Clinical trials

Clinical trials

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EPISTOP

This is the first prospective study of epileptogenesis in humans, beginning before seizures and continuing through age 2+ years, permitting detailed analysis of the onset, drug resistance, and comorbidities of epilepsy. To maximize information derived from the study, we have chosen a homogenous group of patients with prenatal or early infantile diagnosis of tuberous sclerosis complex (TSC). A clinical randomized study of pre-seizure treatment in TSC infants is part of the project. The aim of EPISTOP is to examine the risk factors and biomarkers of epilepsy and to identify possible new therapeutic targets to block or otherwise modify epileptogenesis in humans.

Biomarker analysis will be performed by a multidisciplinary, systematic approach in three clinical settings:

• Prospective study of epilepsy development in infants with TSC, including analysis of clinical, neuroimaging, and molecular, blood-derived biomarkers at predefined time points: before the onset of seizures, at the onset of epileptiform discharges on EEG, at seizure onset and at the age of 24 months.
• Prospective study of blood-based biomarkers in infants with TSC treated with antiepileptic drugs prior to seizure onset in comparison to children treated only after clinical seizures appearance.
• Analysis of biomarkers of epileptogenesis and drug resistant epilepsy in brain specimens obtained from TSC patients who have had epilepsy surgery and TSC autopsy cases.

EPISTOP will be carried out by a consortium of 14 partners from 9 countries, including 2 small and medium enterprises (SMEs). The UMC Utrecht is coordinator of the imaging work package.

HFO study

Here we will compare the use of a new EEG biomarker, high frequency oscillations (HFOs), to the use of interictal spikes in acute corticography during epilepsy surgery. The aim is to see whether HFOs can guide the neurosurgeon better than spikes. Primary objective is to investigate whether delineation of the epileptogenic tissue during aECoG-guided surgery, using HFOs instead of epileptiform spikes, will lead to an equal or improved outcome with respect to postoperative seizure freedom. Secondary objectives are the volume of tissue resected, cognitive functioning, neurologic deficits, surgical complications and duration and health related quality of life (pre- vs. postoperative change).

This will be a single blinded randomized controlled trial. The study population will consist of patients of all ages with refractory epilepsy undergoing epilepsy surgery with aECoG to guide the extent of the cortical resection. At study completion 78 patients should be included in the study.

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Epileptic encephalopathy with electrical status epilepticus in sleep (ESES)

Epileptic encephalopathy with electrical status epilepticus in sleep (ESES) is a rare pediatric epilepsy syndrome with abundant significant aggravation of interictal epileptiform discharges in sleep and acquired impairment of cognition or behavior. Treatment with conventional anti-epileptic drugs yields limited effects. Observational data has suggested that clobazam and steroid treatment may be beneficial. Evidence from randomized controlled trials (RCT) to prove efficacy of both treatment options, or superiority of one over the other, is mandatory and still lacking. 

RESCUE ESES is a European randomized controlled clinical trial in 140 patients aged 2 – 12 years with recent onset epileptic encephalopathy with ESES. This clinical trial will compare the effects of steroids versus clobazam on cognitive functioning. Clobazam treatment will be increased to 0.5-1.2 mg/kg/day if tolerated. Steroids will be given either intravenously (pulsed methylprednisolone 20 mg/kg/day for 3 days, once monthly) or orally (prednisolone 2 mg/kg/day for at one month, followed by tapering in 20 weeks). Primary outcome is cognitive functioning after six months. Secondary outcomes include cognitive functioning at 18 months, spike wave index in sleep, seizure frequency, safety and tolerability. The collaboration with multiple centers within the European network is unique and enables randomization of a large series of patients.

This trial will study the cognitive benefits and safety of early versus late anti-epileptic drug withdrawal after epilepsy surgery in children. In a previous cohort study of 766 children who underwent epilepsy surgery in 15 European centers, we demonstrated that timing of withdrawal does not affect eventual seizure freedom.

In this new prospective European trial, 180 children who fulfil the inclusion criteria (postoperative seizure freedom, anticipated curative surgery, no negative outcome predictors) will be randomized to early (start of medication reduction 4 months following surgery) or late withdrawal (start of reduction after 12 months). Complete discontinuation of drugs will be reached within 8 months following the start of reduction in both arms. The primary outcome measures are attention and IQ at one and two years after surgery. Secondary outcome measures include seizure recurrence, eventual seizure freedom and quality of life. This study, as was its predecessor, will be executed through the framework of “U-task”, the European Task Force of Epilepsy Surgery in Children.

ANSeR

Algorithm for Neonatal Seizure Recognition (ANSeR) is a multicentre, randomised, two arm, parallel controlled, clinical investigation of the ANSeR Software System for Neonatal Seizure Recognition. The performance of the ANSeR Software System is assessed by quantifying and comparing the diagnostic accuracy (sensitivity, specificity) of investigation personnel using the ANSeR Software System with the diagnostic accuracy of investigation personnel not using the ANSeR Software System, for the diagnosis of neonatal seizures. An Expert Committee will be used as the diagnostic reference standard.

• Primary endpoint: diagnostic accuracy of investigation personnel in detecting neonatal seizures with and without the use of ANSeR Software System using an expert EEG review panel as the reference standard.
• Secondary endpoint: total duration of estimated seizure burden measured in minutes in the ANSeR Software System and non ANSeR Software System groups.