BREVAS 2018.

Study characteristics
Methods	Study design: double‐blind parallel RCT (initially planned as phase 3 trial) Location: Australia, Belgium, Canada, Czech Republic, Germany, Ireland, Italy, Mexico, Peru, Poland, Russian Federation, Spain, Switzerland, United Kingdom, United States Setting: Not reported Number of centres: 37 Time frame of the study: 20 March 2013 through 06 February 2017 Duration of follow‐up: approximately up to 4 years
Participants	Inclusion criteria: Diagnosis of Wegener's granulomatosis or microscopic polyangiitis (Chapel Hill criteria). Disease flare in the past 26 weeks, which required treatment with high dose corticosteroids and one of the following drugs: rituximab or intravenous or oral cyclophosphamide. Anti‐proteinase 3 (anti‐PR3) or anti‐myeloperoxidase (anti‐MPO) antibodies positive at any time prior to enrolment. Achieved remission in up to 26 weeks after first dose of induction treatment. Maintenance therapy start no more than 2 weeks after confirmation of remission. Exclusion criteria: The coexistence of another autoimmune disease. Pregnant or breastfeeding. Other than rituximab a B cell targeted therapy at anytime. Investigational biological agent therapy within the last 60 days. Acute or chronic infections within the past 60 days which required management . Current drug or alcohol abuse or dependence. HIV, hepatitis B, or hepatitis C positive status (current and past). History of severe allergic reaction to contrast agents or biological agents. Total number of participants: 106 participants randomised, Belimumab group N = 53, Placebo group N = 52, N = 1 participant randomised in error Characteristics: GPA 79%, MPA 21% (The results of MPA patients were added to the GPA patient analysis) Mean (SD) age: Belimumab 56 ± 14, Placebo 54 ± 14 Female sex: Belimumab 49.1%, Placebo 48.1% CrCl value: NR Disease duration (time since diagnosis, median(SD)): Belimumab 2.3 years (range 0.3‐14.9), placebo 1.3 years (0.01‐20.6) Age at onset of symptoms: NR Race/ethnic group: Belimumab: African American/African Heritage 1, American Indian or Alaskan Native 6, Central/South Asian Heritage 0, White 46. Placebo: African American/African Heritage 1, American Indian or Alaskan Native 5, Central/South Asian Heritage 2, White 44 Disease diagnosed at the enrolment of the study: NR Disease assessment index BVAS (mean(SD)): NR Damage index: NR Global assessment: NR Quality of life: NR Disease severity (limited vs severe): NR Organ involvement: NR Prior treatment: NR ANCA type: anti‐PR3 77%, anti‐MPO 23%
Interventions	Belimumab group: Belimumab 10 mg/kg administered intravenously over 1 hour, on days 0, 14, 28 and every 28 days thereafter until 12 months after the last participant was randomised (In Belgium‐ all participants received belimumab at dose 10mg/day every 28 days until Week 24, and a final evaluation was at Week 28). Placebo group: Placebo administered intravenously over 1 hour on days 0, 14, 28 and every 28 days thereafter until 12 months after the last participant was randomised. (In Belgium‐only open‐label extension, all participants received belimumab 10mg/day every 28 days until Week 24, and a final evaluation was at Week 28). Mean or median treatment duration not reported. Description of treatment and concomitant treatment: All participants received oral azathioprine at a target dose of 2 mg/kg/day.
Outcomes	Major outcomes: Information on Clinicaltrials.gov register: Time to first relapse; Information in the full text publication: Time to first protocol‐specified event. The same definition: the number of days from Day 0 until the patient experienced a relapse (relapse date – treatment start date +1), a BVAS score of ≥ 6, or at least 1 predefined major item on the BVAS, or receiving medications which were prohibited for any reason ‐ which resulted in treatment failure Vasculitis relapse (used for sensitivity analysis only, not described on Clinicaltrials.gov register): defined as a minimum total BVAS score of 6, at least one pre‐defined major BVAS item or receiving prohibited medications for vasculitis Minor outcomes: Information on Clinicaltrials.gov register: major relapse ‐ number of patients experiencing at least 1 major BVAS item during the double‐blind phase of the trial, while in full text publication it was defined as time to the first major vasculitis relapse Other outcomes: AEs ‐ serious and non serious AEs. All AE were collected through 8 weeks following administration of the last dose of drug (Safety Endpoints of Special Interest: all cause mortality, serious and/or severe infections, opportunistic infections, malignant neoplasms, selected serious psychiatric events, suicidality assessment, infusion reactions including hypersensitivity reactions, immunogenicity) Time from Day 0 to first minor or major relapse (defined as experiencing at least 1 minor BVAS item and/or using a dose of rescue medication). At double‐blind Week 48 of year 1 and double‐blind Week 28 (specified in protocol) of year 2 and by visit; Proportion of patients in remission (BVAS=0 and corticosteroid dose < 10 mg/day); Absolute change in VDI (reported at week 48 of year 1 and week 24 of year 2) Proportion of participants with any increase in VDI (not reported); Absolute change in BVAS (not reported); Proportion of participants with any increase in BVAS (not reported); Proportion of participants with any increase in BVAS organ domains, also by domain (not reported); Proportion of patients with no relapse (not reported, but could be calculated from reported data)
Notes	Discontinuation: 32 (9.52%) participants (12 participants from placebo group and 20 participant from belimumab group): 10 (9.52%) due to AEs, 11 (10.48%) lack of efficacy, 1 (0,95%) protocol violation, 2 (1.9%) other‐study closed/terminated, 5 (4.76%) physician decision, 3 (2.86%) consent withdrawal. Funding: GlaxoSmithKline The study was initially planned as phase 3 trial with planned enrolment of approximately 300, then it ws changed to exploratory trial with enrolment of approximately 100 patients, the design changed from "event‐driven" to "fixed completion” specified as 12 months after the randomisation of the last patient.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"A total of 164 participants were screened and 106 were enrolled and randomised in a 1:1 ratio to receive placebo or belimumab" ‐ information from EudraCT and clinicaltrials.gov. Authors reported the use of interactive web response system so it was assumed that the sequence generation was computed based.
Allocation concealment (selection bias)	Low risk	Central randomisation: Use of interactive web response system
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)" ‐ information from EudraCT and clinicaltrials.gov.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)" ‐ information from EudraCT and clinicaltrials.gov.
Incomplete outcome data (attrition bias) All outcomes	Low risk	ITT was performed (all randomised participants who received at least one dose of study drug) and all patients were included in primary analysis, no missing outcome data identified, all reasons of withdrawn were described.
Selective reporting (reporting bias)	High risk	Full protocol available; not all outcomes specified in protocol were reported (see in the description of outcomes).
Other bias	Low risk	No other biases were identified.