E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Paroxysmal Atrial Fibrillation |
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E.1.1.1 | Medical condition in easily understood language |
Sudden onset, tranisient rapid heart beat |
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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 | LLT |
E.1.2 | Classification code | 10034039 |
E.1.2 | Term | Paroxysmal atrial fibrillation |
E.1.2 | System Organ Class | 100000004849 |
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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 evaluate the effect of ranolazine and of low dose dronedarone when given alone and in combination at different dose levels on AFB over 12 weeks of treatment
AFB is defined as the total time a subject is in atrial tachycardia/atrial fibrillation (AT/AF) expressed as a percentage of total recording time. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the effect of ranolazine and of dronedarone when given alone and in combination at different dose levels on:
— Atrial fibrillation burden for each visit period
— Number of atrial fibrillation episodes, duration of atrial fibrillation episodes, and ventricular rate during atrial fibrillation episodes
— Ventricular rate over 12-weeks of treatment and for each visit period
— Percentage of ventricular pacing
— Percentage of atrial pacing
— Incidence of persistent atrial fibrillation
— Incidence of electrical cardioversion
— Incidence of symptomatic episodes
To determine the percentage of subjects who have ≥ 30% (≥ 50%) reduction from baseline in AFB
To determine the percentage of subjects who have total duration of AF episodes ≥ 5.5 hours per day at any point during the treatment period |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Males and females aged 18 years and older
2. Have the ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures
3. History of PAF documented within the prior 12 months
— Patients with PAF undergoing cardioversion greater than 4 weeks prior to Screening are eligible
4. Implanted (at least 3 months prior to Screening) dual chamber programmable pacemakers with AF detection capabilities
5. AFB ≥ 1% and ≤ 70% between the last clinic evaluation and Screening (minimum of 1 month observation period) and AFB ≥ 2% and ≤ 70% during the 4-week Run-in period
6. Sexually active females of childbearing potential must agree to utilize effective methods of contraception during heterosexual intercourse throughout the treatment period and for 14 days following discontinuation of the study medication |
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E.4 | Principal exclusion criteria |
1. Persistent AF or Permanent AF
2. History of atrial flutter or atrial tachycardia without successful
ablation
3. Other acutely reversible causes of AF, including but not limited to:
hyperthyroidism, pericarditis, myocarditis, or pulmonary embolism
4. NYHA Class III and IV heart failure or NYHA Class II heart failure with a recent decompensation requiring hospitalization or referral to a specialized heart failure clinic within 4 weeks prior to Screening.
5. Recent history of left ventricular ejection fraction (LVEF) < 40%
6. Myocardial infarction, unstable angina, or coronary artery bypass graft (CABG) surgery within three months prior to Screening or percutaneous coronary intervention (PCI) within 4 weeks prior to Screening
7. Clinically significant valvular disease in the opinion of the Investigator
8. Stroke within 3 months prior to Screening
9. History of serious ventricular arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation) within 4 weeks prior to Screening
10. Family history of long QT syndrome
11. QTc ≥ 500 msec (Bazett) at Screening ECG if in sinus rhythm (SR). If in AF, evidence of QTc ≥ 500 msec (Bazett) within 4 weeks prior to Screening
12. Prior heart transplant
13. Cardiac ablation within 4 months prior to Screening, or planned
ablation during the course of the study
14. Need for concomitant treatment during the trial, with drugs or
products that are strong inhibitors of CYP3A, or inducers of CYP3A
15. Use of grapefruit juice or Seville orange juice during the study
16. Use of Class I and Class III antiarrhythmic drugs other than
amiodarone
17. Use of amiodarone within 3 months prior to Screening
18. Use of drugs that prolong the QT interval
19. Previous use of ranolazine or dronedarone within 2 months prior to screening
20. Prior use of ranolazine or dronedarone which was discontinued for safety or tolerability
21 Use of dabigatran during the study
22. Use of digitalis preparations (eg, digoxin) during the study
23. Use of a greater than 1000 mg total daily dose of metformin
24. Hypokalemia (serum potassium < 3.5 mEq/L) at
Screening that cannot be corrected to a level of potassium ≥ 3.5 mEq/L prior to randomization
25.Moderate and severe hepatic impairment (ie, Child-Pugh Class B and C), abnormal liver function test defined as ALT, AST, or bilirubin > 2 x ULN at Screening
26. Severe renal impairment defined as creatinine clearance ≤ 30
mL/min at Screening
27. Females who are pregnant or are breastfeeding |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline in atrial fibrillation burden (both percent change and absolute change). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
1. Change from baseline in atrial fibrillation burden for each visit period 2. Change from baseline in number of AF episodes, duration of AF episodes, and ventricular rate for AF episodes
3. Change from baseline in ventricular rate for each visit period
4. Percent ventricular pacing for each visit period
5. Percent atrial pacing
6. Incidence of persistent atrial fibrillation
7. Incidence of electrical cardioversion
8. Incidence of symptomatic episodes |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.6 | Pharmacokinetic | Yes |
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) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 5 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 50 |
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 |
Germany |
Israel |
Italy |
Netherlands |
Poland |
United Kingdom |
United States |
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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 | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |