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

Официальное название

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

Обзор

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).

Подробное описание

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.

Вмешательства

• Препарат single infusion of Rituximab
  single infusion of Rituximab 375 mg/m2
• Препарат single infusion of Obinutuzumab
  single infusion of Obinutuzumab 300mg/1.73 m2

Первичные конечные точки

• Occurrence of a relapse within 12 months following the initiation of treatment [Срок оценки: 12 months]

Вторичные конечные точки (8)

• Occurrence of a relapse within 24 months [Срок оценки: 24 months]
• Time to B-cell depletion [Срок оценки: 24 months]
• Duration of relapse-free survival after B-cell reconstitution [Срок оценки: 24 months]
• Cumulative steroid courses and second line immunosuppressive treatments in patients with relape [Срок оценки: 24 months]
• Safety associated with drug infusion [Срок оценки: 24 months]
• Efficiency defined as incremental cost-effectiveness ratio in cost per relapse prevented [Срок оценки: 24 months]
• Budgetary impact defined as costs and health gains incurred with the generalization of the obinutuzumab strategy [Срок оценки: 24 months]
• Detection of Antidrug Antibodies [Срок оценки: 24 months]

Критерии участия

Критерии включения

• 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

Критерии исключения

• 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)

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Лечение

Центры проведения

Франция · 1 центр

• Robert Debre Hospital — Paris

Публикации

• Dossier C, Sellier-Leclerc AL, Simon T, Parmentier C, Boyer O, Samaille C, Fila M, Roussey-Kesler G, Magnavacca M, Chartier Y, Louillet F, Zaloszyc A, Vrillon I, Elaribi D, Bouatia S, Kaguelidou F, Guilmin-Crepon S, Hogan J. Obinutuzumab versus Rituximab to maintain remission in children with steroid-dependent and frequently relapsing nephrotic syndrome: the OBIRINS study protocol, a double-blind PMID 41448676
• Larkins NG, Hahn D, Liu ID, Willis NS, Craig JC, Hodson EM. Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children. Cochrane Database Syst Rev. 2024 Nov 8;11(11):CD002290. doi: 10.1002/14651858.CD002290.pub6. PMID 39513526
• Dossier C, Bonneric S, Baudouin V, Kwon T, Prim B, Cambier A, Couderc A, Moreau C, Deschenes G, Hogan J. Obinutuzumab in Frequently Relapsing and Steroid-Dependent Nephrotic Syndrome in Children. Clin J Am Soc Nephrol. 2023 Dec 1;18(12):1555-1562. doi: 10.2215/CJN.0000000000000288. Epub 2023 Sep 6. PMID 37678236

Идентификаторы

NCT: NCT05786768 · APHP211038 · 2022-003336-59

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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