Abstract

Alternative C activation is involved in the pathogenesis of ANCA-associated vasculitis. However, glucocorticoids used as treatment contribute to the morbidity and mortality of vasculitis. We determined whether avacopan (CCX168), an orally administered, selective C5a receptor inhibitor, could replace oral glucocorticoids without compromising efficacy. In this randomized, placebo-controlled trial, adults with newly diagnosed or relapsing vasculitis received placebo plus prednisone starting at 60 mg daily (control group), avacopan (30 mg, twice daily) plus reduced-dose prednisone (20 mg daily), or avacopan (30 mg, twice daily) without prednisone. All patients received cyclophosphamide or rituximab. The primary efficacy measure was the proportion of patients achieving a ≥50% reduction in Birmingham Vasculitis Activity Score by week 12 and no worsening in any body system. We enrolled 67 patients, 23 in the control and 22 in each of the avacopan groups. Clinical response at week 12 was achieved in 14 of 20 (70.0%) control patients, 19 of 22 (86.4%) patients in the avacopan plus reduced-dose prednisone group (difference from control 16.4%; two-sided 90% confidence limit, -4.3% to 37.1%; P=0.002 for noninferiority), and 17 of 21 (81.0%) patients in the avacopan without prednisone group (difference from control 11.0%; two-sided 90% confidence limit, -11.0% to 32.9%; P=0.01 for noninferiority). Adverse events occurred in 21 of 23 (91%) control patients, 19 of 22 (86%) patients in the avacopan plus reduced-dose prednisone group, and 21 of 22 (96%) patients in the avacopan without prednisone group. In conclusion, C5a receptor inhibition with avacopan was effective in replacing high-dose glucocorticoids in treating vasculitis.

Details

Original languageEnglish
Article number28400446
Pages (from-to)2756-2767
Number of pages12
JournalJournal of the American Society of Nephrology
Volume28
Issue number9
Early online date11 Apr 2017
Publication statusPublished - Sep 2017

Keywords

  • Adult, Aged, Aniline Compounds, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis, Cyclophosphamide, Double-Blind Method, Drug Therapy, Combination, Female, Glucocorticoids, Humans, Immunosuppressive Agents, Male, Middle Aged, Nipecotic Acids, Prednisone, Receptor, Anaphylatoxin C5a, Rituximab, Severity of Illness Index, Journal Article, Multicenter Study, Randomized Controlled Trial