Precision Medicine in the Treatment of Epilepsy

Study Overview
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Brief Summary
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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: Predict antiseizure medication (ASM) treatment outcome, psychiatric, cognitive, or behavioral comorbidities, and quality of life in newly diagnosed epilepsy patients (Cohort II-III). 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).

Detailed Description
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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: 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). 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). 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). 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).

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

Conditions
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Epilepsy

Intervention / Treatment
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* Drug: Levetiracetam
* Drug: Levetiracetam Tablets
* Drug: Lamotrigine tablet


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Healthy Controls<br>Healthy volunteers with no pre-existing or current psychiatric, neurological or server somatic illness. | Drug: Levetiracetam<br>* 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.<br>* Other names: [11C]-UCB-J PET-MR scan;|
| Cohort I<br>Patients who have a history of only one epileptic seizure. | |
| Cohort II<br>Patients who are newly diagnosed with epilepsy. | Drug: Levetiracetam Tablets<br>* 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.<br>* Other names: Levetiracetam;Drug: Lamotrigine tablet<br>* 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.<br>* Other names: Lamotrigine;|
| Cohort III<br>Patients who are newly diagnosed with epilepsy and have an epileptogenic lesion on MRI concordant with seizure semiology and/or EEG. | Drug: Levetiracetam<br>* 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.<br>* Other names: [11C]-UCB-J PET-MR scan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Categorical effect of anti-seizure medication (ASM) on treatment outcome (Cohort II-III). | 1) Seizure-free within six months after starting ASM treatment and remained seizure-free for at least one year (last observed seizure within the six months after starting ASM treatment); 2) Seizure-free more than six months after starting ASM treatment and the seizure-free period lasts at least one year; 3) Fluctuations with both seizure-freedom and seizure-relapse; or 4) Never seizure-free for a year at the third- and fifth-year follow-up timepoint. | As change over time from the ASM evaluation period (after 4-7 weeks titration period) to six months, one, three and five years after for patients in cohort II-III. | 
| Categorical effect of a second seizure/epilepsy diagnosis for patients in Cohort I. | The proportion of patients in Cohort I with one epileptic seizure who become diagnosed with epilepsy. | As change over time of epilepsy diagnosis at six months, one, three and five years after inclusion of patients in Cohort I. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Continuous treatment outcome using a seizure severity index (Cohort II-III). | Treatment outcome as percentage change in the Seizure Severity Questionnaire (SSQ). | As a monthly change over time from the ASM evaluation period (after 4-7 weeks titration period) to one, three and five years after for patients in cohort II-III. | 
| Continuous treatment outcome rating adverse events (Cohort II-III). | Treatment outcome as percentage change in the Liverpool Adverse Event Profile (LAEP). | As a monthly change over time from baseline and one, three and five years after inclusion for patients in cohort II-III. | 
| Continuous treatment outcome rating impression of change (Cohort II-III). | Treatment outcome as percentage change in in Patient's Global Impression of Change (PGIC). | As a monthly change over time from the ASM evaluation period (after 4-7 weeks titration period) to one, three and five years after for patients in cohort II-III. | 
| A continuous rating of depression diagnosis (Cohort I-III and healthy). | Percentage change in Major Depression Inventory (MDI). | At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort I-III. | 
| A continuous rating of depressive symptoms (Cohort I-III and healthy). | Percentage change in Inventory of Depressive Symptomatology (IDS-SR30). | At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort I-III. | 
| A continuous rating of specific depressive symptoms associated with neurological disease (Cohort I-III and healthy). | Percentage change in the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E). | At baseline between groups (HCs and patients) and as a monthly change over time from baseline to one, three and five years after inclusion for patients in cohort I-III. | 
| Categorical outcome of psychiatric symptoms (Cohort I-III and healthy). | Psychopathology assessed by WHO International Classification of Diseases 10 (ICD-10) diagnostic classification and a semi-structured psychiatric, clinical interview. | At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort I-III. | 
| A continuous rating of symptoms of anxiety (Cohort I-III and healthy). | Percentage change in the Generalized Anxiety Disorder 7-item (GAD-7). | At baseline between groups (HCs and patients) and as a monthly change over time from baseline to one, three and five years after inclusion for patients in cohort I-III. | 
| Performance in EMOTICOM Emotional Recognition Task (ERT-eyes) (Cohort I-III and healthy). | Differences between healthy controls and patients in recognizing facial expressions and emotions. | At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort I-III. | 
| Performance in Rey Auditory Verbal Learning Test (RAVLT) (Cohort I-III and healthy). | Differences between healthy controls and patients in verbal learning and memory. | At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort I-III. | 
| Performance in D-KEFS Color-Word Interference Test (Stroop) (Cohort II-III and healthy). | Differences between healthy controls and patients in executive function. | At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort II-III. | 
| Performance in D-KEFS Verbal Fluency (Fluency) (Cohort II-III and healthy). | Differences between healthy controls and patients in executive function. | At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort II-III. | 
| A continuous rating of Wechsler Adult Intelligence Scale (WAIS-IV) (Cohort I-III and healthy). | Differences between healthy controls and patients in IQ and specific index scores measured as percentage change in Wechsler Adult Intelligence Scale (WAIS-IV). | At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort I-III. | 
| Performance in Rey Complex Figure Test (RCFT) (Cohort II-III and healthy). | Differences between healthy controls and patients in visio-spatial learning. | At baseline between groups (HCs and patients) and as change over time from baseline to 1, 3 and 5 years after inclusion for patients in cohort II-III. | 
| Performance in Boston Naming Test (BNT) (Cohort II-III and healthy). | Differences between patient cohorts in word-retrieval. | At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort II-III. | 
| Performance in Trail Making Test A & B (Trail A & B) (Cohort II-III and healthy). | Differences between patient cohorts in psychomotor speed. | At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort II-III. | 
| A continuous rating of Quality of Life in Epilepsy (QUOLIE-31) (Cohort I-III and healthy). | Differences between healthy controls and patients in quality of life measured as percentage change in Quality of Life in Epilepsy (QUOLIE-31). | At baseline between groups (HCs and patients) and as change over time from baseline to 1, 3 and 5 years after inclusion for patients in cohort I-III. | 
| A continuous rating of Sheehans Disability Score (SDS) (Cohort I-III and healthy). | Differences between healthy controls and patients in quality of life measured as percentage change in Sheehans Disability Score (SDS). | At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort I-III. | 
| A continuous rating of WHO 5 wellbeing index (WHO-5) (Cohort I-III and healthy). | Differences between healthy controls and patients in quality of life measured as percentage change in WHO 5 wellbeing index. | At baseline between groups (HCs and patients) and as a monthly change over time from baseline and one, three and five years after inclusion for patients in cohort II-III. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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precision medicine, neuroimaging, machine learning, treatment response, PET, MRI, Psychometrics, epilepsy, treatment targets, biomarkers, high density EEG, gut microbiome, longitudinal, levetiracetam, lamotrigine