Wechsler 2017.

Study characteristics
Methods	Study design: double‐blinded parallel RCT Location: USA: Boston, Denver, Cleveland, Salt Lake City. Italy: Pisa, Firenze, Milano. France: Montpellier, Marseille, Bron, Paris, Suresnes. UK: Portsmouth, Leicester. Spain: Barcelona. Belgium: Bruxelles. Canada: Hamilton, Toronto. Germany: Kirchheim Gunter Teck, Neumünster, Hessen, Thueringen, Kiel, Freiburg. Japan: Miyagi, Kanagawa. Setting: clinical centres Number of centres: 31 Time frame of the study: February 2014 through June 2015 Duration of follow‐up: continued until September 2016 (8 weeks)
Participants	Inclusion criteria: Informed consent Participants ≥ 18 years A diagnosis of EGPA for at least six months based on the history or presence of: asthma and eosinophilia and two or more of the following additional features: histopathological evidence of eosinophilic vasculitis or perivascular eosinophilic infiltration, or eosinophil–rich granulomatous or Inflammation in biopsy; mono‐ or polyneuropathy, non‐fixed pulmonary infiltrates; sino–nasal abnormality, cardiomyopathy (confirmed in echocardiography or MRI); glomerulonephritis (hematuria, red cell casts, proteinuria); alveolar haemorrhage (confirmed by bronchoalveolar lavage); palpable purpura; positive test for ANCA (MPO or PR3). Relapsing or refractory disease. CS at stable dose at least 4 weeks prior to baseline (Visit 2). Immunosuppressive therapy in stable dose for the 4 weeks prior to baseline and during the study. ECG measurements: QTc(F) < 450 msec or QTc(F) < 480 msec if bundle branch block. Females of childbearing potential practicing an acceptable method of birth control during a clinical trial and for 4 months after the last study drug administration. French participants if either affiliated to, or a beneficiary of, a social security system. Exclusion criteria: Diagnosis of granulomatosis with polyangiitis (Wegener’s) or microscopic polyangiitis. Organ‐threatening EGPA according to EULAR criteria. Life–threatening EGPA defined as any of the following features within 3 months before screening: requirement for intensive care; severe alveolar haemorrhage or haemoptysis which required transfusion or ventilation or haemoglobin level below 8 g/dL (< 80 g/L) or drop in haemoglobin level of more than 2 g/dL (> 20 g/L) within 48‐hour period due to alveolar haemorrhage; rapidly progressive glomerulonephritis (creatinine over 2.5 mg/dL (> 221 μmol/L) or rise in creatinine over 2 mg/dL (> 177 μmol/L) within 48‐hour period; severe involvement of gastrointestinal system, central nervous system, heart; other diseases: a current cancer or history of cancer in remission for less than 12 months before screening; unstable liver disease, cirrhosis or any known biliary abnormalities (except Gilbert’s syndrome or asymptomatic gallstones); severe or clinically significant cardiovascular disease not controlled with standard therapy. and other clinically significant diseases not associated with EGPA and not controlled with standard therapy. Chronic or ongoing active infectious disease which required systemic treatment. Parasitic infection within 6 months before screening . Chronic hepatitis B according to the study definitions, but participants HBsAb positive, only (i.e. negative for HBsAg and HBcAb) with a history of hepatitis B vaccination can be included. Known HIV infection. Known allergy or intolerance to a monoclonal antibody or biologic therapy. Mepolizumab within a year before screening . Receiving prohibited treatment: CS 4 weeks prior to baseline (oral dose of >50 mg/day prednisolone/prednisone or any dose IV or subcutaneous CS); Omalizumab within 130 days before screening; CYC (oral within 2 weeks before baseline, IV within 3 weeks before baseline, if total white blood cell count is at least 4x109/L); rituximab within 12 months before screening and recovery of peripheral B‐cell count to within the normal range; immunoglobulin (IV or SC within 6 months before screening); interferon‐α within 6 months before screening; anti–tumour necrosis factor agent within 12 weeks before screening; anti‐CD52 (alemtuzumab) within 6 months before screening. Creatinine above 2.5 mg/dL (221 μmol/L), White blood cell count below 4 x109/L, Platelet count below 120,000/mm3, Hemoglobin below 8 g/dL (< 80 g/L). Pregnant or breastfeeding or plan to become pregnant during the time of trial. Alcohol or substance abuse within 2 years before screening. Treatment with an investigational drug within the past 30 days or five terminal phase half‐lives of the drug before screening. Current participation in any other interventional clinical study. French participant ‐ had participated in any study using an investigational drug during the previous 30 days or 5 half‐lives. Total number of participants: 136 participants randomised, Mepolizumab group n = 68, Placebo group n = 68 Characteristics: Mean age: Mepolizumab 49 ± 12 Placebo 48 ± 14 Female sex: Mepolizumab 42 (62%); Placebo 38 (56%) BMI mean (SD): Mepolizumab 27.5 (4.4); Placebo 28.2 (5.7) CrCl value: not reported Disease duration (time since diagnosis; mean (SD)): Mepolizumab 5.2 (4.4) years; Placebo 5.9 (4.9) years Age at onset of symptoms: not reported Race/ethnic group (%): Mepolizumab white 89.7% other 10.3% Placebo white 94.1% other 5.9% Disease diagnosed at enrolment to the study: not reported Disease assessment BVAS > 0 Mepolizumab 37 (54%) Placebo 48 (71%) VDI mean (SD): Mepolizumab 4.7 (3.4) Placebo 4.4 (2.8) Global assessment: NR Quality of life assessment: NR Disease severity (limited /severe): NR Organ Involvement n (%): Mepolizumab Asthma and eosinophilia 68 (100%), Neuropathy (mono or poly) 32 (47%), Pulmonary infiltrates (non‐fixed) 50 (74%), sinonasal abnormality 64 (94%), cardiomyopathy 13 (19%), glomerulonephritis 1 (1%), alveolar haemorrhage 3 (4%), palpable purpura 9 (13%), biopsy evidence 25 (37%) Placebo Asthma and eosinophilia 68 (100%), Neuropathy (mono or poly) 24 (35%), Pulmonary infiltrates (non fixed) 48 (71%), sinonasal abnormality 64 (94%), cardiomyopathy 7 (10%), glomerulonephritis 0 (0%), alveolar haemorrhage 1 (1%), palpable purpura 8 (12%), biopsy evidence 31 (46%) Prior treatment: Mepolizumab: Prednisolone or prednisone dose — mg/day median (range) 12 (7.5‐40) Immunosuppressive therapy at baseline 41 (60%) Placebo: Prednisolone or prednisone dose — mg/day median 11 (7.5‐50) Immunosuppressive therapy at baseline number (%): 31 (46%) Patients with ANCA laboratory results number (%): Mepolizumab: ANCA positive (MPO or PR3) 13 (19) Placebo: ANCA positive (MPO or PR3) 13 (19)
Interventions	Mepolizumab group: mepolizumab 300 mg ‐ 3 separate injections (100 mg each) every 4 weeks, in addition to standard care for 52 weeks. Placebo group: subcutaneously, placebo 0.9% sodium chloride 300 mg every 4 weeks, in addition to standard care for 52 weeks Description of treatment and concomitant treatment: Participants taking glucocorticosteroids during treatment period: Mepolizumab: Prednisone 47 (69%) Prednisolone 22 (32%) Methylprednisolone sodium succinate 6 (9%) Methylprednisolone 4 (6%) Dexamethasone 1 (1%) Hydrocortisone sodium succinate 1 (1%) Hydrocortisone 1 (1%) Triamcinolone acetonide 1 (1%) Placebo: Prednisone 49 (72%) Prednisolone 22 (32%) Methylprednisolone sodium succinate 4 (6%) Methylprednisolone 4 (6%) Dexamethasone 3 (4%) Hydrocortisone sodium succinate 2 (3%) Triamcinolone 1 (1%)
Outcomes	Major outcomes: The total accrued weeks of remission ‐ the proportions of participants who had remission for a certain period of time, i.e. 0 weeks, > 0 weeks but < 12 weeks, >= 12 weeks but < 24 weeks, >= 24 weeks but <36 weeks, >= 36 weeks. The accrued number of weeks where BVAS = 0 (scale from 0 to 63) and the dose of prednisolone/prednisone below 4 mg/day over the 52 week study treatment period Remission at both week 36 and week 48 ‐ the proportion of participants who were in remission (i.e., BVAS=0 and prednisolone/prednisone dose below 4 mg/day) at both weeks 36 and 48 of the study treatment period.. Minor outcomes: Remission within the first 24 weeks and continued to have remission until week 52 (proportion of participants). Remission defined as BVAS = 0 and prednisolone/prednisone dose ≤ 4 mg/day. The time to first confirmed relapse of EGPA ‐ relapse was defined as any of the following categories: active vasculitis (BVAS > 0), active asthma symptoms or signs and worsening in the score on the Asthma Control Questionnaire (ACQ‐6; range, 0 to 6 points,with higher scores indicating worse disease control; minimal clinically important difference, 0.5 points), or active nasal or sinus disease and worsening in at least one of the sinonasal‐symptom items which lead to an increase in the glucocorticoid dose to more than 4.0 mg /day of prednisolone (or equivalent), an initiation of or increase in immunosuppressive therapy, or hospitalisation. The proportion of participants with an average daily prednisolone/prednisone dose during the last 4 weeks of the treatment period within the study (week 48 through 52). The following categories were used: zero, > 0 to ≤ 4.0 mg, > 4.0 to ≤ 7.5 mg, > 7.5 mg. Total accrued weeks of remission over the 52‐week period ‐ number of participants in each category of remission duration. Less stringent definition of remission according to the European League against Rheumatism (EULAR) recommendations for clinical studies in systemic vasculitis was used: a BVAS of 0 and a prednisolone or prednisone dose <= 7.5 mg /day. Remission at both week 36 and week 48 and remission within the first 24 weeks and continued to have remission until week 52 with less stringent EULAR definition of remission. AEs ‐ Number of participants with local and systemic AEs. An AE is any untoward medical occurrence in a participant of clinical investigation, which is temporally associated with the use of a medicinal product, regardless if considered or not to be related to the medicinal product. AEs which included systemic allergic and non‐allergic reactions and local site injection‐related reactions were counted throughout the study. Other outcomes: Total duration of sustained remission, i.e., longest period of uninterrupted remission, i.e. BVAS=0 and prednisolone/prednisone ≤ 4 mg/day over the 52 week study treatment period, reported as proportion of participants achieving sustained remission in the following categories: Zero, > 0 to < 12 weeks, >=12 to < 24 weeks, >=24 to < 36 weeks, ≥ 36 weeks.
Notes	Discontinuation: 14 (10.29%) participants (9 participants from placebo group and 9 participant from mepolizumab group): 2 (1.47%) due to AEs, 3 (2.21%) lack of efficacy, 3 (2.21%) met protocol‐defined stopping criteria, 1 (0.74%) physician decision, 5 (3.68%) withdrawal from the trial. Funding: Supported by grants from GlaxoSmithKline (115921) and the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (U01AI097073), and by the Division of Intramural Research, NIAID, National Institutes of Health. Ongoing study: Mepolizumab Long‐term Access Programme for Subjects who Participated in Study MEA115921. Placebo‐controlled Study of Mepolizumab in the Treatment of Eosinophilic Granulomatosis with Polyangiitis in Subjects Receiving Standard‐of‐care Therapy (ID: MEA116841, ClinicalTrials.gov Identifier: NCT03298061). A Phase III, multi‐centre, multinational, non‐randomised, open with one arm: mepolizumab 100mg SC. Estimated Primary Completion Date: September 7, 2018 (Final data collection date for major outcome measure) Authors contacted for the data reported only on the graphs and not usable for the reporting in the systematic review ‐ information that the results will be posted on clinicaltrials.gov, but not posted yet.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Randomization was performed with the use of a centralized computer–generated, permuted‐block schedule, stratified according to three subgroups: participation in a mechanistic–biomarker substudy in the United States, recruitment in Japan, and the remainder of recruited participants."
Allocation concealment (selection bias)	Low risk	"The randomization schedule was generated using the GSK validated randomization software RandAll. Equal numbers of subjects were allocated to each treatment."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"The randomization schedule was sent as a signed, hard copy, controlled document, marked as private, for the attention of the unblinded qualified designee at each centre or sent as a GSK Secure email to the attention of the unblinded qualified designee. Clinicians who were treating and evaluating patients were unaware of the preparation of the trial agents, the trial‐group assignments, and the white‐cell counts and white‐cell differential counts for the duration of the trial."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"Procedures must be in place to ensure the blind is maintained by any site staff involved in administration of the drug or clinical care or assessment of the subject, and by the subject themselves."
Incomplete outcome data (attrition bias) All outcomes	Low risk	ITT was performed and all patients were included in primary analysis, no missing outcome data identified.
Selective reporting (reporting bias)	High risk	Not all of the study’s pre‐specified major outcomes have been reported in the publication such as SF‐36 score or WPAI index. ACQ‐6 and SNOT‐22 score were shown on Figures (and read from them).
Other bias	Low risk	No other biases was identified.