AAVTCZ.

Study name	Clinical trial of tocilizumab versus cyclophosphamide for microscopic polyangiitis and granulomatosis with polyangiitis
Methods	A phase II, randomised, open ‐ but assessors are blinded, controlled trial with two arms: 1. arm: intravenous tocilizumab (TCZ) plus high dose glucocorticoids 2. arm: intravenous cyclophosphamide (IVCY) plus high dose glucocorticoids
Participants	Inclusion criteria: Informed consent. ANCA positive active MPA or GPA meeting the diagnostic criteria of Japanese Ministry of Health, Labor and Welfare, or ANCA positive pauci‐immune glomerulonephritis with no non‐renal vasculitis. Participant ≥ 20 years of age and <80 years old. Body weight ≥ 40 kg. Active disease with BVAS v3 >3 with one or more of the major BVAS items or active organ threatening disease requiring treatment with CY according to the discretion of site investigators. Serum C‐reactive protein > 1.0 mg/dl. Both women and men willing to use an effective means of birth control until 70 days after the last administration of TCZ and until 90 days after the last administration of IVCY or azathioprine. No breastfeeding throughout the trial. Able to comply with treatment and follow‐up procedures. Exclusion criteria: Eosinophilic granulomatosis with polyangiitis or anti‐glomerular basement membrane antibody disease Other collagen diseases. Systemic autoimmune diseases. Limited disease according to EUVAS criteria. Serious lung, renal or heart disease, infarction or bleeding of gastrointestinal tract or having diverticulitis. A history of severe allergic reactions to drugs. An active or a deep‐seated infection within 6 months of the study. Active hepatitis B (HB) or a history of HBV infection, positive anti‐HB surface antibody or anti‐HB core antibody, and DNA of HBV, active hepatitis C or a history of hepatitis C. An alanine aminotransferase or aspartate aminotransferase level >2.5 times of the upper limit of normal. Active tuberculosis or mycosis or active cytomegalovirus infection. A history of malignancy, leukaemia, lymphoma or lymphoproliferative disease in the last 5 years. Uncontrolled other disease. A white blood cell count <4,000/mm3 or a platelet count <120,000/mm3. Intolerant to cyclophosphamide or azathioprine. Previous treatment with tocilizumab or other biologics. Started CS or increased a dosage of CS within 4 weeks before the study. Started CS at or increased a dosage of CS to a prednisone‐equivalent dose >25mg per day between 5 and 8 weeks before the study. Started or increased a dosage of immunosuppressive drugs except for CS within 8 weeks before the study. Treatment with plasma exchange or Intravenous immune globulin within 4 weeks before the study. Received any live vaccines within 4 weeks before the study. Participating in another clinical trial and received an investigational medicine within 12 weeks before the study.
Interventions	Arm 1 Week 0‐16: tocilizumab (8 mg/kg) IV every 2 weeks. Week 20 and 24: tocilizumab (8 mg/kg) IV every 4 weeks. If no response (a participant does not achieve BVAS v3=0) at week 16, tocilizumab continued every 2 weeks until week 24. Week 28‐52: If a complete remission achieved at week 24, tocilizumab (8 mg/kg) continued IV every 4 weeks until week 48. Arm 2 Week 0‐24: cyclophosphamide (15 mg/kg, doses modified for renal dysfunction) IV (IVCY) every 4 weeks (at least 3 times and up to 6 times). 4 weeks after the last dose of IVCY to week 52: If a complete remission achieved azathioprine orally every day until week 52. Prednisolone (PSL) prescribed by the same schedule to both treatment groups. Week 0‐24: Oral PSL at a dose of 0.8 mg/kg/day for the first 4 weeks, then tapered according to the prefixed schedule. Week 25‐52: Continued oral PSL at a dose of 7.5mg per day.
Outcomes	Major outcome measures: Complete remission at week 24 after randomisation Minor outcome measures: Maintaining complete remission (BVAS v3 = 0 and daily prednisolone at a dose of 7.5mg) during week 24 to 52 after randomisation. Percentage of participants who achieved BVAS v3 = 0 at two consecutive visits during 52 weeks after randomisation. Time from randomisation to achieving BVAS v3 = 0 at two consecutive visits. Percentage of participants who were able to taper daily prednisolone to a dose of 7.5 mg during 52 weeks after randomisation. Time from randomisation to tapering daily prednisolone to a dose of 7.5 mg. Total dosage of prednisolone. Percentage of participants who had flare. Time from randomisation to first flare. Changes of BVAS score by categories. VDI SF‐36 EQ5D Safety Pharmacokinetics
Starting date	1 May 2018 (date of first enrolment)
Contact information	Masayoshi Harigai ‐ Tokyo women's medical university Institute of Rheumatology harigai.masayoshi@twmu.ac.jp UMIN000024574
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