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Table 3 Maintenance Trials in AAV

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- 15% in LEF were withdrawn: hypertension, leukopenia, peripheral neuropathy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

  1. RCT Randomized Controlled Trial, GPA Granulomatosis with Polyangiitis, MPA Microscopic Polyangiitis, Cr creatinine, CYC Cyclophosphamide, PO oral, GC Glucocorticoids, AZA Azathioprine, AE Adverse event, LEF Leflunomide, MTX Methotrexate, IV intravenous, PLEX Plasma exchange, MMF Mycophenolate mofetil, HR Hazard ratio, RTX Rituximab, ANCA Anti-neutrophil cytoplasmic antibody, BVAS Birmingham Vasculitis Activity Score