Journal ArticleDOI
Pitolisant versus placebo or modafinil in patients with narcolepsy : a double-blind, randomised trial
Yves Dauvilliers,Claudio L. Bassetti,Gert Jan Lammers,Isabelle Arnulf,Geert Mayer,Andrea Rodenbeck,Philippe Lehert,Philippe Lehert,Claire-Li Ding,Jeanne-Marie Lecomte,J C Schwartz +10 more
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TLDR
Pitolisant at doses up to 40 mg was efficacious on EDS compared with placebo and well tolerated compared with modafinil, and could offer a new treatment option for patients with narcolepsy.Abstract:
Summary Background Narcolepsy is characterised by excessive daytime sleepiness (EDS) and cataplexy. Histamine neurons are crucial to maintain wakefulness. We assessed the safety and efficacy of pitolisant (previously called BF2.649), a selective histamine H3 receptor inverse agonist that activates these neurons, in patients with narcolepsy. Methods For this double-blind, randomised, parallel-group controlled trial, we recruited patients with narcolepsy from 32 sleep disorder centres in five European countries. Patients were eligible if they were aged 18 years or older, had not taken psychostimulants for at least 14 days, and had EDS (defined as an Epworth Sleepiness Scale [ESS] score of at least 14). Using a computer-generated randomisation sequence, we randomly allocated patients to receive pitolisant, modafinil, or placebo (1:1:1). Treatment lasted 8 weeks: 3 weeks of flexible dosing according to investigator's judgment (10 mg, 20 mg, or 40 mg a day of pitolisant; 100 mg, 200 mg or 400 mg a day of modafinil) followed by 5 weeks of stable dosing. Patients took four tablets a day in a double-dummy design to ensure masking. For the primary analysis, assessed in the intention-to-treat population, we assessed the superiority of pitolisant versus placebo, and the non-inferiority of pitolisant versus modafinil. This trial is registered with ClinicalTrials.gov, number NCT01067222. Findings Between May 26, 2009, and June 30, 2010, we screened 110 patients, 95 of whom were eligible and randomly assigned to treatment: 30 to placebo, 32 to pitolisant, and 33 to modafinil. Over the 8-week treatment period, mean ESS score reductions were −3·4 (SD 4·2) in the placebo group, −5·8 (6·2) in the pitolisant group, and −6·9 (6·2) in the modafinil group. Our primary analysis of between-group differences in mean ESS score at endpoint (adjusted for baseline) showed pitolisant to be superior to placebo (difference −3·0, 95% CI −5·6 to −0·4; p=0·024), but not non-inferior to modafinil (difference 0·12, 95% CI −2·5 to 2·7; p=0·250). We recorded 22 adverse events with pitolisant, 26 with modafinil, and ten with placebo. Six severe adverse events were treatment-related: one with pitolisant (abdominal discomfort) and five with modafinil (abdominal pain, abnormal behaviour, amphetamine-like withdrawal symptoms, lymphoadenopathy, and inner ear disorders). Interpretation Pitolisant at doses up to 40 mg was efficacious on EDS compared with placebo and well tolerated compared with modafinil. If these findings are substantiated in further studies, pitolisant could offer a new treatment option for patients with narcolepsy. Funding Bioprojet, France.read more
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Additional file 3: Figure S2. of Development of TASP0410457 (TASP457), a novel dihydroquinolinone derivative as a PET radioligand for central histamine H3 receptors
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References
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Journal ArticleDOI
A new method for measuring daytime sleepiness: the Epworth sleepiness scale.
TL;DR: The development and use of a new scale, the Epworth sleepiness scale (ESS), is described, which is a simple, self-administered questionnaire which is shown to provide a measurement of the subject's general level of daytime sleepiness.
Journal ArticleDOI
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Journal ArticleDOI
A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains
Christelle Peyron,Juliette Faraco,William J. Rogers,Beth Ripley,Sebastiaan Overeem,Sebastiaan Overeem,Yves Charnay,Sona Nevsimalova,Michael S. Aldrich,David Reynolds,Roger L. Albin,Robin Li,Marcel Hungs,Mario Pedrazzoli,Muralidhara Padigaru,Melanie H. Kucherlapati,Jun Fan,Richard A. Maki,Gert Jan Lammers,Constantin Bouras,Raju Kucherlapati,Seiji Nishino,Emmanuel Mignot +22 more
TL;DR: In situ hybridization of the perifornical area and peptide radioimmunoassays indicated global loss of hypocretins, without gliosis or signs of inflammation in all human cases examined, indicating most cases of human narcolepsy are associated with a deficient hypocretin system.