E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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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 |
To demonstrate that aliskiren 300 mg, in addition to standard therapy, has superior efficacy compared to placebo in reducing the primary index of adverse cardiac remodeling (defined as the change in LVESV from baseline to end of study) in patients after high risk acute myocardial infarction. |
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E.2.2 | Secondary objectives of the trial |
For full list, refer to protocol
To evaluate the effect of aliskiren compared to placebo on: • a composite outcome of CV death, hospitalization for heart failure, or a reduction in ejection fraction greater than 6 units (absolute percentage points) • a composite outcome of time to CV death, hospitalization for heart failure, recurrent myocardial infarction, stroke or resuscitated sudden death • change in left ventricular ejection fraction (LVEF) between baseline and end of study Exploratory Objectives: To evaluate the effect of aliskiren compared to placebo on: • renal function as measured by change in estimated glomerular filtration rate (eGFR), cystatin C, and urinary albumin creatinine ration (uacr) from baseline to end of study (in a subset of patients) • other biological markers relevant to the pathophysiology of remodeling and other outcomes after myocardial infarction (in a subset of patients)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female patients 18 years and older. 2. Patients within 7-42 days of an acute myocardial infarction associated with left ventricular systolic dysfunction prior to Visit 1 (see below). A qualifying myocardial infarction will require each of the following: • Typical clinical presentation consistent with myocardial infarction (i.e., chest pain, shortness of breath) • Elevation of cardiac markers (any of the following will fulfill the requirement for an increase in cardiac markers): • Both total CK and CK-MB are above the upper limit of normal (ULN) and either total CK or CK-MB are at least twice the upper limit of normal (2xULN) • CK-MB is elevated to at least twice the upper limit of normal (2xULN) when total CK is not available, and is confirmed by an accompanying Troponin T or I level at least three times the upper limit of normal (3xULN) • Total CK is elevated to at least twice the upper limit of normal (2xULN) when CK-MB is not available, or to above the ULN if confirmed by an accompanying Troponin T or I level at least three times the upper limit of normal (3xULN) • Troponin T or I level is at least five times the upper limit of normal (5xULN) and neither total CK nor CK-MB are available. • Typical ECG changes, including evolving ST-segment or T-wave changes in two or more contiguous ECG leads, the development of new pathological Q/QS waves in two or more contiguous ECG leads, or the development of new left bundle branch block. 3. Documented left ventricular systolic dysfunction associated with the qualifying acute myocardial infarction obtained as a clinical evaluation (study) prior to Visit 1. Systolic dysfunction will be defined by at least one of the following criteria: If the clinical imaging was obtained < 5 days post-MI but prior to Visit 1, the left ventricular ejection fraction (LVEF) must be as follows: • Echocardiography: (LVEF) ≤ 35% • Radionuclide ventriculography: LVEF ≤ 35% • Ventricular contrast angiography: LVEF ≤ 35%. or If the clinical imaging was obtained ≥ 5 days post-MI but prior to Visit 1, the LVEF must be as follows: • Echocardiography: (LVEF) ≤ 40% • Radionuclide ventriculography: LVEF ≤ 40% • Ventricular contrast angiography: LVEF ≤35%. 4. Patients should be on stable doses of the following standard of care post-MI concomitant medications for at least 2 weeks prior to Visit 1 unless contraindicated due to intolerance: • A Beta-blocker • An Anti-platelet agent • A Statin 5. Patients must be on a stable evidence-based dose /see Appendix 3) of an Angiotensin Converting Enzyme Inhibitor (ACEI) or Angiotensin Receptor Blocker (ARB) but not both, for at least 2 weeks prior to Visit 1, unless contraindicated due to intolerance. For patients not on an envidence-based dose of an ACEI or an ARB, the reason (e.g., patient intolerant of these medications) must be documented. 6. Patients who are eligible, able to participate in the study, and who consent to do so after the purpose and nature of the investigation has been clearly explained to them (written informed consent). 7. Qualifying Echocardiogram: • Patients who fulfill the screening inclusion and exclusion criteria will have a qualifying echocardiogram performed and transmitted to the Echo Core Laboratory. To be eligible for randomization, patients must fulfill the following criteria by the core laboratory: • Acceptable image quality • Confirmed LVEF = 45% • Qualifying Myocardial Infarct Percentage = 20% (akinetic or dyskinetic segment length as percent of total cavity perimeter). |
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E.4 | Principal exclusion criteria |
For full list, please see protocol.
1. Patients requiring both ACEI and ARB combination therapy at V1 or any time during the study. 2. Hypertrophic cardiomyopathies due to etiologies other than hypertension (i.e., idiopathic or valvular). 3. Severe refractory hypertension defined as MSSBP = 180 mmHg and/or MSDBP = 110 mmHg) at Visit 2. 4. Hemodynamically significant stenotic or obstructive valvular, subvalvular or supravalvular lesions. 5. Secondary forms of cardiomyopathy such as restrictive cardiomyopathy or infective cardiomyopathy (e.g., Chagas’ disease). 6. Cardiogenic shock or systolic BP < 100 mmHg or diastolic BP < 60 mmHg within the 24 hours prior to Visit 1 or 2. 7. Estimated Glomerular Filtration Rate (eGFR) < 30 ml/min/1.73m2 using the MDRD formula at Visit 1. 8. Stroke or transient ischemic event (TIA) within 6 months of Study Visit 1. 9. Serum potassium = 5.1 mEq/L, or dehydration at Study Visit 1. 10. Significant valvular cardiovascular disease expected to lead to cardiac surgery during the course of the study. Comlpete list of exclusion criteria can be found in the protocole |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy variable is the change in left ventricular end systolic volume (LVESV) as assessed by echocardiography, from baseline to end of study.
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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 | 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) | Information not present in EudraCT |
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) | No |
E.8.2.2 | Placebo | Yes |
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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 105 |
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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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 | 9 |
E.8.9.1 | In the Member State concerned days | 5 |
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 | 9 |
E.8.9.2 | In all countries concerned by the trial days | 5 |