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

Sponsor

Assistance Publique - Hôpitaux de Paris (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05786768

Collaborator

(none)

Enrollment

Location

Arms

Anticipated Duration (Months)

1.6

Patients Per Site Per Month

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Steroid-Dependent Nephrotic Syndrome Steroid-Sensitive Nephrotic Syndrome	Drug: single infusion of Rituximab Drug: single infusion of Obinutuzumab	Phase 2/Phase 3

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

88 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

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

Anticipated Study Start Date :

May 15, 2023

Anticipated Primary Completion Date :

May 15, 2027

Anticipated Study Completion Date :

Dec 15, 2027

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Rituximab 375 mg/m2 single infusion of Rituximab (375 mg/m2)	Drug: single infusion of Rituximab single infusion of Rituximab 375 mg/m2 Other Names: single infusion of Rituximab 375 mg/m2
Experimental: Obinutuzumab 300 mg/1.73 m2 single infusion of Obinutuzumab 300 mg/1.73 m2	Drug: single infusion of Obinutuzumab single infusion of Obinutuzumab 300mg/1.73 m2 Other Names: single infusion of Obinutuzumab 300mg/1.73 m2

Arm

Intervention/Treatment

Active Comparator: Rituximab 375 mg/m2

single infusion of Rituximab (375 mg/m2)

Drug: single infusion of Rituximab

single infusion of Rituximab 375 mg/m2

Other Names:

single infusion of Rituximab 375 mg/m2

Experimental: Obinutuzumab 300 mg/1.73 m2

single infusion of Obinutuzumab 300 mg/1.73 m2

Drug: single infusion of Obinutuzumab

single infusion of Obinutuzumab 300mg/1.73 m2

Other Names:

single infusion of Obinutuzumab 300mg/1.73 m2

Outcome Measures

Primary Outcome Measures

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

Occurrence of a relapse within 24 months [24 months]
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]
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]
Detection of Antidrug Antibodies [24 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

3 Years to 18 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)