E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10011078 |
E.1.2 | Term | Coronary artery disease |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the effect of ivabradine on central aortic systolic blood pressure (CASBP) in comparison to placebo in patients with stable CAD and a resting HR≥ 70 bpm, treated by beta-blockers. |
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E.2.2 | Secondary objectives of the trial |
To investigate the effect of ivabradine in comparison to placebo on:
- other central and radial blood pressure and heart rate parameters obtained through applanation tonometry,
- carotid-femoral pulse wave velocity (PWV),
- skin capillary density (only in patients from centres equipped with intravital video capillaroscopy material),
- brachial blood pressure parameters,
- resting HR from 12-lead Electrocardiogram (ECG),
- safety.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Male or female patients, at least 30 years old at the date of selection,
- Patients with CAD documented,
- Patients in sinus rhythm and with HR≥ 70 bpm on 12-lead ECG after 5 minutes rest,
- Patients with brachial SBP/DBP ≤140/90 mmHg (mean of 3 measurements performed in supine position using a semi-automatic oscillometric device at 5 min intervals),
- Normal (considering the patient disease) fasting lab test results for sampling performed between selection and inclusion visits,
- Patients with stable and appropriate treatment (according to the investigator) with beta-blockers (at the exception of nebivolol and carvedilol), during at least 3 months before the selection visit. |
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E.4 | Principal exclusion criteria |
- Known severe renal disease, including renal failure or serum creatinine ≥ 200 µM or µmol/L or 2.2 mg/dL,
- Known moderate or severe hepatic disease including severe hepatic insufficiency and/ or severe liver function test abnormalities: ALT or AST > 3 times the upper reference limits,
- Significant anaemia defined as blood hemoglobin lower than 110 g/L (in males) or lower than 100 g/L (in females),
- Fasting glucose > 13 mmol/L,
- History of central neuropathy and/or of symptomatic orthostatic hypotension,
- Severe hypotension at the time of selection (blood pressure < 90 / 50 mmHg),
- Patient currently or previously treated with ivabradine within the last 3 months before selection visit,
- Patient currently or previously treated with nebivolol or carvedilol within the last 3 months before selection visit,
- Patients with recent (less than 3 months) MI or coronary revascularisation,
- Patients with recent (less than 3 months) stroke or cerebral transient ischemic attack,
- Patients scheduled for coronary revascularisation procedures (PCI or CABG)
- Patients with Type I diabetes
- Type II diabetes patients diagnosed less than 3 month before selection
- Type II diabetes patients with modification of their anti-diabetic medications within 3 months before selection
- Modification of the anti-diabetic treatment since selection visit for diabetic patients |
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E.5 End points |
E.5.1 | Primary end point(s) |
Central aortic systolic blood pressure (CASBP) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Measured at baseline and after 3weeks of treatment |
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E.5.2 | Secondary end point(s) |
- Other central pressure parameters: Central aortic diastolic blood pressure (CADBP), augmentation index (AIx), augmentation pressure (Ao), aortic pulse pressure (PP), subendocardial viability ratio (SEVR) (Buckberg index), LV ejection time (LVET),
- Radial blood pressure parameters: systolic blood pressure (SBP), diastolic blood pressure (DBP), radial pulse pressure (PP)
- Heart rate derived from applanation tonometry during recording of central pressure parameters
- Carotid-femoral pulse wave velocity (PWV)
- Capillary density
- Resting HR from 12 lead ECG
- Supine brachial blood pressure parameters (SBP, DBP),
- Safety profile |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- resting HR from ECG : at baseline,
- safety profile : over all the sudy period,
- other secondary endpoints : measured at baseline and after 3 weeks of treatment |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Exploratory investigation of a potential safety endpoint |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 4 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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LVLP : Last Visit Last Patient |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |