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 | 15.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10049194 |
E.1.2 | Term | Stable angina pectoris |
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 |
Primary objective of this study is to evaluate the efficacy of ranolazine treatment in terms of changes of wall motion abnormalities in ischemic areas in patients treated with ranolazine compared to patients treated with placebo at follow-up magnetic resonance examination after five weeks of ranolazine treatment. |
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E.2.2 | Secondary objectives of the trial |
Secondary Objectives:
Evaluation of the heart’s perfusion deficit, dynamic geometry and related variables: • transmural extent of perfusion deficit • hyperenhancement • new hyperenhancement • left ventricular ejection fraction (LVEF, %) • left ventricular end-diastolic volume index (LVEDVI, mL/m2) • left ventricular end-systolic volume index (LVESVI, mL/m2) • stroke volume index (SVI, mL/m2) • left ventricular mass index (LVMI, g/m2) • left ventricular mass absolute (LV mass, g)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria to be eligible for participation in this study.
1. Male and female patients (females of childbearing potential must have a negative urine pregnancy test and must be using adequate contraceptive precautions, see also section 17.4)
2. Performed coronary angiography with or without initial PCI more than 24 hours before MRI
3. Remaining ≥ 70% stenosis of a coronary artery bigger than 2 mm diameter (not corrected by PCI)
4. Indication of further interventional treatment
5. Wall motion abnormalities in at least one segment; if segment 17 is affected, an additional segment has to show wall motion abnormalities (for the segment-model, see section 13.3.3)
6. History of chronic angina pectoris
7. Age ≥ 18 years
8. Normalized blood pressure < 140/90 mmHg and heart rate < 70 bpm and ≥ 50 bpm at rest
9. Sinus rhythm
10. Standard therapy: beta-blocker and/or calcium channel blocker (stable for 4 weeks)
11. Signed informed consent
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E.4 | Principal exclusion criteria |
Subjects who meet any of the following exclusion criteria are not enrolled in this study:
1. Cardiac instability, e.g. acute coronary syndrome as indication for the coronary angiography (ST-elevation or positive troponin testing)
2. Contraindication for MRI (e.g. implanted pace maker, internal defibrillator, MRI incompatible devices or metals)
3. Contraindication for dobutamine, atropine, gadolinium based contrast agent, or metoprolol
4. Patients with heart failure classification NYHA III and NYHA IV
5. Myocardial infarction during the last 3 days prior to treatment with ranolazine
6. Severe renal impairment (GFR < 30 ml/min)
7. Moderate or severe hepatic impairment (ALT or AST > 2.5× upper normal limit)
8. Allergic asthma bronchiale
9. Hyperthyroidism or Hashimoto thyreoiditis
10. Myocarditis or inflammatory heart disease
11. Hypertrophic obstructive cardiomyopathy
12. Concomitant administration of class Ia (e.g. quinidine) or class III (e.g. dofetilide, sotalol) antiarrhythmics, except for amiodarone
13. Long acting nitrates
14. Concomitant treatment with potent inhibitors of CYP3A (see also section 11.4)
15. Concomitant treatment with CYP3A inducers (see also section 11.4)
16. Dronedarone
17. Use of greater than 1000 mg daily dose of metformin during the study
18. Hypersensitivity to the active substance or to any of the excipients
19. Hypersensitivity to dobutamine, atropine, gadolinium based contrast agent, or metoprolol
20. Concomitant administration of > 20 mg simvastatin/day
21. History of ECG abnormalities that, in the opinion of the investigator, render the patient unsuitable for the trial, e.g. history of long QT syndrome or significant prolonged QT interval (> 120%)
22. Participation in another trial of an investigational drug or device within 30 days prior to screening
23. Pregnant and breast-feeding women (females of childbearing potential or within two years from the menopause must have a negative urine pregnancy test)
24. Less than 3 months since delivery, abortion, or lactation before the first screening/examination visit
25. Severe psychiatric disorders/neurological disorders
26. Suspected abuse of alcohol, analgesics or psychotropic drugs
27. Disabling or terminal illness
28. Inability or unwillingness to issue the informed consent
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary end point:
The changes of the wall motion abnormalities will be compared between the two treatment groups (ranolazine versus placebo) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After 5 week, day 35 +/- 3 of study drug administration |
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E.5.2 | Secondary end point(s) |
The secondary endpoints are:
to compare the effects of ranolazine versus placebo on the evaluation of the heart’s perfusion deficit, dynamic geometry and related variables:
• transmural extent of perfusion deficit • hyperenhancement • new hyperenhancement • left ventricular ejection fraction (LVEF) • left ventricular end-diastolic volume index (LVEDVI) • left ventricular end-systolic volume index (LVESVI) • stroke volume index (SVI) • left ventricular mass index • left ventricular mass absolute.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
After 5 week, day 35 +/- 3 of study drug administration |
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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 | No |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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 | 1 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 0 |