A Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Lacosamide in Neonates With Repeated Electroencephalographic Neonatal Seizures

Study Overview
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Brief Summary
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The purpose of the study is to evaluate the efficacy of lacosamide (LCM) versus an Active Comparator chosen based on standard of care (StOC) in severe and nonsevere seizure burden (defined as total minutes of electroencephalographic neonatal seizures (ENS) per hour) in neonates with seizures that are not adequately controlled with previous anti-epileptic drug (AED) treatment.

Official Title
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A Multicenter, Open-Label, Randomized, Active Comparator Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Lacosamide in Neonates With Repeated Electroencephalographic Neonatal Seizures

Conditions
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Electroencephalographic Neonatal Seizures, Epilepsy

Intervention / Treatment
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* Drug: Lacosamide intravenous
* Drug: Lacosamide oral
* Other: Active Comparator


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must be ≥34 weeks of corrected gestational age (CGA), <46 weeks of CGA, and <28 days of postnatal age (PNA) Participants who have confirmation on video-electroencephalogram (EEG) of ≥2 minutes of cumulative electroencephalographic neonatal seizures (ENS) or ≥3 identifiable ENS prior to entering the Treatment Period Participants must have received either phenobarbital (PB), levetiracetam (LEV), or midazolam (MDZ) (in any combination) before entering the study Participant weighs at least 2.3 kg at the time of enrollment Informed consent An Independent Ethics Committee (IEC)-approved written informed consent form (ICF) is signed and dated by the participant's parent(s) or legal representative(s) Exclusion Criteria: Participant with seizures responding to correction of metabolic disturbances (hypoglycemia, hypomagnesemia, or hypocalcemia) or with seizures for which a targeted, known treatment is available Participant has seizures related to prenatal maternal drug use or drug withdrawal Participant has a clinically relevant electrocardiogram (ECG) abnormality, in the opinion of the investigator Participant receiving treatment with phenytoin (PHT), lidocaine (LDC), or other sodium channel blockers at any time

Ages Eligible for Study
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Maximum Age: 28 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lacosamide<br>Study participants randomized to this arm will receive lacosamide (LCM) as an intravenous infusion in the Treatment Period and may continue to receive lacosamide in the Extension Period. Participants should be switched to oral dosing of LCM as soon as medically possible during the Extension Period. | Drug: Lacosamide intravenous<br>* Study participants will receive lacosamide (LCM) as an intravenous (iv) infusion during the Treatment Period.<br>* Other names: LCM;Drug: Lacosamide oral<br>* Study participants may receive lacosamide (LCM) as an oral solution during the Extension Period.<br>* Other names: LCM;|
| Active Comparator: Active Comparator<br>Study participants randomized to this arm will receive Active Comparator chosen based on standard of care (StOC) in the Clinical Practice in the Treatment Period and may continue to receive in the Extension Period. | Other: Active Comparator<br>* Active Comparator treatment will be chosen and dosed based on StOC (per local practice and treatment guidelines).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in seizure burden measured in the Evaluation video-electroencephalogram (video-EEG) compared with the Baseline video-EEG | Change in seizure burden measured in the Evaluation video-EEG compared with the Baseline video-EEG. Baseline seizure burden is defined as seizure burden measured on the continuous video-EEG (total electroencephalographic neonatal seizures (ENS) in minutes per hour) during a period of up to 2 hours immediately prior to the first administration of study drug. | During 2-hour Evaluation starting 1 hour after initial treatment (up to 2 hours) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of responders in the Evaluation video-EEG compared with the Baseline video-EEG | A responder is defined as a study participant who achieved the following reduction in seizure burden without need for rescue medication, compared with the seizure burden measured during the Baseline Period immediately prior to investigational medicinal product (IMP) administration, evaluated for a 2-hour period starting 1 hour after the start of initial treatment: At least 80% reduction of seizure burden in participants who were categorized as having nonsevere seizure burden during Baseline OR At least 50% reduction of seizure burden in participants who had at least one 30-minute period of severe seizure burden during Baseline | During 2-hour Evaluation starting 1 hour after initial treatment (up to 2 hours) | 
| Percentage of participants with at least 80% reduction in seizure burden in the Evaluation a video-EEG compared with the Baseline video-EEG | A responder is defined as a study participant who achieved the following reduction in seizure burden without need for rescue medication, compared with the seizure burden measured during the Baseline Period immediately prior to investigational medicinal product (IMP) administration, evaluated for a 2-hour period starting 1 hour after the start of initial treatment: At least 80% reduction of seizure burden in participants who were categorized as having nonsevere seizure burden during Baseline OR At least 50% reduction of seizure burden in participants who had at least one 30-minute period of severe seizure burden during Baseline | During 2-hour Evaluation starting 1 hour after initial treatment (up to 2 hours) | 
| Time to response across the 96-hour Treatment Period | Time to response is presented as median time (in hours) to the 50% reduction in study participants with severe seizure burden or 80% reduction in study participants with nonsevere seizure burden. | Across the Treatment Period (up to 96 hours) | 
| Time to seizure freedom across the 96-hour Treatment Period | Time to seizure freedom will be analyzed as median time (in hours) to seizure freedom. | Across the Treatment Period (up to 96 hours) | 
| Categorized percentage change in seizure burden in the Evaluation video-EEG compared with the Baseline video-EEG | The change in seizure burden will be presented in the following categories: (<-25% [worsening], -25% to <25% [no change], 25% to <50%, 50% to <80%, and ≥80%) | During 2-hour Evaluation starting 1 hour after initial treatment (up to 2 hours) | 
| Percentage of participants with treatment-emergent adverse events (TEAEs) as reported by the investigator | An adverse event (AE) is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study medication, whether or not considered related to the study medication. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study medication. | From first administration of study treatment to the End of Safety Follow-up Period (up to Day 42) | 
| Percentage of participants with treatment-emergent marked abnormalities in 12-lead electrocardiogram (ECG) | Marked abnormalities are defined as abnormalities in predefined parameters based upon grade 2 toxicity lab values and neonatologist expert opinion in the neonate. | From first administration of study treatment to the End of Safety Follow-up Period (up to Day 42) | 
| Plasma/serum concentration of lacosamide (LCM) | Mean plasm/serum concentrations of lacosamide (LCM) will be presented across the Treatment Period. | Across the Treatment Period (up to 96 hours) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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electroencephalographic neonatal seizures, epilepsy, neonatal study participants, Vimpat, lacosamide, LCM, pediatric, video-EEG