HR-lowering Efficacy and Respiratory Safety of Ivabradine in Patients With Obstructive Airway Disease

Asthma, Chronic Obstructive Pulmonary Disease (COPD) Clinical Trial

Official title:

Heart Rate Lowering Efficacy and Respiratory Safety of Ivabradine in Patients With Obstructive Airway Disease

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01365286
• Other study ID #: Ivabradine2009-2011
• Status: Completed
• Phase: Phase 4
• First received: May 31, 2011
• Last updated: June 11, 2012
• Start date: May 2009
• Est. completion date: January 2011

Study information

• Verified date: May 2011
• Source: Medical Universtity of Lodz
• Contact: n/a
• Is FDA regulated: No
• Health authority: Poland: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to investigate heart rate lowering efficacy and respiratory safety of ivabradine in patients with asthma and COPD.

Description:

In this double blind, placebo-controlled, crossover study, 20 asthmatics and 20 COPD patients received ivabradine 7,5 mg b.i.d. and placebo for 5 days in crossover manner. HR in ECG holter monitoring, peak expiratory flow rate (PEFR), symptoms, rescue medication consumption and AEs were evaluated in both periods of treatment.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: January 2011
• Est. primary completion date: January 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

• documented diagnosis of asthma or COPD in accordance with guidelines

• stable condition, defined as a disease without exacerbation for at least 1 month prior to study enrolment

• mean HR in holter ECG recording of = 60 bpm

Exclusion Criteria:

• disease exacerbation in previous month

• inability to understand instructions on study procedures

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Asthma, Chronic Obstructive Pulmonary Disease (COPD)
• Lung Diseases
• Lung Diseases, Obstructive
• Pulmonary Disease, Chronic Obstructive

Intervention

Drug:
• Ivabradine (Procoralan)
Ivabradine 7,5 mg b.i.d. for 5 days and Placebo b.i.d. for 5 days (Ivabradine-Placebo)
• Placebo
Placebo b.i.d. for 5 days and Ivabradine 7,5 mg b.i.d. for 5 days (Placebo-Ivabradine)

Locations

Country	Name	City	State
Poland	Medical University of Lodz, Department of Pneumonology and Allergy	Lodz

Sponsors (1)

Lead Sponsor	Collaborator
Medical Universtity of Lodz

Country where clinical trial is conducted

Poland, 

References & Publications (35)

Ageev FT, Makarova GV, Patrusheva IF, Orlova IaA. [The efficacy and safety of the combination of ß-blocker bisoprolol and if inhibitor I(f) ivabradine in patients with stable angina and chronic obstructive pulmonary disease]. Kardiologiia. 2010;50(10):22-6. Russian. — View Citation

Antonelli Incalzi R, Fuso L, De Rosa M, Forastiere F, Rapiti E, Nardecchia B, Pistelli R. Co-morbidity contributes to predict mortality of patients with chronic obstructive pulmonary disease. Eur Respir J. 1997 Dec;10(12):2794-800. — View Citation

Babu KS, Gadzik F, Holgate ST. Absence of respiratory effects with ivabradine in patients with asthma. Br J Clin Pharmacol. 2008 Jul;66(1):96-101. doi: 10.1111/j.1365-2125.2008.03160.x. Epub 2008 Mar 13. — View Citation

Benson MK, Berrill WT, Cruickshank JM, Sterling GS. A comparison of four beta-adrenoceptor antagonists in patients with asthma. Br J Clin Pharmacol. 1978 May;5(5):415-9. — View Citation

Borer JS, Fox K, Jaillon P, Lerebours G; Ivabradine Investigators Group. Antianginal and antiischemic effects of ivabradine, an I(f) inhibitor, in stable angina: a randomized, double-blind, multicentered, placebo-controlled trial. Circulation. 2003 Feb 18;107(6):817-23. — View Citation

Cazzola M, Calzetta L, Bettoncelli G, Novelli L, Cricelli C, Rogliani P. Asthma and comorbid medical illness. Eur Respir J. 2011 Jul;38(1):42-9. doi: 10.1183/09031936.00140310. Epub 2010 Dec 22. — View Citation

Chang CL, Mills GD, McLachlan JD, Karalus NC, Hancox RJ. Cardio-selective and non-selective beta-blockers in chronic obstructive pulmonary disease: effects on bronchodilator response and exercise. Intern Med J. 2010 Mar;40(3):193-200. doi: 10.1111/j.1445-5994.2009.01943.x. Epub 2009 Mar 10. — View Citation

Demontis GC, Longoni B, Barcaro U, Cervetto L. Properties and functional roles of hyperpolarization-gated currents in guinea-pig retinal rods. J Physiol. 1999 Mar 15;515 ( Pt 3):813-28. — View Citation

DiFrancesco D, Camm JA. Heart rate lowering by specific and selective I(f) current inhibition with ivabradine: a new therapeutic perspective in cardiovascular disease. Drugs. 2004;64(16):1757-65. Review. — View Citation

Farrell MH, Foody JM, Krumholz HM. beta-Blockers in heart failure: clinical applications. JAMA. 2002 Feb 20;287(7):890-7. — View Citation

Fihn SD, Williams SV, Daley J, Gibbons RJ; American College of Cardiology; American Heart Association; American College of Physicians-American Society of Internal Medicine. Guidelines for the management of patients with chronic stable angina: treatment. Ann Intern Med. 2001 Oct 16;135(8 Pt 1):616-32. — View Citation

Ford ES, Giles WH, Croft JB. Prevalence of nonfatal coronary heart disease among American adults. Am Heart J. 2000 Mar;139(3):371-7. — View Citation

Fox K, Borer JS, Camm AJ, Danchin N, Ferrari R, Lopez Sendon JL, Steg PG, Tardif JC, Tavazzi L, Tendera M; Heart Rate Working Group. Resting heart rate in cardiovascular disease. J Am Coll Cardiol. 2007 Aug 28;50(9):823-30. Epub 2007 Aug 13. Review. — 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. Epub 2008 Aug 29. — View Citation

Fox K, Garcia MA, Ardissino D, Buszman P, Camici PG, Crea F, Daly C, De Backer G, Hjemdahl P, Lopez-Sendon J, Marco J, Morais J, Pepper J, Sechtem U, Simoons M, Thygesen K, Priori SG, Blanc JJ, Budaj A, Camm J, Dean V, Deckers J, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo J, Zamorano JL; Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology; ESC Committee for Practice Guidelines (CPG). Guidelines on the management of stable angina pectoris: executive summary: The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology. Eur Heart J. 2006 Jun;27(11):1341-81. Epub 2006 May 30. — View Citation

Freemantle N, Cleland J, Young P, Mason J, Harrison J. beta Blockade after myocardial infarction: systematic review and meta regression analysis. BMJ. 1999 Jun 26;318(7200):1730-7. — View Citation

Frishman WH, Furberg CD, Friedewald WT. The use of beta-adrenergic blocking drugs in patients with myocardial infarction. Curr Probl Cardiol. 1984 Jun;9(3):1-50. Review. — View Citation

Gheorghiade M, Goldstein S. Beta-blockers in the post-myocardial infarction patient. Circulation. 2002 Jul 23;106(4):394-8. — View Citation

Gillum RF, Makuc DM, Feldman JJ. Pulse rate, coronary heart disease, and death: the NHANES I Epidemiologic Follow-up Study. Am Heart J. 1991 Jan;121(1 Pt 1):172-7. — View Citation

Hjalmarson A, Gilpin EA, Kjekshus J, Schieman G, Nicod P, Henning H, Ross J Jr. Influence of heart rate on mortality after acute myocardial infarction. Am J Cardiol. 1990 Mar 1;65(9):547-53. — View Citation

Kaneko A, Tachibana M. A voltage-clamp analysis of membrane currents in solitary bipolar cells dissociated from Carassius auratus. J Physiol. 1985 Jan;358:131-52. — View Citation

Kannel WB, Kannel C, Paffenbarger RS Jr, Cupples LA. Heart rate and cardiovascular mortality: the Framingham Study. Am Heart J. 1987 Jun;113(6):1489-94. — View Citation

Kjekshus JK. Importance of heart rate in determining beta-blocker efficacy in acute and long-term acute myocardial infarction intervention trials. Am J Cardiol. 1986 Apr 25;57(12):43F-49F. — View Citation

Lammers JW, Folgering HT, van Herwaarden CL. Respiratory tolerance of bisoprolol and metoprolol in asthmatic patients. J Cardiovasc Pharmacol. 1986;8 Suppl 11:S69-73. — View Citation

Lechat P. Beta-blocker treatment in heart failure. Role of heart rate reduction. Basic Res Cardiol. 1998;93 Suppl 1:148-55. Review. — View Citation

Lipworth BJ, Irvine NA, McDevitt DG. The effects of chronic dosing on the beta 1 and beta 2-adrenoceptor antagonism of betaxolol and atenolol. Eur J Clin Pharmacol. 1991;40(5):467-71. — View Citation

Masoli M, Fabian D, Holt S, Beasley R; Global Initiative for Asthma (GINA) Program. The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy. 2004 May;59(5):469-78. Review. — View Citation

Palatini P, Casiglia E, Pauletto P, Staessen J, Kaciroti N, Julius S. Relationship of tachycardia with high blood pressure and metabolic abnormalities: a study with mixture analysis in three populations. Hypertension. 1997 Nov;30(5):1267-73. — View Citation

Roche N, Huchon G. [Epidemiology of chronic obstructive pulmonary disease]. Rev Prat. 2004 Sep 15;54(13):1408-13. Review. French. — View Citation

Salpeter SR, Ormiston TM, Salpeter EE. Cardiovascular effects of beta-agonists in patients with asthma and COPD: a meta-analysis. Chest. 2004 Jun;125(6):2309-21. — View Citation

Satoh TO, Yamada M. A bradycardiac agent ZD7288 blocks the hyperpolarization-activated current (I(h)) in retinal rod photoreceptors. Neuropharmacology. 2000 Apr 27;39(7):1284-91. — View Citation

Schwartz S, Davies S, Juers JA. Life-threatening cold and exercise-induced asthma potentiated by administration of propranolol. Chest. 1980 Jul;78(1):100-1. — View Citation

Sears MR. Adverse effects of beta-agonists. J Allergy Clin Immunol. 2002 Dec;110(6 Suppl):S322-8. Review. — View Citation

Tardif JC, Ford I, Tendera M, Bourassa MG, Fox K; INITIATIVE Investigators. Efficacy of ivabradine, a new selective I(f) inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J. 2005 Dec;26(23):2529-36. Epub 2005 Oct 7. — View Citation

Williams IP, Millard FJ. Severe asthma after inadvertent ingestion of oxprenolol. Thorax. 1980 Feb;35(2):160. — View Citation

* Note: There are 35 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Heart rate	Difference in mean heart rate during ivabradine and placebo treatment	Change from baseline in heart rate during 5-day ivabradine and 5-day placebo treatment (24-hour ECG monitoring on the 3rd day)	Yes
Secondary	Peak expiratory flow rate (PEFR)	Difference in mean daily PEFR during ivabradine and placebo treatment	Everyday measurement of morning and evening PEFR during 5-day ivabradine and 5-day placebo treatment	Yes
Secondary	Symptoms	Difference in mean daily symptom score between ivabradine and placebo treatment	Everyday symptom scoring during 5 day ivabradine and 5-day placebo treatment	Yes
Secondary	Rescue medication	Difference in mean daily rescue medication use between ivabradine and placebo treatment	Everyday rescue medication usage assessments during 5-day ivabradine and 5-day placebo treatment	Yes
Secondary	Number of participants with adverse events (AEs)	Difference in number of participants with AEs between ivabradine and placebo treatment	Number of patients with AEs evaluated throughout the study (5-day ivabradine and 5 day placebo treatment)	Yes