Steroid-Dependent Nephrotic Syndrome, Steroid-Sensitive Nephrotic Syndrome
Conditions
Keywords
Rituximab, Obinutuzumab, Anti-Drug Antibodies
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.
Interventions
DRUGsingle infusion of Rituximab
single infusion of Rituximab 375 mg/m2
DRUGsingle infusion of Obinutuzumab
single infusion of Obinutuzumab 300mg/1.73 m2
Sponsors
Assistance Publique - Hôpitaux de Paris
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
3 Years to 18 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| Occurrence of a relapse within 24 months | 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 | — |
| Safety associated with drug infusion | 24 months | Nature, frequency and timing of side effects |
Countries
France
Contacts
Primary ContactClaire DOSSIER, MD
Backup ContactJulien HOGAN, MD PhD
Outcome results
None listed