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Short-term effects of rituximab in children with steroid- and calcineurin-dependent nephrotic syndrome: a randomized controlled trial.

ABSTRACT: BACKGROUND AND OBJECTIVES: Prednisone and calcineurin inhibitors are the mainstay therapy of idiopathic nephrotic syndrome (INS) in children. However, drug dependence and toxicity associated with protracted use are common. Case series suggest that the anti-CD20 monoclonal antibody rituximab (RTX) may maintain disease remission. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This open-label randomized controlled trial was powered to show that a strategy based on RTX and lower doses of prednisone and calcineurin inhibitors was noninferior to standard doses of these agents in maintaining 3-month proteinuria as low as baseline or up to 1 g/d greater (noninferiority margin). Participants were stratified by the presence of toxicity to prednisone/calcineurin inhibitors and centrally assigned to add RTX (Mabthera, 375 mg/m(2) intravenously) to lower doses of standard agents or to continue with current therapy alone. The risk of relapse was a secondary outcome. RESULTS: Fifty-four children (mean age 11 ± 4 years) with INS dependent on prednisone and calcineurin inhibitors for >12 months were randomized. Three-month proteinuria was 70% lower in the RTX arm (95% confidence interval 35% to 86%) as compared with standard therapy arm (intention-to-treat); relapse rates were 18.5% (intervention) and 48.1% (standard arm) (P = 0.029). Probabilities of being drug-free at 3 months were 62.9% and 3.7%, respectively (P < 0.001); 50% of RTX cases were in stable remission without drugs after 9 months. CONCLUSIONS: Rituximab and lower doses of prednisone and calcineurin inhibitors are noninferior to standard therapy in maintaining short-term remission in children with INS dependent on both drugs and allow their temporary withdrawal.

SUBMITTER: Ravani P

PROVIDER: S-EPMC3109926 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Short-term effects of rituximab in children with steroid- and calcineurin-dependent nephrotic syndrome: a randomized controlled trial.

Ravani Pietro P Magnasco Alberto A Edefonti Alberto A Murer Luisa L Rossi Rossella R Ghio Luciana L Benetti Elisa E Scozzola Floriana F Pasini Andrea A Dallera Nadia N Sica Felice F Belingheri Mirco M Scolari Francesco F Ghiggeri Gian Marco GM

Clinical journal of the American Society of Nephrology : CJASN 20110512 6

<h4>Background and objectives</h4>Prednisone and calcineurin inhibitors are the mainstay therapy of idiopathic nephrotic syndrome (INS) in children. However, drug dependence and toxicity associated with protracted use are common. Case series suggest that the anti-CD20 monoclonal antibody rituximab (RTX) may maintain disease remission.<h4>Design, setting, participants, & measurements</h4>This open-label randomized controlled trial was powered to show that a strategy based on RTX and lower doses o ...[more]

PMID: 21566104

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Project description:IntroductionOral steroids induce remission in about 90% of children with idiopathic nephrotic syndrome (INS), which is characterised by severe proteinuria and hypoalbuminaemia. Some children become steroid-dependent (SD) and require addition of calcineurin inhibitors (CNI) to maintain remission. Since these oral agents are toxic, alternative interventions are needed for long-term treatment. The anti-CD20 antibody rituximab has shown promising steroid-sparing properties in clinical trials, but benefits are less convincing in complicated forms of SD-INS. Ofatumumab, a new anti-CD20 antibody with stronger affinity to CD20, may be superior to rituximab in maintaining oral steroid-free and CNI-free disease remission in children with SD-INS.Methods and analysisThis open-label, two-parallel-arm, controlled, phase II randomised clinical trial will enrol children with SD-INS maintained in remission with oral steroids and CNI. Children will be randomised to either ofatumumab or rituximab infusion. After infusion of either antibody, steroids will be maintained for 30 days and then tapered off by 0.3 mg/kg/week until complete withdrawal. 1 week after complete steroid withdrawal, CNI will be decreased by 50% and withdrawn within 2 additional weeks. We will enrol 140 children to detect as significant at the 2-sided p value of 0.01 with a power of >0.8, a reduction in the risk of 1-year relapse (primary end point) of at least 0.3 (ie, from 0.65 to 0.35; (risk ratio 0.54)) in the ofatumumab arm when compared with the rituximab arm. We will compare the amount of steroids required to maintain complete disease remission at 6 and 24 months, relapse-free period, relapse rate per year as secondary end points. Circulating cell populations will be studied as biomarkers or predictors of the anti-CD20 response.Ethics and disseminationThe trial received ethics approval from the local ethics board. We will publish study results and present them at international scientific meetings.Trial registration numbersNCT02394119; 2015-000624-28; Pre-results.

Dataset Information

Short-term effects of rituximab in children with steroid- and calcineurin-dependent nephrotic syndrome: a randomized controlled trial.

Publications

Short-term effects of rituximab in children with steroid- and calcineurin-dependent nephrotic syndrome: a randomized controlled trial.

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