Prevention of relapses with Levamisole as adjuvant therapy to corticosteroids in children with first episode of idiopathic nephrotic syndrome.

Idiopathic nephrotic syndrome (INS) is a relatively rare disease, predominantly
in children and adolescents, with and 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 has 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 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 applicability 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.

This study has been transitioned to CTIS with ID 2024-517467-23-00 check the CTIS register for the current data.

Primary objective:
- 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.

Secondary Objectives:
- To investigate HRQoL at different stages of treatment (before the start of
prednisolone treatment, during steroid treatment, after cessation of steroid
treatment but still on levamisole treatment, and without treatment)
(longitudinal and cross-sectional).
- To identify medical and personal factors related to HRQoL, psychosocial
adaptation and parental distress.
- To investigate the saliva/plasma concentration ratio of prednisolone and
levamisole.
- To determine pharmacokinetics and -dynamics of levamisole and prednisolone in
children with INS.
- To investigate the applicability of saliva for determination of the
prednisolone and levamisole plasma concentrations in daily clinical use.
- To establish the functional immune disorders in INS using full-blood
stimulation before and after start of treatment and upon relapse.
- To establish the phenotype changes of the immune system using 14-colour
flow-cytometry for T-cell, B-cell, DCs and ILCs subsets before and after
treatment and upon relapse.
- To establish the differences of genotype of the immune system in INS using
the Immune Response Array Genotyping.
- To establish the stratification of patients at risk for recurrent disease and
identify immunological pathways involved in INS.
- To provide insight in the mechanism of action of levamisole in the prevention
of relapses using a) full blood stimulation; b) Seahorse technology to assess
metabolism of inflammatory cells; c) inhibitors and activators of the nicotinic
acetylcholine receptors.
- To investigate the consequences of the disease in terms of days of missing
school, outpatient visits, hospital admission and therapy costs

International multi-centre randomized, double blind, placebo-controlled trial.
Patients will be randomized in a 1:1 ratio in two groups, receiving either
levamisole 2.5 mg/kg on alternate days (treatment group) or placebo (control
group). The total duration of the study will be 4 years: 2 years of inclusion
and 2 years of follow-up. For each individual patient, there is a screening
period of 4 weeks, followed by a study treatment period of 6 months. The
patient will be followed up until 2 years after the first presentation of INS.

Treatment group receives levamisole 2.5 mg/kg on alternate days, maximum of 150
mg per day (tablets of 5, 10, 25, and 50 mg). Start of study medication is at 4
weeks after the start of steroid treatment, only when remission is achieved.
Total duration of treatment period with study medication will be 6 months. The
control group receives placebo, similar in appearance, taste and weight. Due to
possible pooling of clinical data with a currently ongoing resembling trial in
France, we will adapt the French prednisolone dosing schedule:
- 60 mg/mm2/day; 4 weeks, followed by
- 60 mg/mm2/alternate days; 8 weeks, followed by
- 45 mg/mm2/alternate days; 2 weeks, followed by
- 30 mg/mm2/alternate days; 2 weeks, followed by
- 15 mg/mm2/alternate days; 2 weeks.

Levamisole has few side effects of which neutropenia is the most common (0-14%)
and most serious for which regular testing is indicated. All reported adverse
effects in previous studies (including skin rash, and, although rarely
reported, vascular necrosis, convulsions and liver toxicity) were reversible
after cessation of the treatment. The number of visits will be around 10 in the
first year of the study and are combined with standard care visits. Still, the
number of visits might be more than is usual for a child with INS (however,
differences exist between hospitals). Visits will be done in one of the
participating centres, therefore, travel distance from home to a participating
hospital might be longer. Blood and urine sampling for biobanking and immunomic
analyses are combined with routine tests in order to avoid unnecessary
punctures. Additional testing (two days in first year, each time 5 blood
samples on different time points) for PK- and PD- analysis is additional to
standard care. To minimize physical and emotional discomfort, an intravenous
catheter is placed for obtaining all blood samples. If the patient wishes so,
these tests can be done at home and will also include regular follow-up, thus
these home visits will be instead of a visit to the hospital. In total, a
maximum of 15 and 18 mL of additional blood samples will be collected from
children <6 year and children of 6 years and older, respectively. The HRQoL
questionnaires can be filled out at home via the KLIK-website. The average time
needed is 15-30 minutes for the child and 30 minutes for the parent(s).
Patients and parents, if applicable, are asked to keep a diary to keep track of
relapses, treatment compliance and prednisolone use (in case of relapse). There
will be a paper as well as a web-based version of the diary (available through
KLIK-website).