Add-on Clioquinol in Drug-resistant Childhood Epilepsy: an Exploratory Study

Study Overview
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Brief Summary
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In this exploratory trial, the potential anti-seizure activity of clioquinol in a small cohort of adolescents with drug-resistant epilepsy will be examined. Subjects will be exposed to clioquinol add-on for a period of maximum 8 weeks (2 weeks low dose, 6 weeks higher dose). The main hypothesis of the study is that 30% of the included subjects will be responders and that the median seizure frequency reduction will be at least 30%.

Detailed Description
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In this exploratory phase 2 trial, adolescents with DRE will be exposed to clioquinol add-on for a period of maximum 8 weeks (2 weeks low dose, 6 weeks higher dose). During the trial concomitant anti-epileptic medication will be kept stable, so that only the add-on effect of clioquinol will be assessed. During a prospective baseline of 2 weeks, the number of seizures will be counted. The effect of first low dose (1mg/kg/day) and later higher dose (4mg/kg/day) of clioquinol on seizure frequency will be calculated using the typical epilepsy trial outcome measures: percent reduction of seizure frequency and number of patients with a >50% seizure frequency reduction ('responders'). PK samples will be collected in the first 4 patients pre-dose and 2, 4 and 8 hours post-dose, both at initiation of the lower dose (1mg/kg/day) and the higher dose (4mg/kg/day) and on visit 4. The obtained PK data will be compared with the available literature data. Since we cannot define 'absolute' PK values (yet), we use a relative stopping rule in this first phase. If >1 of the first 4 patients show a PK pattern which is more than 50% different (max PK values 50% above literature max values), the study will be ended in these 4 patients. If the dosages need to be changed for the following patients, a protocol amendment will be provided to the FAGG and the EC. In the following subjects, a simplified PK study will be done at both dosages to examine whether they follow the findings in the 4 exploratory patients. Here also, a stopping rule when the PK data is more than 50% higher than the PK data obtained in the first 4 patients will be used. Not only the effect of the drug on seizure frequency will be calculated, but also the effect on seizure severity, overall impact of seizures, medication side effects, comorbidities, and overall QoL, using standardized questionnaires (NHS3 and PIES) (1, 2). The main hypothesis of the study is that 30% of the included patients will be responders and that the median seizure frequency reduction will be at least 30%. These numbers are based on very similar trial results with new anti-epileptic drugs in drug-resistant childhood epilepsy.

Official Title
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Add-on Clioquinol in Drug-resistant Childhood Epilepsy: an Exploratory Study

Conditions
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Epilepsy Intractable

Intervention / Treatment
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* Drug: Clioquinol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants eligible for inclusion in this Trial must meet all of the following criteria: Voluntary written informed consent of the participant or their legally authorized representative has been obtained prior to any screening procedures In females with child bearing potential: negative pregnancy test or use of highly effective methods of birth control; defined as those that, alone or in combination, result in low failure rate (i.e., less than 1% per year) when used consistently and correctly; such as implants, injectables, combined oral contraceptives, some intra-uterine devices, true sexual abstinence (i.e. refraining from heterosexual intercourse during the entire period of risk associated with the Trial treatment(s)) or commitment to a vasectomized partner Age ≥ 12 years and < 18 years at time of inclusion Weight ≥ 20 kg at time of inclusion Well defined epilepsy history with convulsive seizures (with observable and countable motor component) Drug-resistant epilepsy: before inclusion failure of at least 2 AEDs Drug-resistant epilepsy: ≥ 4 seizures in the 2 week prospective period (baseline) before visit 2, not all (4) seizures observed in 1 of the 2 weeks. Baseline period can be extended with 1 or 2 weeks. The patient is at the moment of inclusion on max 3 anti-epileptic drugs (VNS and ketogenic diet not included) Exclusion Criteria: Participant has a history of liver or kidney disease. Children with a co-existing active neuropathy (such as neuritis optica, transverse myelitis) Asian ethnicity Abnormal low blood level of vitamin B12 or Zn Patients with hypothyroidism Any disorder, which in the Investigator's opinion might jeopardize the participant's safety or compliance with the protocol Any prior or concomitant treatment(s) that might jeopardize the participant's safety or that would compromise the integrity of the Trial Exposure to clioquinol before the trial Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using an adequate, highly effective contraceptive Participation in an interventional Trial with an IMP or device

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: add - on clioquinol<br>Add-on clioquinol to concomitant anti seizure medications. Clioquinol - magistral suspension preparation (100mg/ml) - oral intake Exposure 2 weeks to low dose: 1 mg/kg/day Exposure 6 weeks to higher dose: 4 mg/kg/day | Drug: Clioquinol<br>* add on clioquinol to concomitant ASM<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Responder rate : seizure frequency reduction | Percentage of 50% responders after 2 weeks and 6 weeks exposure to low (1mg/kg/day) and higher doses (4mg/kg/day) of clioquinol respectively | 8 weeks intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| safety and Quality of Life assessment | Safety during trial (systematic recording of adverse events) . | 8 weeks intervention |