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

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

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).

Study Overview

• Status: Recruiting
• Conditions: Steroid-Dependent Nephrotic Syndrome; Steroid-Sensitive Nephrotic Syndrome
• Intervention / Treatment: Drug: single infusion of Rituximab; Drug: single infusion of Obinutuzumab

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 Type: Interventional
• Enrollment (Estimated): 88
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Claire DOSSIER, MD; Phone Number: +33140032467; Email: claire.dossier@aphp.fr
• Study Contact Backup: Name: Julien HOGAN, MD PhD; Phone Number: +33140032142; Email: julien.hogan2@aphp.fr

Study Locations

• France
  • Paris, France, 75019
    • Recruiting
    • Robert Debré Hospital
    • Contact: Claire DOSSIER, MD; Phone Number: +33140032467; Email: claire.dossier@aphp.fr
    • Contact: Julien HOGAN, MD PhD; Phone Number: +33140032142; Email: julien.hogan2@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Nature, frequency and timing of side effects	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

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Claire DOSSIER, MD, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): October 18, 2023
• Primary Completion (Estimated): October 18, 2027
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: February 10, 2023
• First Submitted That Met QC Criteria: March 14, 2023
• First Posted (Actual): March 28, 2023

Study Record Updates

• Last Update Posted (Estimated): November 9, 2023
• Last Update Submitted That Met QC Criteria: November 8, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Rituximab; Obinutuzumab; Anti-Drug Antibodies
• Additional Relevant MeSH Terms: Pathologic Processes; Kidney Diseases; Urologic Diseases; Disease; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Syndrome; Nephrotic Syndrome; Nephrosis; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Rituximab; Obinutuzumab
• Other Study ID Numbers: APHP211038; 2022-003336-59 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Time Frame: 48 months
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No