title: Randomized Trial of C5a Receptor Inhibitor Avacopan in ANCA-Associated Vasculitis.
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.
authors.affiliation: Department of Medicine, Addenbrooke's Hospital, Cambridge, United Kingdom; dj106@cam.ac.uk.
authors.forename: David R W
authors.initials: DRW
authors.lastname: Jayne
authors.affiliation: Department of Renal Medicine, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
authors.forename: Annette N
authors.initials: AN
authors.lastname: Bruchfeld
authors.affiliation: Department of Nephrology, University of Birmingham Research Laboratories, Queen Elizabeth Hospital Birmingham, Edgbaston, Birmingham, United Kingdom.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Harper
authors.affiliation: Renal Centre, University of Heidelberg, Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schaier
authors.affiliation: Department of Renal Medicine, Manchester Royal Infirmary, Manchester, United Kingdom.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Venning
authors.affiliation: Department of Renal Medicine, Manchester Royal Infirmary, Manchester, United Kingdom.
authors.forename: Patrick
authors.initials: P
authors.lastname: Hamilton
authors.affiliation: Department of Nephrology, Rheumatology, Diabetology and General Internal Medicine, Uniklinik Cologne, Cologne, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Burst
authors.affiliation: Department of Nephrology, Rheumatology, Diabetology and General Internal Medicine, Uniklinik Cologne, Cologne, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Grundmann
authors.affiliation: Service de Nephrologie, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
authors.forename: Michel
authors.initials: M
authors.lastname: Jadoul
authors.affiliation: Budai Irgalmasrendi Korhaz, Budapest, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Szombati
authors.affiliation: Department of Nephrology, Charles University, Prague, Czech Republic.
authors.forename: Vladimír
authors.initials: V
authors.lastname: Tesař
authors.affiliation: Department of Nephrology, Linköping University, Linköping, Sweden; and.
authors.forename: Mårten
authors.initials: M
authors.lastname: Segelmark
authors.affiliation: ChemoCentryx, Inc., Mountain View, California.
authors.forename: Antonia
authors.initials: A
authors.lastname: Potarca
authors.affiliation: ChemoCentryx, Inc., Mountain View, California.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Schall
authors.affiliation: ChemoCentryx, Inc., Mountain View, California.
authors.forename: Pirow
authors.initials: P
authors.lastname: Bekker
mesh_terms: D000328:Adult; D000368:Aged; D000814:Aniline Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000188:drug therapy*; D003520:Cyclophosphamide / Q000627:therapeutic use; D004311:Double-Blind Method; D004359:Drug Therapy, Combination / Q000009:adverse effects; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009557:Nipecotic Acids / Q000009:adverse effects / Q000627:therapeutic use*; D011241:Prednisone / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors*; D000069283:Rituximab / Q000627:therapeutic use; D012720:Severity of Illness Index
chemical_list: D000814:Aniline Compounds; C488033:C5AR1 protein, human; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D009557:Nipecotic Acids; D044087:Receptor, Anaphylatoxin C5a; D000069283:Rituximab; D003520:Cyclophosphamide; C000620232:avacopan; D011241:Prednisone
keywords: ANCA; ANCA-associated vasculitis; avacopan; complement; complement 5a; complement 5a receptor