title: Early-stage comparative effectiveness: randomized controlled trial with histamine inverse agonist MK-7288 in excessive daytime sleepiness patients.
abstract: 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 prolonged MWT sleep 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 -0.1 m 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 cost-effectiveness of drug development.
authors.affiliation: Merck & Co., Inc., Whitehouse Station, NJ, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Sun
authors.forename: Catherine
authors.initials: C
authors.lastname: MacLeod
authors.forename: Kate
authors.initials: K
authors.lastname: Mostoller
authors.forename: Chantal
authors.initials: C
authors.lastname: Mahon
authors.forename: Lingling
authors.initials: L
authors.lastname: Han
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
authors.forename: Junshui
authors.initials: J
authors.lastname: Ma
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Brown
authors.forename: Valerie
authors.initials: V
authors.lastname: Schulz
authors.forename: Gary G
authors.initials: GG
authors.lastname: Kay
authors.forename: W Joseph
authors.initials: WJ
authors.lastname: Herring
authors.forename: Christopher
authors.initials: C
authors.lastname: Lines
authors.forename: Laura B
authors.initials: LB
authors.lastname: Rosen
authors.forename: M Gail
authors.initials: MG
authors.lastname: Murphy
authors.forename: John A
authors.initials: JA
authors.lastname: Wagner
mesh_terms: D000328:Adult; D018592:Cross-Over Studies; D006970:Disorders of Excessive Somnolence / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D017442:Histamine Agonists / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D013141:Spiro Compounds / Q000627:therapeutic use*; D016896:Treatment Outcome; D014851:Wakefulness / Q000187:drug effects; D064690:Wakefulness-Promoting Agents / Q000627:therapeutic use*
chemical_list: D017442:Histamine Agonists; C000589274:MK-7288; D013141:Spiro Compounds; D064690:Wakefulness-Promoting Agents
keywords: MK-7288; excessive daytime sleepiness; histamine subtype-3 receptor; modafinil; obstructive sleep apnea; randomized trial