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

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.