Prevention of the return of nephrotic syndrome in children by adding levamisole to standard prednisone treatment.

Het voorkomen van terugval van het nefrotisch syndroom bij kinderen door het toevoegen van levamisol aan de standaardbehandelng met prednison.

Idiopathic nephrotic syndrome (INS) is a relatively rare disease, predominantly in children and adolescents, with an estimated incidence around 1.5 cases per 100,000 children/year in the Netherlands (approximately 60 newly diagnosed cases a year). After initial treatment with corticosteroids, the vast majority achieves remission. Unfortunately, relapse rates are high (80%), resulting in repeated and high doses of corticosteroids that have major physical and psychological side effects. Therefore, INS with its high risk of relapses might significantly impair the health-related quality of life (HRQoL) of affected children and may lead to substantial parental stress.



Previous randomized controlled studies (RCTs) showed promising results when levamisole, an antihelminthic drug, was added as adjuvant therapy to corticosteroids in children with frequently relapsing INS (FRNS) in reducing the occurrence of relapses. Therefore, we hypothesize that adding levamisole to corticosteroids as initial therapy in children with a first episode of INS will prevent relapses. This is substantiated by the fact that 1) levamisole is a immunomodulator that has the ability to skew Th2 immune response toward the Th1 response and 2) INS is characterized by a skewing of the immune response into Th2. As such levamisole may prevent relapses of INS by restoring that balance between Th1 and Th2.



In comparison to other steroid sparing drugs, levamisole does not induce immunosuppression. It knows only little adverse effects of which neutropenia (<1500/mm3) is the most common and most serious and for which regular testing is required.



In addition, the underlying causes of INS and the prognostic factors to estimate the risk of relapse in INS patients are poorly understood. Also, little is known about the mechanism of action, the pharmacokinetics (PK), and pharmacodynamics (PD) of levamisole in children. Therefore, the RCT will be extended with 1) HRQoL questionnaires, 2) PK/PD analyses of prednisolone and levamisole (as well as the feasibility of measurement of levamisole concentration in saliva), 3) biobanking for future research, 4) study on the pathogenesis of INS, and 5) the mechanism of action of levamisole.



Our primary objective is to investigate the effect of additional levamisole in comparison with placebo from 4 weeks to 6 months after the start of the first episode of steroid sensitive INS in children (age 2 – 16 years) on the occurrence of relapses within 12 months. We hypothesize that adding levamisole to standard therapy with corticosteroids prevents relapses. To test our hypothesis, we will conduct an international (the Netherlands and Belgium), multicentre, double blind, randomized, placebo-controlled clinical trial. If remission is achieved, patients will be randomized in a 1:1 ratio to either levamisole (study group) or placebo (control group). Study medication will be used on alternate days for 24 weeks.

Adjuvant therapy of levamisole to prednisolone prevents relapses in children with a first episode of idiopathic nephrotic syndrome.

Primary endpoint: 12 months after first presentation of INS.

Secondary endpoints: 24 months after first presentation of INS. Secondary endpoints are analysed as time to first occurrence and number of occurrences during 24 months.

- Prednisolone schedule according to French protocol: tapering schedule of 18 weeks (in comparison to 12 weeks of prednisolone according to Dutch protocol 'Werkboek Kindernefrologie').

- Additional 6-month (24 weeks) treatment of either 2.5 mg/kg levamisole or placebo on alternate days.