Efficacy of Rituximab For the Treatment of Calcineurin Inhibitors Dependent Nephrotic Syndrome During Childhood (NEPHRUTIX)

A Prospective, Randomized, Double Blind, Placebo-controlled Phase II/III Study Evaluating the Efficacy of Rituximab in the Prevention of Relapse of Calcineurin Inhibitors Dependent Idiopathic Nephrotic Syndrome of Childhood

Background

Idiopathic nephrotic syndrome is a rare disease beginning during childhood and treated with immunosuppressants (i.e. steroids, mycophenolate mofetil, cyclophosphamide, cyclosporine).

Renal function of patients suffering from severe, steroid-dependent nephrotic syndrome with failure or toxic side effects of other immunosuppressant treatments is a major matter of concern.

Cyclosporine endangers renal parenchyma (fibrosis) in these patients who must take this treatment for years. At the same time, low doses of cyclosporine allow proteinuria to reappear, which provokes degradation of renal function by focal segmental glomerulosclerosis. Some recent data lead to the conclusion that Rituximab may be effective in such a disease, with a cyclosporin sparing effect.

Purpose

The aim of the study is to evaluate the efficacy of Rituximab versus placebo in the treatment of pediatric patients suffering from severe cyclosporine-dependent nephrotic syndrome.

Abstract Patients will be included in the study in a period of remission of proteinuria. Two infusions of Rituximab - at the dose of 375 mg/m²- or placebo will be administered at one week of interval. Other immunosuppressant treatments will be gradually tapered off with the same tapering pattern in both groups. In case of relapse of nephrotic syndrome, the blinding code will be broken. Rituximab will then be infused to patients having received placebo.

Study Overview

• Status: Completed
• Conditions: Childhood Idiopathic Nephrotic Syndrome
• Intervention / Treatment: Drug: Rituximab; Drug: Placebo

Detailed Description

After infusions of Rituximab or placebo, patients will be examined by their nephrologist on a monthly basis during five months. Follow up will be focused on proteinuria, albuminemia, lymphocyte phenotyping and Rituximab pharmacokinetics

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, 1020
    • Queen Fabiola Universitary Children's Hospital
• France
  • Amiens, France, 80054
    • CHU Amiens
  • Besancon, France, 25030
    • CHU Besançon
  • Bordeaux, France, 33076
    • Chu Bordeaux
  • Brest, France, 29609
    • CHU Brest
  • Caen, France, 14033
    • CHU Caen
  • Clermont Ferrand, France, 63058
    • CHU Clermont Ferrand
  • Grenoble, France, 38043
    • CHU Grenoble
  • Lille, France, 59800
    • CHU Lille
  • Limoges, France, 87042
    • CHU Limoges
  • Marseille, France, 13385
    • AP-HM - Hôpital la Timone
  • Montpellier, France, 34295
    • CHU Montpellier
  • Nantes, France, 44033
    • CHU Nantes
  • Nice, France, 06202
    • CHU Nice
  • Paris, France, 75015
    • AP-HP - Hôpital Necker
  • Paris, France, 75571
    • AP-HP - Hôpital TROUSSEAU
  • Reims, France, 51092
    • CHU REIMS - American Memorial Hospital
  • Rennes, France, 35000
    • CHU Rennes
  • Rouen, France, 76031
    • CHU Rouen
  • Saint Etienne, France, 42055
    • Chu Saint Etienne
  • Strasbourg, France, 67098
    • CHU Strasbourg
  • Toulouse, France, 31059
    • CHU Toulouse
  • Tours, France, 37044
    • Chu Tours
  • Vandoeuvre les Nancy, France, 54511
    • CHU Nancy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or Female patients over 2 and under 18 years, with an idiopathic nephrotic syndrome (NS)
• Steroid Sensitive Nephrotic Syndrome (according to the French pediatric protocol).

NEPHRUTIX

• Calcineurin inhibitor Dependent NS or NS for which anticalcineurin treatment has not been effective. Others immunosuppressive treatments (MMF) must have failed to control the disease activity.
• Effective contraception for girls of childbearing age.
• The patient is able to understand and has signed a written informed consent OR the parent or legal guardian is able to understand and has signed a written informed consent, which must be obtained prior to the initiation of any study procedure

Exclusion Criteria:

• Terminal renal failure requiring dialysis/transplantation
• Transcutaneous oxygen stauration < 97%
• Clinical or Radiological brochopulmonar or pleural abnormality
• Asymptomatic carrier of Hepatitis B virus our history of Hepatitis B
• Contraindication to Rituximab (RTX)
• Parents/patient refusing to participate in the study

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rituximab; two infusions of Rituximab - at the dose of 375 mg/m²	Drug: Rituximab; two infusions - at the dose of 375 mg/m²- will be administered at one week of interval
Placebo Comparator: placebo; two infusions of placebo	Drug: Placebo; two infusions - at the dose of 375 mg/m² - will be administrered at one week of interval

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proteinuria with relapse of nephrotic syndrome (Serum albumin < 30 g/L) within 5 months	Proteinuria with relapse of nephrotic syndrome (Serum albumin < 30 g/L) within 5 months	5 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
- dosing of rituximab for toxicity during and/or after infusion	- toxicity during and/or after infusion	5 months
- dosing of rituximab for pharmacokinetics	- dosing of rituximab for pharmacokinetics	5 months
- dosing of lymphocyte	- lymphocyte phenotyping	5 months
Pediatric Quality of life inventory	Pediatric Quality of life inventory	5 months

Collaborators and Investigators

• Sponsor: University Hospital, Limoges
• Collaborators: Hoffmann-La Roche
• Investigators: Principal Investigator: Vincent GUIGONIS, MD, CHU Limoges

Study record dates

Study Major Dates

• Study Start: December 1, 2010
• Primary Completion (Actual): May 1, 2014
• Study Completion (Actual): May 1, 2014

Study Registration Dates

• First Submitted: December 15, 2010
• First Submitted That Met QC Criteria: December 28, 2010
• First Posted (Estimate): December 29, 2010

Study Record Updates

• Last Update Posted (Estimate): March 23, 2015
• Last Update Submitted That Met QC Criteria: March 20, 2015
• Last Verified: March 1, 2015

More Information

Terms related to this study

• Keywords: rituximab; minimal change disease; idiopathic nephrotic syndrome; focal and segmental glomerulosclerosis
• Additional Relevant MeSH Terms: Pathologic Processes; Kidney Diseases; Urologic Diseases; Disease; Syndrome; Nephrotic Syndrome; Nephrosis; Nephrosis, Lipoid; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Rituximab
• Other Study ID Numbers: I08013