Efficiency of Levamisole for Maintaining Remission After the First Flare of Steroid Sensitive Nephrotic Syndrome in Children (NEPHROVIR3)

A Multicenter, Randomised, Double-blind Placebo-controlled Trial Assessing the Efficiency of Levamisole for Maintaining Remission After the First Flare of Steroid Sensitive Nephrotic Syndrome in Children.

Idiopathic Nephrotic Syndrome is sensitive to steroid in 90% of children. However, most patients relapse and become steroid-dependant, with a long lasting relapsing course. The aim of this study is to assess the efficiency of a 6-months levamisole course, given early after first remission, on maintaining a relapse-free course at 12 months.

Study Overview

• Status: Completed
• Conditions: First Manifestation of Steroid Sensitive Nephrotic Syndrome
• Intervention / Treatment: Drug: Levamisole Hydrochloride; Other: Placebo

Detailed Description

Introduction (INS) is likely a primal immune disorder. Initial treatment relies on steroid therapy. NS is sensitive to steroid in more than 90% of cases, with an excellent renal prognosis. Nevertheless, 80% of patients with steroid sensitive NS do relapse, 60% within the first year. 2/3 of them will experience steroid dependency, with a long lasting relapsing course. These patients require further immunosuppressive drugs as steroid sparing agents, such as mycophenolate, cyclophosphamide, calcineurin inhibitors or rituximab. Morbidity is high and related both to the duration of the disease, sometimes until adulthood, and to treatments side effects.

Levamisole is an immunomodulator that has been used for more than thirty years in the treatment of steroid-dependent or frequently relapsing NS. Its major advantages are its immunomodulatory action and lower and reversible toxicity.

Exact physiopathology of both INS and levamisole action remain unknown. Nevertheless, we make the hypothesis that very early treatment with levamisole may enhance its efficiency and modify the disease's course.

This is the first trial to assess the efficiency of levamisole in increasing duration of remission after the first manifestation of INS.

Design :

• A multicenter, double-blind, placebo-controlled, randomised clinical trial.
• 38 centers participate to the recruitment : 3 Pediatric Nephrology units and 35 General Pediatric units.
• 20 centers participate to the randomized phase.

Sample size :

156 patients, 78 in each group

Treatment groups :

1. Levamisole Hydrochloride Dosage : 5, 10, 25 et 50mg. Dosage form : oral tablets Posology : 2.5 mg/kg on alternate days maximum 150mg. Treatment duration : 6 months
2. placebo : matching verum

Assessment :

Study visits at inclusion, M1 (randomisation), M3, M6, M9, M12. Supplementary visit if relapse occurs.

Statistical procedure Analysis of efficiency will be performed on intention to treat population. Analysis of tolerance will be performed on randomized patients who have received at least one dose of treatment.

No intermediary analysis is planned.

• Study Type: Interventional
• Enrollment (Actual): 86
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Paris, France, 75019
    • Hôpital Robert Debré

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 months to 14 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 24 months < age < 16 years
• Diagnosis of first manifestation of INS defined by:
• hypoalbuminemia < 25g/l, proteinuria > 0.20 g/mmol of urinary creatinine
• normal C3 fraction of complement
• Use of mechanical contraception for patients of reproductive age throughout the research period
• Beneficiary of a social protection scheme (except AME)
• Written informed consent from one of both parents
• Ability to realise follow-up in full

Exclusion Criteria:

• Anteriority of INS
• Pregnancy, breast feeding or planned pregnancy during the study
• Malignant pathology (antecedent or ongoing), diabetes, liver disease
• Hypersensitivity to levamisole or its excipients (lactose)

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: Levamisole Hydrochloride; Dosage : 5, 10, 25 et 50mg. Dosage form : oral tablets, coated and non dividable for taste-masking Posology : 2.5 mg/kg on alternate days maximum 150mg. Treatment duration : 6 months	Drug: Levamisole Hydrochloride; Dosage : 5, 10, 25 et 50 mg. Dosage form : oral tablets, coated and non dividable for taste-masking Posology : 2.5 mg/kg on alternate days maximum 150mg. Treatment duration : 6 months
Placebo Comparator: Placebo; matching verum	Other: Placebo; matching verum

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of patients still in remission at 12 months after first flare of INS.	number of patients who did not relapse compared to the number of patients who had relapsed after first flare of INS.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Compare within levamisole and placebo groups the duration of remission.	number of days between the first flare and first relapse or up to the corticodependence level in the event of relapse in the course of decreasing corticosteroid therapy.	first relapse
Compare within levamisole and placebo groups the frequency and level of steroid dependency	Proportion of corticodependent patients and level of steroid dependency	12 months
Compare within levamisole and placebo groups the treatment tolerance	Frequency of adverse events apparition and frequency of discontinuation of treatment secondary at a adverse event.	12 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): September 6, 2017
• Primary Completion (Actual): February 7, 2021
• Study Completion (Actual): February 11, 2021

Study Registration Dates

• First Submitted: June 8, 2016
• First Submitted That Met QC Criteria: June 27, 2016
• First Posted (Estimate): June 30, 2016

Study Record Updates

• Last Update Posted (Actual): June 8, 2022
• Last Update Submitted That Met QC Criteria: June 7, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: Children; Prednisone; Levamisole; Idiopathic nephrotic syndrome; Steroid sensitive nephrotic syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Kidney Diseases; Urologic Diseases; Disease; Hypersensitivity; Syndrome; Nephrotic Syndrome; Nephrosis; Physiological Effects of Drugs; Anti-Infective Agents; Antirheumatic Agents; Immunologic Factors; Adjuvants, Immunologic; Antiparasitic Agents; Antinematodal Agents; Anthelmintics; Levamisole
• Other Study ID Numbers: P150904

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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