E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
NON-PERMANENT ATRIAL FIBRILLATION |
|
E.1.1.1 | Medical condition in easily understood language |
ARRHYTHMIA OF THE CARDIAC ATRIA LEADING TO IRREGULAR ATRIAL
CONTRACTIONS (ARRHYTHMIA ABSOLUTA) |
|
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 |
|
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 doses
regimens (375, 500, 750 MG BID) versus placebo in the maintenance of
sinus rhythm after electrical cardioversion in patients with nonpermanent
AF (defined as a continuous AF with a minimum duration of 7
days to a maximum of 6 months or requiring termination by
cardioversion) |
|
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. |
|
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 and able to independently record transtelephonic electrocardiograms (TT-ECGs) after being instructed by the Investigator. |
|
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 NOTE: Single doses of Intravenous beta-blockers are allowed up to 10 hours from 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
≥450 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 (hazardous consumption defined as >30 g ethanol/day in men and >20 g/day in women), 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.
22. Patients with known cytochrome CYP2D6 enzyme deficiency (poor metabolisers).
23. Patients taking Metformin at a total daily dose greater than 1000 mg.
24. Patients taking Simvastatin at a total daily dose greater than 20 mg daily. |
|
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). |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Max evaluation period of 4 months (112 days). |
|
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. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Max evaluation period of 4 months (112 days). |
|
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 | 9 |
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
|
Last safety follow up telephone contact (or visit, if needed) of the last patient. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |