E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
The aim of the present study is therefore to assess the effect of a 6 month treatment with beta-blocker on left ventricular remodeling and function in patients with asymptomatic moderate to severe aortic regurgitation.
(ii) Patients in stable clinical situation
(iii) Have LVEF >55%,
(iv) Have an end diastolic diameter (on echo) of 50-60 mm
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E.1.1.1 | Medical condition in easily understood language |
Regurgitation of blood during diastole caused by a leak between valve leaflets. |
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E.1.1.2 | Therapeutic area | Body processes [G] - Circulatory and Respiratory Physiological Phenomena [G09] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10002904 |
E.1.2 | Term | Aortic regurgitation |
E.1.2 | System Organ Class | 100000004849 |
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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. The primary objective of this study is to evaluate the effect of metoprolol CR/XL on LV remodeling in patients with aortic regurgitation. LV remodeling will be evaluated with magnetic resonance imaging (MRI) which offers an unsurpassed precision in the measurements of heart volumes and function. End points will be LV end systolic and diastolic volume (LVESV, LVEDV), and LV-ejection fraction (LV-EF). |
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E.2.2 | Secondary objectives of the trial |
2. The secondary objective of this study is to evaluate the effect of metoprolol CR/XL on the B-type natriuretic peptide (BNP), a sensitive marker of the degree of myocardial failure besides being a prognostic indicator in HF patients (17-19).
3. The tertiary objective of this study is to evaluate the effect of metoprolol CR/XL on:
a. Maximal oxygen consumption
b. Effect on immunological variables
i. Inflammatory cytokines: e.g., TNF-, sTNFR2, interleukin-6 (IL-6).
ii. Anti-inflammatory cytokines: e.g., IL-10
iii. Chemokines: e.g., monocyte chemoattractant peptide-1 (MCP-1) and IL-8
iv. Regulators of matrix degradation: e.g., MMPs and their endogenous inhibitors TIMPs.
c. Effect on neurohormones
d. Withdrawals
e. Side effects
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
The criteria for enrollment in the study are asymptomatic aortic regurgitation of moderate to severe degree..
Inclusion criteria
(i) Age of 18-70 years
(ii) Stable clinical situation
(iii) Have LVEF >55%,
(iv) Have an end diastolic diameter (on echo) of 50-60 mm
(v) Have given written informed consent
(vi) No planned surgery
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E.4 | Principal exclusion criteria |
(i) Evidence of unstable disease
(ii) Mixed aortic stenosis and regurgitation (valve gradients > 20 mm Hg).
(iii) evidence of additional valvular or congenital heart disease on echocardiographic or Doppler study
(iv) EF< 55%
(v) LVESD>55 mm
(vi) Heart rate < 50 bpm
(vii) Other illnesses or treatments which reduces the safety and/or efficacy of the treatment
(viii) Participating in other studies
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E.5 End points |
E.5.1 | Primary end point(s) |
Appropriate statistical analysis will be performed. The primary end points are changes in LV-EDV as measured by echo. In order to observe a decrease of LV-EDV of 15% (i.e 21 ml) during Metoprolol CR/XL to placebo at the end of the study with an of 5% and power of 80% we will need approximately 34 patients in each group based on a standard deviation of LV-EDV measurement of 29 ml. To compensate for possible drop out, and increase the chance of significant differences in secondary and tertiary end-points, 70 patients will be included. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
A wide range of biological effects of metoprolol including Left ventricular end-systolic volume, left ventricular function. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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) | 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 | 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 | 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 | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 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 | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |