Clinical trial NCT03545997: Montelukast for Patients With Obstructive Sleep Apnea Syndrome
Official title: Impact of Blocked Cysteinyl Leukotriene Pathway on Endothelial Function in Patients With Obstructive Sleep Apnea Syndrome: Multicenter Randomized Placebo Controlled Crossover Trial
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Sleep Apnea, Obstructive
Keywords: Montelukast
leukotriene pathway
endothelial function
flux-mediated dilation
Lead sponsor: University Hospital, Grenoble
Sponsor class: OTHER
Collaborators: name: Act For Chronic Diseases
name: Direction Générale de l'Offre de Soins
First posted: 2018-06-06
Enrollment: 1
Sex: ALL
Minimum age (years): 45
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: It's a prospective, randomized, comparative vs placebo, double blind, multicenter, national study.
Primary purpose: TREATMENT

Brief summary: This study compares the effect of Montelukast vs Placebo on Flow Mediated Dilatation of the Brachial Artery (FMD) in patients with obstructive sleep apnea syndrome.

Detailed description: Obstructive Sleep Apnea Syndrome (OSAS) induces low-grade systemic and vascular inflammation, including activation of the leukotriene pathway.

In apneic patients, the urinary excretion of LTE4, a systemic marker of CysLT pathway activation, is increased in relation to the severity of OSAS and it's an independent predictor of cardiovascular risk event occurring at 10 years.

Montelukast is a CysLT1 receptor antagonist. By blocking CysLT1 receptors, montelukast prevents vasoconstriction, proliferation and migration of smooth muscle cells, adhesion molecule expression, and leukocyte recruitment induced by CysLTs.Montelukast may improve endothelial function and reduce vascular remodeling in apneic patients.

A pharmacological blockade of CysLT pathway would be an interesting therapeutic strategy to limit the cardiovascular consequences of OSAS.

Eligibility criteria: Inclusion Criteria:

* With mild to moderate obstructive sleep apnea syndrome (apnea / hypopnea index\> 15 and \<30 events per hour)
* Little symptomatic (Epworth sleepiness score \<10)
* Polysomnography within 3 months prior to inclusion
* With a history of myocardial infarction or stroke
* Affiliation to Social Security or beneficiary of such a scheme
* Signed consent

Exclusion Criteria:

* OSAS support by PPC
* Cancer
* Chronic inflammatory disease
* Asthma previously treated with Montelukast
* Chronic infectious disease
* Epworth sleepiness scale ≥10
* Contraindication to Montelukast: Hypersensitivity to the active substance or to the excipients
* Contraindications to trinitrin: hypersensitivity to nitrates, state of shock, severe hypotension, association with sildenafil, obstructive cardiomyopathy, inferior right sided myocardial infarction with right ventricular extension, acute, except in case of signs left ventricular failure, intracranial hypertension, breastfeeding
* Treatment with phenobarbital, phenytoin, rifampicin: risk of montelukast metabolism increase and thus decrease of its effectiveness
* Persons referred in Articles L1121-5 to L1121-8 of the CSP (pregnant woman, parturient, nursing mothers, person deprived of liberty by judicial or administrative decision, person subject to a measure of legal protection, can not be included in clinical trials)
* Subject in exclusion period of another study
* Subject can not be contacted in case of emergency

Primary outcomes:
measure: Change in FMD of the brachial artery between the beginning and end of each treatment period (Montelukast and placebo), expressed as absolute value (FMD unit is %) and measured in a standardized manner.
timeFrame: before and after 3 months treatment
Secondary outcomes:
measure: Concentrations of urinary LTE4 at the beginning and end of each treatment period
timeFrame: before and after 3 months the two periods of treatment
measure: 24h ambulatory blood pressure (systolic and diastolic) measurement
timeFrame: before and after 3 months of the two periods of treatment, and 15 days after the last period
measure: Polysomnography at inclusion and at the end of each treatment period
timeFrame: inclusion and at the end of the two periods of treatment
measure: Plasma concentration of Montelukast measured by HPLC-MS at the end of the Montelukast treatment period
timeFrame: at the end of Montelukast treatment period
measure: Collection of adverse events
timeFrame: from inclusion to 15 days after the last period of treatment
measure: Comparison of Cardiovascular Events occurence (myocardial infarction, Stroke, Cardiovascular Death) between the two periods
timeFrame: from inclusion to 15 days after the last period of treatment
measure: Concentrations of plasma CRPus at baseline and at the beginning and end of each treatment period
timeFrame: before and after 3 months the two periods of treatment
Other outcomes:
Locations:
city: Bron
country: France
facility: University Hospital
city: Chambéry
country: France
facility: Métropole Savoie Hospital
city: Clermont-Ferrand
country: France
facility: University Hospital
city: Grenoble
country: France
facility: University Hospital Grenoble
city: Grenoble
country: France
facility: University Hospital
city: Metz-Tessy
country: France
facility: Annecy Genevois Hospital
city: Pierre-Bénite
country: France
facility: University Hospital
city: Saint-Étienne
country: France
facility: University Hospital
Study officials:
References:
citation: Ingelsson E, Yin L, Back M. Nationwide cohort study of the leukotriene receptor antagonist montelukast and incident or recurrent cardiovascular disease. J Allergy Clin Immunol. 2012 Mar;129(3):702-707.e2. doi: 10.1016/j.jaci.2011.11.052. Epub 2012 Jan 12.
citation: Goldbart AD, Greenberg-Dotan S, Tal A. Montelukast for children with obstructive sleep apnea: a double-blind, placebo-controlled study. Pediatrics. 2012 Sep;130(3):e575-80. doi: 10.1542/peds.2012-0310. Epub 2012 Aug 6.
citation: Cereza G, Garcia Dolade N, Laporte JR. Nightmares induced by montelukast in children and adults. Eur Respir J. 2012 Dec;40(6):1574-5. doi: 10.1183/09031936.00092812. No abstract available.
citation: Marchand MS, Jonville-Bera AP, Autret-Leca E; Association francaise des centres regionaux de pharmacovigilance. [Psychiatric disorders associated with montelukast: data from the National Pharmacovigilance Database]. Arch Pediatr. 2013 Mar;20(3):269-73. doi: 10.1016/j.arcped.2012.12.006. Epub 2013 Feb 1. French.