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

Phase 3RecruitingNCT05786768

Assistance Publique - Hôpitaux de Paris88 enrolled

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).

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Eligibility

Sex: ALLMin age: 3 YearsMax age: 18 Years

Medical Language ↔ Plain English

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)

Outcomes

Primary Outcomes

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

Time frame: 12 months

Secondary Outcomes

Occurrence of a relapse within 24 months

Time frame: 24 months

Time to B-cell depletion

Time frame: 24 months

Duration of relapse-free survival after B-cell reconstitution

Time frame: 24 months

Cumulative steroid courses and second line immunosuppressive treatments in patients with relape

Time frame: 24 months

Safety associated with drug infusion

Nature, frequency and timing of side effects

Time frame: 24 months

Efficiency defined as incremental cost-effectiveness ratio in cost per relapse prevented

Time frame: 24 months

Budgetary impact defined as costs and health gains incurred with the generalization of the obinutuzumab strategy

Time frame: 24 months

Detection of Antidrug Antibodies

Time frame: 24 months

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

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts