Pregabalin as Adjunctive Treatment for Focal Onset Seizures in Pediatric Patients: A Randomized Controlled Trial

Abstract

Efficacy and safety of pregabalin as adjunctive treatment for children (aged 4-16 years) with partial-onset seizures, hereafter termed focal onset seizures for this study, was evaluated. This double-blind, randomized, placebo-controlled, international study had 3 phases: 8-week baseline, 12-week double-blind treatment (2-week dose escalation; 10-week fixed dose), and 1-week taper. Selection criteria included experiencing focal onset seizures and receiving a stable regimen of 1 to 3 antiepileptic drugs. Study treatments were pregabalin 2.5 mg/kg/d, 10 mg/kg/d, or placebo; doses were increased to 3.5 or 14 mg/kg/d for subjects weighing <30 kg. The key endpoints were change in log e (28-day seizure rate), achieving a !50% seizure responder rate, safety, and tolerability during double-blind treatment. Subjects (n ¼ 295; mean age 10.2 years, 55% male, 69% white) were randomized to pregabalin 2.5 mg/kg/d (n ¼ 104), 10 mg/kg/d (n ¼ 97), or placebo (n ¼ 94). A statistically significant reduction in log e (28-day seizure rate) was demonstrated with pregabalin 10 mg/kg/d (a 19.9% improvement over placebo; P ¼ .0185). Seizure frequency was numerically improved (statistically nonsignificant) with pregabalin 2.5 mg/kg/d (P ¼ .2577). Responder rate significantly favored pregabalin 10 mg/kg/d (40.6%, P ¼ .0068) compared with placebo (22.6%) and was numerically improved with pregabalin 2.5 mg/kg/d (29.1%, P ¼ .2600). Common adverse events (!10% of any group) in 10 mg/kg/d, 2.5 mg/kg/d, and placebo groups, respectively, included somnolence (25.8%, 17.3%, 13.8%), increased weight (13.4%, 3.8%, 4.3%), and increased appetite (10.3%, 6.7%, 4.3%). Pregabalin 10 mg/kg/d demonstrated efficacy in seizure frequency reduction in children with focal onset seizures compared with placebo, and both pregabalin doses were generally safe and well tolerated. www.clinicialtrials.gov identifier NCT01389596; EudraCT #2010-020852-79

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

“…Pregabalin 7 mg/kg/d did not show improvement in V‐EEG log e (24‐hour seizure rate + 1) from baseline to end of study in comparison with placebo ( P = .461; Figure 2). The lack of efficacy seen at the lower dose of pregabalin in these children, aged 1 month to <4 years, is similar to the observation seen in older children (4‐16 years) reported from a previously published study . Although the reduction in seizure frequency with lower doses in both studies was not significant, the impact of the relatively high placebo effect in the studies may confound evaluation of the lower doses of pregabalin studied.…”

“…The safety and tolerability assessment indicated that pregabalin administered at both 7 mg/kg/d and 14 mg/kg/d was well tolerated within this pediatric population. Consistent with the clinical trial of children aged 4 to 16 years, the most common TEAE in both pregabalin groups in this trial was somnolence. However, in contrast to older children, weight gain and increased appetite were not commonly reported in children under 4 years.…”

“…Consistent with the clinical trial of children aged 4 to 16 years, the most common TEAE in both pregabalin groups in this trial was somnolence. However, in contrast to older children, weight gain and increased appetite were not commonly reported in children under 4 years. Only one discontinuation in the current study's placebo group was due to an AE, and no AE‐associated discontinuations occurred in either pregabalin group.…”

“…The significant reduction in seizure rate from baseline with pregabalin 14 mg/kg/d versus placebo in the current study is consistent with the primary efficacy outcome in older children with FOS. In a previously published phase III study (NCT01389596; A0081041), children aged 4‐16 years treated with pregabalin (10 mg/kg/d) experienced significant seizure reduction from baseline to the end of treatment compared with patients treated with placebo …”

“…Compared with the adult data, these data showed that pregabalin clearance, normalized for body weight, is higher in pediatric patients weighing <30 kg relative to adults and children weighing >30 kg. In addition, a multinational, double‐blind, randomized, placebo‐controlled trial evaluated pregabalin in pediatric patients with FOS aged 4‐16 years and demonstrated efficacy with pregabalin 10 mg/kg/d compared with those treated with placebo …”