Precision Medicine in the Treatment of Epilepsy (BDE)

Gitte Moos Knudsen

Status: Enrolling

Conditions: Epilepsy

Treatments: Drug: Levetiracetam Tablets; Drug: Lamotrigine tablet; Drug: Levetiracetam

Study type: Observational

Funder types: Other

Identifiers

NCT05450822

H-21031962

Details and patient eligibility

About

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).

Full description

Material and methods:

The BrainDrugs Epilepsy Study will be conducted as an open, longitudinal, prospective cohort study. The study consists of three patient cohorts:

Cohort I includes patients with a first epileptic seizure who will undergo basic clinical, cognitive, psychometric, and biological (blood) assessment, as well as electroencephalography (EEG) and Magnetic Resonance Imaging (MRI) neuroimaging.

Cohort II includes patients newly diagnosed with epilepsy who will undergo additional clinical, cognitive, psychometric, and biological (blood and stool) assessment as well as EEG and MRI neuroimaging.

Cohort III includes a subset of patients from Cohort II who they also undergo Positron Emission Tomography (PET) synaptic vesicle glycoprotein 2A (SV2A) neuroimaging.

Data from healthy controls will be collected, the investigative program for whom will be similar to that of Cohort III.

After completing the baseline investigation program, patients diagnosed with epilepsy will start ASM treatment with lamotrigine or levetiracetam, in accordance with standard treatment procedures. If the first ASM does not lead to seizure-freedom, the patients will be offered to switch to the other. Patients will be monitored every three months in the epilepsy outpatient clinic or by video or telephone consultations. For daily monitoring, a digital solution will be used, including a mobile app for patients and a web dashboard for health professionals

The mobile app contains a study module with content tailor-made for the BrainDrugs Epilepsy Study. Patients will be instructed to use the app once daily to register compliance and disease progression. Patients will complete monthly questionnaires (NDDI-E, GAD-7, LAEP, PGIC, SSQ, STAXI-2 and WHO-5) through the app tracking depressive symptoms, anxiety, adverse reactions, treatment response, seizure frequency and severity, aggression, and quality of life.

The investigators aim to include a total of 350 patients and 50 healthy subjects during the first three years of the study. All patients will be followed for five years. In addition, data from Danish health registries and electronic patient records will be used to characterize patients both retrospectively (e.g., information about birth complications) and prospectively (e.g., clinical status) during the study period.

In Cohort I, investigators will include a total of 200 patients (≥16 years old) who have been referred to clinical care after experiencing their first epileptic seizure, but do not fulfil the diagnostic criteria for epilepsy. In Cohort II, investigators will include a total of 150 newly diagnosed patients with epilepsy (≥16 years old). During the observational period, investigators expect at least 70 patients from Cohort I to be diagnosed with epilepsy upon experiencing their second epileptic seizure. These patients will subsequently be included in Cohort II. Lastly, Cohort III will be a subset of approximately 45 adult patients (≥18 years old) from Cohort II with focal onset seizures who will undergo investigation with PET.

After inclusion in the study, the patients will undergo an examination program at baseline and follow-up (1, 3 and 5 years after inclusion) that includes a study nurse interview with setup of the mobile app, neuropsychiatric interview and examination, neuropsychological tests and self-report questionnaires, high density EEG, MRI brain scan including (T1, T2, fluid-attenuated inversion recovery (FLAIR), diffusion tensor imaging (DTI), arterial spin labeling (ASL) and functional magnetic resonance imaging (fMRI)) and blood and urine samples as well as gut microbiome samples (Cohort II-III). In addition, adult patients in Cohort III will undergo a [11C]-UCB-J PET brain scan followed by intravenous administration of levetiracetam (LEV) in a displacement paradigm.

For patients in Cohort III treated with LEV, if both symptoms and extended examinations are compatible with either 1) the development of an epilepsy-related comorbidity, 2) clinically significant adverse reactions or adverse events, 3) drug treatment failure, or 4) drug resistance, a repeated [11C]-UCB-J PET brain scan will be acquired prior to change in ASM treatment.

After inclusion in the study all healthy controls (HCs) will undergo an examination program similar to Cohort III. HCs will not be followed over time. The mobile app will only be used by patients.

Primary hypotheses:

1. Combined biomarkers from morphometric measurements (e.g., the volume of thalamus and hippocampus, cortical thickness of precentral gyri, parahippocampal cortex, entorhinal and fusiform gyri, precuneus, frontal gyri), within-network resting-state functional connectivity (rsfMRI), whole-brain structural connectomics (Diffusion Tensor Imaging, DTI) and functional connectivity in the theta band (EEG) at baseline can be used to predict the chance of a recurrent seizure (Cohort I).
2. Combined biomarkers from morphometric measurements (e.g., the volume of amygdala and hippocampus, cortical thickness of orbitofrontal cortex), resting-state functional connectivity in the anterior cingulate cortex, between prefrontal-limbic systems, angular gyrus, temporal lobe, precuneus, cerebellum, default mode network, and executive control network (rsfMRI), structural connectivity between temporal lobe, the limbic system and orbitofrontal cortex (DTI) and functional connectivity in the anterior cingulate cortex, frontal and occipital alpha asymmetry and theta current source density in the anterior cingulate cortex (EEG) at epilepsy diagnosis can be used to predict the risk of developing drug-failure and epilepsy-related comorbidities (Cohort II-III).
3. Cerebral [11C]-UCB-J binding at baseline both globally and in primary volumes of interest, i.e., hippocampus, entorhinal cortex, fusiform gyrus, dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, orbitofrontal cortex, striatum, anterior cingulate cortex and amygdala correlate negatively with epilepsy-related comorbidities e.g., depressive episodes and cognitive deficits (Cohort III and healthy).
4. Cerebral [11C]-UCB-J PET SV2A occupancy following a displacement paradigm with levetiracetam is associated with a decrease in cerebral blood flow in the epileptogenic lesions(s) (patients) and in primary volumes of interest, i.e., hippocampus, entorhinal cortex, fusiform gyrus, dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, orbitofrontal cortex, striatum, anterior cingulate, and amygdala cortex in healthy controls and in patients who become seizure free with levetiracetam treatment (Cohort III and healthy).

Enrollment: 550 estimated patients

Sex: All

Ages: 16 to 55 years old

Volunteers: Accepts Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria for healthy subjects:

• No history of current or past psychiatric or other major medical conditions

Exclusion Criteria for healthy subjects:

• 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)

Inclusion Criteria for patients:

• 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 criteria for patients:

• 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

Trial design

550 participants in 4 patient groups

Healthy Controls

Description:

Healthy volunteers with no pre-existing or current psychiatric, neurological or server somatic illness.

Treatment:

Drug: Levetiracetam

Cohort I

Description:

Patients who have a history of only one epileptic seizure.

Cohort II

Description:

Patients who are newly diagnosed with epilepsy.

Treatment:

Drug: Lamotrigine tablet

Drug: Levetiracetam Tablets

Cohort III

Description:

Patients who are newly diagnosed with epilepsy and have an epileptogenic lesion on MRI concordant with seizure semiology and/or EEG.

Treatment:

Drug: Levetiracetam