Efficacy and Safety of Obinutuzumab Versus Rituximab in Childhood Steroid Dependant and Frequent Relapsing Nephrotic Syndrome

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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Efficacy and Safety of Obinutuzumab Versus Rituximab in Childhood Steroid Dependant and Frequent Relapsing Nephrotic Syndrome : a Double-blind Multicenter Randomized Controlled Study

Conditions
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Steroid-Dependent Nephrotic Syndrome, Steroid-Sensitive Nephrotic Syndrome

Intervention / Treatment
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* Drug: single infusion of Rituximab
* Drug: single infusion of Obinutuzumab


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Rituximab 375 mg/m2<br>single infusion of Rituximab (375 mg/m2) | Drug: single infusion of Rituximab<br>* single infusion of Rituximab 375 mg/m2<br>* Other names: single infusion of Rituximab 375 mg/m2;|
| Experimental: Obinutuzumab 300 mg/1.73 m2<br>single infusion of Obinutuzumab 300 mg/1.73 m2 | Drug: single infusion of Obinutuzumab<br>* single infusion of Obinutuzumab 300mg/1.73 m2<br>* Other names: single infusion of Obinutuzumab 300mg/1.73 m2;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of a relapse within 12 months following the initiation of treatment | Relapse is defined as a protein to creatinine ratio of 2 g/g of creatinine (0.20 g/mmol) or higher | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of a relapse within 24 months |  | 24 months | 
| Time to B-cell depletion |  | 24 months | 
| Duration of relapse-free survival after B-cell reconstitution |  | 24 months | 
| Cumulative steroid courses and second line immunosuppressive treatments in patients with relape |  | 24 months | 
| Safety associated with drug infusion | Nature, frequency and timing of side effects | 24 months | 
| Efficiency defined as incremental cost-effectiveness ratio in cost per relapse prevented |  | 24 months | 
| Budgetary impact defined as costs and health gains incurred with the generalization of the obinutuzumab strategy |  | 24 months | 
| Detection of Antidrug Antibodies |  | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rituximab, Obinutuzumab, Anti-Drug Antibodies