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

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.

Time frame: During 2-hour Evaluation starting 1 hour after initial treatment (up to 2 hours), compared to Baseline

Population: The Full Analysis Set (FAS) consisted of all study participants in the SS who had a minimum of 30 minutes of interpretable video-EEG data from both Baseline and the period between 1 and 3 hours (Evaluation Period) after randomization to the initial study medication treatment. The FAS population was based on randomized treatment. Here, overall number of participants analyzed included all participants who were evaluable for this assessment.

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.

Time frame: Treatment Period: 7-8 hours, 15-16 hours, 23-24 hours, 31-32 hours, 39-40 hours, 47-48 hours, compared to Baseline

Population: FAS consisted of all study participants in the SS who had a minimum of 30 minutes of interpretable video-EEG data from both Baseline and the period between 1 and 3 hours (Evaluation Period) after randomization to the initial study medication treatment. FAS population was based on randomized treatment. Here, overall number of participants analyzed included all participants who were evaluable for this assessment and number analyzed signifies participants who were evaluable at specified timepoints.

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.

Time frame: During 2-hour Evaluation starting 1 hour after initial treatment (up to 2 hours), compared to Baseline

Population: FAS consisted of all study participants in the SS who had minimum of 30 minutes of interpretable video-EEG data from both Baseline and period between 1 and 3 hours (Evaluation Period) after randomization to the initial study medication treatment. FAS population was based on randomized treatment. Here, overall number of participants analyzed included all participants who were evaluable for this assessment.

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 frame: During 2-hour Evaluation starting 1 hour after initial treatment (up to 2 hours), compared to Baseline

Population: The FAS consisted of all study participants in the SS who had a minimum of 30 minutes of interpretable video-EEG data from both Baseline and the period between 1 and 3 hours (Evaluation Period) after randomization to the initial study medication treatment. The FAS population was based on randomized treatment.

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.

Time frame: From first administration of study treatment to the End of Safety Follow-up Period (up to Day 42)

Population: The SS consisted of all enrolled study participants who took at least 1 dose of the randomized treatment. The safety population was based on actual treatment.

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.

Time frame: Active Comparator: Screening; Lacosamide: Screening, 1-6 hours, 48 and 96 hours

Population: The SS consisted of all enrolled study participants who took at least 1 dose of the randomized treatment. The safety population was based on actual treatment. Here, overall number of participants analyzed included all participants with a non-missing interpretation for this assessment and number analyzed signifies participants who were evaluable at specified timepoints.

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.

Time frame: Across the first 48 hours of Treatment Period

Population: The FAS consisted of all study participants in the SS who had a minimum of 30 minutes of interpretable video-EEG data from both Baseline and the period between 1 and 3 hours (Evaluation Period) after randomization to the initial study medication treatment. FAS population was based on randomized treatment. Here, overall number of participants analyzed included all participants who were evaluable for this assessment.

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.

Time frame: During 2-hour Evaluation starting 1 hour after initial treatment (up to 2 hours), compared to Baseline

Population: The FAS consisted of all study participants in the SS who had a minimum of 30 minutes of interpretable video-EEG data from both Baseline and the period between 1 and 3 hours (Evaluation Period) after randomization to the initial study medication treatment. The FAS population was based on randomized treatment.

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.

Time frame: 24 hours after the start of Treatment Period, compared to Baseline

Population: FAS consisted of all study participants in the SS who had minimum of 30 minutes of interpretable video-EEG data from both Baseline and period between 1 and 3 hours (Evaluation Period) after randomization to initial study medication treatment. FAS population was based on randomized treatment. Here, N=participants who were evaluable for this assessment and n= participants who were evaluable for specified seizure burden categories.

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.

Time frame: Treatment Period: 7-8 hours, 15-16 hours, 23-24 hours, 31-32 hours, 39-40 hours, 47-48 hours, compared to Baseline

Population: FAS consisted of all study participants in the SS who had a minimum of 30 minutes of interpretable video-EEG data from both Baseline and the period between 1 and 3 hours (Evaluation Period) after randomization to the initial study medication treatment. FAS population was based on randomized treatment. Here, overall number of participants analyzed included all participants who were evaluable for this assessment and number analyzed signifies participants who were evaluable at specified timepoints.

Serum concentrations of lacosamide were measured and concentration data were summarized. PK sparse sampling was performed.

Time frame: 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

Population: The Pharmacokinetic Per-Protocol Set (PK-PPS) consisted of all study participants who provide at least 1 measurable serum sample (with recorded sampling time) on at least 1 post-Baseline visit with documented study drug intake times. Here, overall number of participants analyzed included all participants who were evaluable for this assessment and number analyzed signifies participants who were evaluable at specified timepoints.

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 frame: Across the first 48 hours of Treatment Period, compared to Baseline

Population: The FAS consisted of all study participants in the SS who had a minimum of 30 minutes of interpretable video-EEG data from both Baseline and the period between 1 and 3 hours (Evaluation Period) after randomization to the initial study medication treatment. The FAS population was based on randomized treatment.

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.

Time frame: Across the first 48 hours of Treatment Period, compared to Baseline

Population: The FAS consisted of all study participants in the SS who had a minimum of 30 minutes of interpretable video-EEG data from both Baseline and the period between 1 and 3 hours (Evaluation Period) after randomization to the initial study medication treatment. The FAS population was based on randomized treatment.