Table 4.

Major clinical trials for maintenance therapy in ANCA-associated vasculitis in chronological order

Trial Name (Yeara)	Key Inclusion/Exclusion Criteria	Intervention	Primary Outcome	Major Highlights of Trial
CYCAZAREM (2003) N=155	Inclusion: newly diagnosed GPA/MPA, SCr <5.7 mg/dl, attained remission with oral CYC and GC for at least 3 mo (n=144) Exclusion: cytotoxic drug use in prior 12 mo, SCr ≥5.7 mg/dl	144 patients entered remission Oral CYC (continued at 1.5 mg/kg per day) versus AZA (2 mg/kg per day) for total of 12 mo	Relapse at month 18	1. Long-term CYC had significant side effects 2. AZA suitable as a replacement for CYC 3. Relapse frequency similar at 18 mo  (10% [CYC] versus 11% [AZA]) 4. Similar frequency of SAEs 5. First study to show efficacy of  short-course oral CYC
WEGENT (2008) N=126	Inclusion: newly diagnosed GPA/MPA with remission after pulse CYC and GC	AZA (2 mg/kg per day) versus oral MTX (0.3 mg/kg per week with progressive increase to 25 mg/wk) for total of 12 mo	Adverse event causing discontinuation/death at 29 mo	1. Adverse events and SAEs similar between AZA and MTX (29/63 versus 35/63, P = 0.29; 5/63 versus 11/63, P=0.11, respectively) 2. Primary end point similar between AZA  and MTX (7/63 versus 12/63, P = 0.21) 3. Relapse frequency on AZA or MTX similar (23/63 versus 21/63, P = 0.71) 4. Most relapses occurred after AZA or MTX stopped (32/44)
IMPROVE (2010) N=156	Inclusion: newly diagnosed GPA/MPA and attained remission with oral CYC and GC Exclusion: cytotoxic drug use in prior 12 mo, failure to achieve remission after 6 mo CYC, or progressive disease	AZA: 2 mg/kg per day; reduced to 1.5 mg/kg per day after 12 mo, then to 1 mg/kg per day 18 mo; withdrawal at 42 mo MMF: 2000 mg/d; reduced to 1500 mg/d after 12 mo and 1000 mg/d after 18 mo; withdrawal at month 42	Relapse-free survival	1. AZA superior to MMF 2. Higher relapse frequency with MMF (42/76 MMF versus 30/80 AZA)
MAINRITSAN (2014) N=115	Inclusion: newly diagnosed or relapsing GPA/MPA with remission after pulse CYC and GC	RTX: 2×500 mg IV (14 d apart), then 500 mg IV at month 6, month 12, and month 18 (total 18 mo) AZA: 2 mg/kg per day for 12 mo, then 1.5 mg/kg per day for 6 mo, and then 1 mg/kg per day for 4 mo (total 22 mo)	Major relapse at month 28	1. RTX superior to AZA in remission maintenance: major relapses, 5% versus  29%; minor relapses, 11% versus 16% 2. SAEs similar (19% versus 14%), particularly in patients with PR3-ANCA patients
MAINRITSAN 2 (2018) N=162	Inclusion: newly diagnosed or relapsing GPA/MPA with remission after IV/oral CYC and GC, IV/oral MTX and GC, or RTX and GC	Fixed-dose RTX: 500 mg IV on day 0 and day 14 and at month 6, month 12, and month 18 (total 18 mo) Tailored-dose RTX: 500 mg IV at randomization; peripheral B cells and ANCA serologies measured every 3 mo, further RTX administered if CD19 count >0, ANCA-positive serology reappeared, or ANCA titer doubled from baseline (total 18 mo)	Major relapse at month 28	1. Large trial comparing two RTX regimens;  tailored dose noninferior to fixed dose 2. Relapse in 14/81 patients (major relapse=6) with tailored dose versus 8/81 (major relapse=3) with fixed dose (17.3% versus 9.9%) 3. Fewer SAEs with tailored dose versus fixed dose (37/81 versus 53/81) 4. Fewer infusions and lower cumulative dose with tailored dose
BREVAS (2019) N=105	Inclusion: newly diagnosed or relapsing GPA/MPA with remission after IV/oral CYC and GC or RTX and GC	AZA (2 mg/kg per day)+oral prednisone (≤10 mg/d)+either  1. IV belimumab 10 mg IV on day 0, day 14, day 28, and then every 28 d until study completion or relapse  2. IV placebo on day 0, day 14, day 28, and then every 28 d until study completion or relapse	I. Time to first PSE  1. BVAS ≥6  2. ≥1 major BVAS item  3. Additional IS use  4. Treatment failure II. Vasculitis relapse	1. Belimumab did not reduce risk of PSE  compared with placebo (HR, 1.07;  95% CI, 0.44 to 2.59; P = 0.884) 2. Belimumab did not reduce vasculitis  relapse compared with placebo (HR,  0.88; 95% CI, 0.29 to 2.65; P = 0.821) 3. All vasculitis relapses in belimumab group  (N=6) occurred in PR3-ANCA patients  with CYC induction 4. Vasculitis relapse in the placebo group  (N=8) occurred independent of  induction agent, disease stage, or  ANCA type 5. Overall frequency of PSEs low (18.9%  in belimumab group versus 21.2%  in placebo group)
MAINRITSAN 3 (2020) N=97	Inclusion: patients with GPA/MPA in sustained remission after completing MAINRITSAN 2	Randomization at month 28  1. RTX arm: 500 mg at month 0, month 6, month 12, and month 18 (total 18 mo)  2. Placebo infusion at month 0, month 6, month 12, and month 18 (total 18 mo)	Relapse-free survival at month 28	1. RTX given after long-term remission  (28 mo) superior to no further  maintenance therapy 2. Relapse-free survival (RTX versus  placebo): 96% versus 74%, major  relapse-free survival (RTX versus  placebo): 100% versus 87% 3. SAEs (RTX versus placebo): 24%  versus 30%
RITAZAREM (2023) N=188	Inclusion: relapsed GPA/MPA after re-induction with RTX and GC Exclusion: B-cell depleting agent in prior 6 mo or biologic in prior 3 mo	RTX: 1000 mg IV every 4 mo×5 doses (total 20 mo) AZA: 2 mg/kg per day, tapered after month 24 (total up to 27 mo)	Time to relapse	1. RTX superior to AZA in patients with  relapsing disease (HR, 0.41, P < 0.0001) 2. Fewer SAEs with RTX (19/85 [22%]  versus 31/85 [36%]) 3. Frequency of hypogammaglobulinemia  did not differ by treatment

AZA, azathioprine; BVAS, Birmingham Vasculitis Activity Score; CI, confidence interval; CYC, cyclophosphamide; GC, glucocorticoids; GPA, granulomatosis with polyangiitis; HR, hazard ratio; IS, immunosuppressant; IV, intravenous; MMF, mycophenolate mofetil; MPA, microscopic polyangiitis; MTX, methotrexate; PR3, proteinase 3; PSE, protocol-specified event; RTX, rituximab; SAE, serious adverse event; SCr, serum creatinine concentration.

^aYear of publication of report.