Long-term efficacy, safety, and tolerability, including behavior and executive functioning, during adjunctive lacosamide treatment in pediatric patients with uncontrolled epilepsy

Objectives: To evaluate long-term efficacy, safety, and tolerability, including behavior and executive functioning, during adjunctive lacosamide (LCM) treatment in pediatric patients ( ≥ 1 month to < 18 years of age) with focal-onset or generalized seizures enrolled in 2 open-label, long-term follow-up trials. Methods: Two open-label extension trials (SP848: NCT00938912; EP0034: NCT01964560) were conducted in pediatric patients who had participated in previous trials of adjunctive LCM (SP0847/NCT00938431; SP0966/ NCT01969851; EP0060


Introduction
Epilepsy is a chronic disease requiring long-term pharmacological management.Approximately 25 %-30 % of children with epilepsy have uncontrolled seizures despite treatment with antiseizure medications (ASMs) [1].Long-term tolerability, safety, and efficacy data of ASMs in children with epilepsy are clinically valuable and help physicians, patients, and caregivers make informed treatment decisions [2].Children with epilepsy are at increased risk of cognitive or behavioral problems [3,4], and some ASMs have been associated with cognitive or behavioral side effects [5][6][7].
Lacosamide (LCM) is an ASM that selectively enhances the slow inactivation of neuronal voltage-gated sodium channels [8].LCM is indicated as mono-and adjunctive therapy for focal-onset (partial-onset) seizures in patients 1 month of age and older in the United States, and in patients 2 years of age and older in the European Union [9,10].LCM is also approved as adjunctive therapy for primary generalized tonic-clonic seizures in patients ≥4 years of age in the United States and the European Union.Previous trials of various short-term durations (maximum up to 18 weeks titration/maintenance) assessed the safety, tolerability, and efficacy of adjunctive LCM in pediatric patients [11][12][13][14].
This article assesses the long-term safety, tolerability, efficacy, and retention of adjunctive LCM in pediatric patients with epilepsy and focal-onset or generalized seizures in a large pool of patients enrolled in two long-term, open-label extension trials.We also evaluated behavior and executive functioning and quality of life during long-term adjunctive LCM treatment.Pooling data from similarly designed clinical trials provides the opportunity to evaluate clinically relevant outcomes in the resulting large data pool [15], and provides more robust overall data on the long-term efficacy, safety, and tolerability of adjunctive LCM treatment.Data from the individual trials are provided as supplementary material.

Methods
This is an analysis of pooled data from trials SP848 (ClinicalTrials.gov: NCT00938912) and EP0034 (NCT01964560).For both trials, the trial protocol, amendments, and patient informed consent were reviewed by a national, regional, or Independent Ethics Committee or Institutional Review Board.
These trials were conducted in accordance with the current version of the applicable regulatory and International Council for Harmonisation-Good Clinical Practice requirements, the ethical principles that have their origin in the principles of the Declaration of Helsinki, and the local laws of the countries involved.

Trial SP848
SP848 (NCT00938912) was a phase 2, multicenter, open-label extension trial to evaluate the long-term safety, tolerability, and efficacy of adjunctive LCM in children with focal-onset seizures.SP848 was designed as an open-label extension trial for pediatric patients ≥1 month to ≤17 years of age with focal-onset seizures enrolled in SP0847 (NCT00938431 [11]), and was later amended to be open to patients completing other pediatric trials of LCM in focal-onset seizures and other epilepsy syndromes (SP0966 [NCT01969851; patients ≥1 month to <18 years of age with epilepsy syndromes associated with generalized seizures [13]], and EP0060 [NCT02710890; patients ≥1 month to <17 years of age with epilepsy [16]]).In addition, up to ~200 eligible pediatric patients (≥4 years to ≤ 17 years of age) with focal-onset seizures who had not previously participated in a clinical trial of LCM were enrolled directly.The maximum duration of LCM administration for each patient was to be approximately 2 years or until approval of the marketing application (for Japan only), whichever came first.Inclusion and exclusion criteria are presented in the Supplementary methods.
In SP848, patients who enrolled from one of the previous trials entered SP848 on the LCM dose they had achieved in the previous trial.For directly enrolled patients in SP848, LCM was up-titrated over a period of up to 6 weeks from a starting dose of 2 mg/kg/day or 100 mg/ day to a maximum dose of 12 mg/kg/day or 600 mg/day based on body weight, whichever was lower.LCM was administered as oral solution or tablets twice daily at approximately 12-hour intervals.

Trial EP0034
EP0034 (NCT01964560) was a phase 3, multicenter, open-label extension trial to evaluate the long-term safety, tolerability, and efficacy of adjunctive LCM in children with focal-onset seizures.Patients in EP0034 had completed trials SP0967 (NCT02477839; patients ≥1 month to <4 years of age with focal-onset seizures [14]) or SP0969 (NCT01921205; patients ≥4 to <17 years of age with focal-onset seizures [12]).The maximum duration of this trial was approximately 2 years.Inclusion and exclusion criteria are presented in the Supplementary Methods.
In EP0034, after completing the blinded transition period of the primary trial, patients were transitioned to a maximum LCM dose of 12 mg/kg/day or 600 mg/day based on body weight, whichever was lower.LCM was administered as oral solution or tablets twice daily at approximately 12-hour intervals.

Outcomes
Endpoints were assessed for the pooled trial data.Data from the individual trials are provided as supplementary material.Retention was assessed using Kaplan-Meier estimates for time to LCM discontinuation.Efficacy endpoints were median percent reduction in focal-onset seizure frequency from baseline, 50 %/75 % responder rates (patients with ≥50 %/≥75 % reduction in focal-onset seizure frequency from baseline), ≥12-month seizure freedom (all seizure types), and Clinician's and Caregiver's Global Impression of Change.Safety and tolerability endpoints were the incidence of treatment-emergent adverse events (TEAEs), 12-lead electrocardiogram (ECG) results, and behavior and executive functioning (as measured by the Achenbach Child Behavior Checklist [CBCL] 1.5-5 and 6-18, Behavior Rating Inventory of Executive Function® [BRIEF], and BRIEF-Preschool Version [BRIEF-P] scores).Quality of life was assessed with Pediatric Quality of Life Inventory (PedsQL TM ).A list of predefined primary and secondary endpoints in trials SP848 and EP0034 is provided in the Supplementary methods.
TEAEs were defined as adverse events that started on or after the date of first dose of LCM in the trials, or adverse events with worsened intensity on or after the date of first dose of LCM.Based on general safety considerations and safety data from clinical trials with LCM, additional TEAEs termed "other significant TEAEs" were given special consideration.

Statistical analyses
Descriptive analyses were performed for all efficacy and safety assessments.Retention, safety, and quality of life were assessed in the Safety Set (SS), which was defined as all patients who took ≥1 LCM dose in SP848 or EP0034.Efficacy was assessed in the Full Analysis Set (FAS), which included all patients in the SS who had ≥1 completed postbaseline seizure diary.
Patients were classified as belonging to one of the following seizure classification subgroups based on their seizure classification history: focal-onset seizure population (patients from SP0966 who reported only focal-onset seizures; patients from all other core trials who reported any focal-onset seizure; direct enrollers into SP848); and generalized seizure population (patients from SP0966, unless they reported only focal-onset seizures; patients from EP0060 who reported only generalized seizures; all other core trials only enrolled patients with focal-onset seizures, and no patients from these trials were included in the generalized seizure population).Data are presented for all patients, the focal-onset seizure population, and the generalized seizure population.The focal-onset seizure population was further divided into subgroups by age at entry into SP848/EP0034: ≥1 month to <4 years and ≥4 years to <18 years.
For seizure analyses, completer cohorts were defined as subsets of patients in the FAS who received LCM for a specified duration of time (6, 12, or 24 months, where a month was defined as 28 days), and had seizure diary data available for the specified interval.Seizure freedom was defined as 0 seizures reported and no more than 10 % of days in the specified completer cohort/time interval for which seizure data were not available.
Achenbach CBCL 1.5-5 and 6-18 were used for patients 1.5-5 and 6-18 years of age, respectively.The mean change in syndrome scores and the proportion of patients with a shift in T-score categories from baseline to last evaluation were assessed.Last evaluation was the last non-missing assessment during the treatment period.T-score categories were defined as "Normal" (T-score < 65) and "Borderline or Clinical Range" (T-score ≥ 65).
BRIEF-P and BRIEF were used for patients 2-<5 and 5-18 years of age, respectively.The mean change in subscale scores and the shift in T-score categories from baseline to last evaluation were assessed.T-score categories were defined as "Normal" (T-score <65) and "Elevated" (T-score ≥65).
The PedsQL measurement model consists of developmentally appropriate forms for pediatric patients ≥1 month to ≤ 12 months, ≥ 13 months to ≤ 24 months, > 2 to ≤ 4 years, ≥ 5 to ≤ 7 years, ≥ 8 to ≤ 12 years, and ≥13 to ≤ 18 years of age.The changes in subscale and total scores from baseline to last evaluation in patients 1-12 months, 13-24 months, 2-4 years, and ≥5 years of age were assessed.
For behavior and executive functioning and quality of life, standardized mean difference (SMD) was calculated according to Hedges g, which is used to calculate the size of the effect between time points.

Patients
A total of 905 patients from SP848 and EP0034 were included in the pooled SS (851 in the focal-onset seizure population and 47 in the generalized seizure population) and 901 patients were included in the FAS (847 in the focal-onset seizure population and 47 in the generalized seizure population) (Fig. 1).
Patients had a mean age of 8.2 years and 54.8 % were male (Table 1; individual trial data in Supplementary Table S1).On average, patients had an epilepsy duration of 4.9 years.Overall, 536 (59.2 %) patients had ≥1 comorbid condition at trial initiation.The most common comorbid condition was mental retardation (11.6 %).Fewer patients in the generalized seizure population (2.1 %) than in the focal-onset seizure population (62.7 %) had comorbid conditions.In the age subgroups within the focal-onset seizure population, the proportion of patients with comorbid conditions was generally similar (64.9 % in patients ≥1 month to <4 years of age; 61.8 % in patients ≥4 to <18 years of age).

Disposition, reasons for discontinuation, and exposure
The overall trial completion rate was 71.7 % (individual trial data in Supplementary Table S2).The proportion of patients completing the trial was numerically higher in the generalized seizure population (78.7 %) than in the focal-onset seizure population (71.3 %), mainly due to a lower proportion of patients in the generalized seizure population discontinuing due to withdrawal by patient.The completion rates in the age subgroups within the focal-onset seizure population were similar (71.4 % in patients ≥1 month to <4 years of age; 71.3 % in patients ≥4  to <18 years of age).Similar proportions of patients in the focal-onset seizure population and generalized seizure population discontinued the trials due to adverse events (5.2 % and 6.4 %, respectively) or lack of efficacy (10.0 % and 8.5 %, respectively) (Fig. 2).
For all patients, median duration of LCM exposure was 679 days, median maximum daily dose was 10 mg/kg/day, and median modal daily dose was 9.9 mg/kg/day.Duration of exposure, maximum daily dose, and modal dose were similar in the focal-onset seizure population and generalized seizure population, and in patients ≥1 month to <4 years and ≥4 to <18 years of age within the focal-onset seizure population (Supplementary Table S3; individual trial data in Supplementary Table S2).

Retention
The Kaplan-Meier-estimated retention of patients at 1 year (day 360) was 80 % for all patients, 80 % for patients in the focal-onset seizure population, and 83 % for patients in the generalized seizure population (Fig. 3).

Seizure outcomes
At baseline, patients in the focal-onset seizure population (FAS) had a median seizure frequency per 28 days of 12.5 for focal-onset seizures and 12.6 for all seizure types (n = 606) (13.0 and 13.0 in patients ≥1 month to <4 years [n = 37]; 12.4 and 12.5 in patients ≥4 to <18 years of age [n = 569]).
In the focal-onset seizure population, median percent reduction from baseline to the end of the treatment period in focal-onset seizure frequency per 28 days was 60.4 %, 50 % responder rate was 55.4 %, and 75 % responder rate was 40.8 %.Median percent reduction from baseline in focal-onset seizure frequency per 28 days, 50 % responder rates, and 75 % responder rates were numerically higher in patients within the focal-onset seizure population who were ≥1 month to <4 years of age than in those ≥4 to <18 years of age (Fig. 4; individual trial data in Supplementary Fig. S1).A similar pattern was seen in the analysis by completer cohort.
In patients exposed to LCM for ≥12 months, a clinically relevant proportion of patients in the focal-onset seizure population and generalized seizure population achieved seizure freedom (all seizure types) for ≥12 months (Fig. 5A).The proportion of patients who achieved ≥12 months of seizure freedom was numerically higher in the focal-onset seizure population than in the generalized seizure population, and numerically higher in patients ≥1 month to <4 years of age than in those ≥4 to <18 years of age within the focal-onset seizure population.
The proportion of patients who were seizure free during the first year of LCM treatment (12-month completer cohort) was similar in all seizure and age subgroups (Fig. 5B; individual trial data in Supplementary Table S4).Among patients treated with LCM for ≥2 years (24-month completer cohort), the proportion of patients with ≥12 months of seizure freedom was numerically higher in the focal-onset seizure population than in the generalized seizure population, and numerically higher in patients ≥1 month to <4 years of age than in those ≥4 to <18 years of age within the focal-onset seizure population (Fig. 5C).

Clinician's and Caregiver's global impression of change
At last evaluation, 76.7 % of all patients were considered by the investigator to have improved (focal-onset seizure population: 75.4 %; generalized seizure population: 95.7 %), 17.4 % of all patients were considered to have had no change (focal-onset seizure population: 18.4 %; generalized seizure population: 2.1 %), and 5.8 % of all patients were considered to have worsened (focal-onset seizure population: 6.1 %; generalized seizure population: 2.1 %) during LCM treatment (Fig. 6A; individual trial data in Supplementary Fig. S2).
At last evaluation, 76.6 % of all patients were considered by the caregiver to have improved (focal-onset seizure population: 76.1 %; generalized seizure population: 85.1 %), 16.6 % of all patients were considered to have had no change (focal-onset seizure population: 17.1 %; generalized seizure population: 8.5 %), and 6.8 % of all patients were considered to have worsened (focal-onset seizure population: 6.9 %; generalized seizure population: 6.4 %) during LCM treatment (Fig. 6B; individual trial data in Supplementary Fig. S2).
The incidence of TEAEs was 82.4 % in the focal-onset seizure population and 89.4 % in the generalized seizure population.The incidence of drug-related TEAEs was numerically higher in patients ≥4 to <18 years of age (39.2 %) than in those ≥1 month to <4 years of age (14.9 %) within the focal-onset seizure population (generalized seizure population: 27.7 %).The proportion of patients with serious TEAEs was numerically higher in the focal-onset seizure population (21.4 %) than in the generalized seizure population (8.5 %), and numerically higher in patients ≥1 month to <4 years of age (26.7 %) than in those ≥4 to <18 years of age (19.0 %) within the focal-onset seizure population.The proportion of patients who discontinued due to TEAEs was similar in the focal-onset seizure population (overall: 5.8 %; patients ≥1 month to <4 years of age: 4.6 %; patients ≥4 to <18 years of age: 6.3 %) and generalized seizure population (6.4 %).
The most common TEAEs (reported in ≥10 % of all patients) were pyrexia, upper respiratory tract infection, nasopharyngitis, vomiting, and somnolence.The most common drug-related TEAEs (reported in ≥5 % of all patients) were somnolence, dizziness, and vomiting.
A total of 16.9 % of patients had ≥1 TEAE related to pediatric growth, neurodevelopment, behavior, or endocrine function.Most of these TEAEs were mild (11.0 %) or moderate (5.7 %); only 1 patient had a severe TEAE related to pediatric growth, neurodevelopment, behavior, or endocrine function (irritability).
Overall, 21 patients (2.3 %) experienced a total of 29 other significant TEAEs.Eight patients experienced TEAEs of suicidal ideation (12 events); 4 patients experienced TEAEs of bradycardia; 3 patients experienced TEAEs of syncope; 2 patients each experienced TEAEs of sinus bradycardia, ECG QT prolonged (3 events), and self-injurious behavior; and 1 patient each experienced an event of defect conduction intraventricular and suicidal attempt (2 events).
One patient died during trial SP848 due to sudden death and 6 patients died during trial EP0034, 1 due to status epilepticus, cardiac arrest, and respiratory failure; 1 due to pneumonia aspiration; 1 due to respiratory failure; 1 due to influenzal pneumonia; 1 due to status epilepticus; and 1 due to death (unknown causes; reported as suspected car accident or suicide attempt).One additional patient died post treatment in trial EP0034 due to respiratory failure.None of these deaths were considered related to LCM by the investigator.

ECG parameters
In the pooled analysis, none of the relatively small changes from baseline in ECG parameters appeared to be clinically relevant.

Behavior, executive functioning, and quality of life
Data from the Achenbach CBCL and BRIEF/BRIEF-P checklists are only reported for all patients in the pooled dataset, due to the low numbers in the generalized seizure population and in the age subgroups of the focal-onset seizure population.
Median time from baseline to last evaluation was 25.2 months for Achenbach CBCL 1.5-5 and 28.8 months for Achenbach CBCL 6-18.In patients 1.5-5 years of age, mean changes from baseline to last evaluation in raw syndrome scores were generally minimal, indicating stability or minimal improvements (SMD = − 0.2 for Sleep Problems and Somatic Complaints) in patients' behavioral and emotional function (Fig. 7A).At last evaluation, most patients (range: 77.6 %-86.2 %) remained in their baseline T-score category ("Normal" or "Borderline or Clinical Range").Of those that changed category, a generally similar proportion of patients worsened and improved in category (Fig. 7B).In patients 6-18 years of age, mean changes from baseline to last evaluation in raw syndrome scores indicated a small improvement in all syndromes (SMD= − 0.2 or − 0.3 for all syndrome scores) (Fig. 7A).At last evaluation, most patients (range: 73.2 %-88.8 %) remained in their baseline T-score category.Of those that changed category, a slightly higher proportion of patients improved (range: 6.9 %-16.7 %) than worsened (range: 2.9 %-10.3 %) for all syndromes (Fig. 7B).Individual trial data are shown in Supplementary Fig. S3.
Median time from baseline to last evaluation was 19.7 months for BRIEF-P and 28.8 months for BRIEF.In patients <5 years of age, mean changes from baseline to last evaluation in BRIEF-P raw subscale scores fluctuated around 0 and were of minimal amplitude, indicating stability in executive functioning (Fig. 7A).At last evaluation, most patients (range: 76.6 %-84.0 %) remained in their baseline T-score category.Of those who changed category, a generally similar proportion of patients worsened and improved in category (Fig. 7B).In patients 5-18 years of age, mean changes from baseline to last evaluation in BRIEF raw subscale scores showed small improvements (SMD = − 0.2 for Inhibit, Shift, Working Memory, Organization of Materials, and Monitor; SMD = − 0.3 for Emotional Control) (Fig. 7A).At last evaluation, most patients (range: 72.1 %-84.8 %) remained in their baseline T-score category.Of those who changed category, a higher proportion of patients improved (range: 9.3 %-18.1 %) than worsened (range: 5.4 %-10.0 %) in all

Fig. 4. Seizure outcomes in patients with FOS from baseline to the end of the entire treatment period and by completer cohort. (A) Median percent reduction in FOS frequency per 28 days; (B) 50 % responder rates for FOS; (C) 75 % responder rates for FOS (pooled population; FAS)
. n is the number of patients with non-missing daily diary data for the specified interval.Completer cohorts were defined as subsets of patients in the FAS who received LCM for a specified duration of time (6, 12, and 24 months, where a month was defined as 28 days), and had seizure diary data available for the specified interval.Baseline seizure frequency per 28 days among the FOS population was 13.0 in the ≥1 month to <4 years group, 12.4 in ≥4 to <18 years group, and 12.5 in all patients in the FOS population.FAS, Full Analysis Set; FOS, focal-onset seizure; LCM, lacosamide.subscales (Fig. 7B).Individual trial data are shown in Supplementary Fig. S4.
Median time from baseline to last evaluation for the PedsQL was 6.4 months for patients 1-12 months of age and patients 13-24 months of age, 14.7 months for patients 2-4 years of age, and 28.9 months for patients ≥5 years of age.Health-related quality of life generally showed small positive numerical changes in most of the subscales, with consistent small improvement across all age subgroups in Emotional Functioning (Fig. 8; individual trial data in Supplementary Fig. S5).

Discussion
In this analysis of a large patient pool from two long-term, open-label trials, adjunctive LCM was efficacious and generally well tolerated in pediatric patients (≥1 month to <18 years of age) with epilepsy.
In the focal-onset seizure population, clinically relevant reduction in seizures was observed (median percent reduction from baseline in focalonset seizure frequency: 60.4 %; 50 % responder rate: 55.4 %; 75 % responder rate: 40.8 %).50 % and 75 % responder rates were within the ranges seen in long-term studies (≥12 months) in clinical practice (50 % responder rate: 38.6 %-69 %; 75 % responder rate: 20.5 %-41 %) [19,21,[24][25][26].Efficacy results were generally consistent with a previous short-term (6-week titration and 10-week maintenance), doubleblind, placebo-controlled trial (SP0969) of LCM in pediatric patients (≥4 to <17 years of age) with focal-onset seizures (median percent reduction in focal seizure frequency per 28 days: 51.7 %; 50 % responder rate: 52.9 %; 75 % responder rate: 31.2 %) [12].In another previous short-term (20-day titration and 7-day maintenance), double-blind, placebo-controlled trial (SP0967) in pediatric patients (≥1 month to <4 years of age) with focal-onset seizures, adjunctive LCM did not show superior efficacy versus placebo based on ≤72 h videoelectroencephalogram (EEG) [14].Patients enrolling from trial SP0967 made up the majority of patients in the ≥1 month to <4 years of age subgroup of the focal-onset population in the current analysis.It is encouraging that a clinically relevant reduction in seizures was seen in this subgroup during long-term adjunctive LCM treatment based on seizure diary data (median percent reduction from baseline in focalonset seizure frequency: 91.5 %; 50 % responder rate: 77.8 %; 75 % responder rate: 69.4 %).This supports the finding that using video-EEG as a measure of efficacy may have contributed to the negative results in the previous trial, and suggests that LCM can be efficacious in pediatric patients ≥1 month to <4 years of age with focal-onset seizures [14,27].
At least 12-month seizure freedom during the LCM treatment period was achieved by 29.9 % of patients in the focal-onset seizure population and 24.4 % of patients in the generalized seizure population (patients with ≥12 months of LCM treatment in the open-label extension) which was slightly higher than the ≥12-month seizure freedom rates reported in patients with focal and generalized seizures in clinical practice (10.2 %-20 %) [19,24,25].The generalized seizure population was small (n = 47), and these data should therefore be interpreted with caution.Further, patients' epilepsy syndromes or etiologies were not consistently collected in these trials, limiting the information available on these patients.These trials were not powered to detect significant differences in efficacy and/or safety between different ASM combinations, limiting the ability to explore this more thoroughly.
Children with epilepsy are at increased risk of cognitive or Seizure freedom was defined as 0 seizures reported and no more than 10 % of days in the specified completer cohort/time interval for which seizure data were not available.N is the number of patients with an evaluable seizure-free status for the specified interval.Completer cohorts were defined as subsets of patients in the FAS who received LCM for a specified duration of time (12 and 24 months, where a month was defined as 28 days), and had seizure diary data available for the specified interval.FAS, Full Analysis Set; FOS, focal-onset seizure; GS, generalized seizure; LCM, lacosamide.
behavioral problems [3,4].Although many ASMs are available for use in the pediatric population [49], some have been associated with negative outcomes on cognition or behavior [5][6][7], highlighting the importance of cognitive and behavioral assessments using validated tools in clinical trials [7].Results from the individual trials were generally aligned with the findings from the pooled analysis.

Conclusions
The results of this pooled analysis of data from two large open-label extension trials showed that long-term adjunctive LCM was efficacious (with clinically relevant ≥12-month seizure freedom rates) and generally well tolerated (with low discontinuation rate due to TEAEs) in pediatric patients with focal-onset or generalized seizures.Behavior and executive functioning were generally stable without observable worsening during long-term adjunctive LCM treatment.Improvement during LCM treatment was reported in >75 % of patients by both physicians and caregivers.

Ethical publications statement
We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Data statement
Underlying data from this manuscript may be requested by qualified researchers 6 months after product approval in the United States and/or Europe, or global development is discontinued, and 18 months after trial completion.Investigators may request access to anonymized individual patient-level data and redacted trial documents, which may include: analysis-ready datasets, study protocol, annotated case report form, statistical analysis plan, dataset specifications, and clinical study report.Before use of the data, proposals need to be approved by an independent review panel at https://www.Vivli.organd a signed data sharing agreement will need to be executed.All documents are available in English only, for a prespecified time, typically 12 months, on a password protected portal.

Role of the funding source
These trials and post hoc analysis were funded by UCB Pharma, which was involved in the design of the trials and post hoc analysis, the collection, analysis, interpretation of data, and manuscript review, and in the decision to publish the manuscript.The authors, some of whom are UCB Pharma employees, were responsible for data interpretation, revising the manuscript for intellectual content, and approving of the manuscript for submission.S Dimova: Data analysis, data interpretation, reviewing/revising the manuscript for intellectual content, and approval of the manuscript for submission.
F Floricel: Data interpretation, reviewing/revising the manuscript for intellectual content, and approval of the manuscript for submission.
C McClung: Data interpretation, reviewing/revising the manuscript for intellectual content, and approval of the manuscript for submission.
B Moseley: Data interpretation, reviewing/revising the manuscript for intellectual content, and approval of the manuscript for submission.
S Therriault: Data interpretation, reviewing/revising the manuscript for intellectual content, and approval of the manuscript for submission.
JE Pina-Garza: Data collection, data interpretation, reviewing/ revising the manuscript for intellectual content, and approval of the manuscript for submission.

Declaration of competing interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MK Farkas and I Makedonska report no conflicts of interest.C Beller, D Bourikas, S Dimova, F Floricel, C McClung, and B Moseley are salaried employees of UCB Pharma and have received UCB Pharma stocks from their employment.C de la Loge (PCOM Analytics, Avallon, France) is contracted by UCB Pharma.S Therriault was an employee of UCB Pharma at the time the trials were conducted.JE Pina-Garza has served as a consultant and speaker for Catalyst Pharmaceuticals, Jazz Pharmaceuticals, Marinus Pharmaceuticals, Neurelis, SK Life Science, and UCB Pharma; and received payment from Elsevier for services as book editor.
Fig. 8. Change from baseline to last evaluation in subscale, summary, and total scores for the PedsQL (pooled population; SS).Baseline data were obtained from the first trial screening visit (core trial screening visit for patients from SP0966, SP0967, and SP0969, or else from the SP848 screening visit; baseline data were not available from core trials SP0847 and EP0060).Last evaluation was the last non-missing assessment during the treatment period.Only includes patients with baseline and ≥1 post-baseline result.Median time from baseline to last evaluation was 6.4 months (n = 25) (1-12 months of age), 6.4 months (n = 31) (13-24 months of age), 14.7 months (n = 153) (2-4 years of age), and 28.9 months (n = 428) (≥5 years of age).Subscale scores are shown in gray, summary scores in blue, and total scores in green.PedsQL, Pediatric Quality of Life Inventory; SD, standard deviation; SMD, standardized mean difference; SS, Safety Set.

Fig. 1 .
Fig. 1.Patients in the pooled dataset.a Seven patients in trial SP848 did not have any seizures recorded in the seizure count history case report form and could not be assigned to the FOS/GS populations.DB, double-blind; FAS, Full Analysis Set; FOS, focal-onset seizure; GS, generalized seizure; OL, open-label; PBO, placebo; SS, Safety Set.

Fig. 3 .
Fig. 3. Kaplan-Meier estimates for time to discontinuation of LCM due to (A) any reason, (B) lack of efficacy a , and (C) TEAEs b (pooled population; SS). a Patients who discontinued for reasons other than lack of efficacy were censored.b Patients who discontinued for reasons other than TEAEs were censored.FOS, focal-onset seizure; GS, generalized seizure; SS, Safety Set; TEAE, treatment-emergent adverse event.

Fig. 5 .
Fig.5.Seizure freedom (all seizure types) for ≥12 months at any time during LCM treatment in (A) patients with ≥12 months of LCM treatment, (B) 12-month completer cohort, and (C) 24-month completer cohort (pooled population; FAS).Seizure freedom was defined as 0 seizures reported and no more than 10 % of days in the specified completer cohort/time interval for which seizure data were not available.N is the number of patients with an evaluable seizure-free status for the specified interval.Completer cohorts were defined as subsets of patients in the FAS who received LCM for a specified duration of time (12 and 24 months, where a month was defined as 28 days), and had seizure diary data available for the specified interval.FAS, Full Analysis Set; FOS, focal-onset seizure; GS, generalized seizure; LCM, lacosamide.

Fig. 7 .
Fig. 7. (A) Mean changes in Achenbach CBCL syndrome scores and BRIEF/BRIEF-P subscales a,b and (B) shift in T-score categories c from baseline to last evaluation (pooled population; SS).Baseline data were obtained from the first trial screening visit (core trial screening visit for patients from SP0966, SP0967, and SP0969, or else from the SP848 screening visit; baseline data were not available from core trials SP0847 and EP0060).Last evaluation was the last non-missing assessment during the treatment period.a Reductions in scores indicate improvements.b Only includes patients with baseline and ≥1 post-baseline result for each syndrome/subscale.c Only patients providing data at both baseline and last evaluation were included for each syndrome/subscale.Median time from baseline to last evaluation was 25.2 months (Achenbach CBCL 1.5-5; n = 196), 28.8 months (Achenbach CBCL 6-18; n = 448), 19.7 months (BRIEF-P; n = 131), and 28.8 months (BRIEF; n = 408).BCR, Borderline or Clinical Range; BRIEF, Behavior Rating Inventory of Executive Function; BRIEF-P, Behavior Rating Inventory of Executive Function-Preschool Version; CBCL, Child Behavior Checklist; SD, standard deviation; SMD, standardized mean difference; SS, Safety Set.

Table 1
Patient baseline demographics and epilepsy characteristics (pooled population; SS).
[51]lative to date of diagnosis.bSeizuresexperiencedatany point before entry into the previous pediatric trial, and at any time before SP848 for direct enrollers.cForpatientsfromprevious trial SP0847 and direct enrollers, no information was collected on generalized and unclassified seizures.dPatientscouldhave>1 response in a classification level and/or category; seizure types are listed per the trial protocol (International League Against Epilepsy 1981 classification[50]), with the newer terminology[51]provided in parentheses.e ASMs stopped before the start of the SP848/EP0034 treatment period and also ASMs taken concomitantly with LCM at the time of first dose of LCM in SP848/EP0034.f ASMs taken concomitantly with LCM at the time of first dose of LCM in SP848/EP0034.ASM, antiseizure medication; FOS, focal-onset seizure; GS, generalized seizure; LCM, lacosamide; Q1, quartile 1; Q3, quartile 3; SD, standard deviation; SS, Safety Set.

Table 2
Incidence of TEAEs during the LCM treatment period (pooled population; SS).