efficacy and safety of obinutuzumab versus rituximab in childhood steroid dependant and frequent relapsing nephrotic syndrome

Conditions: Steroid-Dependent Nephrotic Syndrome; Steroid-Sensitive Nephrotic Syndrome

Summary: b-cell depletion with rituximab induces sustained remission in children with steroid-dependent or frequent relapsing nephrotic syndrome (sd/frns). however, most patients relapse after b-cell recovery and some do not achieve b-cell depletion. obinutuzumab is a 2nd generation humanized monoclonal anticd20 antibody, with enhanced b cell-depleting potential. it has been reported safe and efficient in different renal autoimmune diseases including childhood nephrotic syndrome. this double-blind, randomized multicenter study is designed to assess the efficacy and safety of a single infusion of low-dose obinutuzumab compared to a single infusion of rituximab in children with frequently relapsing nephrotic syndrome (frns) or steroid-dependent nephrotic syndrome (sdns).

idiopathic nephrotic syndrome (ins) is the most frequent acquired glomerulopathy in children. the initial treatment relies on steroids, which enables remission of proteinuria in 90% of children. however, 80 % of steroid-sensitive patients will relapse, and 2/3 will become steroid-dependant with a long lasting disease over years. in this situation, immunosuppressive drugs are added as steroid-sparing agents. there is no international consensus on the second line treatment strategy after initial steroid therapy. rct have demonstrated the efficacy of rituximab (rtx) to maintain remission in fr/sdns after oral treatments withdrawal, however most patients relapse within 2 years, and some patients are resistant or allergic to rituximab. obinutuzumab (obi) is a second generation anticd20 mab, that has been designed to overcome rituximab resistance in b-cell malignancies. additional mechanisms of rituximab failure support the hypothesis that b-cell depletion could be optimized with obi in autoimmune diseases. obi has met its primary endpoint in lupus nephritis and a few randomized controlled trials are currently ongoing in nephrology for lupus nephritis and membranous nephropathy. we believe that a single infusion of obi could reduce the risk of subsequent relapse in fr/sdns and the cumulative exposure to immunosuppressive drugs.

Eligibility criteria:
inclusion criteria: * age between 3 and 18 years * steroid dependant nephrotic syndrome defined as: * 2 or more relapses during steroids or within 2 weeks following discontinuation. * 2 or more relapses including one under steroid-sparing agent (mmf, calcineurin inhibitors, cyclophosphamide, levamisole) or within 6 months following treatment withdrawal or frequent relapsing nephrotic syndrome defined as: * 2 or more relapses within 6 months following first remission * 3 or more relapses within any 12-month period * last relapse within 3 months prior to inclusion * in remission, defined as 3 consecutive urinary dipsticks without proteinuria, at the time of randomization * vaccination schedule in accordance with the current recommendations in france * informed consent from parents exclusion criteria: * secondary cause of nephrotic syndrome (such as membranous nephropathy, iga nephropathy, lupus nephritis) * primary or secondary steroid resistance nephrotic syndrome * prior treatment with rituximab within 6 months * prior treatment with obinutuzumab at any time * cd20+ b-cell count \< 2.5% * patient with neutrophils \< 1.5 g/l and/or platelets \< 75 g/l * gfr \< 80 ml/min/1.73m2 * weight \<16kg * history of severe infection such as tuberculosis, hepatitis b, hepatitis c or hiv infection or lemp * history of malignancy- uncontrolled infection (viral, bacterial and fungal) * vaccination with a live vaccine within 4 weeks prior to assignment/randomization * known hyperprolinemia * hypersensitivity to the active substance (obi or rtx) or to proteins of murine origin, or to any of the other excipients * pregnancy or breastfeeding or ability to become pregnant and refusal to use effective contraception during the 18 months following the study treatment (only 1 infusion of obinutuzumab/rituximab at the beginning of the study) * patient without medical insurance coverage (beneficiary or legal)

Keywords: rituximab obinutuzumab anti-drug antibodies