Table 2 Induction Trials in AAV
From: Hallmark trials in ANCA-associated vasculitis (AAV) for the pediatric rheumatologist
Reference, Country | Study Design | Patient Selection | Experiment | Comparators | Primary Outcome | Results | Adverse Events |
|---|---|---|---|---|---|---|---|
NORAM, Groot et al., 2005, Germany | Unblinded, prospective RCT | GPA or MPA limited/non-severe disease | MTX PO 15 mg/week escalated to a maximum of 20–25 mg/week by 12 weeks, until month 10, then tapered and discontinued by month 12 Prednisone 1 mg/kg/day, tapered to 7.5 mg by 6 months, discontinued by 12 months | CYC PO 2 mg/kg/day (maximum 150 mg/day) × 3–6 months until remission then 1.5 mg/kg to month 10, then tapered and discontinued by month 12 Prednisone 1 mg/kg/day, tapered to 7.5 mg by 6 months, discontinued by 12 months | Remission within 6 months | MTX (89.8%) CYC (93.5%) | 83 patients: adverse events 68 patients: mild/moderate infection 15 patients: severe infection MTX: liver toxicity (p 0.036) CYC: leukopenia (p 0.012) |
MEPEX, Jayne et al., 2007, Europe | RCT | GPA, MPA with severe renal vasculitis | PLEX 60 ml/kg for 7 cycles within 14 days CYC PO 2.5 mg/kg/day, reduced to 1.5 mg/kg/day at 3 months and discontinued at 6 months Prednisone 1 mg/kg/day tapered until 10 mg/day from 5 to 12 months | Pulse GC 1 g for 3 days CYC PO 2.5 mg/kg/day, reduced to 1.5 mg/kg/day at 3 months and discontinued at 6 months Prednisone 1 mg/kg/day tapered until 10 mg/day from 5 to 12 months | Renal recovery at 3 months | PLEX 69% IV GC 49% | No difference between 2 groups PLEX: 50% Pulse GC: 48% |
CYCLOPS, Groot et al., 2009, Europe | Open label RCT | GPA, MPA, renal limited MPA (GFR < 500) | CYC IV pulses 15 mg/kg, given 2 weeks apart, followed by pulses at 3-week interval until remission, and then for 3 months Prednisone 1 mg/kg/day tapered to 12.5 mg by 3 months then 5 mg at 18 months | CYC PO 2 mg/kg/day until remission, followed by 1.5 mg/kg/day for 3 months Prednisone 1 mg/kg/day tapered to 12.5 mg by 3 months then 5 mg at 18 months | Time to remission | 87.9% achieved remission by 9 months (no difference between the two groups, 88% in the IV group, 87.7% in the PO group) Relapses: CYC IV: 13 patients CYC PO: 6 patients CYC IV: lower cumulative dose (p 0.001) | IV group: less leukopenia (26% vs 45%) Death: CYC IV: 5 patients CYC PO: 9 patients No difference in the rate of life threatening events |
RITUXVAS, Jones et al., 2010, Europe/Australia | Open label RCT | Newly diagnosed AAV with evidence of renal involvement | RTX, 375 mg/m2 weekly for 4 weeks plus CYC IV 15 mg/kg with 1st and 3rd dose Pulse GC 1 g, followed by prednisone 1 mg/kg/day, tapered to 5 mg by 6 months | CYC IV 15 mg/kg every 2 weeks for the first 3 doses then every 3 weeks, until remission (3–6 months) then AZA 2 mg/kg to end of study (12 months) prednisone 1 mg/kg/day, tapered to 5 mg by 6 months | Sustained remission at 12 months Time to remission | RTX was not superior to CYC. Sustained remission: RTX: 76% CYC: 82% Median time of remission: RTX: 90 days CYC: 94 days | Similar rate of adverse events RTX: 42% CYC: 36% Similar death rate in both groups: 18% |
RAVE, Stone et al., 2010, USA | Double blinded RCT | Severe AAV (period of 6 months) | RTX 375 mg/m2 weekly for 4 weeks then placebo AZA for 18 months Pulse GC 1 g for 1–3 doses followed by prednisone 1 mg/kg/day, discontinued by 5 months | CYC PO 2 mg/kg/day until remission (3–6 months) then AZA for 18 months Pulse GC 1 g for 1–3 doses followed by prednisone 1 mg/kg/day, discontinued by 5 months | Disease remission off steroids by 5 months | RTX was not inferior to CYC. RTX regimen was superior to CYC in inducing remission in previously relapsing disease | No difference in the number of adverse events CYC higher rate for leukopenia (10% vs 3%) |
MYCYC, Jones et al., 2019, UK | Open label RCT | Newly diagnosed AAV, non- life threatening | MMF 2–3 g (BSA dose for patients < 17 years old) Prednisone 1 mg/kg/day tapered to 5 mg by 6 months | CYC IV 15 mg/kg, given 2 weeks apart, followed by pulses at 3-week intervals until remission, and then for 3 months Prednisone 1 mg/kg/day tapered to 5 mg by 6 months | Remission by 6 months | MMF (67%) was not inferior to IV CYC (61%). Relapse rate higher in MMF (33%) vs IV CYC (19%) | No significant difference in serious adverse events between two groups MMF (50%) IVCYC (40%) |