Randomized trial of adjunctive topiramate therapy in infants with refractory partial seizures

Abstract

Objective: To evaluate the efficacy and safety of adjunctive topiramate (sprinkle capsules or oral liquid) in reducing daily rates of partial-onset seizures (POS) in infants with refractory POS. Methods:In this double-blind, placebo-controlled, parallel-group, international study, infants (n ϭ 149) with clinical or EEG evidence of refractory POS were randomly allocated (1:1:1:1) to receive adjunctive topiramate 5, 15, or 25 mg/kg/d or placebo for 20 days. The primary variable was the median percentage reductions in daily POS rate from baseline to final assessment as recorded on a 48-hour video-EEG. Results:Of the 149 infants (mean age 12 months) included in the intent-to-treat analysis set, 130 completed the study. Median percentage reduction from baseline in daily POS rate was not significantly different (p ϭ 0.97) between topiramate 25 mg/kg (20.4%) and placebo (13.1%). Lower doses were not formally tested, but nominal p values for comparisons with placebo were not significant (15-mg/kg/d dose: p ϭ 0.97; 5-mg/kg/d dose: p ϭ 0.91). Treatment-emergent fever, diarrhea, vomiting, anorexia, weight decrease, somnolence, and viral infection occurred more frequently (Ն10% difference) with topiramate than with placebo. The incidence of newly diagnosed epilepsy is highest in the first year of life and includes many syndromes that are unique and are difficult to diagnose and classify. Conclusion:1,2 Also, seizure types and epilepsy syndromes evolve with age, making accurate diagnoses difficult or retrospectively incorrect in up to 25% of cases. 3,4 Contributing to the treatment challenges, many randomized controlled trials of newer antiepileptic drugs (AEDs) did not assess efficacy in children, and most available AEDs have not been rigorously investigated in infants, leaving physicians with incomplete data on which to base treatment decisions.5 A sizeable number of epilepsy syndromes are significantly different from those in adults. Therefore, clinical trial design in this population requires careful evaluation and must be different from adult trials.6 Drug dosing is also more difficult in children and often requires adjustment as the child matures. e-Pub ahead of print on January 20, 2010, at www.neurology.org. Investigators and institutions at which trials were performed are listed in appendix e-1 on the Neurology ® Web site at www.neurology.org.

Long-Term Open-Label Study of Adjunctive Topiramate in Infants With Refractory Partial-Onset Seizures

“…The phase-1 study 17 consisted of a 7-day pretreatment phase, an up to 6 weeks randomized open-label ''core'' treatment phase (to evaluate the pharmacokinetics, safety, and tolerability of topiramate administered at fixed dosages of 3, 5, 15, and 25 mg/kg/d), an optional 54 weeks open-label extension phase, and a posttreatment phase. The phase-3 controlled study 18 included a 3-day screening phase, a 20-day randomized, placebo-controlled, double-blind ''core'' phase (to evaluate the efficacy, safety, and tolerability of topiramate administered at dosages of 5, 15, and 25 mg/kg/d), a 1-year open-label extension phase and a posttreatment phase. Seventy-four centers in 24 countries (from America, Asia, Australia, and Europe) participated in the open-label extension phase of these studies.…”

“…Fifty-eight infants (20%) had been withdrawn from the studies when the open-label extension phases were terminated early by the sponsor, because efficacy was not demonstrated in the ''core'' double-blind phase of the phase-3 controlled study. 18 Otherwise, major reasons for voluntary discontinuation were withdrawal of consent (30 infants, 11%) or 'other' (30 infants, 11%), which was most commonly related to lack of efficacy (especially in infants coming from the phase-3 controlled study).…”

“…The ''core'' phase of 1 of the studies was open label 17 and for the other was double blind. 18 Both studies had a 1-year open-label extension phase. The open-label extension phase of each study was prematurely terminated when the 20-day ''core double-blind phase'' of the phase-3 controlled study 18 did not demonstrate efficacy of adjunctive topiramate (up to 25 mg/kg/d) in the treatment of partial-onset seizures in infants, in contrast to earlier retrospective data that suggested topiramate was efficacious in infants with refractory epilepsy.…”

“…18 Both studies had a 1-year open-label extension phase. The open-label extension phase of each study was prematurely terminated when the 20-day ''core double-blind phase'' of the phase-3 controlled study 18 did not demonstrate efficacy of adjunctive topiramate (up to 25 mg/kg/d) in the treatment of partial-onset seizures in infants, in contrast to earlier retrospective data that suggested topiramate was efficacious in infants with refractory epilepsy. 14 Here, we report the long-term (up to 1 year) safety, tolerability, and effectiveness data of adjunctive topiramate in treating infants with refractory partial-onset seizures.…”

Plasma topiramate concentrations resulting from doses associated with neuroprotection against white matter injury and stroke in two strains of rat pups

“…TPM may be suitable for human newborn neuroprotection trials because it is approved by the Food and Drug Administration for the prevention of seizures in children older than 2 y and has been safely given to infants as young as 1 mo of age (7). It has also been safely administered to neonates with HI encephalopathy who underwent therapeutic hypothermia (8,9).…”