Clinical trial NCT05786768: Efficacy and Safety of Obinutuzumab Versus Rituximab in Childhood Steroid Dependant and Frequent Relapsing Nephrotic Syndrome
Official title: Efficacy and Safety of Obinutuzumab Versus Rituximab in Childhood Steroid Dependant and Frequent Relapsing Nephrotic Syndrome : a Double-blind Multicenter Randomized Controlled Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Steroid-Dependent Nephrotic Syndrome
Steroid-Sensitive Nephrotic Syndrome
Keywords: Rituximab
Obinutuzumab
Anti-Drug Antibodies
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2023-03-28
Enrollment: 88
Sex: ALL
Minimum age (years): 3
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Occurrence of a relapse within 12 months following the initiation of treatment
timeFrame: 12 months
Secondary outcomes:
measure: Occurrence of a relapse within 24 months
timeFrame: 24 months
measure: Time to B-cell depletion
timeFrame: 24 months
measure: Duration of relapse-free survival after B-cell reconstitution
timeFrame: 24 months
measure: Cumulative steroid courses and second line immunosuppressive treatments in patients with relape
timeFrame: 24 months
measure: Safety associated with drug infusion
timeFrame: 24 months
measure: Efficiency defined as incremental cost-effectiveness ratio in cost per relapse prevented
timeFrame: 24 months
measure: Budgetary impact defined as costs and health gains incurred with the generalization of the obinutuzumab strategy
timeFrame: 24 months
measure: Detection of Antidrug Antibodies
timeFrame: 24 months
Other outcomes:
Locations:
city: Paris
country: France
facility: Robert Debre Hospital
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Claire DOSSIER, MD
role: PRINCIPAL_INVESTIGATOR
References: