E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients, 65 years or older, suffering from chronic heart failure and who are so far not treated with betablockers or treated with a low dose betablocker (<1/4 standard dose) |
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MedDRA Classification |
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 |
Are there differences in the tolerance of the betablockers Bisoprolol vs. Carvedilol when used in accordance with European Guidelines? |
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E.2.2 | Secondary objectives of the trial |
Analysis of differences regarding the secondary endpoints: Analysis of possible influence of baseline data, laboratory data, the CYP polymorphism, depression, quality of life and general compliance on the endpoints. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1. Biomaterial databank; 12.05.2004; objective: pooling of blood and DNA samples from each trial within the Competence Network Heart Failure, for genetic testing with regard to aetiology, progression and prognosis of HF. 2.Titrate-HF/BNP guided Titration; 12.05.2004; objective: assessment and analysis of the relationship between BNP levels, titration speed and maximal tolerated beta-blocker dose. 3. Pharmacogenetic influence; 12.05.2004; objective: : to gain insight into the impact of the genotypes CYP2D6, ADRB1, ADRB2 and ADRA2C on HF therapy with beta-blockers. 4. Physical performance during beta-blocker titration; 12.05.2004; objective: to determine the level of beta-receptor-blockade for correlation with beta-blocker dosage |
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E.3 | Principal inclusion criteria |
• Age ≥ 65 years • Current diagnosis of HF with symptoms consistent with NYHA II or above • Left ventricular ejection fraction (LVEF) ≤ 45 % (documented by echocardiography, levocardiography or magnetic resonance imaging (MRI)) and/ or echocardiographic parameters of diastolic dysfunction Stage ≥ I • Chronic heart failure was stable for the previous two weeks • Written informed consent was obtained
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E.4 | Principal exclusion criteria |
• A previously prescribed basic therapy consisting of ACE inhibitors (or angiotensin receptor antagonists or vasodilators), diuretics and, where applicable, aldosterone antagonists and digoxin was changed within the last two weeks before the study • Intake of beta-blockers for longer than 14 days within the last three months in a dose which is more than ¼ of the recommended daily intake. • Other systemically administered beta-blockers except for the study medication during participation (including sotalol) • Acute or de-compensated HF • Cardiogenic shock • Acute pulmonary embolism • Obstructive or restrictive cardiomyopathy • Severe pulmonary dysfunction or severe asthma • Uncontrolled hypertension (systolic BP > 190 mmHg or diastolic BP >110 mmHg) • Endocarditis and myocarditis • History of heart transplant surgery within two months prior to the study or planned • Uncontrolled hypo – or hyperthyroidism • Known alcohol or drug abuse • Known significant diseases or clinically relevant abnormal lab results which are deemed by the investigator to have a disadvantageous effect on either the patients’ prognosis or the possibility of their participation • Participation in another clinical study within the last 30 days • Legal incapacity or reduced legal capacity • Known hypersensitivity to bisoprolol or carvedilol • Advanced peripheral vascular disease and/ or Raynaud’s disease • Hypotension (systolic < 90 mmHg in supine position at inclusion) • Known predisposition to orthostatic hypotension • Bradycardia with less than 55 bpm prior to commencement of the therapy • First or second degree sinoatrial or atrioventricular block (without pacemaker) or known sick sinus syndrome • Strict fasting • Current desensitisation therapy • Known pheochromocytoma or clinical suspicion for this disease (-) • Clinically relevant liver function abnormalities • Intake or current need for the intake of any of the contraindicated concomitant medication
Contraindications to beta-blocker therapy • Inotropic substances with the exception of digoxin • Ergotamine derivates • Calcium-channel-blockers of the phenylalkylamine type • Clonidine • Rifampicin • Antiarrhythmic medications except amiodarone • Monoamine oxidase inhibitors (except MAO-B inhibitors) • α1-Antagonists or α2-Agonists
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is tolerance (yes/no) of the study medication target dose as per cardiology guidelines. Tolerance (=yes) is defined when • Dose titration was possible up to the target dose. • The study medication dose was not reduced. It is irrelevant whether unscheduled T-visits took place if the titration aim was not affected. • The target dose is to be taken at the point of last visit F (visit B + 10 or 12 weeks). This dose has remained stable for at least 10 days. Tolerance is ascertained (i.e. there is no reason for dose reduction and the patient did not reduce it independently either).
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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 | Yes |
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 | 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) | Yes |
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 | Yes |
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) | 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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 37 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
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 trial is defined as 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 | 9 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 2 |