| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Persistent atrial fibrillation |
|
| E.1.1.1 | Medical condition in easily understood language |
| Persistent cardiac arrhythmia with an irregular activity of the atria of the heart |
|
| 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 |
|
| 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 three different doses of OMT-28 administered once daily versus placebo in the maintenance
of normal sinus rhythm after electrical direct current cardioversion (DCC) in patients with persistent AF treated with an appropriate anticoagulant therapy. |
|
| E.2.2 | Secondary objectives of the trial |
• To assess the safety of three different doses of OMT-28 administered once daily versus placebo after electrical DCC in patients with persistent AF.
• To assess the pharmacokinetics (PK) of OMT-28 administered once daily in patients with persistent AF, by means of population pharmacokinetic (popPK) analysis.
Exploratory objectives:
• To assess exploratory PD of OMT 28 in patients with AF.
• To assess the data collected through the patient diary.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Males or females between 18 and 85 years of age.
2. Patients with persistent AF for > 7 days but ≤ 3 months who are suitable for electrical DCC. At randomization, the duration of the current episode of persistent AF must be shown to be greater than 7 days and not greater than 3 months, as confirmed by two ECGs (one ECG must be a 12 lead ECG).
3. Male patients must be surgically sterile for at least 90 days or, for males capable of fathering children and who are sexually active with female partners of childbearing potential, will be required to use a male condom with spermicide, and will refrain from donating sperm from the time of the first dose until 90 days after the last dose of study medication.
4. Females of childbearing potential will agree to follow contraception requirements from the time of signing the Informed Consent Form (ICF) until 90 days after the last administration of study drug.
o Females are considered of childbearing potential if they are postmenarchal, have not been surgically sterile for at least 6 weeks (i.e., total hysterectomy, bilateral salpingo oophorectomy, or tubal ligation), and are premenopausal (menopause is defined as cessation of menstruation for at least 1 year without an alternative medical cause). Postmenopausal status will be confirmed with a serum follicle stimulating hormone (FSH) test at Screening (FSH > 40 mIU/mL).
5. Willing and able to give written informed consent before any study-related procedure.
6. Willing and able to attend all the visits scheduled in the study. |
|
| E.4 | Principal exclusion criteria |
1. Patients with known concurrent temporary secondary causes of AF such as alcohol intoxication, pulmonary embolism, myocardial infarction, hyperthyroidism, pneumonia, hypoxemia, acute pericarditis or myocarditis, or chronic electrolyte imbalances that may cause cardiac arrhythmias (e.g., potassium < 3.5 mmol/L or > 5.5 mmol/L).
2. Patients that have undergone surgical or catheter ablation for AF or atrial flutter.
3. Patients with an existing cardiac treatment device, pacemaker, implantable cardioverter defibrillator, or cardiac resynchronization therapy.
4. Patients with a history of ECG abnormalities that, in the opinion of the investigator (or designee), render the patient unsuitable for the study, including history of congenital or a family history of long QT syndrome, a QTcF ≥ 500 msec and/or a QRS interval ≥ 130 msec at Screening.
5. Patients with congestive heart failure New York Heart Association class III and IV.
6. Patients with left atrium size ≥ 55 mm.
7. Patients with left ventricular ejection fraction ≤ 40 %.
8. Known presence of a thrombus in the left atrial appendage, left atrium, left ventricle, aorta, or intracardial mass.
9. Patients with moderate or severe mitral stenosis, mitral valve rheumatic disease, unresected atrial myxoma, or a mechanical heart valve (patients with bioprosthetic heart valves and/or valve repair can be included) and/or other conditions, such as pulmonary embolism, considered to be formal indication for conventional anticoagulation (patients who have had coronary artery bypass grafts that occurred more than 6 months prior to randomization will not be excluded).
10. Patients with any acute coronary event, stroke, or percutaneous coronary intervention within 6 months prior to randomization or who are receiving dual antiplatelet therapy (regardless of when the event occurred).
11. Uncontrolled/therapy-resistant bradycardia (defined as persistent bradycardia with a heart rate of < 40 beats per minute at Screening) and/or uncontrolled/therapy-resistant hypertension (defined as multiple readings with seated systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg) within a 3-month period prior to randomization.
12. Patients having more than two DCCs in the last 6 months. Any unsuccessful pharmacological and/or electrical cardioversion (within prior 3 months). For the purposes of this study, unsuccessful cardioversion is defined as maintaining sinus rhythm for < 2 hours after cardioversion.
13. Patients with signs of bleeding or conditions associated with a high risk of bleeding including major surgeries or biopsies in the 30 days prior to randomization or planned procedures during the study duration.
14. Patients with a positive hepatitis panel and/or positive human immunodeficiency virus test at Screening. Patients whose results are compatible with prior immunization may be included at the discretion of the investigator.
15. Patients taking antiarrhythmic agents (including dronedarone) within 3 days of planned randomization will be excluded.
16. Patients taking oral amiodarone within 3 months of planned randomization.
17. Patients with any contraindication to anticoagulant agents.
18. Patients planning to take any dose of omega-3 fatty acid derivative during the study.
19. Patients with active cancer who are undergoing chemotherapy, radiation, or major surgery within the next 3 months.
20. Patients with any serious intercurrent illness (including psychiatric and neurological disorders) which, in the opinion of the investigator, is incompatible with the protocol; or who have a life expectancy of < 6 months.
21. Abuse of alcohol, analgesics, or psychotropic drugs.
22. Pregnant women (i.e., positive serum ß-human-chorionic-gonadotropin test or other signs of pregnancy), or breastfeeding women, or women with childbearing potential not using a combination of two effective contraception methods (as laid out in Inclusion Criterion # 4) throughout the study.
23. Patients concurrently participating in another study, or who have received an investigational drug within 30 days prior to Screening.
24. Patients unable to communicate well with the investigator and to comply with the requirements of the entire study.
25. Any chronic kidney disease (estimated glomerular filtration rate < 30 mL/min/1.73 m² and/or serum creatinine > 2.5 mg/dL [> 221 µmol/L]).
26. Patients taking medications known to prolong the QT interval.
27. Patients with unstable angina pectoris.
28. Any severe hepatic dysfunction (aspartate aminotransferase or alanine aminotransferase ≥ 3 × the upper limit of normal [ULN]), total bilirubin (TBL) ≥ 2 × ULN (however, patients whose elevated TBL is due to known Gilbert’s syndrome may be included in the study). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoints are:
• AF burden (% time with any AF after electrical cardioversion). This is defined as the area under the curve for daily estimates. In case of repeated DCC, the burden for the day of DCC and all following days will be estimated as the median of burden from onset of the current AF episode until DCC.
The exploratory efficacy endpoints are:
• RecR of non-persistent AF (defined as at least one AF episode not fulfilling the persistent AF definition)
• TTR of non persistent AF (defined as at least one AF episode not fulfilling the persistent AF definition)
• AF burden during the first week of study drug intake prior to cardioversion
• AF burden during the first week of study drug intake prior to cardioversion compared to baseline
• AF burden after DCC compared to baseline
• Incidence of conversion to sinus rhythm during the first week of study drug intake prior to cardioversion
• Incidence of DCC procedures after successful DCC on Visit 4
• Incidence and duration of atrial flutter/atrial tachycardia
• Data collected from the patient diaries
Safety endpoints are:
• Incidence, severity, seriousness, and treatment-causality of AEs
• Clinically significant changes in safety laboratory evaluations, vital signs, 12 lead ECGs, ICM data, and physical examinations
Pharmacokinetic endpoints are:
• Plasma concentrations of OMT-28 at each timepoint
• Trough plasma concentration (Ctrough)
Additional PK parameters may be calculated as appropriate using a popPK approach. OMT 28 metabolites will be evaluated.
Exploratory PD endpoints may include measurement of the following biomarkers:
• Growth differentiation factor 15 (GDF15)
• Interleukin-6 (IL-6)
• High-sensitivity C-reactive protein (hs-CRP)
• Transforming growth factor beta 1 (TGF-β1)
• N-terminal pro-A-type natriuretic peptide (NT-proANP)
• N terminal pro-B-type natriuretic peptide (NT-proBNP)
• Tissue inhibitors of metalloproteinases metallopeptidase inhibitor 1 (TIMP 1)
• Matrix metallopeptidase 9 (MMP-9)
• Galectin-3
• Glycated hemoglobin (HbA1c)
• High-sensitivity troponin 1
• Cholesterol
• Triglycerides
• High-density lipoprotein (HDL)
• Low-density lipoprotein (LDL)
• Very low-density lipoprotein (VLDL)
• Oxidized low-density lipoprotein (oxLDL)
• Markers of oxidative stress, inflammation, remodeling, and lipid metabolism
• Omega-3 index and endogenous metabolites of fatty acids
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| An interim analysis will be conducted once approximately 15 patients per study arm have completed the treatment phase (Visit 8) of the study. |
|
| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints are:
• Recurrence rate (RecR) of persistent AF (defined as AF burden ≥ 23/24 hours over 7 consecutive days) in at least one 7 day period
• Time (days) from the successful cardioversion to first documented recurrence (TTR) of persistent AF (defined as AF burden ≥ 23/24 hours over 7 consecutive days) in at least one 7 day period
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| An interim analysis will be conducted once approximately 15 patients per study arm have completed the treatment phase (Visit 8) of the study. |
|
| 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 | 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) | 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 |
| Bulgaria |
| Czech Republic |
| Hungary |
| Ukraine |
|
| 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
|
|
| 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 | 10 |
| 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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