E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Non-ST Segment Elevation Acute Coronary Syndrome |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10051592 |
E.1.2 | Term | Acute coronary syndrome |
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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 |
To determine whether ranolazine is superior to placebo for reducing the rate of CV death, MI, or severe recurrent ischemia during long term treatment of patients with non-ST elevation acute coronary syndrome receiving standard therapy |
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E.2.2 | Secondary objectives of the trial |
1) To determine whether ranolazine is superior to placebo for reducing the rate of major cardiovascular events (CV death, MI, or severe recurrent ischemia) during long term treatment of patients with non-ST elevation acute coronary syndrome receiving standard therapy 2) To determine whether ranolazine is superior to placebo for reducing the rate of failure of therapy (CV death, MI, recurrent ischemia, positive Holter for ischemia, hospitalisation for new/worsening heart failure or an early positive exercise test) during long term treatment of patients with non-ST elevation acute coronary syndrome receiving standard therapy 3) To evaluate the safety of treatment with ranolazine compared to placebo 4) Other secondary objectives as detailed in the Protocol (refer to Protocol section 4) |
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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 |
Substudies are in the MERLIN protocol version 25May2005. Appendix G - Genetic Substudy Appendix H - Percutaneous Coronary Intervention Substudy Appendix I - Platelet density Substudy Appendix J - Pharmacokinetic Substudy Appendix K - Transthoracic Echo Substudy
Genetic Substudy Objectives
To determine the association between specific polymorphisms in atherothrombotic genes and recurrent ischemic events.
To determine whether significant gene-environment interactions exist between pro- atherothrombotic polymorphisms and traditional clinical cardiovascular risk factors.
To determine whether significant pharmacogenomic interactions exist between pro- atherothrombotic polymorphisms and the efficacy and safety of treatment with ranolazine.
PCI Sutbstudy Objectives
To evaluate the effect of ranolazine on development of distal myocardial infarction and enzymatic infarct size during percutaneous coronary intervention (PCI)
To evaluate the effect of ranolazine on the total duration of ischemia detected on continuous holter monitoring during and after percutaneous coronary intervention
Platelet Density Substudy Objectives
1. To evaluate the degree of platelet activation in patients with NSTE ACS, as assessed by MPC determination
2. To correlate the degree of baseline platelet activation and the change in platelet activation in response to therapy with clinical cardiovascular events
3. To evaluate whether the degree of baseline platelet activation is associated with the efficacy of ranolazine compared to placebo
PK Substudy Objectives
1) To determine plasma ranolazine levels following intravenous and orally administered ranolazine in patients presenting with acute coronary syndromes
2) To evaluate the plasma ranolazine levels in patients experiencing profound and persistent QTc prolongation or specific adverse events
ECHO Objectives
1. To determine if ranolazine improves diastolic and systolic function among patients early after presentation with ACS and during follow-up.
2. To determine if an association exists between measures of diastolic function and clinical outcomes in patients with NSTE-ACS and whether this relationship is altered by ranolazine.
3. To assess the association between myocardial ischemia and newer echocardiographic measures of LV diastolic function
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E.3 | Principal inclusion criteria |
All inclusion criteria must be met:- 1) Aged 18 years or older, and 2) Hospitalisation with non-ST elevation acute coronary syndrome defined as chest discomfort or anginal equivalent occurring at rest, lasting for 10 minutes or more and consistent with myocardial ischemia, and 3) At least one episode of ischemic symptoms (5 minutes or longer) at rest within 48 hours of enrollment (may include index episode), and 4) At least one of the indicators of moderate-high risk as detailed in the protocol, and 5) Willing and able to provide written informed consent |
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E.4 | Principal exclusion criteria |
Any of the criteria will result in exclusion:- 1) Persistent (> 20 mins) acute ST-segment elevation of 0.1 mV or greater, in two or more contiguous leads 2) Successful revascularisation of the culprit stenosis during the qualifying hospitalisation prior to randomisation 3) Acute pulmonary edema requiring endotracheal intubation, sustained blood pressure < 90 mm Hg or evidence of cardiogenic shock 4) Left bundle branch block, electronic pacemaker, or LVH with severe repolarizartion abnormality that would interfere with interpretation of the Holter 5) Other exclusion criteria in the Protocol |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint is the time to first occurence of any element of the composite of CV death, MI or recurrent ischemia.
Other endpoints in the Protocol |
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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 | No |
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 | Yes |
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) | 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 | 43 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 267 |
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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Until the trial has accumulated 730 major CV events (CV death, MI, severe recurrent ischemia) and 310 deaths from any cause are recorded. (This will prompt the last visit for trial patients.)
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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 | 10 |
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 | 10 |