| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Reduction of Stroke and/or systemic embolic event (SEE) in subjects with atrial fibrillation (AF). |
|
| 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 | 13.1 |
| 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 |
| The primary objective is to compare DU-176b to warfarin with regard to the composite primary endpoint of stroke and SEE. Each DU-176b regimen will be compared with warfarin for non-inferiority. If non-inferiority is established for the DU-176b High Exposure regimen, the DU-176b High Exposure regimen will be compared with warfarin for superiority. |
|
| E.2.2 | Secondary objectives of the trial |
To compare DU-176b to warfarin with regard to the composite clinical outcome of stroke, SEE, and all-cause mortality as well as each component separately.
To compare DU-176b to warfarin with regard to major adverse cardiovascular events (MACE), defined for this Phase 3 study as a composite of non-fatal myocardial infarction (MI), non-fatal stroke, non-fatal SEE, and death due to cardiovascular (CV) cause or bleeding, as well as each component separately.
To compare DU-176b to warfarin with regard to major bleeding as well as major plus clinically relevant non-major bleeding.
Details of further trial objectives are specified in the protocol. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Subjects in this study may participate in one or more substudies. Substudy objectives are exploratory and the data or reports from the substudies will not be included in the registration dossier or will not be part of any initial marketing applications. Substudy requirements and procedures will be provided as addenda to this main study protocol. Database lock and analyses for the main study will not include substudy data. Results for the substudies will be reported separately from those of the main study and will not be included in initial marketing registration packages.
Not all substudies will be conducted at all sites based on the number of subjects required globally to meet the objectives. Approval of the substudy addenda by Regulatory Authorities and IRBs/IECs can be considered separately from the approval of the main study protocol.
Substudy requirements and procedures will be provided as addenda to this main study protocol. |
|
| E.3 | Principal inclusion criteria |
1. Male or female subjects with age ≥ 21 years;
2. Able to provide written informed consent;
3. History of AF documented by any electrical tracing (routine 12-lead electrocardiographic reading [ECG], Holter monitor [continuous ECG recording], rhythm strip, intracardiac electrogram, or pacemaker [PM] or implantable cardiac defibrillator [ICD] interrogation) within the prior 12 months and for which anticoagulation therapy is indicated and planned for the duration of the study; subjects with AF includes subjects with paroxysmal, persistent, or permanent AF and subjects with or without previous VKA (including warfarin) experience (it is anticipated that approximately 40% of subjects will be VKA-naive);
4. Subjects must have a CHADS2 index score of ≥ 2. The CHADS2 scoring is performed by assigning 1 point each for a history of congestive heart failure, hypertension, age ≥ 75 years, or diabetes mellitus; and by assigning 2 points for history of stroke or TIA. |
|
| E.4 | Principal exclusion criteria |
Subjects who meet any of the criteria below will be disqualified from entering the study.
1. Transient AF secondary to other reversible disorders (e.g., thyrotoxicosis, cardiac or thoracic surgery, pneumonia, severe anemia);
2. Subjects with moderate or severe mitral stenosis due to rheumatic heart disease, unresected atrial myxoma, or a mechanical heart valve (subjects with bioprosthetic heart valves and/or valve repair can be included);
• However, subjects with AF and valvular heart diseases such as mitral valve prolapse, mitral valve regurgitation, and aortic valve disease are allowed in the study as long as the valvular heart disease is not due to rheumatic heart disease;
3. Subjects with a history of left atrial appendage exclusion (either by surgery or by a procedure);
4. Subjects with intracardial mass or left ventricular thrombus;
5. Subjects for whom discontinuation of chronic anticoagulation therapy will be considered if a planned pharmacologic, electrical or surgical therapy were to be successful in converting the subject to normal sinus rhythm (NSR) and maintaining that rhythm;
6. Subjects with any contraindication for anticoagulant agents;
7. Subjects with conditions associated with high risk of bleeding such as past history of spontaneous intracranial, intraocular, spinal, retroperitoneal, or intra-articular bleeding; overt gastrointestinal (GI) bleeding or active ulcer within the previous year; recent severe trauma, major surgery, or deep organ biopsy within the previous 10 days; active infective endocarditis; uncontrolled hypertension (blood pressure [BP] above 170/100 mmHg); or hemorrhagic disorder including known or suspected hereditary or acquired bleeding or coagulation disorder;
8. Subjects receiving dual antiplatelet therapy (e.g. aspirin plus thienopryridine such as ticlopidine or clopidogrel) or anticipated to receive such therapy unless all but one of the antiplatelet medications can be safely stopped prior to randomization and while receiving study drug;
9. Subjects receiving chronic cyclosporine therapy;
10. Subjects receiving prohibited concomitant medications (fibrinolytics, non-study anticoagulants other than those used as a bridge to/from study drug, chronic non-aspirin NSAID use for ≥ 4 days/week, and potent P-gp inhibitors as defined for this study;
11. Subjects with acute MI, stroke, acute coronary syndrome (ACS), or percutaneous coronary intervention (PCI) within the previous 30 days;
12. Subjects with active liver disease or persistent (confirmed by repeat assessments at least a week apart) elevation of liver enzymes/bilirubin:
• ALT or AST ≥ 2 times the ULN;
• TBL ≥1.5 times the ULN (however, subjects whose elevated TBL is due to known Gilbert's syndrome may be included in the study);
13. Subjects with severe renal insufficiency (calculated CrCL <30 mL/min);
14. History of testing positive Hepatitis B antigen or Hepatitis C antibody before randomization;
15. Any other clinically relevant laboratory abnormality as judged by the Investigator;
16. Subjects with a known history of testing positive for human immunodeficiency virus (HIV);
17. Subjects with hemoglobin < 10 g/dL or platelet count < 100,000 cells/μL or white blood cell count (WBC) < 3000 cells/μL;
18. Subjects with pre-planned invasive procedures (other than routine endoscopy) or surgeries in which bleeding is anticipated during the study period;
19. Subjects who received any investigational drug or device within 30 days prior to randomization, or plan to receive such investigational therapy during the study period;
20. Subjects previously randomized in a DU-176b study;
21. Females of childbearing potential including including the following:
• Females with a history of tubal ligation;
• Females less than 2 years postmenopausal;
22. Subjects with the following diagnoses or situations:
• Active malignancy (diagnosed within 5 years) except for adequately treated non-melanoma skin cancer or other non-invasive or in-situ neoplasm (e.g., cervical cancer in situ);
• Treatment with anti-cancer therapy (drug, radiation and/or surgery) within the last 5 years;
• Significant active concurrent medical illness or infection;
• Life expectancy < 12 months;
23. Subjects who are unlikely to comply with the protocol (e.g., uncooperative attitude, inability to return for subsequent visits, and/or otherwise considered by the Investigator to be unlikely to complete the study);
24. Subjects with a known drug or alcohol dependence within the past 12 months as judged by the Investigator.
25. Subjects with any condition that, in the opinion of the Investigator, would place the subject at increased risk of harm if he/she participated in the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is a composite of stroke and SEE. The primary safety endpoint is major bleeding |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Throughout the participation in the study. Information on possible endpoints will also be collected during 1 month follow-up after treatment termination. |
|
| E.5.2 | Secondary end point(s) |
| The secondary efficacy endpoints are a composite of stroke, SEE, and all-cause mortality and MACE: a composite of non-fatal MI, non-fatal stroke, non-fatal SEE, and death due to CV cause or bleeding. The secondary safety endpoint is major and clinically relevant non-major bleeding. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Throughout the participation in the study. Information on possible endpoints will also be collected during 1 month follow-up after treatment termination. |
|
| 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 | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| 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 | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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 | 2 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 372 |
| 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 |
| Argentina |
| Australia |
| Belgium |
| Brazil |
| Bulgaria |
| Canada |
| Chile |
| China |
| Colombia |
| Croatia |
| Czech Republic |
| Denmark |
| Estonia |
| Finland |
| France |
| Germany |
| Greece |
| Guatemala |
| Hungary |
| India |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Mexico |
| Netherlands |
| New Zealand |
| Norway |
| Peru |
| Philippines |
| Poland |
| Portugal |
| Romania |
| Russian Federation |
| Serbia |
| Slovakia |
| South Africa |
| Spain |
| Sweden |
| Switzerland |
| Taiwan |
| Thailand |
| Turkey |
| Ukraine |
| United Kingdom |
| United States |
|
| 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
|
| The clinical end of trial will be defined as the date of the last subject's follow-up visit |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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