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Mycophenolate mofetil versus cyclophosphamide for remission induction in ANCA-associated vasculitis: a randomised, non-inferiority trial
  1. Rachel B Jones1,
  2. Thomas F Hiemstra2,3,
  3. Jose Ballarin4,
  4. Daniel Engelbert Blockmans5,
  5. Paul Brogan6,7,
  6. Annette Bruchfeld8,
  7. Maria C Cid9,
  8. Karen Dahlsveen1,
  9. Janak de Zoysa10,11,
  10. Georgína Espigol-Frigolé9,
  11. Peter Lanyon12,
  12. Chen Au Peh13,
  13. Vladimir Tesar14,
  14. Augusto Vaglio15,16,
  15. Michael Walsh17,
  16. Dorothy Walsh1,
  17. Giles Walters18,
  18. Lorraine Harper19,
  19. David Jayne1,2
  20. for the European Vasculitis Study Group (EUVAS)
    1. 1 Department of Renal Medicine, Addenbrooke’s Hospital, Cambridge, UK
    2. 2 School of Clinical Medicine, University of Cambridge, Cambridge, UK
    3. 3 Cambridge Clinical Trials Unit, Addenbrooke’s Hospital, Cambridge, UK
    4. 4 Department of Nephrology, Fundació Puigvert, Barcelona, Spain
    5. 5 Department of General Internal Medicine, University Hospitals Leuven, Leuven, Belgium
    6. 6 Department of Paediatric Rheumatology, University College London Great Ormond Street Institute of Child Health, London, UK
    7. 7 Department of Paediatric Rheumatology, Great Ormond Street Hospital NHS Foundation Trust, London, UK
    8. 8 Department of Renal Medicine, Karolinska University Hospital, Stockholm, Sweden
    9. 9 Department of Autoimmune Diseases, Hospital Clinic, University of Barcelona, Institut d’investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
    10. 10 Renal Service, Waitemata District Health Board, Auckland, New Zealand
    11. 11 Department of Medicine, University of Auckland, Auckland, New Zealand
    12. 12 Department of Rheumatology, Nottingham University Hospitals NHS Trust, Nottingham, UK
    13. 13 Department of Renal Medicine, Royal Adelaide Hospital, Adelaide, South Australia, Australia
    14. 14 Department of Nephrology, Charles University and General University Hospital, Prague, Czech Republic
    15. 15 Department of Biomedical, Experimental and Clinical Sciences 'Mario Serio', University of Firenze, Firenze, Italy
    16. 16 Nephrology and Dialysis Unit, Meyer Children's University Hospital, Firenze, Italy
    17. 17 Departments of Medicine and Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
    18. 18 Department of Renal Medicine, Canberra Hospital, Canberra, Australian Capital Territory, Australia
    19. 19 Institute of Clinical Sciences, University of Birmingham, Birmingham, UK
    1. Correspondence to Dr Lorraine Harper, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK; l.harper{at}; Dr Lorraine Harper, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK; l.harper{at}


    Objectives Cyclophosphamide induction regimens are effective for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but are associated with infections, malignancies and infertility. Mycophenolate mofetil (MMF) has shown high remission rates in small studies of AAV.

    Methods We conducted a randomised controlled trial to investigate whether MMF was non-inferior to cyclophosphamide for remission induction in AAV. 140 newly diagnosed patients were randomly assigned to MMF or pulsed cyclophosphamide. All patients received the same oral glucocorticoid regimen and were switched to azathioprine following remission. The primary endpoint was remission by 6 months requiring compliance with the tapering glucocorticoid regimen. Patients with an eGFR <15 mL/min were excluded from the study.

    Results At baseline, ANCA subtype, disease activity and organ involvement were similar between groups. Non-inferiority was demonstrated for the primary remission endpoint, which occurred in 47 patients (67%) in the MMF group and 43 patients (61%) in the cyclophosphamide group (risk difference 5.7%, 90% CI −7.5% to 19%). Following remission, more relapses occurred in the MMF group (23 patients, 33%) compared with the cyclophosphamide group (13 patients, 19%) (incidence rate ratio 1.97, 95% CI 0.96 to 4.23, p=0.049). In MPO-ANCA patients, relapses occurred in 12% of the cyclophosphamide group and 15% of the MMF group. In PR3-ANCA patients, relapses occurred in 24% of the cyclophosphamide group and 48% of the MMF group. Serious infections were similar between groups (26% MMF group, 17% cyclophosphamide group) (OR 1.67, 95% CI 0.68 to 4.19, p=0.3).

    Conclusion MMF was non-inferior to cyclophosphamide for remission induction in AAV, but resulted in higher relapse rate.

    Trial registration number NCT00414128.

    • ANCA-associated vasculitis
    • induction therapy
    • cyclophosphamide
    • mycophenolate
    • randomised trial
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    • LH and DJ are joint senior authors.

    • Handling editor Josef S Smolen

    • Collaborators Prof Alan D Salama, University College London; Dr David Milford, Birmingham Children's Hospital; Dr David Kluth, University of Edinburgh; Prof Raashid Luqmani, University of Oxford, Dr Oliver Flossmann, Royal Berkshire NHS Foundation Trust; Dr Andrew Short, University Hospitals Coventry and Warwick; Dr Eileen Baildam, Alder Hey Children's Hospital; Dr John Stoves, Bradford Teaching Hospitals NHS Foundation Trust; Dr Lars Erwig (was University of Aberdeen at time of study) now GlaxoSmith Kline Pharmaceuticals; Dr Martin Christian, Nottingham University Hospitals; Prof Caroline O Savage, (was University of Birmingham at time of study) now GlaxoSmith Kline Pharmaceuticals; all UK. All collaborators recruited at least 1 patient

    • Contributors All authors contributed to the design, conduct and/or analysis of the study. All authors reviewed the manuscript prior to submission and gave final approval.

    • Funding Sponsorship for this trial was provided by the Cambridge University Hospitals NHS Foundation Trust. Funding for this trial and the cost of the mycophenolate mofetil was provided in the form of a research grant from Vifor Pharma (previously Aspreva Pharmaceuticals). TFH is supported by NIHR 14/49/127, 16/167/120 and 17/27/11, and by the NIHR Cambridge Biomedical Research Centre. MCC and GEF acknowledge the support from Ministerio de Economía, Industria y Competitividad (SAF 14/57708-R and 17/88275-R) and Instituto de Salud Carlos III (PI 15/00092 cofunded by FEDER and Juan Rodés programme), respectively. The study was conducted within the Birmingham and Cambridge National Institute for Health Research (NIHR)/Wellcome Trust (WT) Clinical Research Facilities (CRF) at these sites.

    • Disclaimer The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

    • Competing interests RBJ: consulting for ChemoCentryx; academic secondment with GlaxoSmithKline 2011–2013. US: consulting for Genentech/Roche. PAM: consulting for Actelion, Alexion, Bristol Myers Squibb, ChemoCentryx, Genzyme/Sanofi, GlaxoSmithKline, Genentech/Roche, PrincipioBio; research support from Actelion, Bristol Myers Squibb, Celgene, ChemoCentryx, Genentech/Roche, GlaxoSmithKline. DJ: consulting for Alexion, ChemoCentryx, Genzyme/Sanofi, GlaxoSmithKline, Genentech/Roche and Takeda; research support from ChemoCentryx, Genentech/Roche, Genzyme/Sanofi, Medimmune and GlaxoSmithKline. LH: consulting for ChemoCentryx; honorarium from Roche. TFH: research support from GlaxoSmithKline, Otsuka and AstraZeneca.

    • Patient consent for publication Not required.

    • Ethics approval Oxfordshire Research Ethics Committee B (reference number 06/Q1605/120).

    • Provenance and peer review Not commissioned; externally peer reviewed.

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