Evaluation of Levamisole Hydrochloride as an Adjunct to Prednisolone in Preventing Relapse of Steroid-Sensitive Idiopathic Nephrotic Syndrome in Pediatric Patients

The primary objective of this study is to evaluate the effect of additional **levamisole** compared to placebo on the occurrence of relapses within 12 months in children aged 2 to 16 years with the first episode of steroid-sensitive idiopathic nephrotic syndrome (INS). This is clinically relevant as it aims to determine the efficacy of levamisole as an adjuvant therapy to corticosteroids, potentially reducing the frequency of relapses and improving long-term outcomes for pediatric patients with INS.

Secondary objectives include: - Investigating health-related quality of life (HRQoL) at different stages of treatment. - Identifying medical and personal factors related to HRQoL, psychosocial adaptation, and parental distress. - Investigating the saliva/plasma concentration ratio of prednisolone and levamisole. - Determining the pharmacokinetics and pharmacodynamics (PK/PD) of levamisole and prednisolone. - Investigating the applicability of saliva for determining prednisolone and levamisole plasma concentrations. - Establishing functional immune disorders in INS using full-blood stimulation before and after treatment and upon relapse. - Establishing phenotype changes and differences in genotype of the immune system. - Establishing the stratification of patients at risk for recurrent disease and identifying immunological pathways. - Providing insight into the mechanism of action of levamisole in the prevention of relapses. - Investigating the consequences of INS in terms of days of missing school, outpatient visits, hospital admission, and therapy costs.

The clinical trial focuses on children aged 2 to 16 years diagnosed with **steroid-sensitive idiopathic nephrotic syndrome**. The study population includes both male and female participants, with no specific data provided on the total number of participants, as the sponsor has not disclosed this information. Participants are required to be in remission after four weeks of corticosteroid treatment and must weigh more than 9 kg. They should be able to swallow a 5 mg tablet, with a successful swallowing test required for children under 6 years. Girls of childbearing potential must have a negative pregnancy test. The trial population is selected based on their ability to comply with the study protocol and the absence of contraindications for levamisole use, such as neutropenia below 1500/mm³. Written informed consent is mandatory for participation. The study does not specify any particular lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the efficacy of **levamisole hydrochloride** as an adjuvant therapy to corticosteroids in children with steroid-sensitive idiopathic nephrotic syndrome. This study is a randomized, double-blind, placebo-controlled trial. The trial aims to assess the impact of levamisole on the occurrence of relapses within 12 months following the first episode of the syndrome. The trial is expected to run until March 2027, with recruitment having commenced in April 2018.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as remission after corticosteroid treatment, weight, and ability to swallow tablets. The study will include follow-up visits to monitor the occurrence of relapses, adverse events, and treatment compliance. The end-of-study visit will evaluate the primary endpoint, which is the occurrence of relapses within 12 months, and secondary endpoints such as time to first relapse and cumulative steroid dosage over two years.

The expected length of participant involvement is up to 24 months, with conditions for early termination including the occurrence of severe adverse events or inability to comply with the study protocol. Participants will receive either levamisole or a placebo, both administered orally in the form of film-coated tablets. The maximum daily dose of levamisole is 2.5 mg/kg, with a total dose not exceeding 420 mg over the treatment period. The trial is conducted under the authorization of the relevant regulatory bodies, ensuring adherence to ethical and safety standards throughout its duration.

The clinical trial involves the administration of **ELMISOL 5**, a film-coated tablet containing **levamisole hydrochloride** as the active substance. The pharmaceutical form is a film-coated tablet, and the medication is administered orally. The dosage is calculated based on body weight, with a maximum daily dose of 2.5 mg/kg and a total maximum dose of 420 mg. The treatment period extends up to 24 weeks. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.

**ELMISOL 10** is another experimental medication used in the trial, also in the form of a film-coated tablet containing **levamisole hydrochloride**. It shares the same administration route, dosage, and treatment period as ELMISOL 5. The oral administration of the medication is designed to optimize absorption and efficacy, with compliance monitored throughout the study duration.

Additionally, the trial includes **ELMISOL 25**, which is similarly a film-coated tablet with **levamisole hydrochloride** as the active ingredient. The administration, dosage, and treatment period are consistent with the other ELMISOL formulations, ensuring uniformity in the experimental conditions. The oral route of administration is maintained, and participant adherence is closely monitored.

**ELMISOL 50** is also utilized in the trial, maintaining the same pharmaceutical form and active substance, **levamisole hydrochloride**. The administration is oral, with a dosage of 2.5 mg/kg per day and a maximum total dose of 420 mg over a 24-week period. Compliance is assessed regularly to ensure the integrity of the trial data.

The study employs a **placebo** that mimics the composition of the tested investigational medicinal products (IMPs) except for the active substance. The placebo is used to provide a comparator for evaluating the efficacy of the active treatments. The administration and monitoring procedures for the placebo group are identical to those of the active treatment groups to maintain blinding and reduce bias.

The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint is the occurrence of relapses within 12 months after the first presentation of **idiopathic nephrotic syndrome**. A relapse is defined as the recurrence of proteinuria, indicated by a 3+ urine dipstick or proteinuria greater than 200 mg/mmol creatinine for three consecutive days.

Secondary endpoints include several parameters: time to first relapse, relapse rate over a two-year period, cumulative steroid dosage up to two years, occurrence of adverse events and treatment discontinuation, and the proportion of frequent relapsers or steroid dependency over a two-year period. Additionally, the study will assess the toxicity of levamisole, including the proportion of patients with elevated ASAT-/ALAT-levels, neutropenia, or positive ANCA. The toxicity of corticosteroids will also be evaluated by examining differences in BMI, blood pressure, height, weight, and serum glucose between groups, as well as the proportion of patients with overweight, hypertension, and hyperglycemia. Furthermore, macro-economic analysis will be conducted by measuring days of school missed, outpatient visits, and hospitalization days, along with the number of treatment interruptions.