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

• Lacosamide intravenous (Drug), also known as LCM: Study participants will receive lacosamide (LCM) as an intravenous (iv) infusion during the Treatment Period.
• Lacosamide oral (Drug), also known as LCM: Study participants may receive lacosamide (LCM) as an oral solution during the Extension Period.
• Active Comparator (Other): Active Comparator treatment will be chosen and dosed based on StOC (per local practice and treatment guidelines).

Primary outcomes

• Change in Seizure Burden Measured in the Evaluation Video-electroencephalogram (Video-EEG) Compared With the Baseline Video-EEG [During 2-hour Evaluation starting 1 hour after initial treatment (up to 2 hours), compared to Baseline]: Baseline seizure burden was 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. An ENS was defined as an EEG seizure lasting for at least 10 seconds on video-EEG. The seizure burden in the Evaluation Period was calculated as the total duration of seizures between 1 and 3 hours after the first dose of study medication divided by the duration of interpretable video-EEG available in the same period. Change in seizure burden measured in the Evaluation video-EEG compared with the Baseline video-EEG was analyzed such that a positive value indicates a reduction in seizure burden from baseline.

Secondary outcomes

• Percentage of Responders in the Evaluation Video-EEG Compared With the Baseline Video-EEG [During 2-hour Evaluation starting 1 hour after initial treatment (up to 2 hours), compared to Baseline]: 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 the study medication 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 by the Investigator as having non-severe seizure burden during Baseline OR - At least 50% reduction of seizure burden in participants who were categorized by the Investigator as having severe seizure burden during Baseline.
• Percentage of Participants With at Least 80% Reduction in Seizure Burden in the Evaluation a Video-EEG Compared With the Baseline Video-EEG [During 2-hour Evaluation starting 1 hour after initial treatment (up to 2 hours), compared to Baseline]: 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: A reduction in seizure burden from Baseline of >=80% regardless of baseline seizure severity. Percentage of Participants With at least 80% Reduction in Seizure Burden in the Evaluation (starting 1 hour after treatment) of a Video-EEG Compared with the Baseline Video-EEG were reported.
• Time to Response Across the 48-hour Treatment Period Compared With the Baseline Video-EEG [Across the first 48 hours of Treatment Period, compared to Baseline]: Time to response where response was defined as a reduction in seizure burden from Baseline of at least 80% in participants with non-severe seizure burden, and of at least 50% for participants with severe seizure burden. Time to response was censored at the date/time the participant received rescue medication or stopped video-EEG monitoring, or otherwise at the end of the 48-hour period.
• Time to Seizure Freedom Across the First 48-hour Treatment Period Compared With the Baseline Video-EEG [Across the first 48 hours of Treatment Period, compared to Baseline]: Seizure freedom was defined as 0 minutes of seizures in a 1-hour period (or 2-hour period for the 3-hour time point) and was analyzed across the 48 hours. The time to seizure freedom was measured in hours, defined as the first time point when the response criterion was met minus the date and time of the first dose of randomized study medication administration. Time to seizure freedom was censored at the time of receiving rescue medication, stopping video-EEG monitoring or otherwise at 48 hours after first dose.
• Absolute Change in Seizure Burden Across the First 48-hours of the Treatment Period Measured by Continuous Video-EEG Compared With the Baseline Video-EEG [Treatment Period: 7-8 hours, 15-16 hours, 23-24 hours, 31-32 hours, 39-40 hours, 47-48 hours, compared to Baseline]: Baseline seizure burden was calculated as total duration of seizures (in minutes) between -2 hour and 0 hours before first dose of study medication divided by total duration of interpretable video-EEG (in hours) in the same period. Seizure burden for 8, 16, 24, 32, 40 and 48 hour time points was calculated as total duration of seizures in the hour prior to time point divided by duration of interpretable video-EEG available in same period. If <30 minutes of interpretable video-EEG were available in the 1 hour prior to the time point, response was calculated based on seizure burden for most recent 30 minutes of interpretable video-EEG in the 2 hours (for 8 and 16 hour points) or 4 hours (for 24, 32, 40 and 48 hour points) prior to time point. The 30 minutes of video-EEG did not need to be continuous. Absolute reduction in seizure burden for these time points was calculated as seizure burden in Baseline Period minus seizure burden at that time point.
• Percent Change in Seizure Burden Across the First 48-hours of the Treatment Period Measured by Continuous Video-EEG Compared With the Baseline Video-EEG [Treatment Period: 7-8 hours, 15-16 hours, 23-24 hours, 31-32 hours, 39-40 hours, 47-48 hours, compared to Baseline]: The percent change in seizure burden for the 8, 16, 24, 32, 40 and 48 hour time points was calculated as the seizure burden at Baseline minus the seizure burden at the respective time point, divided by the seizure burden in the Baseline Period, multiplied by 100. Percent change in seizure burden was analyzed such that a positive value indicates a reduction in seizure burden from baseline.
• Percentage of Responders at the End of the First 48-hours of the Treatment Period [Across the first 48 hours of Treatment Period]: 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. The denominator for the percentages was based on the number of participants with video- EEG data available at the 48 hour time point.
• Percentage of Study Participants Who Are Seizure-free (100% Reduction in Seizure Burden From Baseline) at 24 Hours After Start of the Treatment Period, Categorized by Study Participants With Non Severe or Severe Seizure Burden at Baseline [24 hours after the start of Treatment Period, compared to Baseline]: Seizure free was defined as 100% reduction in seizure burden or having no seizures in the assessment period (23 to 24 hours after first dose) from Baseline. For the study participants with severe seizure burden at Baseline (as determined by the Investigator), the numerator was defined as the number of participants with severe seizure burden at Baseline who had no seizures between 23 and 24 hours after the start of the Treatment Period. The denominator for the percentages was based on the number of participants with video-EEG data available at the 24 hour time point. Here, N='overall number of participants analyzed' and n='number analyzed' in categories.
• Categorized Percentage of Participants With Change in Seizure Burden in the Evaluation Video-EEG Compared With the Baseline Video-EEG [During 2-hour Evaluation starting 1 hour after initial treatment (up to 2 hours), compared to Baseline]: Baseline seizure burden was calculated as total duration of seizures (in minutes) between -2 and 0 hours before the first dose of study medication divided by total duration of interpretable video-EEG (in hours) in same period. Seizure burden in Evaluation Period was calculated as total duration of seizures between 1 and 3 hours after first dose of study medication divided by duration of interpretable video-EEG available in same period. Percent change in seizure burden for Evaluation period was calculated as seizure burden at Baseline minus seizure burden at respective time point, divided by seizure burden in Baseline Period, multiplied by 100. Participants classified in one of following categories based on their percent reduction from Baseline to Evaluation Period: < -25% (worsening), -25% to <25% (no change), 25% to <50%, 50% to <80%, and >=80%. Percent change in seizure burden was analyzed and categorized such that positive value indicates reduction in seizure burden from baseline.
• Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) as Reported by the Investigator [From first administration of study treatment to the End of Safety Follow-up Period (up to Day 42)]: 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. TEAEs are defined as AEs which have onset on or after the start date and time of initial study medication administration.
• Percentage of Participants With Treatment-emergent Marked Abnormalities in 12-lead Electrocardiogram (ECG) [Active Comparator: Screening; Lacosamide: Screening, 1-6 hours, 48 and 96 hours]: The ECG treatment-emergent marked abnormalities values are based on grade 2 toxicity based on abnormal values or clinical experience based on investigator's discretion. Participants randomized to Lacosamide and enrolled under this version of the protocol have planned assessments at Screening, 1-6 hours, 48, and 96 hours only. For participants randomized to Active Comparator treatment, only the Screening assessment was applicable.
• Serum Concentration of Lacosamide [Day 1: 30-90 minutes and 6 - 8 hours after start of first infusion, 30 - 90 minutes and 6 - 8 hours after start of second or third infusion, Days 2, 3 and 4]: Serum concentrations of lacosamide were measured and concentration data were summarized. PK sparse sampling was performed.

Sex: All, ages: any to 28 Days

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

Participant flow

Outcome results

• Change in Seizure Burden Measured in the Evaluation Video-electroencephalogram (Video-EEG) Compared With the Baseline Video-EEG (Primary), Mean, minute per hour (min/hour): Active Comparator 2.45 +/- 14.83; Lacosamide 6.64 +/- 6.55
• Percentage of Responders in the Evaluation Video-EEG Compared With the Baseline Video-EEG (Secondary), Number, percentage of participants: Active Comparator 66.7; Lacosamide 60.0
• Percentage of Participants With at Least 80% Reduction in Seizure Burden in the Evaluation a Video-EEG Compared With the Baseline Video-EEG (Secondary), Number, percentage of participants: Active Comparator 44.4; Lacosamide 60.0
• Time to Response Across the 48-hour Treatment Period Compared With the Baseline Video-EEG (Secondary), Median, hours: Active Comparator 3.0 (3.0 to 8.0); Lacosamide 3.0 (NA to NA)
• Time to Seizure Freedom Across the First 48-hour Treatment Period Compared With the Baseline Video-EEG (Secondary), Median, hours: Active Comparator 8.0 (3.0 to NA); Lacosamide 3.0 (NA to NA)
• Absolute Change in Seizure Burden Across the First 48-hours of the Treatment Period Measured by Continuous Video-EEG Compared With the Baseline Video-EEG (Secondary), Mean, mins/hour: Active Comparator -2.74 +/- 15.53; Lacosamide 6.30 +/- 6.74
• Percent Change in Seizure Burden Across the First 48-hours of the Treatment Period Measured by Continuous Video-EEG Compared With the Baseline Video-EEG (Secondary), Mean, percent change: Active Comparator 39.85 +/- 147.33; Lacosamide 80.92 +/- 45.56
• Percentage of Responders at the End of the First 48-hours of the Treatment Period (Secondary), Number, percentage of participants: Active Comparator 66.7; Lacosamide 76.9
• Percentage of Study Participants Who Are Seizure-free (100% Reduction in Seizure Burden From Baseline) at 24 Hours After Start of the Treatment Period, Categorized by Study Participants With Non Severe or Severe Seizure Burden at Baseline (Secondary), Number, percentage of participants: Active Comparator 33.3; Lacosamide 66.7
• Categorized Percentage of Participants With Change in Seizure Burden in the Evaluation Video-EEG Compared With the Baseline Video-EEG (Secondary), Number, Percentage of participants: Active Comparator 22.2; Lacosamide 0.0
• Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) as Reported by the Investigator (Secondary), Number, percentage of participants: Active Comparator 41.7; Lacosamide 64.3
• Percentage of Participants With Treatment-emergent Marked Abnormalities in 12-lead Electrocardiogram (ECG) (Secondary), Number, percentage of participants: Active Comparator 0.0; Lacosamide 0.0
• Serum Concentration of Lacosamide (Secondary), Geometric mean, microgram per milliliter (mcg/mL): Lacosamide 7.003 +/- 37.6

Adverse events

Time frame: Enrolment: Screening (-36 hours) up to 0 hours (pre-dose); Treatment: From first administration of study treatment to the End of Safety Follow-up (up to Day 42)

Serious adverse events by term

Other adverse events by term

Limitations and caveats: The study ended prematurely after agreed PIP modification; the termination was not linked to any safety issues/reasons.

• Study Protocol (PDF, 2022-02-11)
• Statistical Analysis Plan (PDF, 2023-05-04)

• UCB Cares, Study director, 001 844 599 2273