Efficacy and tolerability of adjunctive lacosamide in patients aged <4 years with focal seizures

Abstract

Objective: Primary objective was to evaluate efficacy of lacosamide administered concomitantly with 1-3 antiseizure medications in young children with uncontrolled focal (partial-onset) seizures.

Methods: Double-blind, parallel-group trial (SP0967: NCT02477839/2013-000717-20) conducted between June 2015 and May 2020 at hospitals and clinics in 25 countries. Patients (aged ≥1 month to <4 years) with uncontrolled focal seizures were randomized 1:1 to adjunctive lacosamide or placebo using an interactive voice/web response system and stratified by age. After a 20-day titration period, patients who reached target-dose range (8-12 mg/kg/day) entered a 7-day maintenance period. Region-specific primary efficacy variables were based on ≤72-h video-electroencephalograms: change in average daily frequency (ADF) of electrographic focal seizures as measured on end-of-maintenance video-electroencephalogram versus end-of-baseline video-electroencephalogram (United States); 50% responder rate (≥50% reduction in ADF of focal seizures) during maintenance (European Union).

Results: In total, 255 patients were randomized (lacosamide/placebo: 128/127) and received ≥1 trial medication dose. Percentage reduction in ADF of focal seizures for lacosamide (116 patients) versus placebo (120 patients) was 3.2% (95% confidence interval = -13.6 to 17.5, p = 0.69). 50% responder rate was 41.4% for lacosamide (116 patients), 37.5% for placebo (120 patients) (p = 0.58). Treatment-emergent adverse events were reported by 44.5% of lacosamide-treated patients (placebo 51.2%).

Interpretation: Adjunctive lacosamide did not show superior efficacy versus placebo in young children with focal seizures. However, efficacy variables were potentially affected by high variability and low reliability between readers in video-electroencephalogram interpretation. Lacosamide was generally well tolerated; safety profile was acceptable and consistent with that in adults and children aged ≥4 years.

Figure 1

SP0967 trial design. PBO, placebo. ^aA blinded 12‐day transition period was required for eligible patients who completed the maintenance period and were entering the open‐label extension trial EP0034. During this period, patients on lacosamide remained on their maintenance dose, whereas patients on PBO were transitioned in a double‐blind manner to lacosamide 8 mg/kg/day. At visit 1 of EP0034 (the final transition visit of SP0967), all patients were to be transitioned to lacosamide 10 mg/kg/day.

Figure 2

Patient disposition.

Figure 3

Analyses of (A) change in 50% responder rate^a from the EOB to the EOM and (B) seizure‐free status^b (FAS). ADF, average daily frequency; CI, confidence interval; EOB, end‐of‐baseline period; EEG, electroencephalogram; EOM, end‐of‐maintenance period; FAS, full analysis set. ^aThe 50% responder rate was the proportion of patients who experienced a ≥50% reduction in ADF of electrographic focal seizures recorded on the EOM video‐EEG compared with the EOB video‐EEG. Patients with 0 seizures on the EOB video‐EEG were considered nonresponders. The analysis consists of all patients in the FAS who had ≥48 h of interpretable recording during both the EOB and the EOM video‐EEGs. Patients who had ≥48 h of interpretable recording during the EOB video‐EEG, but who discontinued the trial before the first 48 h of the EOM video‐EEG for reasons related to lack of efficacy, were considered nonresponders and were included in the analysis, whereas all other patients were excluded from the analysis. Note that no patients in the trial discontinued due to lack of efficacy. Odds ratio, 95% CI, and p‐value were from a logistic regression model with factors for treatment, pooled randomized age stratum, and pooled center. ^bPercentages were based on the number of patients in the FAS who completed ≥48 h of interpretable recording during the EOM video‐EEG. A patient was considered seizure‐free from all seizures if the EOM video‐EEG had 0 seizures reported. A patient was considered seizure‐free from focal seizures if the EOM video‐EEG had 0 focal seizures reported.

Figure 4

Proportion of patients who experienced a reduction, no change response, or increase response in ADF of electrographic focal seizures from the EOB to the EOM^a (full analysis set). ADF, average daily frequency; EEG, electroencephalogram; EOB, end‐of‐baseline period; EOM, end‐of‐maintenance period. ^aPercentages were based on the number of patients in the full analysis set who had ≥48 h of interpretable recording during both the EOB and the EOM video‐EEGs. A ≥25% to <50% response was defined as a ≥25% to <50% reduction in ADF of electrographic focal seizures from the EOB video‐EEG to the EOM video‐EEG. A ≥50% to ≤75% response was defined as a ≥50% to ≤75% reduction in ADF of electrographic focal seizures from the EOB video‐EEG to the EOM video‐EEG. A >75% response was defined as a >75% reduction in ADF of electrographic focal seizures from the EOB video‐EEG to the EOM video‐EEG. No change was defined as between a <25% reduction and <25% increase in ADF of electrographic focal seizures from the EOB video‐EEG to the EOM video‐EEG. An increase was defined as a ≥25% increase in ADF of electrographic focal seizures from the EOB video‐EEG to the EOM video‐EEG.