Elsevier

The Lancet

Volume 384, Issue 9950, 4–10 October 2014, Pages 1273-1281
The Lancet

Articles
Rituximab for childhood-onset, complicated, frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome: a multicentre, double-blind, randomised, placebo-controlled trial

https://doi.org/10.1016/S0140-6736(14)60541-9Get rights and content

Summary

Background

Rituximab could be an effective treatment for childhood-onset, complicated, frequently relapsing nephrotic syndrome (FRNS) and steroid-dependent nephrotic syndrome (SDNS). We investigated the efficacy and safety of rituximab in patients with high disease activity.

Methods

We did a multicentre, double-blind, randomised, placebo-controlled trial at nine centres in Japan. We screened patients aged 2 years or older experiencing a relapse of FRNS or SDNS, which had originally been diagnosed as nephrotic syndrome when aged 1–18 years. Patients with complicated FRNS or SDNS who met all other criteria were eligible for inclusion after remission of the relapse at screening. We used a computer-generated sequence to randomly assign patients (1:1) to receive rituximab (375 mg/m2) or placebo once weekly for 4 weeks, with age, institution, treatment history, and the intervals between the previous three relapses as adjustment factors. Patients, guardians, caregivers, physicians, and individuals assessing outcomes were masked to assignments. All patients received standard steroid treatment for the relapse at screening and stopped taking immunosuppressive agents by 169 days after randomisation. Patients were followed up for 1 year. The primary endpoint was the relapse-free period. Safety endpoints were frequency and severity of adverse events. Patients who received their assigned intervention were included in analyses. This trial is registered with the University Hospital Medical Information Network clinical trials registry, number UMIN000001405.

Findings

Patients were centrally registered between Nov 13, 2008, and May 19, 2010. Of 52 patients who underwent randomisation, 48 received the assigned intervention (24 were given rituximab and 24 placebo). The median relapse-free period was significantly longer in the rituximab group (267 days, 95% CI 223–374) than in the placebo group (101 days, 70–155; hazard ratio: 0·27, 0·14–0·53; p<0·0001). Ten patients (42%) in the rituximab group and six (25%) in the placebo group had at least one serious adverse event (p=0·36).

Interpretation

Rituximab is an effective and safe treatment for childhood-onset, complicated FRNS and SDNS.

Funding

Japanese Ministry of Health, Labour and Welfare.

Introduction

Childhood nephrotic syndrome is a disorder affecting the kidneys in which a large amount of protein passes through the glomerular filter, resulting in hypoproteinaemia and generalised oedema. Idiopathic nephrotic syndrome occurs in two or more of every 100 000 children1 and is the most common chronic glomerular disease in paediatric nephrology practice. Minimal change nephrotic syndrome is the most common form of the disorder, for which steroid therapy is effective for most patients.2 Those who respond well rarely progress to chronic renal failure, but up to half develop frequently relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS; table 1).2 Moreover, 10–20% of patients with idiopathic nephrotic syndrome have steroid-resistant nephrotic syndrome (table 1).2

Standard treatments for FRNS, SDNS, and steroid-resistant nephrotic syndrome are immunosuppressive agents: cyclophosphamide, chlorambucil, ciclosporin, tacrolimus, and levamisole are used for paediatric FRNS or SDNS, and ciclosporin for paediatric steroid-resistant nephrotic syndrome.3, 4, 5 Most children are effectively treated with these drugs; however, some have frequent relapses. In two studies,6, 7 10–20% of children taking ciclosporin had frequent relapses, and in another study,8 about 30% of the patients with steroid-resistant nephrotic syndrome after ciclosporin had steroid-sensitive, frequent relapses after complete remission. In addition to being ineffective in some patients, ciclosporin can cause side-effects—the most common of which is chronic nephrotoxicity9, 10—suggesting that it should be discontinued within 24 months. However, discontinuation of ciclosporin almost always results in frequent relapses requiring long-term steroid treatment,11 which also poses a long-term risk to children. Therefore, a new treatment that does not involve steroids or immunosuppressive agents is urgently needed.

In the past 10 years, rituximab has had some success in complicated FRNS and SDNS,12, 13 and several research groups have done single-arm or short-term studies of this drug.14, 15, 16 The 2012 Kidney Disease: Improving Global Outcomes clinical practice guidelines17 introduced rituximab as a treatment option for childhood-onset, complicated FRNS and SDNS. However, the efficacy and safety of rituximab for complicated FRNS and SDNS are yet to be established.17 We aimed to assess the efficacy and safety of rituximab in patients with high disease activity.

Section snippets

Study design and participants

In a multicentre, double-blind, randomised, placebo-controlled trial, we enrolled patients at nine centres in Japan. Full eligibility criteria are listed in the appendix. Briefly, we screened patients aged 2 years or older experiencing a relapse of FRNS or SDNS, which had originally been diagnosed as nephrotic syndrome when aged 1–18 years (appendix). Patients with complicated FRNS or SDNS (table 1) who met all other criteria were eligible for inclusion after remission of the relapse they were

Results

Between Nov 13, 2008, and May 19, 2010, 52 patients were randomly assigned to rituximab or placebo. Follow-up ended on Nov 10, 2011. The preplanned interim analysis showed that rituximab was superior to placebo, after which the independent data and safety monitoring committee advised us to discontinue randomisation as specified in the protocol. Therefore, randomisation ended earlier than planned, on May 21, 2010.

52 patients underwent randomisation (figure 2). 48 patients received the assigned

Discussion

We have shown that the relapse-free period increases with rituximab in patients with childhood-onset, complicated FRNS and SDNS. Adverse events were generally mild and the frequency of serious adverse events did not differ significantly between groups. As far as we are aware, we are the first to show that rituximab is safe and effective for at least 1 year of treatment in a multicentre, double-blind, randomised, placebo-controlled trial (panel).

Patients with complicated FRNS or SDNS usually

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