Precision Medicine in the Treatment of Epilepsy

NCT05450822 | Recruiting

• 1 other identifier: H-21031962
• Study Type: observational
• Target: 550
• Locations: 1 country
• Sites: 1

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. 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. 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).

Conditions

Epilepsy

Keywords

epilepsy; precision medicine; treatment targets; biomarkers; high density EEG; gut microbiome; longitudinal; levetiracetam; lamotrigine; neuroimaging; machine learning; treatment response; PET; MRI; Psychometrics

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (19)

• 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.

• 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.

• 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.

• 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.

• 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.

Other Outcomes (43)

• Continuous treatment outcome rating state aggression (Cohort II-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.

• Continuous treatment outcome rating trait aggression (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.

• Continuous treatment outcome as a measure of self-management of epilepsy (Cohort II-III).

  As change over time from baseline to one, three and five years after inclusion for patients in cohort II-III.

Study Arms (4)

Healthy Controls

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

Drug: Levetiracetam

Cohort I

Patients who have a history of only one epileptic seizure.

Cohort II

Patients who are newly diagnosed with epilepsy.

Drug: Levetiracetam Tablets; Drug: Lamotrigine tablet

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

Interventions

Levetiracetam DRUG

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.

Also known as: [11C]-UCB-J PET-MR scan

Cohort III; Healthy Controls

Levetiracetam Tablets DRUG

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.

Also known as: Levetiracetam

Cohort II

Lamotrigine tablet DRUG

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.

Also known as: Lamotrigine

Cohort II

Eligibility Criteria

• Age: 16 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)
• 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.

You may qualify if:

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

You may not qualify if:

• Current or previous neurological disease, severe somatic disease, or consumption of medical drugs likely to influence the test results
• Non-fluent in Danish or pronounced visual or auditory impairments
• Current or past learning disability
• Pregnancy or lactation (females)
• Participation in experiments with radioactivity (\>10 mSv) within the last year or significant occupational exposure to radioactivity
• Contraindications for MRI (pacemaker, metal implants, etc.)
• Severe head injury
• Alcohol or drug abuse
• Drug use other than tobacco and alcohol within the last 30 days
• Hash \> 50 x lifetime
• Drugs \> 10 x lifetime (for each substance)
• Current psychoactive medication
• Any current or former primary psychiatric disorder (Axis I WHO ICD-10 diagnostic classification)
• Cohort I-II: Age between 16 and 55 years
• Cohort III: Age between 18 and 55 years

Sponsors & Collaborators

• Gitte Moos Knudsen: lead

Study Sites (1)

Neurobiology Research Unit, Rigshospitalet

Copenhagen, 2100, Denmark

RECRUITING

Related Publications (196)

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Biospecimen

Retention: SAMPLES WITH DNA

Blood and stool. Blood-derived neurotrophic factor (BDNF), S100B, inflammatory markers and purine concentrations. 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. Epigenetics: microRNA, TSC1/2, NPRL2/3, DEPDC5, AK3, MECP2, ARX, SCN2/3/8A, KCNQ3, GABRG2, GABRA1, GABRB2/3. Shotgun DNA sequencing will be performed on gut microbial DNA. The analysis of genetic biomarkers may change during the study period.

MeSH Terms

Conditions

Epilepsy

Interventions

Levetiracetam; Lamotrigine

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Acetamides; Amides; Organic Chemicals; Acetates; Acids, Acyclic; Carboxylic Acids; Pyrrolidinones; Pyrrolidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Triazines

Study Officials

• Lars Hageman Pinborg, MD

  Neurobiological Research Unit

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Maja Marstrand-Jørgensen, MD

CONTACT

+45 35 45 36 43; maja.marstrand-jorgensen@nru.dk

Lars Hageman Pinborg, MD

CONTACT

+45 35 45 67 12; lars.pinborg@nru.dk

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: professor, MD neurology

Study Record Dates

• First Submitted: July 5, 2022
• First Posted: July 11, 2022
• Study Start: February 18, 2022
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2031
• Last Updated: April 11, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will share
• Time Frame: Upon completion of the study.
• Access Criteria: Researchers may apply for access to the data.

Locations

DK (1)