Rituximab or Cyclophosphamide in the Treatment of Membranous Nephropathy: The RI-CYCLO Randomized Trial

Abstract

Background: A cyclic corticosteroid-cyclophosphamide regimen is the first-line therapy for membranous nephropathy. Compared with this regimen, rituximab therapy might have a more favorable safety profile, but a head-to-head comparison is lacking.

Methods: We randomly assigned 74 adults with membranous nephropathy and proteinuria >3.5 g/d to rituximab (1 g) on days 1 and 15, or a 6-month cyclic regimen with corticosteroids alternated with cyclophosphamide every other month. The primary outcome was complete remission of proteinuria at 12 months. Other outcomes included determination of complete or partial remission at 24 months and occurrence of adverse events.

Results: At 12 months, six of 37 patients (16%) randomized to rituximab and 12 of 37 patients (32%) randomized to the cyclic regimen experienced complete remission (odds ratio [OR], 0.4; 95% CI, 0.13 to 1.23); 23 of 37 (62%) receiving rituximab and 27 of 37 (73%) receiving the cyclic regimen had complete or partial remission (OR, 0.61; 95% CI, 0.23 to 1.63). At 24 months, the probabilities of complete and of complete or partial remission with rituximab were 0.42 (95% CI, 0.26 to 0.62) and 0.83 (95% CI, 0.65 to 0.95), respectively, and 0.43 (95% CI, 0.28 to 0.61) and 0.82 (95% CI, 0.68 to 0.93), respectively, with the cyclic regimen. Serious adverse events occurred in 19% of patients receiving rituximab and in 14% receiving the cyclic regimen.

Conclusions: This pilot trial found no signal of more benefit or less harm associated with rituximab versus a cyclic corticosteroid-cyclophosphamide regimen in the treatment of membranous nephropathy. A head-to-head, pragmatic comparison of the cyclic regimen versus rituximab may require a global noninferiority trial.

Clinical trial registry name and registration number: Rituximab versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy (RI-CYCLO), NCT03018535.

Keywords: glomerulonephritis; membranous nephropathy; nephrotic syndrome.

Graphical abstract

Figure 1.

CONSORT diagram. Patients were randomly assigned, in a 1:1 ratio, to receive cyclic regimen or rituximab. One patient who was assigned to the rituximab group was diagnosed with sarcoidosis-associated MN after randomization. Premature discontinuation occurred in four patients in the rituximab arm, and in one patient in the cyclic-regimen arm. The remaining patients received the complete intervention: 32 in the rituximab arm and 36 in the cyclic-regimen arm. During the follow-up of patients in the rituximab arm, one was switched to a nonstudy intervention (cyclosporine) because of no response, another patient reached ESKD.

Figure 2.

Kaplan–Meier estimates of complete or composite remission. Kaplan–Meier estimates of (A) complete remission and (B) composite remission (complete or partial) in the cyclic-regimen and rituximab arms.

Figure 3.

Proteinuria and serum albumin over time. Data are presented as median (IQR) over time, by assigned treatment.