Abstracts

Rationale: Pregabalin (PGB) is registered for adjunctive treatment of partial onset seizures (POS) in many countries. This study investigated the efficacy and safety of PGB monotherapy for POS, using a historical-controlled conversion-to-monotherapy (CTM) design recently endorsed by an advisory panel of the US Food and Drug Administration (FDA). CTM trials employing an internal control of ‘pseudo-placebo', used in the past to support FDA approval of antiepileptic drug (AED) monotherapy, are not favored in contemporary epilepsy research due to ethical concerns. This is the second reported historical-controlled trial of AED monotherapy. Methods: Patients with POS and inadequate seizure control (≥4 partial seizures during an 8-week baseline phase) while on 1 or 2 AEDs were randomized to double-blind monotherapy with PGB 600 or 150 mg/day (4:1) at 54 centers in the US, Hong Kong, Ukraine, and Czech Republic. Following an 8-week prospective baseline phase, patients entered a 20-week double-blind phase comprising an 8-week conversion period (during which PGB dose was escalated and other AEDs tapered) and a 12-week monotherapy period. Primary endpoint was the seizure-related exit rate in the 600 mg/day group, based on discontinuations due to predefined exit criteria. Efficacy was declared if the upper limit of the 95% confidence interval (CI) for the exit rate was below a historical-control threshold of 74%. If successful, testing proceeded to step-wise evaluation using a threshold of 68%. Following an interim analysis, the trial was stopped early for efficacy. Results: Results for the interim analysis (n=134, with 125 evaluable for efficacy) and full study population (n=161, with 148 evaluable for efficacy) are shown in Table 1. Interpretation of PGB 150 mg/day results must reflect the small sample size. For the full study population: At screening, 70.2% of patients were receiving 1 and 29.8% 2 AEDs. Common seizure types during baseline included complex partial seizures (64.9% of patients) and simple partial seizures (62.8%). Overall, 58.3% of patients in the 600 mg/day group, and 53.6% in the 150 mg/day group, completed 20 weeks' double-blind treatment without experiencing an exit criterion. Seizure-related exit rate in the 600 mg/day group (27.5%; 95% CI 17.8, 37.2) was significantly below both the 74% and 68% thresholds. Eight patients on 600 mg/day and 2 on 150 mg/day were seizure-free throughout the PGB monotherapy period. The overall safety profile of PGB was consistent with prior trials. One patient on PGB 600 mg/day died of cardiorespiratory arrest (probable SUDEP) which was considered not treatment-related. Conclusions: This historical-controlled study showed that PGB 600 mg/day was safe and demonstrated efficacy as monotherapy for patients with POS and inadequate seizure control while receiving 1 or 2 AEDs.