Efficacy of rituximab versus tacrolimus in difficult-to-treat steroid-sensitive nephrotic syndrome: an open-label pilot randomized controlled trial

Abstract

Background: Rituximab and tacrolimus are therapies reserved for patients with frequently relapsing or steroid-dependent nephrotic syndrome who have failed conventional steroid-sparing agents. Given their toxicities, demonstrating non-inferiority of rituximab to tacrolimus may enable choice between these medications.

Methods: This investigator-initiated, single-center, open-label, pilot randomized controlled trial examined the non-inferiority of two doses of intravenous (IV) rituximab given one-week apart to oral therapy with tacrolimus (1:1 allocation), in maintaining sustained remission over 12 months follow-up, in patients with difficult-to-treat steroid-sensitive nephrotic syndrome, defined as frequently relapsing or steroid-dependent disease that had failed ≥ 2 steroid-sparing strategies. Secondary outcomes included frequency of relapses, proportion with frequent relapses, time to relapse and frequent relapses, and adverse events (CTRI/2018/11/016342).

Results: Baseline characteristics were comparable for 41 patients randomized to receive rituximab (n = 21) or tacrolimus (n = 20). While 55% of patients in each limb were in sustained remission at 1 year, non-inferiority of rituximab to tacrolimus was not demonstrated (mean difference 0%; 95% CI - 30.8%, 30.8%; non-inferiority limit - 20%; P = 0.50). Frequent relapses were more common in patients administered rituximab compared to tacrolimus (risk difference 30%, 95% CI 7.0, 53.0, P = 0.023). Both groups showed similar reductions in relapse rates and prednisolone use. Common adverse events were infusion-related with rituximab and gastrointestinal symptoms with tacrolimus.

Conclusions: Therapy with rituximab was not shown to be non-inferior to 12-months treatment with tacrolimus in maintaining remission in patients with difficult-to-treat steroid-sensitive nephrotic syndrome. Frequent relapses were more common with rituximab. While effective, both agents require close monitoring for adverse events. A higher resolution version of the Graphical abstract is available as Supplementary information.

Keywords: Children; Frequently relapsing nephrotic syndrome; Rituximab; Steroid dependence; Tacrolimus.

Fig. 1

Patient flow. Modified intention-to-treat population excluded one patient who did not return to receive IV rituximab after randomization. Per-protocol analysis excluded this patient and 5 patients with non-compliance to tacrolimus for > 3 weeks

Fig. 2

Proportions with sustained remission and treatment failure at 12 months. Point estimates and two-sided 95% confidence intervals (CI) are shown for the treatment effect, defined as the risk difference for each outcome between groups in the intention-to-treat analysis. The non-inferiority margin for rituximab as compared with tacrolimus was − 20 percentage points for the primary outcome. The lower end of the two-sided 95% CI of the risk difference in the primary outcome of sustained remission at 12 months was below – 20 percentage points; P value for non-inferiority of 0.50 did not meet the prespecified alpha level of P < 0.025. Per the statistical analysis plan, no test for non-inferiority was performed for the secondary outcomes of frequent relapses and treatment failure (composite of frequent relapses, late steroid resistance; CTCAE grade 4–5 adverse events related to intervention or corticosteroids; or occurrence of two or more serious adverse events related to disease or intervention) at 12 months

Fig. 3

Kaplan–Meier survival analysis for time to (a) first relapse and (b) treatment failure. (a) At 3, 6 and 9 and 12 months of follow-up, the proportions of patients in remission were similar for those receiving rituximab (100%, 85%, 65%, and 55%) and tacrolimus (85%, 80%, 70%, and 55%, respectively) (logrank P = 0.99). The median time to relapse could not be estimated. (b) The proportions of patients with treatment failure (frequent relapses, late steroid resistance; one CTCAE grade 4–5 adverse event or two or more serious adverse events related to disease or intervention) at 3, 6, and 9 months were similar in patients receiving rituximab (0%, 0%, and 10%, respectively) and tacrolimus (5% at each time point). However, compared to tacrolimus, a significantly higher proportion of patients treated with rituximab showed treatment failure at 12 months or end of study (35 versus 5%; logrank P = 0.026). The median time to treatment failure could not be estimated