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

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.

Long-term incobotulinumtoxinA treatment for chronic sialorrhea: Efficacy and safety over 64 weeks.

BACKGROUND: Botulinum neurotoxin (BoNT) is an effective treatment for chronic sialorrhea; however, reliable and robust evidence supporting long-term efficacy and safety is lacking. This study investigated the efficacy and safety of repeated incobotulinumtoxinA injections for chronic sialorrhea over 64 weeks. METHODS: Adults with sialorrhea were randomized (2:2:1) to incobotulinumtoxinA 75 U, incobotulinumtoxinA 100 U (n = 74 each), or placebo (n = 36) in the double-blind, placebo-controlled main period (NCT02091739). Eligible subjects entered the extension period and received dose-blinded incobotulinumtoxinA 75 or 100 U in three further 16±2-week injection cycles. Efficacy and safety assessments in subjects who received incobotulinumtoxinA throughout the study included unstimulated salivary flow rate (uSFR), subjects' Global Impression of Change Scale (GICS), Drooling Severity and Frequency Scale (DSFS), modified Radboud Oral Motor Inventory for Parkinson's Disease (mROMP) drooling, speech, and swallowing symptom scores, and incidence of adverse events (AEs). RESULTS: In total, 173/184 subjects (94%) completed the main period and entered the extension period; 141 subjects received incobotulinumtoxinA 75 U (n = 69) or 100 U (n = 72) in both periods. Mean uSFR decreased consistently with repeated incobotulinumtoxinA 75 and 100 U treatment and by -0.16 and -0.17, respectively, at the end-of-study visit. Subjects' GICS, DSFS, and mROMP drooling scores also improved at all assessments. mROMP speech and swallowing scores remained stable. The most common treatment-related AEs during the extension period were dry mouth (4.4% and 11.1%) and dysphagia (1.5% and 4.2%). CONCLUSIONS: Data support long-term efficacy and safety of repeated incobotulinumtoxinA treatment for sialorrhea, with no additional safety concerns reported over 64 weeks.

SIAXI: Placebo-controlled, randomized, double-blind study of incobotulinumtoxinA for sialorrhea.

OBJECTIVE: This pivotal phase III study, SIAXI, investigated the efficacy and safety of incobotulinumtoxinA for the treatment of chronic sialorrhea due to Parkinson disease (PD), atypical parkinsonism, stroke, or traumatic brain injury (TBI). METHODS: Adult patients with PD (70.7%), atypical parkinsonism (8.7%), stroke (19.0%), or TBI (2.7%) were randomized (2:2:1) to double-blind treatment with placebo (n = 36), or total doses of incobotulinumtoxinA 75 U (n = 74) or 100 U (n = 74), in a single treatment cycle. The coprimary endpoints were change in unstimulated salivary flow rate from baseline to week 4, and patients' Global Impression of Change Scale score at week 4. Adverse events were recorded throughout. RESULTS: A total of 184 patients were randomized. Both incobotulinumtoxinA dose groups showed reductions in mean unstimulated salivary flow rate at week 4, with a significant difference vs placebo in the incobotulinumtoxinA 100 U group (p = 0.004). Patients' Global Impression of Change Scale scores also improved at week 4, with a significant difference vs placebo in the incobotulinumtoxinA 100 U group (p = 0.002). A lasting effect was observed at week 16 post injection. The most frequent treatment-related adverse events in the incobotulinumtoxinA 75 U and 100 U groups were dry mouth (5.4% and 2.7% of patients) and dysphagia (2.7% and 0.0% of patients). CONCLUSIONS: IncobotulinumtoxinA 100 U is an effective and well-tolerated treatment of chronic sialorrhea in adults. CLINICALTRIALSGOV IDENTIFIER: NCT02091739. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that incobotulinumtoxinA reduces salivary flow rates in patients with chronic sialorrhea due to PD, atypical parkinsonism, stroke, or TBI.