Overview
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).
Description
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
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)