E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Aortic valve stenosis with reduced ejection fraction |
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E.1.1.1 | Medical condition in easily understood language |
Valvular heart disease with heart failure |
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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 | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10002918 |
E.1.2 | Term | Aortic valve stenosis |
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 |
The purpose of this study is to examine the safety and feasibility of oral admission of Ivabradine to patients with low-flow low-gradient severe Aortic stenosis (AS) and to compare the ability of Ivabradine with Dobutamine in differentiating true-severe AS from pseudo-severe AS. Primary objective
In a population of patients with low-flow low-gradient severe AS with LVEF<50% to compare a. Changes in heart rate b. Changes in invasively measured SV, pulmonary wedge pressure (PCWP), mean pulmonary artery pressure (mPAP) and mean arterial pressure (MAP) c. Changes on echocardiography in LVEF, SV, global longitudinal strain, diastolic E/e’, mean and peak gradient, RV function and pulmonary pressure estimated by the tricuspid regurgitation gradient. After intravenous administration of Ivabradine compared to conventional low dose Dobutamine infusion
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E.2.2 | Secondary objectives of the trial |
Safety 1. In a population of patients with low-flow low-gradient severe AS to monitor a. Occurrence of bradycardia with heart rate <40 beats per min. b. Occurrence of symptoms (shortness of breath, angina, dizziness) c. Occurrence of cardiac arrhythmias on continuous ECG monitoring.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion criteria 1. Low-flow (SV index<35 ml/m2) low-gradient (meangradient <40 mmHg) AS with AVA<1,0 cm2 2. Age > 18 years 3. Signed informed consent 4. Heart rate > 60 beats per minute
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E.4 | Principal exclusion criteria |
1. Other moderate-severe valvular heart disease other than AS 2. Unwilling to participate in the study 3. Mental disorder precluding informed consent 4. Poor echocardiographic window 5. Chronic atrial fibrillation 6. Sinus node dysfunction 7. Bradycardia < 60 BPM 8. Complete AV block or permanent cardiac pacemaker 9. Hypotension <90/50 mmHg 10. Concomitant treatment with diltiazem or verapamil 11. Liver dysfunction with ALAT twice upper limit of normal. 12. Pregnancy |
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E.5 End points |
E.5.1 | Primary end point(s) |
a. Changes in heart rate b. Changes in invasively measured SV, pulmonary wedge pressure (PCWP), mean pulmonary artery pressure (mPAP) and mean arterial pressure (MAP) c. Changes on echocardiography in LVEF, SV, global longitudinal strain, diastolic E/e’, mean and peak gradient, RV function and pulmonary pressure estimated by the tricuspid regurgitation gradient.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Will be evaluated every half our during the first 8 hours after administration. |
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E.5.2 | Secondary end point(s) |
1. In a population of patients with low-flow low-gradient severe AS to monitor serious adverse events a. Occurrence of bradycardia with heart rate <40 beats per min. b. Occurrence of symptoms (shortness of breath, angina, dizziness) c. Occurrence of cardiac arrhythmias on continuous ECG monitoring.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Patients will be hemodynamically monitored at our intensive care unit during the first 8 hours after administration of Ivabradine. This will take place at the intensive care unit of our hospital. If any sign of adverse events occur monitoring will continue Potential serious adverse events (expected and unexpected) will be registered. As part of the safety objective (see 3.2), serious adverse events (described section 3.2) will be reported to the Principal investigator of this study (Sponsor) and the Danish Medicines Agency. In case of suspected unexpected serious adverse events the Danish Medicines Agency will be informed prior to 7 days. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
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 | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
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 | No |
E.8.2.3 | Other | No |
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 | No |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |