Precision Medicine in the Treatment of Epilepsy (BDE)

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

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).

Study Overview

• Status: Recruiting
• Conditions: Epilepsy
• Intervention / Treatment: Drug: Levetiracetam; Drug: Levetiracetam Tablets; Drug: Lamotrigine tablet

Detailed 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).

• Study Type: Observational
• Enrollment (Estimated): 550

Contacts and Locations

• Study Contact: Name: Maja Marstrand-Jørgensen, MD; Phone Number: +45 35 45 36 43; Email: maja.marstrand-jorgensen@nru.dk
• Study Contact Backup: Name: Lars Hageman Pinborg, MD; Phone Number: +45 35 45 67 12; Email: lars.pinborg@nru.dk

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • Recruiting
    • Neurobiology Research Unit, Rigshospitalet
    • Contact: Gitte M Knudsen, DMSc; Phone Number: +45 35456720; Email: gmk@nru.dk
    • Principal Investigator: Lars H. Pinborg, DMSc
    • Sub-Investigator: Maja R. Marstrand-Joergensen, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 55 years (Child, Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

This study consists of three patients cohorts: In Cohort I, we 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 fulfill the diagnostic criteria for epilepsy. In Cohort II, we will include a total of 150 newly diagnosed epilepsy patients (≥16 years old), with the expectation that at least 70 patients from Cohort I will move into Cohort II during the observational period. Additionally, a subset of approximately 45 adult patients (≥18 years old) from Cohort II with focal onset seizures will be enrolled in Cohort III. We will also collect data from 50 healthy subjects to compare group differences at baseline.

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

4

Cohorts and Interventions

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

What is the study measuring?

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.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Continuous treatment outcome rating state aggression (Cohort II-III and healthy).	Treatment outcome as percentage change in the State-Trait Anger Expression Inventory 2 (STAXI-2).	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.
Continuous treatment outcome rating trait aggression (Cohort II-III and healthy).	Treatment outcome as percentage change in the Aggression Questionnaire (AQ).	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.
Continuous treatment outcome as a measure of self-management of epilepsy (Cohort II-III).	Treatment outcome as percentage change in the Epilepsy Self-management Scale.	As change over time from baseline to one, three and five years after inclusion for patients in cohort II-III.
Continuous treatment outcome as a measure of expectations to treatment outcome (Cohort II-III).	Treatment outcome as percentage change in the Epilepsy Outcome Expectancy Scale.	As change over time from baseline to one, three and five years after inclusion for patients in cohort II-III.
Continuous outcome as epilepsy stigmatization (Cohort II-III).	Percentage change in the Epilepsy Stigmatization Scale.	As change over time from baseline to one, three and five years after inclusion for patients in cohort II-III.
A continuous rating of depression (Cohort I-III and healthy).	Percentage change in the Becks Depression Inventory (BDI).	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.
Continuous outcome of subjective, cognitive complains (Cohort I-III and healthy).	Percentage change in the self-report Cognitive Complaints in Bipolar Disorder Rating Assesment.(COBRA).	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.
Continuous outcome of perceived stress (Cohort I-III and healthy).	Percentage change in the Cohen's Perceived Stress Scale (PSS).	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.
Continuous outcome of personality traits (Cohort I-III and healthy).	Percentage change in NEO Personality Inventory 3 (NEO-FFI-3).	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.
Continuous outcome of the psychological impact of traumatic event (first seizure/epilepsy diagnosis) (Cohort I-III).	Percentage change in Impact of Event Scale-Revised (IES-R).	As change over time from baseline to one, three and five years after inclusion for patients in cohort I-III.
Continuous outcome of coping strategies (Cohort I-III and healthy).	Percentage change in Coping Self-Efficacy Scale (CSES).	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.
Continuous outcome of sleep quality (Cohort II-III and healthy).	Percentage change in Pittsburgh Sleep Quality Index (PSQI).	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.
Continuous outcome of negative life events (Cohort II-III and healthy).	Percentage change in Stressful Life Event scale (SLE).	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.
Genotyping of epilepsy candidate genes at baseline between Cohort I-III and healthy controls.	Genotyping of epilepsy candidate genes at baseline such as genes involved with GABA-ergic, glutamatergic and dopaminergic neurotransmission, GRIN2A/B, CLDN5, PIGA, PIGV, PIGT, ALDH7A1, PNPO, SLC2A1, PDYN, MTHFR, PCDH7, NRG, BDNF, MMP-2/3, TRKB, SV2A, SYNGAP1, SNAP25, HLA-B*15:02, HLA-A*31:01, HLA-A*11:01, CYP2D6, CYP2C9, CYP2C19, UGT1A1, ABCB1, ABCC1, CLCN4, SCN1-3A, SCN8A, KCNA2, KCNT1, KCNQ2/3, KCNJ10, HCN1A, GABRA1, ASIC1a, AQP4, neuropeptide Y.	At baseline between groups (HCs and patients).
Epigenetic changes in Cohort I-III and healthy controls.	Epigenetic mechanisms and regulation of microRNA, TSC1/2, NPRL2/3, DEPDC5, AK3, MECP2, ARX, SCN2/3/8A, KCNQ3, GABRG2, GABRA1, GABRB2/3.	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.
Gut microbial biomarkers for drug treatment response (Cohort II-III).	Identify microbial biomarkers between patients with drug failure vs. patients with no drug failure in Cohort II-III.	As change over time from baseline to one year after inclusion for patients in cohort II-III.
Baseline gut microbial biomarkers (Cohort II-III and healthy).	Identify microbial biomarkers between healthy subjects and patients in cohort II-III.	At baseline between groups (HCs and patients) and as change over time from baseline to one years after inclusion for patients in cohort II-III.
Gut microbial signatures between epilepsy subtypes (Cohort II-III).	Identify functional microbial signatures between patients in cohort II-III.	As change over time from baseline to one year after inclusion for patients in cohort II-III.
Gut microbial signatures for psychiatric symptoms (Cohort II-III).	Identify functional microbial signatures between patients with and without psychiatric symptoms in cohort II-III.	As change over time from baseline to one year after inclusion for patients in cohort II-III.
Changes from baseline to follow-up in intelligence quotient (IQ) and index scores and cerebral synaptic vesicle glycoprotein 2A (SV2A) binding as imaged by [11C]-UCB-J PET (Cohort III and healthy).	Latent variable construct of [11C]-UCB-J binding and IQ measured as percentage change in Wechsler Adult Intelligence Scale (WAIS-IV) and quantification of binding both globally and in primary volumes of interest; neocortex, hippocampus, entorhinal cortex, fusiform gyrus, dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, orbitofrontal cortex, striatum, anterior cingulate cortex and amygdala in patients from cohort III and healthy controls.	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 III.
Cerebral SV2A binding in patients with cognitive impairment vs. no cognitive impairment imaged by [11C]-UCB-J PET (Cohort III and healthy).	Latent variable construct of [11C]-UCB-J binding between patients without cognitive impairment vs. patients with cognitive impairment in primary volumes of interest; neocortex, hippocampus, entorhinal cortex, fusiform gyrus, dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, orbitofrontal cortex, striatum, anterior cingulate cortex and amygdala in patients from cohort III and healthy controls.	At baseline between groups (HCs and patients) and as change over time from baseline to the development of a potential cognitive dysfunction and one, three and five years after inclusion for patients in cohort III.
Cerebral SV2A binding as imaged by [11C]-UCB-J PET (Cohort III and healthy).	Latent variable construct of [11C]-UCB-J binding both globally and in primary volumes of interest; neocortex, hippocampus, entorhinal cortex, fusiform gyrus, dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, orbitofrontal cortex, striatum, anterior cingulate cortex and amygdala in patients and healthy controls.	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 III.
Cerebral SV2A binding between drug failure vs. no drug failure as imaged by [11C]-UCB-J PET (Cohort III).	Latent variable construct of [11C]-UCB-J binding and SV2A occupancy in the epileptogenic lesion(s) in patients with drug failure vs. no drug failure.	As change over time from baseline to potential drug failure and one, three and five years after inclusion for patients in cohort III.
Cerebral SV2A binding between patients with drug resistance vs. no drug resistance as imaged by [11C]-UCB-J PET (Cohort III).	Latent variable construct of [11C]-UCB-J binding and SV2A occupancy in the epileptogenic lesion(s) in patients with drug resistance vs. no drug resistance.	As change over time from baseline to potential drug resistance and one, three and five years after inclusion for patients in cohort III.
Cerebral [11C]-UCB-J PET SV2A occupancy and arterial spin labeling following intravenous administration of the ASM levetiracetam (Cohort III and healthy).	Latent variable construct of the [11C]-UCB-J PET SV2A occupancy and arterial spin labeling after a levetiracetam displacement paradigm in healthy controls compared with patients.	At baseline between groups (HCs and patients) and as change over time from baseline to potential drug failure and one, three and five years after inclusion for patients in cohort III.
Cerebral [11C]-UCB-J PET SV2A occupancy and arterial spin labeling following intravenous administration of the ASM levetiracetam (Cohort III and healthy).	Latent variable construct of the [11C]-UCB-J PET SV2A occupancy and arterial spin labeling after a levetiracetam displacement paradigm in healthy controls compared with patients.	At baseline between groups (HCs and patients) and as change over time from baseline to potential development of side effects and one, three and five years after inclusion for patients in cohort III.
Cerebral [11C]-UCB-J PET SV2A occupancy and resting-state functional connectivity following intravenous administration of the ASM levetiracetam (Cohort III and healthy).	Latent variable construct of the [11C]-UCB-J PET SV2A occupancy and resting-state functional connectivity after a levetiracetam displacement paradigm in healthy controls compared with patients.	At baseline between groups (HCs and patients) and as change over time from baseline to potential drug failure and one, three and five years after inclusion for patients in cohort III.
Cerebral [11C]-UCB-J PET SV2A occupancy and resting-state functional connectivity following intravenous administration of the ASM levetiracetam (Cohort III and healthy).	Latent variable construct of the [11C]-UCB-J PET SV2A occupancy and resting-state functional connectivity after a levetiracetam displacement paradigm in healthy controls compared with patients.	At baseline between groups (HCs and patients) and as change over time from baseline to potential development of side effects and one, three and five years after inclusion for patients in cohort III.
Cerebral SV2A binding between patients with side effects vs. no side effects as imaged by [11C]-UCB-J PET (Cohort III).	Latent variable construct of [11C]-UCB-J binding and SV2A occupancy in the epileptogenic lesion(s) in patients with side effects vs. no side effects.	As change over time from baseline to potential development of side effects and one, three and five years after inclusion for patients in cohort III.
Cerebral SV2A binding in patients with psychiatric symptoms vs. no psychiatric symptoms imaged by [11C]-UCB-J PET (Cohort III and healthy).	Latent variable construct of [11C]-UCB-J binding between patients without psychiatric symptoms vs. patients with psychiatric symptoms in primary volumes of interest; neocortex, hippocampus, entorhinal cortex, fusiform gyrus, dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, orbitofrontal cortex, striatum, anterior cingulate cortex and amygdala in patients from cohort III and healthy controls.	At baseline between groups (HCs and patients) and as change over time from baseline to a potential psychiatric diagnosis and one, three and five years after inclusion for patients in cohort III.
Cerebral [11C]-UCB-J PET SV2A occupancy and the plasma concentration of the ASM levetiracetam (Cohort III and healthy).	Estimation of the occupied SV2A binding sites from the plasma concentration of levetiracetam.	At baseline between groups (HCs and patients).
Hippocampal volume is associated with drug failure (Cohort II-III and healthy).	Structural MRI scans of hippocampus in healthy subjects and patients in cohort II-III.	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.
Volume of thalamus and hippocampus is associated with seizure recurrence (Cohort I-III and healthy).	Structural MRI scans and volume of thalamus and hippocampus.	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.
Cortical thickness is associated with seizure recurrence (Cohort I-III and healthy).	Structural MRI scans of cortical thickness of precentral gyri, parahippocampal cortex, entorhinal and fusiform gyri, precuneus and frontal gyri.	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.
Volume of amygdala is associated with psychiatric symptoms (Cohort I-III and healthy).	Structural MRI scans and volume of amygdala.	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.
Cortical thickness is associated with psychiatric symptoms (Cohort I-III and healthy).	Structural MRI scans and cortical thickness of orbitofrontal cortex.	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.
Within network resting-state functional connectivity (rsfMRI) is associated with seizure recurrence (Cohort I-III and healthy).	Resting-state functional MRI scans and within network connectivity.	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.
Whole-brain structural connectomics is associated with seizure recurrence (Cohort I-III and healthy).	Diffusion Tensor MRI scans and structural connectomics.	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.
Structural connectivity is associated with psychiatric symptoms and drug failure (Cohort I-III and healthy).	Diffusion Tensor MRI scan and structural connectivity between temporal lobe, the limbic system and orbitofrontal cortex (DTI).	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.
Between network resting-state functional connectivity (rsfMRI) is associated with psychiatric symptoms and drug failure (Cohort I-III and healthy).	Resting-state functional MRI scans and between the anterior cingulate cortex, between prefrontal-limbic systems, angular gyrus, temporal lobe, precuneus, cerebellum, default mode network and executive control network (rsfMRI).	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.
High density EEG functional connectivity is associated with seizure recurrence (Cohort I-III and healthy).	High density EEG functional connectivity in the theta band.	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.
High density EEG functional connectivity is associated with psychiatric symptoms (Cohort I-III and healthy).	High density EEG functional connectivity in the anterior cingulate cortex.	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.
High density EEG asymmetry and current source is associated with psychiatric symptoms (Cohort I-III and healthy).	High density EEG and frontal and occipital alpha asymmetry and theta current source density in the anterior cingulate cortex.	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.

Collaborators and Investigators

• Sponsor: Gitte Moos Knudsen
• Investigators: Principal Investigator: Lars Hageman Pinborg, MD, Neurobiological Research Unit

Publications and helpful links

General Publications

• Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, Engel J Jr, Forsgren L, French JA, Glynn M, Hesdorffer DC, Lee BI, Mathern GW, Moshe SL, Perucca E, Scheffer IE, Tomson T, Watanabe M, Wiebe S. ILAE official report: a practical clinical definition of epilepsy. Epilepsia. 2014 Apr;55(4):475-82. doi: 10.1111/epi.12550. Epub 2014 Apr 14.
• Christensen J, Vestergaard M, Mortensen PB, Sidenius P, Agerbo E. Epilepsy and risk of suicide: a population-based case-control study. Lancet Neurol. 2007 Aug;6(8):693-8. doi: 10.1016/S1474-4422(07)70175-8.
• Fazel S, Wolf A, Langstrom N, Newton CR, Lichtenstein P. Premature mortality in epilepsy and the role of psychiatric comorbidity: a total population study. Lancet. 2013 Nov 16;382(9905):1646-54. doi: 10.1016/S0140-6736(13)60899-5. Epub 2013 Jul 22.
• Kanner AM. Do psychiatric comorbidities have a negative impact on the course and treatment of seizure disorders? Curr Opin Neurol. 2013 Apr;26(2):208-13. doi: 10.1097/WCO.0b013e32835ee579.
• Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000 Feb 3;342(5):314-9. doi: 10.1056/NEJM200002033420503.
• Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Allen Hauser W, Mathern G, Moshe SL, Perucca E, Wiebe S, French J. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia. 2010 Jun;51(6):1069-77. doi: 10.1111/j.1528-1167.2009.02397.x. Epub 2009 Nov 3. Erratum In: Epilepsia. 2010 Sep;51(9):1922.
• DiMatteo MR, Lepper HS, Croghan TW. Depression is a risk factor for noncompliance with medical treatment: meta-analysis of the effects of anxiety and depression on patient adherence. Arch Intern Med. 2000 Jul 24;160(14):2101-7. doi: 10.1001/archinte.160.14.2101.
• Andersen LP, Gogenur I, Rosenberg J, Reiter RJ. The Safety of Melatonin in Humans. Clin Drug Investig. 2016 Mar;36(3):169-75. doi: 10.1007/s40261-015-0368-5.
• Glauser T, Ben-Menachem E, Bourgeois B, Cnaan A, Guerreiro C, Kalviainen R, Mattson R, French JA, Perucca E, Tomson T; ILAE Subcommission on AED Guidelines. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia. 2013 Mar;54(3):551-63. doi: 10.1111/epi.12074. Epub 2013 Jan 25.
• Howren MB, Lamkin DM, Suls J. Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med. 2009 Feb;71(2):171-86. doi: 10.1097/PSY.0b013e3181907c1b. Epub 2009 Feb 2.
• Scheffer IE, Berkovic S, Capovilla G, Connolly MB, French J, Guilhoto L, Hirsch E, Jain S, Mathern GW, Moshe SL, Nordli DR, Perucca E, Tomson T, Wiebe S, Zhang YH, Zuberi SM. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017 Apr;58(4):512-521. doi: 10.1111/epi.13709. Epub 2017 Mar 8.
• Dmitrienko A, D'Agostino R Sr. Traditional multiplicity adjustment methods in clinical trials. Stat Med. 2013 Dec 20;32(29):5172-218. doi: 10.1002/sim.5990. Epub 2013 Sep 30.
• Lynch BA, Lambeng N, Nocka K, Kensel-Hammes P, Bajjalieh SM, Matagne A, Fuks B. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci U S A. 2004 Jun 29;101(26):9861-6. doi: 10.1073/pnas.0308208101. Epub 2004 Jun 21.
• Brodie MJ, Barry SJ, Bamagous GA, Norrie JD, Kwan P. Patterns of treatment response in newly diagnosed epilepsy. Neurology. 2012 May 15;78(20):1548-54. doi: 10.1212/WNL.0b013e3182563b19. Epub 2012 May 9.
• Abou-Khalil BW. Update on Antiepileptic Drugs 2019. Continuum (Minneap Minn). 2019 Apr;25(2):508-536. doi: 10.1212/CON.0000000000000715.
• Finnema SJ, Nabulsi NB, Eid T, Detyniecki K, Lin SF, Chen MK, Dhaher R, Matuskey D, Baum E, Holden D, Spencer DD, Mercier J, Hannestad J, Huang Y, Carson RE. Imaging synaptic density in the living human brain. Sci Transl Med. 2016 Jul 20;8(348):348ra96. doi: 10.1126/scitranslmed.aaf6667.
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• McCormack M, Alfirevic A, Bourgeois S, Farrell JJ, Kasperaviciute D, Carrington M, Sills GJ, Marson T, Jia X, de Bakker PI, Chinthapalli K, Molokhia M, Johnson MR, O'Connor GD, Chaila E, Alhusaini S, Shianna KV, Radtke RA, Heinzen EL, Walley N, Pandolfo M, Pichler W, Park BK, Depondt C, Sisodiya SM, Goldstein DB, Deloukas P, Delanty N, Cavalleri GL, Pirmohamed M. HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J Med. 2011 Mar 24;364(12):1134-43. doi: 10.1056/NEJMoa1013297.
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• Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Bond DJ, Frey BN, Sharma V, Goldstein BI, Rej S, Beaulieu S, Alda M, MacQueen G, Milev RV, Ravindran A, O'Donovan C, McIntosh D, Lam RW, Vazquez G, Kapczinski F, McIntyre RS, Kozicky J, Kanba S, Lafer B, Suppes T, Calabrese JR, Vieta E, Malhi G, Post RM, Berk M. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018 Mar;20(2):97-170. doi: 10.1111/bdi.12609. Epub 2018 Mar 14.
• Solmi M, Veronese N, Zaninotto L, van der Loos ML, Gao K, Schaffer A, Reis C, Normann C, Anghelescu IG, Correll CU. Lamotrigine compared to placebo and other agents with antidepressant activity in patients with unipolar and bipolar depression: a comprehensive meta-analysis of efficacy and safety outcomes in short-term trials. CNS Spectr. 2016 Oct;21(5):403-418. doi: 10.1017/S1092852916000523.
• Brodie MJ, Richens A, Yuen AW. Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. UK Lamotrigine/Carbamazepine Monotherapy Trial Group. Lancet. 1995 Feb 25;345(8948):476-9. doi: 10.1016/s0140-6736(95)90581-2. Erratum In: Lancet 1995 Mar 11;345(8950):662.
• Brodie MJ, Perucca E, Ryvlin P, Ben-Menachem E, Meencke HJ; Levetiracetam Monotherapy Study Group. Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy. Neurology. 2007 Feb 6;68(6):402-8. doi: 10.1212/01.wnl.0000252941.50833.4a.
• Weintraub D, Buchsbaum R, Resor SR Jr, Hirsch LJ. Psychiatric and behavioral side effects of the newer antiepileptic drugs in adults with epilepsy. Epilepsy Behav. 2007 Feb;10(1):105-10. doi: 10.1016/j.yebeh.2006.08.008. Epub 2006 Oct 31.
• Holmes SE, Scheinost D, Finnema SJ, Naganawa M, Davis MT, DellaGioia N, Nabulsi N, Matuskey D, Angarita GA, Pietrzak RH, Duman RS, Sanacora G, Krystal JH, Carson RE, Esterlis I. Lower synaptic density is associated with depression severity and network alterations. Nat Commun. 2019 Apr 4;10(1):1529. doi: 10.1038/s41467-019-09562-7.
• Vanhaute H, Ceccarini J, Michiels L, Koole M, Sunaert S, Lemmens R, Triau E, Emsell L, Vandenbulcke M, Van Laere K. In vivo synaptic density loss is related to tau deposition in amnestic mild cognitive impairment. Neurology. 2020 Aug 4;95(5):e545-e553. doi: 10.1212/WNL.0000000000009818. Epub 2020 Jun 3.
• Chen MK, Mecca AP, Naganawa M, Finnema SJ, Toyonaga T, Lin SF, Najafzadeh S, Ropchan J, Lu Y, McDonald JW, Michalak HR, Nabulsi NB, Arnsten AFT, Huang Y, Carson RE, van Dyck CH. Assessing Synaptic Density in Alzheimer Disease With Synaptic Vesicle Glycoprotein 2A Positron Emission Tomographic Imaging. JAMA Neurol. 2018 Oct 1;75(10):1215-1224. doi: 10.1001/jamaneurol.2018.1836.
• Finnema SJ, Toyonaga T, Detyniecki K, Chen MK, Dias M, Wang Q, Lin SF, Naganawa M, Gallezot JD, Lu Y, Nabulsi NB, Huang Y, Spencer DD, Carson RE. Reduced synaptic vesicle protein 2A binding in temporal lobe epilepsy: A [11 C]UCB-J positron emission tomography study. Epilepsia. 2020 Oct;61(10):2183-2193. doi: 10.1111/epi.16653. Epub 2020 Sep 18.
• Mohanraj R, Brodie MJ. Early predictors of outcome in newly diagnosed epilepsy. Seizure. 2013 Jun;22(5):333-44. doi: 10.1016/j.seizure.2013.02.002. Epub 2013 Apr 11.
• Yao L, Cai M, Chen Y, Shen C, Shi L, Guo Y. Prediction of antiepileptic drug treatment outcomes of patients with newly diagnosed epilepsy by machine learning. Epilepsy Behav. 2019 Jul;96:92-97. doi: 10.1016/j.yebeh.2019.04.006. Epub 2019 May 20.
• Pauli C, Thais ME, Claudino LS, Bicalho MA, Bastos AC, Guarnieri R, Nunes JC, Lin K, Linhares MN, Walz R. Predictors of quality of life in patients with refractory mesial temporal lobe epilepsy. Epilepsy Behav. 2012 Oct;25(2):208-13. doi: 10.1016/j.yebeh.2012.06.037. Epub 2012 Sep 30.
• Hitiris N, Mohanraj R, Norrie J, Sills GJ, Brodie MJ. Predictors of pharmacoresistant epilepsy. Epilepsy Res. 2007 Jul;75(2-3):192-6. doi: 10.1016/j.eplepsyres.2007.06.003.
• Nogueira MH, Yasuda CL, Coan AC, Kanner AM, Cendes F. Concurrent mood and anxiety disorders are associated with pharmacoresistant seizures in patients with MTLE. Epilepsia. 2017 Jul;58(7):1268-1276. doi: 10.1111/epi.13781. Epub 2017 May 26.
• Hamid H, Ettinger AB, Mula M. Anxiety symptoms in epilepsy: salient issues for future research. Epilepsy Behav. 2011 Sep;22(1):63-8. doi: 10.1016/j.yebeh.2011.04.064. Epub 2011 Jul 8.
• Kanner AM. Psychiatric comorbidities and epilepsy: is it the old story of the chicken and the egg? Ann Neurol. 2012 Aug;72(2):153-5. doi: 10.1002/ana.23679. No abstract available.
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• Salpekar JA, Mula M. Common psychiatric comorbidities in epilepsy: How big of a problem is it? Epilepsy Behav. 2019 Sep;98(Pt B):293-297. doi: 10.1016/j.yebeh.2018.07.023. Epub 2018 Aug 25.
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• Hesdorffer DC, Ishihara L, Mynepalli L, Webb DJ, Weil J, Hauser WA. Epilepsy, suicidality, and psychiatric disorders: a bidirectional association. Ann Neurol. 2012 Aug;72(2):184-91. doi: 10.1002/ana.23601. Epub 2012 Aug 7.
• Brandt C, Schoendienst M, Trentowska M, May TW, Pohlmann-Eden B, Tuschen-Caffier B, Schrecke M, Fueratsch N, Witte-Boelt K, Ebner A. Prevalence of anxiety disorders in patients with refractory focal epilepsy--a prospective clinic based survey. Epilepsy Behav. 2010 Feb;17(2):259-63. doi: 10.1016/j.yebeh.2009.12.009. Epub 2010 Jan 13.
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Study record dates

Study Major Dates

• Study Start (Actual): February 18, 2022
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2031

Study Registration Dates

• First Submitted: July 5, 2022
• First Submitted That Met QC Criteria: July 5, 2022
• First Posted (Actual): July 11, 2022

Study Record Updates

• Last Update Posted (Actual): April 11, 2024
• Last Update Submitted That Met QC Criteria: April 9, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: MRI; machine learning; neuroimaging; biomarkers; PET; epilepsy; gut microbiome; Psychometrics; longitudinal; precision medicine; levetiracetam; lamotrigine; treatment response; high density EEG; treatment targets
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epilepsy; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Membrane Transport Modulators; Sodium Channel Blockers; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Nootropic Agents; Lamotrigine; Anticonvulsants; Levetiracetam
• Other Study ID Numbers: H-21031962

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Via database of Center for Integrated Molecular Brain Imaging (Knudsen et al 2016, NeuroImage) data will be available for the research community upon request and after approval by the scientific board at Neurobiological Research Unit. The data will be stored on a password protected survey system behind secure "firewalls" in accordance with the General Data Protection Regulation (GDPR, Regulation European Union (EU) 2016/679 April 27, 2016) and the Danish Data Protection Act and the regulation (Act No. 502 of 23 May 2018). Potential further processing in other national and international laboratories may occur, yet always in accordance with the GDPR (Regulation EU 2016/679 April 27, 2016) and the Danish Data Protection Act and the regulation (Act No. 502 of 23 May 2018).
• IPD Sharing Time Frame: Upon completion of the study.
• IPD Sharing Access Criteria: Researchers may apply for access to the data.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No