E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10010684 |
E.1.2 | Term | Congestive heart failure |
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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 |
1. To analyse whether the hypercoagulable response to sympathetic activation in heart failure patients is reduced more effectively by carvedilol than metoprolol and whether this response differs from that in healthy controls.. 2. To analyse whether the hypercoagulable response to sympathetic activation in heart failure patients and in healthy controls is determined by the beta2-adrenergic genotype.
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E.2.2 | Secondary objectives of the trial |
1. To investigate the efficacy of non-selective and selective beta-blockers in downregulating the hypercoagulable response in patients with chronic heart failure. 2. To analyse the beta2-adrenergic genotype-specific effect of carvedilol on hypercoagulable activity in patients with chronic heart failure. 3. To analyse if the increase in sympathetic and procoagulant activity after postural change in healthy controls is determined by the beta2-adrenergic genotype and whether this haplotype determines the response to carvedilol. 4. To analyse if patients have a preference for one of the two beta-blockers and whether this correlates with their haplotypes.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients 1. Between 18 and 80 years of age, competent and willing of giving informed consent; 2. With stable symptoms of chronic heart failure (NYHA II-III); 3. With left ventricular ejection fraction ≤40%, measured within the previous 6 months; if the ejection fraction is not determined, a left-ventricular end diastolic diameter of greater then 6.0 cm and a fractional shortening of less than 20% as measured by echocardiography; 4. With sinusrhythm; (necessary to perform spectral analysis); 5. On stable medical therapy with ACE-inhibitors for at least three months, unless contraindicated; otherwise angiotensin receptor blockers (ARBs); 6. Already on beta-blocker therapy with maximal tolerated doses; are included in the study.
Digitalis or other vasodilatators can be used at the discretion of the treating physicians;
Healthy subjects between 18 and 80 years of age serve as controls to compare sympathetic and hypercoagulable activity with heart failure patients.
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E.4 | Principal exclusion criteria |
Excluded are patients 1. With a history of adverse reaction on beta-blockers; 2. With a contraindication to β-blocker therapy (Sick-sinussyndrome, second and third AV-block), severe hypotension (systolic blood pressure < 100 mm Hg), cardiogenous shock, clinical relevant sinusbradycardia. Asthma, COPD. Liverfunctiondisorder (defined as elevation of aspartamine transaminase, alanine transaminase or bilirubin levels more than three times upper limit of normal range), renal disease (creatinine clearance <50ml/min).Insulin dependent diabetes mellitus.); 3. With an acute coronary syndrome or myocardial revascularisation within the preceding 3 months; 4. Who are using anticoagulant therapy. Aspirin is allowed; 5. With severe aortic or mitral valve disease or aortic regurgitation; 6. With right ventricle failure; 7. Requirement for intravenous inotropic therapy, current treatment with calcium channel blockers (of the diltiazem or verapamil class), amiodaron (>200mg per day) or class-I antiarrhythmic drugs, or administration of any investigational drug in the preceding 30 days. 8. Uncontrolled hypertension (blood pressure systolic >170 mmHg or diastolic >105mmHg), 9. Symptomatic and sustained ventricular arrhythmias within the preceding two months not adequately treated with antiarrhythmic drugs or without implantation of an automatic defibrillator; 10. With implanted pacemaker (necessary for spectral analysis); ICD is allowed 11. Pregnancy and women with childbearing potential on inadequate contraception 12. Known drug or alcohol misuse 13. Poor compliance with treatment 14. Any other serious systemic disease that might complicate management and reduce life expectancy. 15. Known with an allergy for iodine
Excluded are healthy controls 1. Taking any medication that will affect our outcome measurements for at least 2 weeks before entering the study 2. With a history of adverse reaction on beta-blockers 3. With a contraindication to beta-blocker therapy as described for patients with heart failure 4. With pregnancy and women with childbearing potential on inadequate contraception 5. Known drug or alcohol misuse 6. Known with poor compliance with treatment
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E.5 End points |
E.5.1 | Primary end point(s) |
We will assess two primary endpoints at rest and during exercise: 1. Hypercoagulable activity by platelet function and thrombin generation; 2. Sympathetic activity as measured by plasma norepinephrine and epinephrine concentration, spectral analysis of heart rate and blood pressure variability.
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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 | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
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 | Yes |
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) | Yes |
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 | Information not present in EudraCT |
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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The end of the study is defined as the last patient’s last visit |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |