Rituximab in Children with Steroid-Dependent Nephrotic Syndrome: A Multicenter, Open-Label, Noninferiority, Randomized Controlled Trial

Abstract

Steroid-dependent nephrotic syndrome (SDNS) carries a high risk of toxicity from steroids or steroid-sparing agents. This open-label, noninferiority, randomized controlled trial at four sites in Italy tested whether rituximab is noninferior to steroids in maintaining remission in juvenile SDNS. We enrolled children age 1-16 years who had developed SDNS in the previous 6-12 months and were maintained in remission with high prednisone doses (≥0.7 mg/kg per day). We randomly assigned participants to continue prednisone alone for 1 month (control) or to add a single intravenous infusion of rituximab (375 mg/m(2); intervention). Prednisone was tapered in both groups after 1 month. For noninferiority, rituximab had to permit steroid withdrawal and maintain 3-month proteinuria (mg/m(2) per day) within a prespecified noninferiority margin of three times the levels among controls (primary outcome). We followed participants for ≥1 year to compare risk of relapse (secondary outcome). Fifteen children per group (21 boys; mean age, 7 years [range, 2.6-13.5 years]) were enrolled and followed for ≤60 months (median, 22 months). Three-month proteinuria was 42% lower in the rituximab group (geometric mean ratio, 0.58; 95% confidence interval, 0.18 to 1.95 [i.e., within the noninferiority margin of three times the levels in controls]). All but one child in the control group relapsed within 6 months; median time to relapse in the rituximab group was 18 months (95% confidence interval, 9 to 32 months). In the rituximab group, nausea and skin rash during infusion were common; transient acute arthritis occurred in one child. In conclusion, rituximab was noninferior to steroids for the treatment of juvenile SDNS.

Keywords: nephrotic syndrome; primary glomerulonephritis; randomized controlled trials.

Figure 1.

Study design.

Figure 2.

Flowchart. The parents of one participant in the treatment group withdrew consent immediately after randomization. All remaining participants remained in the study for at least 1 year. *Intention-to-treat principle.

Figure 3.

Graphical representation of the analysis of covariance model. The effect of rituximab is measured as ratio of geometric means of proteinuria at 3 months (0.58; 95% CI, 0.18 to 1.95). The upper limit of the CI (1.95) is smaller than the prespecified noninferiority margin of 3, corresponding to a 200% increment in proteinuria compared with the control group. For results of this analysis see Table 2.

Figure 4.

Proportion of children with proteinuria >500 mg/m² per day (top), receiving prednisone (middle) or steroid-sparing agents (bottom) by treatment group. Light gray indicates rituximab group; dark gray indicates control group.

Figure 5.

One-year relapse-free survival by treatment group in the prednisone (control; dark gray) and rituximab (intervention; light gray) groups. The risk of relapse was reduced by 98% in children treated with rituximab (hazard ratio, 0.02; 95% CI, 0.01 to 0.15). C, comparator group; I, intervention group; R, randomization.