Early-stage comparative effectiveness: Randomized controlled trial with histamine inverse agonist mk-7288 in excessive daytime sleepiness patients

Histaminergic neurons are regulators of the sleep.wake cycle. We evaluated the alerting effects of MK]7288 (10, 20 mg), a novel histamine]3 receptor inverse agonist (H3RIA), along with modafinil (200 mg), a standard treatment, in a randomized, double]blind, placebo controlled, crossover study of 56 patients with excessive daytime sleepiness (EDS). Efficacy was assessed using maintenance of wakefulness tests (MWT) and car driving simulation tests. MK]7288 and modafinil significantly prolongedMWTsleep latency (improvements vs. placebo of 8.1 to 8.2 min for MK]7288 and 10.2 min for modafinil), and improved car driving simulation standard deviation of lane position (reduction vs. placebo of 0.1m for each treatment). MK]7288 was associated with more insomnia (29%) than modafinil (9%) and placebo (6%). The study demonstrated the potential of the H3RIA mechanism for treating EDS, but did not show efficacy differentiation from modafinil. Early]stage comparative effectiveness can help prevent late]stage failure and increase the costeffectiveness of drug development.