Antiepileptic Drug Monotherapy Designs in Clinical Trials

Abstract

SummaryEvaluation of new antiepileptic drugs (AEDs) in monotherapy used to be performed by comparative trials between new AEDs and classical AEDs. However, the majority of these studies showed no difference in outcome, which could result in conflicting interpretations. Therefore, novel designs that avoid this problem have been developed to evaluate new AEDs. Three approaches have been proposed, each with advantages and disadvantages. The attenuated active control design compares new AEDs to suboptimal doses of a control AED. However, this situation brings about ethical concerns and strict entry criteria must be applied. The presurgical design compares new AEDs to placebo treatment. Rapid dose escalation to the therapeutic level of the new AED must be undertaken to avoid seizures resulting from extended suboptimal doses of the AED, and ethical concerns about the use of placebo also apply. The concentration controlled design is based on the assumption that a stronger correlation exists between drug blood level and therapeutic response in comparison to correlation between dose and effect. In this design, patients are randomized to be treated with different blood concentrations of a new AED, and efficacy data at these different concentrations are compared. All of these designs allow a definitive demonstration of efficacy early in the development of a new AED.