E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Excercise angina in patients with Coronary Artery Disease |
|
E.1.1.1 | Medical condition in easily understood language |
ECG alteration during exercise test in patients suffering from Coronary Artery Disease, which is a condition due to a constriction of the vessels which conduct the blood to the cardiac muscle |
|
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 | LLT |
E.1.2 | Classification code | 10015648 |
E.1.2 | Term | Exercise induced angina |
E.1.2 | System Organ Class | 100000004849 |
|
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 study objective will be to verify whether ranolazine 750 mg b.i.d. is effective in increasing exercise capacity (exercise treadmill time at peak). |
|
E.2.2 | Secondary objectives of the trial |
The secondary study objectives will be to verify whether ranolazine is effective in reducing angina frequency and nitroglycerin and/or nitrates consumption/week.
The assessment of safety by evaluation of adverse events, laboratory findings and physical examination will also be considered a secondary study objective.
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Male and female patients (females of childbearing potential must be using adequate contraceptive precautions such as implants, injectables, combined oral contraceptives, intrauterine devices, sexual abstinence or vasectomised partner).
• Patients aged ≥ 18 years.
• Patients with coronary artery disease confirmed by angiography or prior MI or prior revascularization (PCI, CABG) and with exercise angina not controlled by the current therapy, with or without anginal pain.
• ST-segment depression ≥ 1mm during exercise ECG.
• Capacity to perform the exercise test.
• Able and willing to sign informed consent and to comply with study procedures.
• Written informed consent prior to enrolment into the study.
• Females of childbearing potential or within two years from the menopause must have a negative urine pregnancy test
Inclusion criterion at visit 1
• Reproducible ST-segment depression ≥ 1mm during two exercise tests performed 1 week apart (difference in exercise no more than 20%).
|
|
E.4 | Principal exclusion criteria |
• Angina at rest.
• ECG abnormalities at rest (left bundle-branch block, right bundle-branch block, resting ST-segment depression ≥ 1mm, tachyarrhythmia).
• Presence of factors that preclude satisfactory interpretation of the ECG (e.g. resting ST-segment depression ≥ 1mm in any lead, left bundle-branch block, digoxin therapy) or repolarisation and conduction abnormalities.
• Heart failure (class III or IV NYHA).
• Moderate-severe hypertension (SBP>160 mmHg and/or DBP>100 mmHg).
• Hypotension.
• Acute coronary syndrome or coronary revascularization procedure within the prior 3 months before enrolment.
• Already planned revascularization (PTCA or CABG )
• Implant of a pacemaker
• Females who are pregnant or nursing.
• Any clinically relevant haematological or biochemical abnormality on routine screening, according to Investigator’s judgment.
• Severe concurrent pathology, including terminal illness (cancer, AIDS, etc.).
• Renal impairment defined as creatinine clearance< 30 mL/min.
• Mild, moderate or severe hepatic impairment or hepatic insufficiency defined as: SGOT or SGPT > 3 times greater than normal upper limit or total serum bilirubin > 1.5 times greater than normal upper limit
• Use of greater than 1000 mg daily dose of metformin during the study.
• Use of greater than 20 mg daily dose of simvastatin during the study.
• Pre-existing QT prolongation (including congenital long QT syndrome, uncorrected hypokalemia).
• Use of following concomitant medications: potent CYP3A4 inhibitors (e.g. ketoconazole and other azole antifunginals, macrolide antibiotics, HIV protease inhibitors and grapefruit juice or grapefruit-containing product); CYP3A4 inducers (e.g. rifampicin, phenytoin, phenobarbital, carbamazepine, hypericum (St. John’s wort); P-glycoprotein inhibitor (e.g. ritonavir, quinidine, ciclosporin); QT-prolonging drugs such as Class Ia (e.g quinidine) and class III (e.g. dofetilide, sotalol, dronedarone) antiarrhytmics (aside from amiodarone), and antipsychotics (e.g., thioridazine, ziprasidone); CYP2D6 inhibitor (e.g paroxetine); other products for which interactions with the products under study have been recorded.
• Existing contraindications for exercise testing (e.g. acute myocarditis or pericarditis, DVT, severe aortic stenosis)
• Dementia, psychosis, alcoholism (>350 g ethanol/week) or chronic abuse of medicines, drugs or psychoactive substances.
Only for Germany:
• Dementia, psychosis, alcoholism (for women >140 g ethanol/week; for men >210 g ethanol/week according to the German Office for Questions Regarding Addiction) or chronic abuse of medicines, drugs or psychoactive substances.
• Conditions which in the Investigator’s opinion may interfere with the study’s execution or due to which the patient should not participate for safety reasons.
• Participation to other clinical trials in the previous three months.
• Prescription and use of off-label medications
• Risk of low patient cooperation.
• Inability or unwillingness to issue the informed consent.
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
Change in treadmill total exercise duration with ranolazine or placebo at peak ranolazine plasma levels (4 hrs after dosing) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
After 24 weeks of full-dose treatment. |
|
E.5.2 | Secondary end point(s) |
To assess the changes in the following Parameters of the treadmill exercise test with ranolazine or Placebo at Peak ranolazine Plasma Levels (4 hours after dosing) after 4 (Visit 6) and 12 (Visit 7) weeks of full-dose Treatment:
- Change in treadmill total exercise Duration
- Change in time to 1 mm ST-segment depression.
- Change in % of time variation from baseline to 1 mm ST-segment depression.
- Change in time to angina.
- Change in % of time variation from baseline to Angina
- To assess the number of angina attacks/week and the number of sublingual nitroglycerin/nitrates consumption/week.
- To assess use and changes in antianginal therapy (beta blockers, calcium channel antagonists, nitrates, ACE-inhibitors, Ivabradine, Trimetazidine, Nicorandil-where present in Europe) and changes in their doses, from baseline to the end of the study. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
If not specified has to be intended at each visit when the parameter is assessed |
|
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) | 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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 70 |
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 |
Albania |
Russian Federation |
Switzerland |
Ukraine |
|
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 8 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 8 |