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

Study Overview
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Brief Summary
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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.

Detailed Description
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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 : 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 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.

Official Title
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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.

Conditions
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First Manifestation of Steroid Sensitive Nephrotic Syndrome

Intervention / Treatment
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* Drug: Levamisole Hydrochloride
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 24 Months
Maximum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Levamisole Hydrochloride<br>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<br>* 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<br>|
| Placebo Comparator: Placebo<br>matching verum | Other: Placebo<br>* matching verum<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Idiopathic nephrotic syndrome, Steroid sensitive nephrotic syndrome, Levamisole, Prednisone, Children