Study Results
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Basic Information
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TERMINATED
PHASE4
12 participants
INTERVENTIONAL
2013-08-07
2017-03-16
Brief Summary
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The investigators assume an increase in arterial resistance during the intermittent hypoxia compared to the control group, these being dependent on sympathetic tone.
The investigators hypothesize that the metabolic alterations that will be observed after experimental simulation (IH and fragmentation of sleep for 15 consecutive nights) will be less severe in the valsartan group than in the amlodipine group in comparison with the placebo group.
A serum bank and a gene bank will be performed for the requirements of subsequent studies if necessary.
Detailed Description
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Hypoxia associated with altitude is frequently marked by the presence of sleep during periodic breathing induces a particular pattern of hypoxia called intermittent hypoxia. Also some subjects are "intolerant altitude" and develop specific pathologies at high altitude (acute mountain evil, pulmonary edema ...).
We recently demonstrated that subjects tolerate the altitude had just intermittent hypoxia while they were sleeping during the simulated altitude. The protective role of intermittent hypoxia in the mechanisms of occurrence of intolerance to altitude remains to be understood more precisely. In fact those who were intolerant to altitude has no periodic breathing and therefore intermittent hypoxia during the oxygen-deficient atmosphere.
Conversely, the sleep apnea syndrome (SAS) also characterized by a HI. It is produced by repeated episodes of airway obstruction during sleep, producing a sequence: respiratory effort, hypoxia / re-oxygenation and sleep interruption.
The HI is associated with both a well established cardiovascular morbidity but also to cardioprotection. This relates to cardiovascular morbidity rise in blood pressure can certainly promote the development after many years of hypertension. On the other hand the presence of sleep apnea syndrome is advanced as a factor favoring the coronary collateral circulation and therefore will bring a cardioprotective effect for patients.
Understanding the mechanisms of physiological adaptations to intermittent hypoxia by passing a deleterious evolution of a protective HI is therefore critical.
Exposure to altitude or OSAS induces the activation of intermediary mechanisms such as sympathetic activation, altered vascular reactivity, systemic inflammation and low-grade oxidative stress. The direct involvement of these mechanisms is dependent mainly intermediate of intermittent hypoxia. The shift in equilibrium between activator and inhibitor factors will evolve either to a protective mode (adaptation to altitude) or pathologic (cardiovascular complication of OSA).
Sympathetic activation has been demonstrated in patients with OSAS, reversible with effective treatment. The importance of cardiovascular sympathetic activation in elevating blood pressure by intermittent hypoxia is shown in animal models of HI. We also found an increase in sympathetic activation in our reversible model of HI in healthy subjects.
The elevation of that sympathetic activity is assumed to be multifactorial. An increase in tone but also a central potentiation thereof by an increase in peripheral chemoreflex sensitivity (sensitive to hypoxia) and against a lack of regulation by the arterial baroreflex.
Moreover angiotensin system modulates the central sympathetic tone and peripheral chemoreflex sensitivity. These actions are complementary in a signaling pathway of particular interest in exposure to intermittent hypoxia.
Conditions
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Keywords
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Study Design
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RANDOMIZED
CROSSOVER
BASIC_SCIENCE
TRIPLE
Study Groups
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Arm 1: Real hypoxia and ¨Placebo
This arm last 4 weeks with 2 periods of 2 weeks separated by a 6 weeks wash-out. The subjects of this arm receive the real hypoxia and the placebo during the first two weeks and, after the wash-out, receive the treatment of the arm 2.
Placebo
The subjects receive 1 oral pill of placebo each morning during the second week of the two periods, so 14 pills in all.
Arm 2: Hypoxia placebo and Placebo
This arm last 4 weeks with 2 periods of 2 weeks separated by a 6 weeks wash-out. The subjects of this arm receive the hypoxia placebo and the placebo during the first two weeks and, after the wash-out, receive the treatment of the arm 1.
Placebo
The subjects receive 1 oral pill of placebo each morning during the second week of the two periods, so 14 pills in all.
Arm 3: Hypoxia and Valsartan
This arm last 4 weeks with 2 periods of 2 weeks separated by a 6 weeks wash-out. The subjects of this arm receive the real hypoxia and the Valsartan during the first two weeks and, after the wash-out, receive the treatment of the arm 4.
Valsartan
The subjects receive 1 oral pill of Valsartan each morning during the second week of the two periods, so 14 pills in all. 1 pill equal 40 mg.
Arm 4: Hypoxia and Amlodipine
This arm last 4 weeks with 2 periods of 2 weeks separated by a 6 weeks wash-out. The subjects of this arm receive the real hypoxia and the amlodipine during the first two weeks and, after the wash-out, receive the treatment of the arm 3.
Amlodipine
The subjects receive 1 oral pill of Amlodipine each morning during the second week of the two periods, so 14 pills in all. 1 pill equal 6,944 mg of amlodipine besilate with 5 mg of amlodipine.
Interventions
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Placebo
The subjects receive 1 oral pill of placebo each morning during the second week of the two periods, so 14 pills in all.
Placebo
The subjects receive 1 oral pill of placebo each morning during the second week of the two periods, so 14 pills in all.
Valsartan
The subjects receive 1 oral pill of Valsartan each morning during the second week of the two periods, so 14 pills in all. 1 pill equal 40 mg.
Amlodipine
The subjects receive 1 oral pill of Amlodipine each morning during the second week of the two periods, so 14 pills in all. 1 pill equal 6,944 mg of amlodipine besilate with 5 mg of amlodipine.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Subject aged of 18 years-old at least
* Diagnostic AHI\<15/h and \<5% of total sleep time spent with a SaO2\<90%
* Free and informed consent signed
* Subject covered by social security
* Negative pregnancy test
Exclusion Criteria
* Tobacco consumption \> 5 cigarettes/days
* Alcohol consumption \> 3 units/days (1 unit=1 drink)
* Subject under trusteeship or guardianship
* Subject unaffiliated with the social security
* Person deprived of their liberty, adult protected by laws, person hospitalized
* Ongoing participation in another clinical research study
* Subject non-cooperative or respectful of obligations inherent in the participation in the study
18 Years
ALL
Yes
Sponsors
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Institut National de la Santé Et de la Recherche Médicale, France
OTHER_GOV
University Hospital, Grenoble
OTHER
Responsible Party
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Principal Investigators
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Renaud RT Tamisier, PhD
Role: PRINCIPAL_INVESTIGATOR
University Hospital of Genoble
Locations
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Laboratoire EFCR - Functional Cardio-respiratory Exploration Laboratory
La Tronche, Isère, France
Countries
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References
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Shamsuzzaman AS, Gersh BJ, Somers VK. Obstructive sleep apnea: implications for cardiac and vascular disease. JAMA. 2003 Oct 8;290(14):1906-14. doi: 10.1001/jama.290.14.1906.
Carlson JT, Hedner J, Elam M, Ejnell H, Sellgren J, Wallin BG. Augmented resting sympathetic activity in awake patients with obstructive sleep apnea. Chest. 1993 Jun;103(6):1763-8. doi: 10.1378/chest.103.6.1763.
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Narkiewicz K, van de Borne PJ, Montano N, Dyken ME, Phillips BG, Somers VK. Contribution of tonic chemoreflex activation to sympathetic activity and blood pressure in patients with obstructive sleep apnea. Circulation. 1998 Mar 17;97(10):943-5. doi: 10.1161/01.cir.97.10.943.
Carlson JT, Hedner JA, Sellgren J, Elam M, Wallin BG. Depressed baroreflex sensitivity in patients with obstructive sleep apnea. Am J Respir Crit Care Med. 1996 Nov;154(5):1490-6. doi: 10.1164/ajrccm.154.5.8912770.
Punjabi NM, Beamer BA. Alterations in Glucose Disposal in Sleep-disordered Breathing. Am J Respir Crit Care Med. 2009 Feb 1;179(3):235-40. doi: 10.1164/rccm.200809-1392OC. Epub 2008 Nov 14.
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Braun B, Rock PB, Zamudio S, Wolfel GE, Mazzeo RS, Muza SR, Fulco CS, Moore LG, Butterfield GE. Women at altitude: short-term exposure to hypoxia and/or alpha(1)-adrenergic blockade reduces insulin sensitivity. J Appl Physiol (1985). 2001 Aug;91(2):623-31. doi: 10.1152/jappl.2001.91.2.623.
Spiegel K, Knutson K, Leproult R, Tasali E, Van Cauter E. Sleep loss: a novel risk factor for insulin resistance and Type 2 diabetes. J Appl Physiol (1985). 2005 Nov;99(5):2008-19. doi: 10.1152/japplphysiol.00660.2005.
Spiegel K, Leproult R, Colecchia EF, L'Hermite-Baleriaux M, Nie Z, Copinschi G, Van Cauter E. Adaptation of the 24-h growth hormone profile to a state of sleep debt. Am J Physiol Regul Integr Comp Physiol. 2000 Sep;279(3):R874-83. doi: 10.1152/ajpregu.2000.279.3.R874.
Spiegel K, Leproult R, L'hermite-Baleriaux M, Copinschi G, Penev PD, Van Cauter E. Leptin levels are dependent on sleep duration: relationships with sympathovagal balance, carbohydrate regulation, cortisol, and thyrotropin. J Clin Endocrinol Metab. 2004 Nov;89(11):5762-71. doi: 10.1210/jc.2004-1003.
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Gilmartin GS, Lynch M, Tamisier R, Weiss JW. Chronic intermittent hypoxia in humans during 28 nights results in blood pressure elevation and increased muscle sympathetic nerve activity. Am J Physiol Heart Circ Physiol. 2010 Sep;299(3):H925-31. doi: 10.1152/ajpheart.00253.2009. Epub 2010 Jun 25.
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Spiegel K, Tasali E, Penev P, Van Cauter E. Brief communication: Sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite. Ann Intern Med. 2004 Dec 7;141(11):846-50. doi: 10.7326/0003-4819-141-11-200412070-00008.
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Somers VK, White DP, Amin R, Abraham WT, Costa F, Culebras A, Daniels S, Floras JS, Hunt CE, Olson LJ, Pickering TG, Russell R, Woo M, Young T; American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology; American Heart Association Stroke Council; American Heart Association Council on Cardiovascular Nursing; American College of Cardiology Foundation. Sleep apnea and cardiovascular disease: an American Heart Association/american College Of Cardiology Foundation Scientific Statement from the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council On Cardiovascular Nursing. In collaboration with the National Heart, Lung, and Blood Institute National Center on Sleep Disorders Research (National Institutes of Health). Circulation. 2008 Sep 2;118(10):1080-111. doi: 10.1161/CIRCULATIONAHA.107.189375. Epub 2008 Aug 25. No abstract available.
Other Identifiers
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P-2011-32-HI2
Identifier Type: OTHER
Identifier Source: secondary_id
2011-32
Identifier Type: -
Identifier Source: org_study_id