E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Paroxysmal or persistent, non-valvular, atrial fibrillation |
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E.1.1.1 | Medical condition in easily understood language |
Paroxysmal or persistent, non-valvular, atrial fibrillation |
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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 | 20.0 |
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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10034039 |
E.1.2 | Term | Paroxysmal atrial fibrillation |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10071667 |
E.1.2 | Term | Persistent 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 |
Antiarrhythmic potential for cardioversion from AF to SR after i.v. administration of doxapram |
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E.2.2 | Secondary objectives of the trial |
• Recommended i.v. doxapram dose for cardioversion • Time to cardioversion from AF to SR after i.v. doxapram administration • Time to recurrence of AF within 7 ± 2 d of cardioversion • Doxapram PK after i.v. administration of one or two equal consecutive bolus doses • Doxapram PK after continuous i.v. administration over 8 h • Safety and tolerability of doxapram after i.v. administration
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age 18 – 80 years, 2. Patient meets in-house eligibility criteria for non-emergent, electrical or pharmacological cardioversion (absence of AF-inducing medical conditions such as e.g. valvular disease, sufficient anticoagulation, and/or exclusion of cardiac thrombus), 3. Available previous ECG in sinus rhythm to allow for an assessment of QT time, 4. Ability to understand and willingness to comply with study interventions, and 5. Voluntarily signed informed consent after full explanation of the study to the patient.
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E.4 | Principal exclusion criteria |
1. Any participation in a clinical drug trial within 5 times the documented terminal half-life of the respective active drug or if half-life is unknown within the last four weeks before inclusion, 2. Any physical disorder as judged by the investigator that could interfere with the patient’s safety during the clinical trial or with the study objectives, 3. Inability to communicate well with the investigator due to language problems or poor mental development, 4. Pregnancy or lactation, 5. Intake of antiarrhythmic agents as co-medication (Vaughan Williams classification), except class II beta-blockers, within less than 5 half-lives of the respective drug as related to planned exposure: class Ia: e.g. quinidine, ajmaline, procainamide, or disopyramide, class Ib: e.g. lidocaine, phenytoin, mexiletine, or tocainide, class Ic: e.g. encainide, flecainide, propafenone, or moricizine, class III: e.g. amiodarone, sotalol, ibutilide, dofetilide, dronedarone, or vernakalant, class IV: e.g. verapamil ordiltiazem, class V: e.g. adenosine, digoxin, or digitoxin, unclassified: ranolazine, 6. Any adenosine like drugs (e.g. ticagrelor) within less than 5 half-lives of the respective drug, 7. Any magnesium intake (> 500 mg) within 4 h of planned exposure, if magnesium has been applied within 24 h prior to planned exposure magnesium blood level must not higher than the upper limit of normal (+ 10%), 8. Any theophylline intake within 3 d as related to planned exposure, 9. Contraindication for doxapram use present such as a) known intolerance to doxapram, b) systolic blood pressure < 100 mmHg or > 170 mmHg, c) diastolic blood pressure < 60 mmHg or > 100 mmHg, d) Heart rate < 50 / min, e) acute coronary syndrome, f) decompensated heart failure or chronic heart failure (NYHA) class III or IV, g) hyperthyreodism, h) history of pheochromocytoma, i) impaired breathing function (due to a history of e.g. accidental injury, pneumothorax, pulmonary embolism, neuromuscular impairment, lung fibrosis, asthma, or other impairment of breathing), j) history of epilepsy or other convulsive disorders, k) history of cerebral injury, cerebral edema, cerebral ischemia or cerebral bleeding, 10. Any emergency situation which requires emergency treatment, 11. Any immediate need of sympathomimetics, monoaminooxidase inhibitors, halothane, isoflurane, enflurane, theophylline, 12. Hemoglobin < 10 g/dl, 13. Known channelopathy, or 14. Signs of long QT syndrome (male participants with QTc > 430 ms, female participants with QTc > 450ms) or short QT syndrome in an ECG in sinus rhythm recorded. 15. Body weight > 140 kg |
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E.5 End points |
E.5.1 | Primary end point(s) |
Number of patients with cardioversion from AF to SR (yes/no) within 6 h after i.v. doxapram as measured by 12-lead ECG. For the primary objective SR is defined as any rhythm originating in the atrium, the junctional area or the His bundle, which is not atrial fibrillation. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
6 h (i.v.) after application depending on the route of administration. |
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E.5.2 | Secondary end point(s) |
• Time to cardioversion from AF to SR as documented by 12-lead ECG • Persistence of rhythm over 7 ± 2 d of cardioversion as measured by 7-d Holter ECG • Doxapram PK: plasma concentrations of doxapram and derived PK parameters after bolus injection or continuous i.v. infusion (e.g. highest concentration (Cmax), time to highest concentration (Tmax), area under the curve from 0 to 6 h (AUC0-6) after i.v. administration, and half-life (t1/2). • AEs as assessed by open questions and predefined procedures including assessment of well-being, physical examination, vital signs, and laboratory measurements. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
From exposure till end of 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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
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) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Efficacy study in a new indication |
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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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | No |
E.8.2.3 | Other | No |
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 | 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 | Yes |
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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End of trial is defined as the date of database closure, which must occur not later than 4 months after the last patient last visit. |
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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 | 0 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |