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 |
An irregular and often fast heart beat which usually comes and goes and stops within 48 hours without any treatment. |
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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 | 16.1 |
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 assess the reduction in AF burden (time spent in AF as a proportion of the analysis period) by XEN-D0103 (50 mg BID) compared to placebo in patients with paroxysmal AF. |
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E.2.2 | Secondary objectives of the trial |
• To assess the safety and tolerability of 28 days dosing with XEN D0103 (50 mg BID) in patients with paroxysmal AF. • To assess mean duration of AF episodes following XEN D0103 (50 mg BID) compared to placebo. • To assess the frequency of AF episodes following XEN D0103 (50 mg BID) compared to placebo. • To assess trough XEN D0103 concentrations. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Written informed consent. 2. Patients of either sex, aged 18 years and older with paroxysmal AF confirmed within 6 months prior to Screening and Washout. 3. Dual chamber pacemaker with appropriate arrhythmia diagnostics for at least 1 month prior to Screening and Washout 4. Able to tolerate withdrawal of Class I and III antiarrhythmic drugs (such as Flecainide, Sotalol, Dronedarone or Amiodarone). 5. Able to tolerate pacemaker antiarrhythmic algorithms being turned off at Screening and Washout, if applicable. 6. Evidence of AF burden 1% and 50% prior to Visit 2 (Day 1). 7. Anticoagulated in accordance with European Society of Cardiology (ESC) Guidelines. 8. Women must be of non child bearing potential. Non-child bearing potential is defined as amenorrheic for at least 2 years AND have serum follicle stimulating hormone [FSH] level of at least 30 IU/L) or have undergone a hysterectomy or bilateral oophorectomy (tubal ligation is not acceptable). If partners of male patients are of childbearing potential, the patient must be willing to use contraception (e.g. condoms).In addition, their female partner must also be using contraception (e.g. hormonal, intra-uterine device etc). This double contraception must be used from the first dose of study drug until at least 90 days after the last dose of study drug |
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E.4 | Principal exclusion criteria |
1. Cardiac ablation procedure within 3 months prior to Screening and Washout. 2. QTc interval >450 ms on Day 1. 3. History of clinically significant ventricular arrhythmia. 4. History of long QT syndrome. 5. Concomitant treatment with any Class I or III anti-arrhythmic drugs (such as Flecainide, Sotalol, Dronedarone or Amiodarone) on Day 1. Treatment with oral Amiodarone must be stopped 6 weeks prior to Study Day 1. In the case of intravenous Amiodarone, a cumulative dose of >5g in the period between Screening and Washout and Day 1 is unacceptable. In the case of all other Class I or III anti-arrhythmic drugs, they must be stopped for at least 2 weeks prior to Day 1. 6. Heart failure with symptoms consistent with New York Heart Association [NYHA] classes III-IV. Patients with NYHA I-II heart failure can be enrolled if there have beenno hospital admissions for exacerbations of heart failure within 6 months prior to screening 7. Myocardial infarction within 3 months of Screening and Washout; coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass graft [CABG]) within 6 months of Screening and Washout, or unstable angina within 3 months of the Screening and Washout. 8. Transient ischaemic attack (TIA) or stroke within 3 months of Screening and Washout. 9. Body mass index (BMI) >36 kg/m2 at Screening and Washout. 10. Patient is unable or unwilling to co-operate with the study procedures. 11. Participation in any other clinical trials within 30 days prior to Screening and Washout. 12. Substance or alcohol abuse (as defined by Diagnostic and Statistical Manual of Mental Disorders Forth Edition) within 6 months of Screening and Washout. 13. The following laboratory abnormalities at Screening and Washout, with the provision that repeat samples may be considered for this criterion at the discretion of the Sponsor: a. Serum potassium of <3.5mmol/L or >5.5mmol/L b. Serum magnesium <0.7mmol/L c. Calculated creatinine clearance (using the Cockcroft-Gault method) of <50ml/min d. Serum alanine transaminase (ALT), aspartate transaminase (AST) or gamma-glutamyl transpeptidase (GGT) greater than twice the upper limit of normal (ULN). e. Total serum bilirubin >1.5x ULN. f. Serum haemaglobin <9g/L (women) or 11g/L (men) 14. Taking medication which is a CYP3A4 substrate with a narrow therapeutic window (see section 9.8.3) 15. Evidence of any other clinically significant disease or condition which in the opinion of the Investigator would preclude the patient's participation in this study |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint will be AF burden, which is defined as the time spent in AF as a proportion of the analysis period. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Time spent in AF as a proportion of the analysis period |
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E.5.2 | Secondary end point(s) |
Secondary endpoints include: • the mean duration of AF episodes, • the frequency of AF episodes over the analysis period, • XEN D0103 plasma concentrations • the safety and tolerability of XEN-D0103
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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 | Yes |
E.6.6 | Pharmacokinetic | Yes |
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) | 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 | No |
E.8.1.6 | Cross over | Yes |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
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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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 | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |