Cognitive testing in early phase clinical trials: outcome according to adverse event profile in a Phase I study.

摘要

BACKGROUND: It has been proposed that objective cognitive testing provides additional information to that collected via adverse event (AE) recordings. However, in clinical trials of compounds with potentially negative effects on cognition, the results of cognitive testing may overlap with AE recordings. AIMS: To examine cognitive function in subjects who do and do not report sedation-related AEs in a Phase I clinical trial. METHODS: Five computerized cognitive tasks were administered to 28 healthy male volunteers enrolled in a simulated Phase I study using midazolam to induce sedation-related AEs and cognitive dysfunction. For each subject, the magnitude of cognitive change between pre-dose and 1 hr post-dose assessments was calculated. Group and individual level cognitive outcome was compared between subjects who did and did not report sedation-related AEs following administration of 1.75 and 5.25 mg midazolam. RESULTS: At both doses of midazolam, cognitive dysfunction was observed in both subject groups (i.e., those who did and did not report AEs). Analysis of individual outcomes identified consistent cognitive dysfunction among subjects who reported sedation-related AEs. Further, in the 5.25 mg condition a subset of individuals (66.7%) who did not report sedation-related AEs nevertheless displayed substantial cognitive dysfunction. CONCLUSIONS: Following administration of oral midazolam, there is a dissociation between sedation-related AE recordings and performance on computerized cognitive tests of motor function, attention, strategy use and problem solving, learning and delayed recall. Inclusion of computerized cognitive tests in early phase trials may allow identification of subtle cognitive change, beyond that which is possible by self-report and clinical observation.