Safety of oral chronic administration of ivabradine modified release formulation compared to ivabradine immediate release formulation, in patients with stable coronary artery disease. A 6 to 12-month randomised double blind parallel groups multicentre study.
- Conditions
- Atherosclerosis/ hardening of the coronary arteries1001108210003216
- Registration Number
- NL-OMON36887
- Lead Sponsor
- Servier R&D Benelux
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 80
selection criteria:
-Women or men,
-Age *18 years (or having reached majority if the legal age of majority is over 18 years).
-obtained informed consent
-Documented stable CAD with or without chronic stable angina pectoris:
*CAD documented by:
.Prior myocardial infarction *3 months before selection,
.or prior coronary revascularisation *3 months before selection,
.or angiographically proven significant coronary atherosclerosis (*50% lumen diameter
reduction of any major coronary artery),
.or reliable non-invasive evidence of myocardial ischaemia (i.e. myocardial perfusion
scintigraphy, stress echography, stress MRI).
*In stable condition for at least 1 month before selection with regards to clinical symptoms and
cardiovascular treatments.
-In case of history of chronic stable angina pectoris:
*At least one angina attack within the 2 months preceding the selection visit, defined as chest
pain or discomfort, typically elicited by exertion or emotional stress and relieved by rest or short
acting nitrates.
*CCS class I to IV.
*Clinical stability within 1 month preceding selection (no significant change in frequency,
duration, precipitating causes or ease to relief of angina).
-Normal sinus rhythm.
-Resting heart rate * 60bpm (measured on 12-lead ECG recording in supine position after a 10-minute rest).;
-Documented sinus rhythm and HR * 60 bpm on 12-lead ECG recording in supine position after a 10-minute rest.
Non-selection criteria:
-Women who are pregnant, breast-feeding or women of childbearing potential not using estro-progestative oral or intra-uterine contraception or implants, or women using estro-progestative or intra-uterine contraception or implants but who consider stopping it during the planned duration of the study.
-Participation in another interventional study within the previous 30 days or within a prior time of 5 half-lives of the investigational drug.
-Contra-indication to ivabradine, ivabradine not recommended or not effective, or requirement for a not recommended concomitant treatment (cf ivabradine SmPC):
*Resting heart rate below 60 bpm prior to ivabradine treatment.
*Hypersensitivity to the active substance or to any of the excipients, galactose intolerance, Lapp
lactase deficiency or glucose-galactose malabsorption.
*Cardiogenic shock.
*Severe hypotension (< 90/50 mmHg).
*Acute myocardial infarction or coronary revascularisation within less than 3 months.
*Unstable angina within less than 1 month.
*Recent stroke (within less than 1month).
*Hepatic insufficiency (child-pugh score >7).
*Severe renal insufficiency (creatinine clearance <15ml/min).
*Sick sinus syndrome.
*Sino-atrial block, 2nd or 3rd degree atrio-ventricular block.
*Pacemaker dependent more than 40% of the time or with a stimulation threshold *60bpm.
*Permanent atrial fibrillation or flutter or other cardiac arrhythmia that interfere with sinus node
function.
*Congenital long QT syndrome or patient requiring treatment with QT prolonging products.
*Patient requiring treatment with strong cytochrome P450 3A4 inhibitors such as azole
antifungals (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, erythromycin per
os, josamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone.
*Patient requiring treatment with heart rate reducing agents, which are moderate CYP3A4
inhibitors (e.g: diltiazem or verapamil).
-Heart failure patients with NYHA functional classification II, III or IV.
-Patient treated with ivabradine in the month preceding the selection.
-Known alcohol or drug abuse.
-Known carriers of hepatitis B surface antigen or human immunodeficiency virus antibodies or hepatitis C virus antibodies.;Non-inclusion criteria:
-Creatinine clearance <15ml/min.
-ALT or AST > 3 times the laboratory upper limit of normal (ULN).
-Late discovery of any condition not in accordance with selection/non-selection criteria.
-Other ECG or laboratory abnormalities or clinical deterioration excluding the patient from this study according to the investigator.
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Safety endpoint: occurrence of emergent adverse events over 6 months (including<br /><br>clinically significant 12-lead ECG abnormalities).</p><br>
- Secondary Outcome Measures
Name Time Method <p>Safety endpoints:<br /><br>-Occurrence of emergent adverse events over 12 months (including clinically<br /><br>significant 12-lead ECG abnormalities),<br /><br>-Other safety criteria over 6 and 12 months:<br /><br>*Blood pressure,<br /><br>*Laboratory test parameters.<br /><br><br /><br>Efficacy endpoints:<br /><br>- HR change from baseline on resting 12-lead ECG over 6 and 12 months,<br /><br>- Change in CCS (Canadian Cardiovascular Society) class, number of angina<br /><br>attacks and short acting nitrates consumption<br /><br>over 6 and 12 months for angina patients.<br /><br><br /><br>Safety and efficacy endpoints for switch:<br /><br>-Occurrence of emergent adverse events after switch over 3 months,<br /><br>-Blood pressure change,<br /><br>-HR change on resting 12-lead ECG after switch over 3 months,<br /><br>-Change in CCS class, number of angina attacks and short acting nitrates<br /><br>consumption after switch over 3 months for angina patients.</p><br>