E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Atrial fibrillation is the most common arrhythmia encountered in clinical practice. Atrial fibrillation is usually associated with age and general physical condition, rather than with a specific cardiac event. While not directly life-threatening, atrial arrhythmias can cause discomfort and can lead to stroke or congestive heart failure, and overall, increase morbidity. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10066664 |
E.1.2 | Term | Recurrent symptomatic atrial fibrillation |
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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 safety, tolerability and efficacy of 3 doses of vernakalant (oral) (150 mg, 300 mg and 500 mg b.i.d.) administered for up to 90 days in subjects with sustained symptomatic atrial fibrillation (AF duration > 72 hours and < 6 months) |
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E.2.2 | Secondary objectives of the trial | |
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Comprehend and sign a written informed consent form, (per local and national regulations, as applicable); - Be 18 to 85 years of age; - Women must not be pregnant, be non-nursing and if pre-menopausal, must be using an effective form of birth control from time of screening until 3 months after the last dose of medication. Methods of birth control considered to be effective may include hormonal contraception (the pill), an intrauterine device (IUD), condoms in combination with a sprermicidal cream, total abstinence or sterilisation. Men should be advised not to conceive a child and are advised to use an effective form of birth control from admission until 3 months after the last dose of study medication; - Have symptomatic AF that has been sustained for greater than 72 hours and less than 6 months duration and is clinically indicated for cardioversion; - Have adequate anticoagulant therapy for cardioversion in accordance with standard of practice as recommended by ACC/AHA/ESC guidelines (Fuster V. et al, 2006); - Be haemodynamically stable (100 mmHg < systolic blood pressure < 190 mmHg) at screening and on Day 1 before dosing (while taking rate control drugs, if required). After resting supine for 3 minutes, blood pressures should be measured 3 times in 5 minutes with at least one minute between assessments; - Have a body weight between 45 and 113 kg (99 and 250 lbs). |
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E.4 | Principal exclusion criteria |
- Have known prolonged QT syndrome or QTcB interval of >0.500 sec as measured at screening on a 12-lead ECG; familial long QT syndrome; previous Torsades de Pointes; ventricular fibrillation; or sustained ventricular tachycardia (VT); - Have a QRS >0.140 sec; - Documented previous episodes of second or third-degree atrioventricular block; - Have clinically significant persistent bradycardia with ventricular rate below 50 beats/min, sick-sinus syndrome or pacemaker; - Have clinically significant moderate or severe aortic valvular stenosis (gradient >25 mmHg), hypertrophic obstructive cardiomyopathy, restrictive cardiomyopathy or constrictive pericarditis; - Have Class III or Class IV congestive heart failure at screening or admission, or have been hospitalized for heart failure in the previous 6 months; - Have a myocardial infarction (MI), cardiac surgery, angioplasty, unstable angina or acute coronary syndrome within 30 days prior to the entry into the study; - Have a serious pulmonary, hepatic, metabolic, renal (serum creatinine > 2.0 mg/dl), gastrointestinal, central nervous system (CNS) or psychiatric disease, end-stage disease states, or any other disease that could interfere with the conduct or validity of the study or compromise subject safety; - Have known concurrent temporary secondary causes of AF such as alcohol intoxication, pulmonary embolism, hyperthyroidism, pneumonia, hypoxemia (oxygen saturation < 90% on room air), acute pericarditis, or myocarditis; - Potassium (K+) <3.5 mmol/L or >5.5 mmol/L or magnesium (Mg2+) below the lower limit of normal (Mg2+ <0.65 mmol/L in subjects 65 years or younger and <0.80 mmol/L in subjects 66 years or older). (Both K+ and Mg2+ should be corrected prior to dosing); - Have a clinical evidence of digoxin toxicity; - Have received an oral Class I or Class III antiarrhythmic agent (including sotalol) within 3 days of randomisation or oral amiodarone within 4 weeks, or have received intravenous Class I or Class III antiarrhythmic agent or i.v. amiodarone within 24 hours prior to start of dosing; - Have any other surgical or medical condition that, in the judgement of the clinical Investigator might warrant exclusion or be contraindicated for safety reasons; - Be concurrently participating in another drug study or have received an investigational drug within 30 days prior to screening; - Be 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) |
Safety Assessments Safety Assessments will consist of monitoring and recording of all adverse events (AE) and serious adverse events (SAE), the regular measurement of vital signs and 12-lead ECGs. Safety laboratory assays and physical exams will also be performed.
Efficacy Assessments All efficacy parameters based on ECG data will be evaluated based on ECGs from TTMs and 12-lead ECGs. AF symptoms (with patient diary and SCL) and Quality of Life will also be assessed.
Pharmacokinetic Assessments Population PK approach will be used to evaluate the vernakalant (oral) PK profile in this study.
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
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) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
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 | 110 |
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 | Information not present in EudraCT |
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 |
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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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All subjects are required to undergo a follow-up telephone interview 30 ± 7 days after the last dose of study medication, the Investigator or his/her designee will contact the subject by telephone or see the subject at the hospital (at Investigator’s discretion). |
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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 | 4 |
E.8.9.1 | In the Member State concerned days | |
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 | 4 |