Effect of Pharmacological Heart Rate Reduction on Visco-elastic Properties of the Arterial Wall (BRADYVASC)

Healthy Clinical Trial

— BRADYVASC  

Official title:

Effect of Pharmacological Heart Rate Reduction on Visco-elastic Properties of the Arterial Wall (BRADYVASC)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02584439
• Other study ID #: 2015/077/HP
• Secondary ID: 2015-002060-17
• Status: Recruiting
• Phase: Phase 3
• First received: October 21, 2015
• Last updated: December 6, 2016
• Start date: October 2015
• Est. completion date: September 2017

Study information

• Verified date: December 2016
• Source: University Hospital, Rouen
• Contact: Frederic Roca, MD
• Phone: +33 2 32 88 56 34
• Email: frederic.roca[@]chu-rouen.fr
• Is FDA regulated: No
• Health authority: France: Agence Nationale de Sécurité du Médicament et des produits de santéFrance: Committee for the Protection of Personnes
• Study type: Interventional

Clinical Trial Summary

The conduit arteries exhibit a viscoelastic behavior. Visco-elasticity is partially regulated by endothelium and contributes to the optimization of the heart-vessel coupling. Aging or high resting heart rate (HR) could alter visco-elastic properties leading to increase stiffness of the conduit arteries, an independent cardiovascular risk factor, and degradation of heart-vessel coupling. Lowering HR with ivabradine could reduce these effects.

The objective of this study is to assess the effect of HR reduction by repeated administration of ivabradine on visco-elastic properties, vascular geometry and function of common carotid artery, and on cardiovascular hemodynamic in healthy subject. The influence of aging on ivabradine effects are studied too.

30 healthy volunteers aged between 25 and 65 years old, with a HR ≥ 70 bpm, will receive ivabradine or placebo during 8 days in a single center, randomized, cross-group, double blinded, placebo-controlled study. Each period of treatment will be separate by 12 to 16 days of wash-out. Each subject will participate in an exploration visit, including evaluation of visco-elastic properties, vascular geometry and function of common carotid artery, and cardiovascular hemodynamic, before and after ivabradine or placebo taking.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: September 2017
• Est. primary completion date: August 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 25 Years to 65 Years

Eligibility

Inclusion Criteria:

• Healthy volunteers

• Caucasian

• Resting heart rate =70 bpm (mean of 3 measures after 15 minutes of rest)

• No significant EKG abnormality

• No significant biological abnormalities at inclusion

• Healthy volunteers able to read and understand information letter and to give written informed consent

• Healthy volunteers with medical insurance

• Contraception for two months for women of childbearing age (Estrogen contraceptive or intrauterine device or tubal ligation) (NB : women with amenorrhea for more than 2 years will be considered postmenopausal)

Exclusion Criteria:

• Subjects who don't understand french language

• Person deprived of liberty by an administrative or judicial decision or protected adult subject (under guardianship)

• Pregnant women, nursing mother or women without contraception

• Healthy volunteers who participate to an other trial / participated to an other trial without drugs during the last month or a trial with drugs during the last 3 months

• Hypersensitivity to the active substance or to any of the excipients

• Congenital galactosemia, lactase deficiency, or glucose-galactose malabsorption

• Body mass index (BMI) < 18 kg/m² or > 30 kg/m²

• Severe hypotension (< 90/50 mmHg) (3 measures after 15 minutes of rest)

• Essential or secondary Hypertension (SBP =140 mmHg and/or DBP =90 mmHg) (3 measures after 15 minutes of rest)

• Active smoking at the day of inclusion (>5 cigarettes/day)

• Severe hypercholesterolemia (Total cholesterol >2,5 g/L)

• Practice sports intensively (= 1 hour/day)

• Renal insufficiency (creatinine clearance = 60 ml/min/1,73 m² Cockroft and Gault formula)

• Known liver failure

• Known heart failure or suspected heart failure (congestive episode)

• Atrial fibrillation

• High-grade conduction block (Sick sinus syndrome, sino-atrial block or grade 2 or 3 atrio-ventricular block)

• Abnormal corrected QT with Bazett formula (cQT > 450 ms (men) or > 470 ms (women)).

• Pacemaker

• All cardiac or extra cardiac diseases, active or with sequelae, which, in the opinion of the investigator, is accompanied by a risk of cardiac or vascular consequences

• Retinal disease

• Taking any medication is prohibited during the study except oral contraceptive, acetaminophene or decision of the investigator. In addition, the administration of drugs listed in schedule 2 during the previous 4 weeks prohibits inclusion.

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Aging
• Healthy
• Vascular Stiffness

Intervention

Drug:
• ivabradine
It is a cross over study with two arms : either ivabradine-placebo or placebo-ivabradine. The capsules containing the placebo or ivabradine are completely identical.
• lactose capsule (placebo)
It is a cross over study with two arms : either ivabradine-placebo or placebo-ivabradine. The capsules containing the placebo or ivabradine are completely identical.

Locations

Country	Name	City	State
France	Department of Pharmacology, Rouen university Hospital	Rouen

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital, Rouen	Institut National de la Santé Et de la Recherche Médicale, France

Country where clinical trial is conducted

France, 

References & Publications (16)

Bellien J, Iacob M, Remy-Jouet I, Lucas D, Monteil C, Gutierrez L, Vendeville C, Dreano Y, Mercier A, Thuillez C, Joannides R. Epoxyeicosatrienoic acids contribute with altered nitric oxide and endothelin-1 pathways to conduit artery endothelial dysfunction in essential hypertension. Circulation. 2012 Mar 13;125(10):1266-75. doi: 10.1161/CIRCULATIONAHA.111.070680. — View Citation

Bellien J, Remy-Jouet I, Iacob M, Blot E, Mercier A, Lucas D, Dreano Y, Gutierrez L, Donnadieu N, Thuillez C, Joannides R. Impaired role of epoxyeicosatrienoic acids in the regulation of basal conduit artery diameter during essential hypertension. Hypertension. 2012 Dec;60(6):1415-21. doi: 10.1161/HYPERTENSIONAHA.112.201087. — View Citation

Benetos A, Rudnichi A, Thomas F, Safar M, Guize L. Influence of heart rate on mortality in a French population: role of age, gender, and blood pressure. Hypertension. 1999 Jan;33(1):44-52. — View Citation

Bolduc V, Drouin A, Gillis MA, Duquette N, Thorin-Trescases N, Frayne-Robillard I, Des Rosiers C, Tardif JC, Thorin E. Heart rate-associated mechanical stress impairs carotid but not cerebral artery compliance in dyslipidemic atherosclerotic mice. Am J Physiol Heart Circ Physiol. 2011 Nov;301(5):H2081-92. doi: 10.1152/ajpheart.00706.2011. — View Citation

Boutouyrie P, Beaussier H, Achouba A, Laurent S; EXPLOR trialists.. Destiffening effect of valsartan and atenolol: influence of heart rate and blood pressure. J Hypertens. 2014 Jan;32(1):108-14. doi: 10.1097/HJH.0000000000000014. — View Citation

Drouin A, Gendron ME, Thorin E, Gillis MA, Mahlberg-Gaudin F, Tardif JC. Chronic heart rate reduction by ivabradine prevents endothelial dysfunction in dyslipidaemic mice. Br J Pharmacol. 2008 Jun;154(4):749-57. doi: 10.1038/bjp.2008.116. — View Citation

Fox K, Ford I, Steg PG, Tardif JC, Tendera M, Ferrari R; SIGNIFY Investigators.. Ivabradine in stable coronary artery disease without clinical heart failure. N Engl J Med. 2014 Sep 18;371(12):1091-9. doi: 10.1056/NEJMoa1406430. — View Citation

Fox K, Ford I, Steg PG, Tendera M, Ferrari R; BEAUTIFUL Investigators.. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet. 2008 Sep 6;372(9641):807-16. doi: 10.1016/S0140-6736(08)61170-8. — View Citation

Franklin SS, Khan SA, Wong ND, Larson MG, Levy D. Is pulse pressure useful in predicting risk for coronary heart Disease? The Framingham heart study. Circulation. 1999 Jul 27;100(4):354-60. — View Citation

Joannides R, Moore N, Iacob M, Compagnon P, Lerebours G, Menard JF, Thuillez C. Comparative effects of ivabradine, a selective heart rate-lowering agent, and propranolol on systemic and cardiac haemodynamics at rest and during exercise. Br J Clin Pharmacol. 2006 Feb;61(2):127-37. — View Citation

Lantelme P, Mestre C, Lievre M, Gressard A, Milon H. Heart rate: an important confounder of pulse wave velocity assessment. Hypertension. 2002 Jun;39(6):1083-7. — View Citation

Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D, Pannier B, Vlachopoulos C, Wilkinson I, Struijker-Boudier H; European Network for Non-invasive Investigation of Large Arteries.. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J. 2006 Nov;27(21):2588-605. — View Citation

Maltete D, Bellien J, Cabrejo L, Iacob M, Proust F, Mihout B, Thuillez C, Guegan-Massardier E, Joannides R. Hypertrophic remodeling and increased arterial stiffness in patients with intracranial aneurysms. Atherosclerosis. 2010 Aug;211(2):486-91. doi: 10.1016/j.atherosclerosis.2010.04.002. — View Citation

Reil JC, Tardif JC, Ford I, Lloyd SM, O'Meara E, Komajda M, Borer JS, Tavazzi L, Swedberg K, Böhm M. Selective heart rate reduction with ivabradine unloads the left ventricle in heart failure patients. J Am Coll Cardiol. 2013 Nov 19;62(21):1977-85. doi: 10.1016/j.jacc.2013.07.027. — View Citation

Tropeano AI, Boutouyrie P, Pannier B, Joannides R, Balkestein E, Katsahian S, Laloux B, Thuillez C, Struijker-Boudier H, Laurent S. Brachial pressure-independent reduction in carotid stiffness after long-term angiotensin-converting enzyme inhibition in diabetic hypertensives. Hypertension. 2006 Jul;48(1):80-6. — View Citation

Williams B, Lacy PS, Thom SM, Cruickshank K, Stanton A, Collier D, Hughes AD, Thurston H, O'Rourke M; CAFE Investigators.; Anglo-Scandinavian Cardiac Outcomes Trial Investigators.; CAFE Steering Committee and Writing Committee.. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation. 2006 Mar 7;113(9):1213-25. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change from baseline in viscosity of the common carotid artery		8 days after first administration of ivabradine or placebo	No
Secondary	Change from baseline in diameter of the common carotid artery		8 days after first administration of ivabradine or placebo	No
Secondary	Change from baseline in intima-media thickness of the common carotid artery		8 days after first administration of ivabradine or placebo	No
Secondary	Change from baseline in carotid distensibility		8 days after first administration of ivabradine or placebo	No
Secondary	Change from baseline in carotid-femoral pulse wave velocity		8 days after first administration of ivabradine or placebo	No
Secondary	Change from baseline in plasma levels of biomarkers of endothelial function		8 days after first administration of ivabradine or placebo	No
Secondary	Change from baseline in peripheral and central pressures		8 days after first administration of ivabradine or placebo	No
Secondary	Change from baseline in Buckberg index		8 days after first administration of ivabradine or placebo	No
Secondary	Change from baseline in cardiac output		8 days after first administration of ivabradine or placebo	No