Montelukast for Patients With Obstructive Sleep Apnea Syndrome

Study Overview
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Brief Summary
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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
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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.

Official Title
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Impact of Blocked Cysteinyl Leukotriene Pathway on Endothelial Function in Patients With Obstructive Sleep Apnea Syndrome: Multicenter Randomized Placebo Controlled Crossover Trial

Conditions
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Sleep Apnea, Obstructive

Intervention / Treatment
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* Drug: Montelukast 10mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: It's a prospective, randomized, comparative vs placebo, double blind, multicenter, national study.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Montelukast<br>Drug :Montelukast, capsule, 10mg, one per day in the evening, one hour before or 2 hours post meal, length of treatment 3 months | Drug: Montelukast 10mg<br>* The capsules will be presented in box of 95 capsules packaged in unit blister<br>Drug: Placebo<br>* Mannitol 350mg The capsules will be presented in box of 95 capsules packaged in unit blister<br>|
| Placebo Comparator: Placebo<br>Drug: Mannitol, capsule, 350mg, one per day in the evening, one hour before or 2 hours post meal, length of treatment 3 months | Drug: Montelukast 10mg<br>* The capsules will be presented in box of 95 capsules packaged in unit blister<br>Drug: Placebo<br>* Mannitol 350mg The capsules will be presented in box of 95 capsules packaged in unit blister<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. |  | before and after 3 months treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentrations of urinary LTE4 at the beginning and end of each treatment period |  | before and after 3 months the two periods of treatment | 
| 24h ambulatory blood pressure (systolic and diastolic) measurement |  | before and after 3 months of the two periods of treatment, and 15 days after the last period | 
| Polysomnography at inclusion and at the end of each treatment period |  | inclusion and at the end of the two periods of treatment | 
| Plasma concentration of Montelukast measured by HPLC-MS at the end of the Montelukast treatment period |  | at the end of Montelukast treatment period | 
| Collection of adverse events |  | from inclusion to 15 days after the last period of treatment | 
| Comparison of Cardiovascular Events occurence (myocardial infarction, Stroke, Cardiovascular Death) between the two periods |  | from inclusion to 15 days after the last period of treatment | 
| Concentrations of plasma CRPus at baseline and at the beginning and end of each treatment period |  | before and after 3 months the two periods of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Montelukast, leukotriene pathway, endothelial function, flux-mediated dilation