RecruitingNCT05450822

Precision Medicine in the Treatment of Epilepsy

The BrainDrugs-Epilepsy Study: A Prospective Open-label Cohort Precision Medicine Study in Epilepsy

Sponsor

Gitte Moos Knudsen

Enrollment

550 participants

Start Date

Feb 18, 2022

Study Type

OBSERVATIONAL

Conditions

Epilepsy

Summary

Primary objectives: The purpose of this study is to identify single and composite biomarkers (from neuroimaging, electrophysiological, and non-imaging biological measures), clinical measures (from cognitive, psychometric, and behavioral test scores), and risk/protective factors (e.g., from medical history, socioeconomic status, coping, lifestyle) that can: 1. Predict antiseizure medication (ASM) treatment outcome, psychiatric, cognitive, or behavioral comorbidities, and quality of life in newly diagnosed epilepsy patients (Cohort II-III). 2. Predict a second epileptic seizure/epilepsy diagnosis and behavioral, cognitive, psychiatric dysfunction and quality of life in patients after a first epileptic seizure (Cohort I).

Eligibility

Min Age: 16 YearsMax Age: 55 Years

Inclusion Criteria6

No history of current or past psychiatric or other major medical conditions
Cohort I-II: Age between 16 and 55 years
Cohort III: Age between 18 and 55 years
Cohort I: Semiology of first seizure raises a strong suspicion of epilepsy but do not fulfill International League Against Epilepsy (ILAE) diagnostic criteria
Cohort II-III: Diagnosed with epilepsy according to ILAE criteria
Cohort III: Epileptogenic lesion on MRI concordant with seizure semiology and/or EEG

Exclusion Criteria26

Current or previous neurological disease, severe somatic disease, or consumption of medical drugs likely to influence the test results
Non-fluent in Danish or pronounced visual or auditory impairments
Current or past learning disability
Pregnancy or lactation (females)
Participation in experiments with radioactivity (>10 mSv) within the last year or significant occupational exposure to radioactivity
Contraindications for MRI (pacemaker, metal implants, etc.)
Severe head injury
Alcohol or drug abuse
Drug use other than tobacco and alcohol within the last 30 days
Hash > 50 x lifetime
Drugs > 10 x lifetime (for each substance)
Current psychoactive medication
Any current or former primary psychiatric disorder (Axis I WHO ICD-10 diagnostic classification)
Cohort I-III: Life expectancy < 10 years
Cohort I-III: Known genetic syndromes, psychomotor retardation or disease associated with gross morphological brain changes such as brain tumor, major stroke or major traumatic brain injury
Cohort I-III: Body weight less than 40 kg
Cohort I-III: Reduced kidney function (i.e., glomerular filtration rate (GFR) < 80 ml/min or 50 ml/min for patients 16-17 years old or ≥18 years old, respectively),
Cohort I-III: Moderate reduced liver function
Cohort I-III: Cardiac conduction disorders (e.g., Brugada syndrome, long QT-syndrome)
Cohort I-III: Medication incompatible with study aims or causing interactions with the administered levetiracetam or lamotrigine therapy (e.g., SV2A binding agents, monoamine oxidase inhibitors, fluvoxamin, methotrexate, benzodiazepines, phenobarbital, carbamazepine, valproate, regular use of other ASMs)
Contraindication for MRI (e.g., magnetic implants, pacemaker)
Inability to complete PET (Cohort III) or MRI scans (Cohort I-III) (e.g., claustrophobia, issues with back pain)
Cohort III: Exposure to radioactivity >10 mSv within the last year or significant occupational exposure to radioactivity
Pregnancy or lactation
Cohort I-III: Non-fluency in Danish or pronounced visual or auditory impairments or severe intellectual disability
Cohort I-III: Current or previous alcohol or drug abuse

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Interventions

DRUGLevetiracetam

Healthy subjects and patients in Cohort III will undergo a 120 min. \[11C\]-UCB-J PET-MR brain scan followed by intravenous administration of levetiracetam after approx. 60 min. in a displacement paradigm. Before, during and after the intervention arterial spin labeling and resting-state functional MRI will be acquired. To measure the radiolabelled tracer's arterial input function, including its radiolabelled metabolites, blood samples will be drawn during the PET scan from an arterial catheter. The selected regions for the primary analyses are the epileptogenic lesion(s) (patients) and the neocortex, hippocampus, entorhinal cortex, fusiform gyrus, dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, orbitofrontal cortex, striatum, anterior cingulate cortex and amygdala. \[11C\]-UCB-J binding, volume of distribution and SV2A occupancy will be quantified by analyzing the PET images with well-validated kinetic models.

DRUGLevetiracetam Tablets

Patients in Cohort II will be randomized to treatment with an ASM (levetiracetam) in accordance with standard treatment procedures. The patients will enter a 4 weeks titration period receiving increasing doses. During weeks 5-30, patients will enter an evaluation period where the dose can be increased (continued seizures) or decreased (adverse reactions). In cases of unacceptable seizure control and/or intolerable adverse reactions; shift to lamotrigine arm.

DRUGLamotrigine tablet

Patients in Cohort II will be randomized to treatment with an ASM (lamotrigine) in accordance with standard treatment procedures. The patients will enter a 6 weeks titration period receiving increasing doses. During weeks 5-30, patients will enter an evaluation period where the dose can be increased (continued seizures) or decreased (adverse reactions). In cases of unacceptable seizure control and/or intolerable adverse reactions; shift to levetiracetam arm.