Monotherapy comparative trials: placebos and suboptimal comparators.

Abstract

The superiority of a drug can be demonstrated using several comparative designs against either placebo, or a low dose of the study drug or standard anti-epileptic drug (AED). Firstly, the population could consist of inpatients admitted for presurgical monitoring. Although these trials are scientifically interpretable, and involve direct comparison of the study drug against placebo, they are, in general, too short in duration to be able to define clinical relevance. Secondly, patients with refractory epilepsy can participate in monotherapy substitution studies during which patients are randomised to one of at least two arms with the baseline AED subsequently tapered and discontinued. These patients are maintained on monotherapy for the rest of the trial. An enriched design can also be used in which patients successfully converted to a high dose of the study drug, are then randomised to either the high or low dose of the treatment. The ethics of such enriched designs is questionable. More recently, studies have been carried out in patients with new onset seizures. In such designs, patients are randomised to the study drug (possibly at different dosages), versus a placebo or pseudo-placebo control. Comparative trials in patients with newly-diagnosed epilepsy makes it more difficult to obtain significant differences due to the high number of patients needed and the usually lengthy time course of the study.