From: Hallmark trials in ANCA-associated vasculitis (AAV) for the pediatric rheumatologist
Reference, Country | Study Design | Patient Selection | Induction | Experiment | Comparators | Primary Outcome | Results | Adverse Events |
---|---|---|---|---|---|---|---|---|
CYCAZAREM, Jayne et al., 2003, Europe | Open label RCT | Newly diagnosed GPA, MPA, renal-limited vasculitis (serum Cr < 500 μmol/L) | CYC PO and GC | AZA 2 mg/kg/day, tapered to 1.5 mg/kg/day at month 12, and discontinued at month 18 and Prednisolone 10 mg/day until month 12, tapered to 7.5 mg/day until month 18 | CYC PO 1.5 mg/kg/day until month 12 then AZA 1.5 mg/kg/day until month 18 and Prednisolone 10 mg/day until month 12, tapered to 7.5 mg/day until month 18 | Relapse rate (major and minor) | 15.5% in AZA, 13.7% in CYC (p 0.65) | - Severe AEs: 11% in AZA, 10% in CYC (p 0.94) |
Metzler et al., 2007, Germany | Open label RCT | Generalized GPA Serum Cr < 115 μmol/L | CYC PO and GC | LEF 100 mg for 3 days, followed by 20 mg/day until week 4 then 30 mg/day and Prednisolone 10 mg/day or below and tapered by 2.5 mg/month until 5 mg and by 1 mg/month thereafter | MTX PO 7.5 mg/week, gradually increased to 20 mg/week after week 8 and Prednisolone 10 mg/day or below and tapered by 2.5 mg/month until 5 mg and by 1 mg/month thereafter | Relapse rate (major and minor) | 23% in LEF, 46% in MTX (p 0.09) | - No difference of AEs in LEF and MTX - 15% in LEF were withdrawn: hypertension, leukopenia, peripheral neuropathy |
WEGENT, Pagnoux et al., 2008, France | Open label RCT | Newly diagnosed GPA or MPA with systemic involvement | CYC IV and GC | AZA 2 mg/kg/day for 12 months then withdraw over 3 months and Prednisolone 12.5 mg at 6 months and tapered to 5 mg/day at 18 months and discontinued at month 24 | MTX 0.3 mg/kg, increased every week to 25 mg/week for 12 months then withdraw over 3 months and Prednisolone 12.5 mg at 6 months and tapered to 5 mg/day at 18 months and discontinued at month 24 | AEs causing death or drug discontinuation | 11% in AZA, 19% in MTX (p 0.21) Death: 1 in MTX (hematotoxicity and sepsis) Relapse: 36% in AZA vs 33% in MTX (p 0.71) | - Any AEs: 46% in AZA, 56% in MTX (p 0.29) |
IMPROVE, Hiemstra et al., 2010, Europe | Open label RCT | Newly diagnosed GPA, MPA | CYC PO/IV and GC ± PLEX | MMF 2 g/day, reduced to 1.5 g/day after 12 months, 1 g/day after 18 months and discontinued after 42 months and Prednisolone until month 24 | AZA 2 mg/kg/day, reduced to 1.5 mg/kg after 12 months, 1 mg/kg after 18 months, and discontinued after 42 months and Prednisolone until month 24 | Relapse-free survival | 55% in MMF, 37.5% in AZA (p 0.03, HR 1.69) | - Severe AEs: 7.5% in MMF, 16% in AZA (p 0.12) - Death: 1 in MMF (fungal septicemia), 1 in AZA (sudden cardiac death) |
MAINRITSAN, Guillevin et al., 2014, France | Open label RCT | Newly diagnosed or relapsing GPA, MPA, renal-limited vasculitis | CYC IV and GC | RTX 500 mg at day 0, 14, month 6, 12, 18 Prednisone 5 mg/day for at least 18 months | AZA 2 mg/kg/day 12 months then 1.5 mg/kg 6 months, then 1 mg/kg 4 months Prednisone 5 mg/day for at least 18 months | Major relapse rate at 28 months | 5% in RTX, 29% in AZA (p 0.002, HR 6.61) Minor relapse: 11% in RTX, 16% in AZA (p 0.43) | - Severe AEs: no significant difference - Death: 2 in AZA (sepsis and pancreatic cancer) |
REMAIN, Karras et al., 2017, Europe | Open label RCT | GPA, MPA, renal-limited vasculitis | CYC and GC ± PLEX | Continuation group: AZA 1 mg/kg/day to end of study and prednisolone 5 mg/day for 12 months then tapered and discontinued by 24 months | Withdrawal group: AZA 0.75 mg/kg/day for 3 months and prednisolone 5 mg/day, tapered and discontinued by month 5 | Relapse rate (major and minor) by 30 months | 63% in withdrawal group, 22% in continuation group (p < 0.0001, RR 2.84) No difference of relapse severity | - Severe AEs: 15% in continuation group, 6% in withdrawal group (p 0.13) |
MAINRITSAN2, Charles et al., 2018, France | Open label RCT | Newly diagnosed or relapsing GPA, MPA | GC and CYC, RTX or MTX | Individually tailored: RTX 500 mg at randomization and then reinfused based on CD19+ B lymphocytes and ANCA titers until month 18 and low-dose prednisone | Fixed-schedule: RTX 500 mg at day 0, 14, month 6, 12, 18 and low-dose prednisone | Relapse rate at month 28 | 17.3% in individually tailored group, 9.9% in fixed-schedule group (p 0.22) | - Severe AEs: 32.1% in individually tailored group, 38.3% in fixed-schedule group (p 0.51) |
BREVAS, Jayne et al., 2019 | Double blind RCT | Newly diagnosed or relapsing GPA, MPA with ANCA positivity | GC and either CYC or RTX | Belimumab IV 10 mg/kg and AZA 2 mg/kg/day and low-dose GC (≤10 mg/day) | Placebo and AZA 2 mg/kg/day and low-dose GC (≤10 mg/day) | Time to first protocol-specified event (BVAS ≥6, presence of ≥1 major BVAS, or receipt of prohibited medications for any reason) | 18.9% in belimumab, 21.2% in control (p 0.89) | - Serious AEs: 34% in belimumab, 30.8% in placebo |