Pregabalin adjunctive therapy for focal onset seizures in children 1 month to <4 years of age: A double‐blind, placebo‐controlled, video‐electroencephalographic trial

Abstract

Objective: To evaluate the efficacy and safety of pregabalin as adjunctive treatment for children (aged 1 month-<4 years) with focal onset seizures (FOS) using videoelectroencephalography (V-EEG). Methods: This randomized, placebo-controlled, international study included V-EEG seizure monitoring (48-72 hours) at baseline and over the last 3 days of 14-day (5-day dose escalation; 9-day fixed dose) double-blind pregabalin treatment (7 or 14 mg/kg/d in three divided doses). This was followed by a double-blind 1-week taper. The primary efficacy endpoint was log-transformed seizure rate (log e [24-hour seizure rate + 1]) for all FOS recorded during the double-blind V-EEG monitoring, evaluated in subjects who took ≥1 dose of study medication, experienced ≥1 baseline seizure(s), and had a treatment phase V-EEG. Safety and tolerability were assessed by adverse events (AEs), clinical laboratory data, physical/neurological examinations, vital signs, and electrocardiograms. Results: Overall, 175 patients were randomized (mean age = 28.2 months; 59% male, 69% white, 30% Asian) in a 2:1:2 ratio to pregabalin 7 or 14 mg/kg/d (n = 71 or n = 34, respectively), or placebo (n = 70). Pregabalin 14 mg/kg/d (n = 28) resulted in a statistically significant 35% reduction of log e (24-hour seizure rate + 1) versus placebo (n = 53; P = .022), an effect that was not observed with pregabalin 7 mg/kg/d (n = 59; P = .461). The most frequently reported treatment-emergent AEs for pregabalin 7 mg/kg/d, 14 mg/kg/d, and placebo, respectively, were somnolence (11.3%, 17.6%, and 5.7%) and upper respiratory tract infection (7.0%, 11.8%, and 11.4%). All AEs were mild to moderate in severity. |MANN et Al.

Pregabalin Population Pharmacokinetic and Exposure‐Response Analyses for Focal Onset Seizures in Children (4–16 years) and Adults, to Support Dose Recommendations in Children

“…The pregabalin pediatric FOS program was started in 2005, prior to regulatory guidelines on Paediatric Investigational Plans (PIP), 19 Pediatric Study Plans (PSP), 11 and the acceptance of efficacy extrapolation by the FDA from adult to pediatric patients with FOS. 11 , 12 The program included a phase I PK study in pediatric patients with FOS (1 month to 16 years), 10 and two randomized, double‐blind, placebo‐controlled efficacy and safety studies in pediatric patients with FOS, aged 4–16 years (PERIWINKLE) 4 or 1 month to < 4 years, 20 in addition to long‐term safety and tolerability assessments. Shortly before completion of PERIWINKLE in 2016, the FDA announced that efficacy data could be extrapolated from adults to represent pediatric patients with FOS, 21 in order to improve pediatric drug development efficiency and early access to therapeutics.…”

Pregabalin as adjunctive therapy in adult and pediatric patients with generalized tonic‐clonic seizures: A randomized, placebo‐controlled trial

“…As such, 66 children were recruited, of whom 48 were treated with pregabalin, thus adding to the safety information already available for pregabalin in children with epilepsy. [17][18][19] Importantly, no new safety signals were seen in these 48 children (4-16 years) with GTC seizures who received adjunctive pregabalin. AEs commonly observed in pediatric patients with FOS include somnolence and weight gain, [17][18][19] both of which were observed in ≥10% of patients in this GTC population, suggesting the safety profile of pregabalin is consistent regardless of seizure type.…”

“…[17][18][19] Importantly, no new safety signals were seen in these 48 children (4-16 years) with GTC seizures who received adjunctive pregabalin. AEs commonly observed in pediatric patients with FOS include somnolence and weight gain, [17][18][19] both of which were observed in ≥10% of patients in this GTC population, suggesting the safety profile of pregabalin is consistent regardless of seizure type. The discontinuation rate due to AEs was relatively low (10.7%, 6.9%, and 5.6% with pregabalin 5 mg/kg/ day, 10 mg/kg/day, and placebo, respectively), although we observed higher discontinuation rates due to AEs in adults (12.2%, 10.0%, and 7.4%, respectively) than in children (2%, 0%, and 0%, respectively).…”

“…This study specifically recruited patients aged <16 years, per requirements from the FDA for this postmarketing safety commitment. As such, 66 children were recruited, of whom 48 were treated with pregabalin, thus adding to the safety information already available for pregabalin in children with epilepsy 17‐19 . Importantly, no new safety signals were seen in these 48 children (4‐16 years) with GTC seizures who received adjunctive pregabalin.…”

“…16 Pregabalin is an alpha-2-delta ligand, approved in certain countries as adjunctive therapy for partial-onset seizures in adults and pediatric patients from 1 month or older. 17 Efficacy data have demonstrated that pregabalin reduces seizure frequency in patients with focal-onset seizures (FOS) [18][19][20][21][22][23][24] (according to ILAE 2017 terminology, FOS will be used throughout 4 ). For example, a ≥50% reduction in seizure frequency was observed in 43%-51% of adults receiving pregabalin 600 mg/day [20][21][22]24 and 41% of pediatric patients (aged 4-16 years) receiving pregabalin 10 mg/kg/day.…”