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

Study Overview
=================
Brief Summary
-----------------
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.

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

Official Title
-----------------
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

Conditions
-----------------
Childhood Idiopathic Nephrotic Syndrome

Intervention / Treatment
-----------------
* Drug: Rituximab
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 2 Years
Maximum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

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

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
rituximab, idiopathic nephrotic syndrome, minimal change disease, focal and segmental glomerulosclerosis