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

Phase 2

Recruiting

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

Interventions: Drug: single infusion of Rituximab
Drug: single infusion of Obinutuzumab

Brief 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).

Detailed 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.

Recruitment & 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)

Arm && Interventions

Group	Intervention	Description
Rituximab 375 mg/m2	single infusion of Rituximab	single infusion of Rituximab (375 mg/m2)
Obinutuzumab 300 mg/1.73 m2	single infusion of Obinutuzumab	single infusion of Obinutuzumab 300 mg/1.73 m2

Primary Outcome Measures

Name	Time	Method
Occurrence of a relapse within 12 months following the initiation of treatment	12 months	Relapse is defined as a protein to creatinine ratio of 2 g/g of creatinine (0.20 g/mmol) or higher

Secondary Outcome Measures

Name	Time	Method
Time to B-cell depletion	24 months
Occurrence of a relapse within 24 months	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
Detection of Antidrug Antibodies	24 months
Safety associated with drug infusion	24 months	Nature, frequency and timing of side effects
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