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

Abstract

Objective: Generalized tonic-clonic (GTC) seizures are the most common type of generalized seizure and more common in children than adults. This phase 3 study evaluated the efficacy and safety of pregabalin for GTC seizures in adults and children with epilepsy.

Methods: This randomized, double-blind, multicenter study evaluated pregabalin (5 mg/kg/day or 10 mg/kg/day) vs placebo as adjunctive therapy for 10 weeks (following a 2-week dose escalation), in pediatric and adult patients (aged 5-65 years) with GTC seizures. Primary endpoint was change in log-transformed 28-day seizure rate during active treatment. Secondary endpoints included responder rates, defined as proportion of patients with ≥50% reduction in 28-day GTC seizure rate from baseline. Safety was monitored throughout.

Results: Of 219 patients, 75, 72, and 72 were randomized to adjunctive pregabalin 5 mg/kg/day, 10 mg/kg/day, and placebo, respectively. Fifteen, 11, and 6 patients discontinued from the 5 mg/kg/day, 10 mg/kg/day, and placebo arms, respectively, most commonly due to adverse events (AEs; 10.7%, 6.9%, and 5.6%, respectively). A nonsignificant change in log-transformed mean 28-day seizure rate was seen with pregabalin 10 mg/kg/day vs placebo (least-squares [LS] mean difference -0.01 [95% confidence interval (CI) -0.19 to 0.16]; P = .8889) and with pregabalin 5 mg/kg/day vs placebo (LS mean difference 0.02 [CI -0.15 to 0.19]; P = .8121). Similar observations were noted for adults and children. No significant differences were seen for secondary endpoints with pregabalin vs placebo, including responder rate. The most common AEs (≥10%) were dizziness, headache, and somnolence. Most were of mild/moderate intensity. Seven patients had serious AEs, with one death in the placebo arm (sudden unexpected death in epilepsy).

Significance: Adjunctive pregabalin treatment did not change GTC seizure rate in adults or children. The safety profile of pregabalin was similar to that known; treatment was well tolerated with few discontinuations due to AEs.

Trial registration: ClinicalTrials.gov NCT01747915.

Keywords: antiepileptic drug; epilepsy; generalized tonic-clonic seizures; pregabalin.

FIGURE 1

Flow of patients through the study. ^aPatients continued their AED regimen. ^bAE‐related withdrawals were all considered related to the study drug, with the exception of one patient in the placebo arm (where the AE was considered not to be study drug–related). AE, adverse event and AED, antiepileptic drug

FIGURE 2

28‐day GTC seizure rate during the double‐blind, multicenter study (ITT population; primary endpoint). The primary endpoint was the log‐transformed 28‐day seizure rate for all GTC seizures collected during the double‐blind assessment phase. The ITT population consisted of all randomized patients who took ≥1 dose of investigational product during the 12‐week double‐blind assessment phase, had a baseline value, and ≥1 postbaseline efficacy assessment (diary entry). GTC, generalized tonic‐clonic and ITT, intent‐to‐treat

FIGURE 3

Patients with ≥50% reduction in 28‐day GTC seizure rate (ITT population). A, Overall cohort. B, pediatric patients (aged 5‐16 years), and C, adult patients (aged 17‐65 years). GTC, primary generalized tonic‐clonic and ITT, intent‐to‐treat