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 = 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 = 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 = 0.97; 5-mg/kg/d dose: p = 0.91). Treatment-emergent fever, diarrhea, vomiting, anorexia, weight decrease, somnolence, and viral infection occurred more frequently (> or = 10% difference) with topiramate than with placebo.

Conclusion: In infants aged 1-24 months, topiramate 5, 15, or 25 mg/kg/d was not effective as adjunctive treatment for refractory partial-onset seizures. No new safety concerns associated with topiramate use were noted.

Classification of evidence: This interventional study provides Class I evidence that topiramate 5, 15, or 25 mg/kg/d compared with placebo does not significantly reduce seizure rates in infants aged 1 month to 2 years with refractory partial-onset seizures.

Figure 1 Patient disposition in the double-blind phase (intent-to-treat analysis set) “Other” reasons for withdrawal included meeting the escape criterion, doubling of seizure rate, multiple seizures, more than 1 dose reduction, incorrect dosing, withdrawal of consent, and unknown. AE = adverse event.

Figure 2 Percentage reduction in partial-onset seizures from baseline to the end of double-blind treatment period Based on modified intent-to-treat analysis set; n = 28 (placebo), 34 (topiramate [TPM] 5 mg/kg/d), 34 (TPM 15 mg/kg/d), 34 (TPM 25 mg/kg/d). Based on video-EEG data; for infants who had 0 baseline seizures and the postseizure number was greater than 0, value −8,999 was imputed as the percent reduction in accordance with the worst-rank analysis. Differences in interpretation of the baseline video-EEG between the investigator and the blinded central reader resulted in infants with 0 baseline seizures per the central reader entering the study. The lower and higher boundaries of the boxes are the 25th and 75th percentiles. Whiskers below and above indicate the 10th and 90th percentiles. The solid lines within the boxes mark the medians. Outlying data points are extreme values. 25-mg/kg/d dose: p = 0.97; 15-mg/kg/d dose: p = 0.97; 5-mg/kg/d dose: p = 0.91 vs placebo.

Figure 3 Treatment-emergent adverse events experienced by ≥5% of patients in any of the topiramate groups Based on safety analysis set (n = 149). For each of the treatment-emergent adverse events, data for all treatment groups are shown, but there were many points of overlap among groups. TPM = topiramate.