Precision Medicine in the Treatment of Epilepsy
- Conditions
- Epilepsy
- Interventions
- Registration Number
- NCT05450822
- Lead Sponsor
- Gitte Moos Knudsen
- Brief 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).
- 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).
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 550
Not provided
Not provided
Study & Design
- Study Type
- OBSERVATIONAL
- Study Design
- Not specified
- Arm && Interventions
Group Intervention Description Cohort II Levetiracetam Tablets Patients who are newly diagnosed with epilepsy. Cohort II Lamotrigine tablet Patients who are newly diagnosed with epilepsy. Healthy Controls Levetiracetam Healthy volunteers with no pre-existing or current psychiatric, neurological or server somatic illness. Cohort III Levetiracetam Patients who are newly diagnosed with epilepsy and have an epileptogenic lesion on MRI concordant with seizure semiology and/or EEG.
- Primary Outcome Measures
Name Time Method Categorical effect of a second seizure/epilepsy diagnosis for patients in Cohort I. As change over time of epilepsy diagnosis at six months, one, three and five years after inclusion of patients in Cohort I. The proportion of patients in Cohort I with one epileptic seizure who become diagnosed with epilepsy.
Categorical effect of anti-seizure medication (ASM) on treatment outcome (Cohort II-III). 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. 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.
- Secondary Outcome Measures
Name Time Method Continuous treatment outcome rating impression of change (Cohort II-III). 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. Treatment outcome as percentage change in in Patient's Global Impression of Change (PGIC).
Performance in D-KEFS Verbal Fluency (Fluency) (Cohort II-III and healthy). 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. Differences between healthy controls and patients in executive function.
A continuous rating of Sheehans Disability Score (SDS) (Cohort I-III and healthy). 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. Differences between healthy controls and patients in quality of life measured as percentage change in Sheehans Disability Score (SDS).
A continuous rating of WHO 5 wellbeing index (WHO-5) (Cohort I-III and healthy). 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. Differences between healthy controls and patients in quality of life measured as percentage change in WHO 5 wellbeing index.
Continuous treatment outcome rating adverse events (Cohort II-III). As a monthly change over time from baseline and one, three and five years after inclusion for patients in cohort II-III. Treatment outcome as percentage change in the Liverpool Adverse Event Profile (LAEP).
A continuous rating of depression diagnosis (Cohort I-III and healthy). 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. Percentage change in Major Depression Inventory (MDI).
A continuous rating of depressive symptoms (Cohort I-III and healthy). 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. Percentage change in Inventory of Depressive Symptomatology (IDS-SR30).
A continuous rating of symptoms of anxiety (Cohort I-III and healthy). 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. Percentage change in the Generalized Anxiety Disorder 7-item (GAD-7).
Categorical outcome of psychiatric symptoms (Cohort I-III and healthy). 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. Psychopathology assessed by WHO International Classification of Diseases 10 (ICD-10) diagnostic classification and a semi-structured psychiatric, clinical interview.
Performance in Trail Making Test A & B (Trail A & B) (Cohort II-III and healthy). 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. Differences between patient cohorts in psychomotor speed.
Performance in Rey Auditory Verbal Learning Test (RAVLT) (Cohort I-III and healthy). 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. Differences between healthy controls and patients in verbal learning and memory.
Performance in D-KEFS Color-Word Interference Test (Stroop) (Cohort II-III and healthy). 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. Differences between healthy controls and patients in executive function.
Performance in Boston Naming Test (BNT) (Cohort II-III and healthy). 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. Differences between patient cohorts in word-retrieval.
Continuous treatment outcome using a seizure severity index (Cohort II-III). 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. Treatment outcome as percentage change in the Seizure Severity Questionnaire (SSQ).
A continuous rating of specific depressive symptoms associated with neurological disease (Cohort I-III and healthy). 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. Percentage change in the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E).
A continuous rating of Quality of Life in Epilepsy (QUOLIE-31) (Cohort I-III and healthy). 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. Differences between healthy controls and patients in quality of life measured as percentage change in Quality of Life in Epilepsy (QUOLIE-31).
Performance in EMOTICOM Emotional Recognition Task (ERT-eyes) (Cohort I-III and healthy). 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. Differences between healthy controls and patients in recognizing facial expressions and emotions.
A continuous rating of Wechsler Adult Intelligence Scale (WAIS-IV) (Cohort I-III and healthy). 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. Differences between healthy controls and patients in IQ and specific index scores measured as percentage change in Wechsler Adult Intelligence Scale (WAIS-IV).
Performance in Rey Complex Figure Test (RCFT) (Cohort II-III and healthy). 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. Differences between healthy controls and patients in visio-spatial learning.
Trial Locations
- Locations (1)
Neurobiology Research Unit, Rigshospitalet
🇩🇰Copenhagen, Denmark