E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
NON-PERMANENT ATRIAL FIBRILLATION |
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E.1.1.1 | Medical condition in easily understood language |
ARRHYTHMIA OF THE CARDIAC ATRIA LEADING TO IRREGULAR ATRIAL CONTRACTIONS (ARRHYTHMIA ABSOLUTA) |
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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 | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10003658 |
E.1.2 | Term | Atrial fibrillation |
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 |
To assess the efficacy of Ranolazine administered as 3 different dose regimens (375, 500, 750 MG BID) versus placebo in the maintenance of sinus rhythm after electrical cardioversion in patients with non-permanent AF (defined as a continuous AF with a minimum duration of 7 days to a maximum of 6 months or requiring termination by cardioversion)
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E.2.2 | Secondary objectives of the trial |
- To evaluate the dose-effect relationship of Ranolazine to support the choice of the dose to be studied in a subsequent phase III study. - To assess the safety of Ranolazine versus placebo after electrical cardioversion in patients with non permanent AF. |
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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 with persistent AF suitable for electrical direct current cardioversion (DCC); NOTE: According to the ESC classification, persistent AF is defined as a continuous AF with a minimum duration of 7 days or requiring termination by cardioversion. Prior to randomisation, successful electrical cardioversion and maintenance of sinus rhythm at 2 hours shall be documented; 3. A female of childbearing potential may be enrolled providing she: - has a negative pregnancy test at baseline and - is routinely using an effective method of birth control resulting in a low failure rate (e.g.. hormonal contraception, intrauterine device, condoms in combination with a spermicidal cream, total sexual abstinence orsterilisation) until end of study which corresponds to the follow-up safety call, 2 weeks after end of treatment; 4. Able to give written informed consent before any study related procedure; 5. Able to attend all the visits scheduled in the study. |
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E.4 | Principal exclusion criteria |
1. Patients with first diagnosed AF (namely first onset of AF irrespective of duration of arrhythmia or presence and severity of AF related symptoms) or patients with paroxysmal AF (namely self-terminating AF usually within 48 hours although it may continue for up to 7 days); 2. Patients with long-standing persistent AF (for this protocol defined as AF longer than 6 months) or permanent AF (i.e. AF accepted by the patient and by the physician); 3. Patients having known concurrent temporary secondary causes of AF such as alcohol intoxication, pulmonary embolism, hyperthyroidism, pneumonia, hypoxemia, acute pericarditis or myocarditis; 4. Patients having undergone atrial catheter ablation for AF; 5. Patients carrying a pacemaker; 6. Patients with electrolytes imbalances that may cause cardiac arrhythmias, e.g. potassium < 3.5 mmol/L or > 5.5 mmol/L; 7. Patients with severe renal impairment (creatinine clearance < 30 ml/min); 8. Patients with ALT or AST > 2.5x upper limits of normal at screening or severe hepatic impairment of any kind; 9. Patients taking potent CYP3A4 inhibitors (e.g. Itraconazole, Ketoconazole, Voriconazol, Posaconazol, HIV protease inhibitors, Clarithromycin, Telithromycin, Nefazodone); 10. Patients taking CYP3A4 inducers (e.g. Rifampicin, Phenytoin, Phenobarbital, Carbamazepine, St. John's Wort); 11. Patients taking class I or Class III antiarrhythmic agents within 3 days of planned randomisation. NOTE: intravenous flecainide or propafenone are allowed up to 72 hours and 24 hours from the planned randomisation, respectively; 12. Patients taking beta-blockers unless used on stable doses for at least 2 weeks prior to the planned randomisation; 13. Patients taking Dronedarone or oral Amiodarone within 2 weeks and 3 months of planned randomisation, respectively. NOTE: Intravenous administration of Amiodarone is prohibited within 72 hours from planned randomisation; 14. Patients with a history of ECG abnormalities that in the opinion of the Investigator render the subject unsuitable for the trial, including history of congenital or a family history of long QT syndrome and a QTc interval ≥500 msec at Screening; 15. Patients with congestive heart failure NYHA grade III and IV; 16. Patients known to be hypersensitive to Ranolazine or to any of the components of the formulation; 17. Pregnant or breast feeding women; 18. Patients with any serious intercurrent illness (including psychiatric and neurological disorders) which, in the opinion of the Investigator, is incompatible with the protocol; 19. Abuse of alcohol (>350 g ethanol/week), analgesics, or psychotropic drugs; 20. Patients concurrently participating in another study, or who have received an investigational drug within 30 days prior to screening; 21. Patients unable to communicate well with the Investigator and to comply with the requirements of the entire study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
- Time (median [days]) from randomisation to the first documented AF recurrence. Documented recurrence is defined as AF detected on TTECGs by the Core Central Lab or on 12-Lead ECGs performed during a study visit (scheduled or unscheduled). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Max evaluation period of 4 months (112 days). |
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E.5.2 | Secondary end point(s) |
- Time (median [days]) from randomisation to first documented and confirmed AF recurrence. Confirmed AF recurrence is defined as a documented AF which is confirmed by a consecutive ECG performed at least 1 hour after its first documentation. - Time (median [days]) from randomisation to first documented AF recurrence in the subpopulation of patients who are still in sinus rhythm 2 days after the electrical cardioversion. - Dose-effect relationship comparing the time (median, days) from randomisation to first documented AF recurrence between Ranolazine doses. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Max evaluation period of 4 months (112 days). |
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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 | Yes |
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 | 4 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
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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Last safety follow up telephone contact (or visit, if needed) of the last patient. |
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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 | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |