Proof of principle trials: EEG surrogate endpoints

Abstract

Pivotal studies in man require prolonged administration to demonstrate efficacy for most seizure types. Earlier evidence of human efficacy can be of value for decision making, and EEG surrogate endpoints can be of value in this respect. Studies of spontaneous EEG discharges under standard recording conditions can demonstrate meaningful acute EEG effects of antiepileptic drugs (AEDs). These require a rapidly effective formulation of the product, preferably intravenous. The EEG recording conditions are standardised and the subject is required to perform a task to maintain a constant level of vigilance. The outcome measure of efficacy is spike count per minute or, if the discharges are more protracted (as generalised no spike and wave), the percentage of recording time occupied by discharges. Sub-acute experiments are conducted under less rigorously standardised conditions, but over longer periods, using ambulatory monitoring or telemetry to record the EEG. The photoparoxysmal responses (PPRs) of photosensitive subjects, evoked using a standardised stimulation protocol, are subject to less variability than spontaneous epileptiform activity. The PPR is elicited over a range of flash rates that can be used as a measure of sensitivity, and an effective treatment will reduce the range or abolish the PPR. Reduction in photosensitivity is demonstrable after a single dose of various AEDs, at clinically relevant plasma concentrations, even using drugs that are not generally effective for long-term treatment of photosensitive epilepsy. Evoked potential and nerve conduction studies and electronystagmography can be used to assess possible neurotoxicity, and quantitative EEG analysis can be employed to assess sedative effects.