E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10011078 |
E.1.2 | Term | Coronary artery disease |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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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 |
The primary objective of this study is to evaluate the efficacy of ranolazine as compared with placebo when used as part of standard medical therapy in chronic angina subjects with incomplete revascularization post-PCI on the composite of ischemia-driven revascularization or ischemia-driven hospitalization without revascularization.
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are to:
-Evaluate the efficacy of ranolazine as compared with placebo when used as part of standard medical therapy in chronic angina subjects with incomplete revascularization post-PCI on the incidence of sudden cardiac death
-Evaluate the efficacy of ranolazine as compared with placebo when used as part of standard medical therapy in chronic angina subjects with incomplete revascularization post-PCI on the incidence of CV death
-Evaluate the efficacy of ranolazine as compared with placebo when used as part of standard medical therapy in chronic angina subjects with incomplete revascularization post-PCI on the incidence of MI
-Assess quality of life (QoL) in the ranolazine group as compared to the placebo group at Months 1, 6 and 12
-Assess the pharmacoeconomic benefit of ranolazine post-PCI
-Evaluate the tolerability and safety of ranolazine post-PCI |
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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 |
Integrated Quality of Life Study and Health Economics Sub-Study. Date/Version: 15Feb2012
Health Economics sub-study current planned for US only.
Quality of Life is planned globally.
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E.3 | Principal inclusion criteria |
1. Written informed consent
2. Males and females aged 18 years and older
3. History of chronic angina defined as at least 2 episodes of anginal pain or discomfort in the chest, jaw, shoulder, back, neck, or arm that is precipitated by exertion or emotional stress and relieved by rest or sublingual nitroglycerin which occurred on at least 2 separate days and at least 14 days prior to PCI (in the case of staged PCI procedures, at least 14 days prior to the first PCI in the series). Subjects may or may not have additional angina episodes within the 14 days prior to their first PCI in the series, as well as anytime prior to Randomization.
4. PCI for any indication (ACS or non-ACS). For the purposes of stratification at randomization, ACS will be defined as hospitalization for anginal pain or discomfort within the previous 24 hours to their hospitalization with any one (or more) of the following criteria:
i. Elevated troponin or creatinine kinase-MB (CK-MB) consistent with MI, as reported by local laboratory and measured prior to index PCI
ii. Electrocardiographic changes (including transient changes)comprising new or presumably new ST segment depression ≥ 0.1 mV (≥ 1 mm), or ST segment elevation ≥ 0.1 mV (≥ 1 mm) in at least 2 contiguous leads, or new or presumably new Left Bundle Branch Block
5. Randomization within 14 days post-PCI. In case of staged PCI procedures, randomisation has to occur within 14 days of last PCI in the series. The first day of the 14-day randomisation window is the day after the PCI. PCI is defined as an attempt to cross the lesion with a wire.
6.Post-PCI (post the last PCI for staged procedures) evidence of incomplete revascularization defined as the presence of one or more visually estimated ≥ 50% stenosis in one or more coronary arteries with reference vessel diameter of at least 2.0 mm, whether in the target vessel or in a non-target vessel regardless of the presence or absence of coronary collaterals. In the case of a subject post-CABG, incomplete revascularization is defined as the presence of one or more visually estimated ≥ 50% stenosis in an unbypassed epicardial vessel with a reference diameter ≥ 2.0 mm in diameter, or one or more visually estimated ≥ 50% stenosis in a bypass graft supplying an otherwise unrevascularized myocardial territory.
7.Clinically stable post-PCI. Subjects randomized in-hospital on day of planned discharge or in clinic are considered stable. Subjects randomized in-hospital prior to day of planned discharge are considered stable if they meet all of the following criteria:
i.CK-MB < 3 times the upper limit of normal (ULN) at least 3 hours post-PCI, or if ≥ 3 times the ULN with evidence of decreasing CK-MB (decreased by at least 20% from the prior measure), as reported by local laboratory. If CK-MB is not available, a subject must have evidence of normal or decreasing troponin levels (decreased by at least 20% from the prior measure) at least 3 hours post-PCI, as reported by local laboratory.
ii.Systolic blood pressure ≥ 90 mm Hg and not receiving pressors or inotropes
iii.No current requirement for an intra-aortic balloon pump (IABP) or any left ventricular assist device
iv.No current requirement for intravenous (IV) nitroglycerin
8. Ability and willingness to comply with all study procedures during the course of the study
9. Females of childbearing potential must have a negative pregnancy test at Screening (unless surgically sterile or post-menopausal) and must agree to use highly effective contraception methods from Screening throughout the duration of study treatment and for 14 days following the last dose of study drug. |
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E.4 | Principal exclusion criteria |
1.Any future planned revascularization (including staged procedures) or possible planned revascularization (ie, planned stress test to assess the imminent need for additional revascularization). Future planned stress tests for purposes of monitoring are permitted but strongly discouraged. If a stress test is performed following Randomization, the test should be performed on the subject’s concurrent medical treatment regimen including all antianginals and study drug. Medications should therefore not be held for the test. Subjects may be enrolled after the last PCI in the staged series or once a decision is made not to perform a follow up PCI, as long as Randomization occurs within 14 days from the last PCI. If a subject has had a stress test post-PCI and prior to Randomization and no further intervention is planned, the subject may be enrolled within 14 days from the last PCI.
2. Unrevascularized left main coronary artery stenosis ≥ 50%. Subjects with history of CABG to the left coronary system will be considered to have a revascularised left main if at least one graft is patent.
3. Major complication during or after the index PCI (in the case of staged PCI, the last in the series) including:
i. Major bleeding (TIMI Bleeding classification or any bleeding requiring ≥ 2 units of red blood cells)
ii. Coronary perforation requiring treatment
iii. Procedural complication requiring surgery (including CABG or peripheral vascular surgery)
4. Stroke within 90 days prior to Randomization, or any history of stroke with permanent major neurologic disability (eg, aphasia or significant motor dysfunction)
5. Cardiogenic shock within 90 days prior to Randomization (transient decreases in the blood pressure without clinical sequelae are not considered to be cardiogenic shock)
6. New York Heart Association (NYHA) Class III or IV heart failure
7. Severe renal insufficiency as assessed by an estimated GFR < 30 mL/min/1.73m2 using the 4 variable modification of diet in renal disease (MDRD) equation, per local laboratory (based on the last available measurement prior to Randomization, collected within 1 month prior to the index PCI [in the case of staged PCI, the last in the series])
8. Liver cirrhosis
9. Use of Class Ia, Ic, or Class III antiarrhythmics, except for amiodarone
10. Current treatment with strong inhibitors of CYP3A
11. Current treatment with CYP3A4 inducers or P-gp inducers
12. Subjects taking > 20 mg simvastatin daily or > 40 mg lovastatin daily who cannot reduce the dose to 20 mg once daily for simvastatin or 40 mg once daily for lovastatin, or who cannot switch to another statin
13. Subjects taking greater than a total of 1000 mg daily of metformin who cannot reduce the dose to a maximum total of 1000 mg daily (additional anti-diabetic medications may be added as clinically indicated to allow subjects to decrease their metformin dose and maintain glycemic control)
14.Previous treatment with ranolazine for > 7 consecutive days within 30 days prior to Randomization, or known hypersensitivity or intolerance to ranolazine or to any of the excipients
15. Participation in another investigational drug or device study within 30 days prior to Randomization (participation in registries is allowed)
16. Women who are pregnant or breast feeding
17. Non-CAD comorbid conditions (e.g. advanced malignancy, severe aortic stenosis) which are likely to result in death within 2 years of Randomization
18. Any condition that in the opinion of the investigator would preclude compliance with the study protocol. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint of this study is time from randomization to the first occurrence of ischemia-driven revascularization or ischemia-driven hospitalization without revascularization.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoints will be adjudicated throughout the study by the Clinical Events Committee. |
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E.5.2 | Secondary end point(s) |
The secondary endpoints are:
• Time from randomization to sudden cardiac death
• Time from randomization to CV death
• Time from randomization to MI
Additional secondary endpoints will include:
• Evaluation of QoL and health related costs, as detailed in the Integrated QoL Study and Health Economics Sub-Study |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The secondary points will be adjudicated throughout the study by the Clinical Events Committee. |
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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 | 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) | 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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 90 |
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 | No |
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 |
Austria |
Belgium |
Canada |
Czech Republic |
France |
Germany |
Israel |
Italy |
Netherlands |
Poland |
Russian Federation |
Spain |
Sweden |
United Kingdom |
United States |
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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 study will continue until at least 1 year post-randomization follow-up has been achieved for all subjects and at least 720 adjudicated first post-randomization primary endpoint events (ischemia-driven revascularization or ischemia-driven hospitalization without revascularization) have been observed.
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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 | 6 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |