| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Prevention of Stroke and/or systemic embolic event (SEE) in subjects with atrial fibrillation (AF). |
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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 | 10003658 |
| E.1.2 | Term | 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 |
| 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. Any non-inferior DU-176b regimen will be compared with warfarin for superiority. |
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| 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. 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. |
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| 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 |
The sub study is included in the main protocol DU176b-C-U301. Specifically this study is a Pharmacogenomics study.
Objective - Information from this study may be useful in increasing the knowledge of differences among individuals in the way they metabolize the study drug, as well as helping in the development of new drugs or improvement of existing drugs.
Exploratory Biomarkers and Pharmacoeconomics and Health Outcomes substudies which are also mentioned in the protocol will not be conducted as part of this protocol and are not the subject of this of this application
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| 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 a 12-lead electrocardiographic reading and/or continuous electrocardiogram (ECG) (e.g., Holter monitoring) consistent with AF (notation of AF as the abnormal rhythm on the local ECG report with evidence of irregularly irregular rhythm and an absence of P-waves on the ECG for diagnosis of AF) within the prior 12 months and for which anticoagulation therapy is indicated and planned for the duration of the study, including 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. A moderate to high risk of stroke, as defined by CHADS2 index score of at least 2, is required to be eligible for the study. 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
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| 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, unresected atrial myxoma, or a mechanical heart valve (subjects with bioprosthetic heart valves and/or valve repair can be included);
3. Subjects for whom the AF management plan is rhythm control with subsequent discontinuation of oral anticoagulation if sinus rhythm is restored or maintained, including subjects in whom successful electrical or surgical ablation has been performed or is planned during the course of the study;
4. Subjects with any contraindication for anticoagulant agents;
5. 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;
6. Subjects receiving thienopyridines (such as ticlopidine or clopidogrel) or other non-aspirin antiplatelet agents that cannot be stopped at randomization, or who are anticipated to receive non-aspirin antiplatelet agents as chronic therapy during the study;
7. Subjects receiving chronic cyclosporine for organ transplant, rheumatoid arthristis, or psoriasis;
8. 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 or for a chronic condition, potent P-gp inhibitors [ritonavir, cyclosporine, ketoconazole, itraconazole, erythromycin, clarithromycin];
9. Subjects with acute MI, stroke, acute coronary syndrome (ACS), or percutaneous coronary intervention (PCI) within the previous 30 days;
10. Subjects with active liver disease or persistent (confirmed by repeat assessment within a week) elevation of liver enzymes/bilirubin:
• ALT or AST ≥ 2 times the ULN,
• TBL ≥1.5 times the ULN,
• ALP ≥2 times the ULN;
11. Subjects with severe renal insufficiency (calculated CrCL <30 mL/min);
12. History of positive Hepatitis B antigen or Hepatitis C antibody;
13. Any other clinically relevant laboratory abnormality as judged by the Investigator;
14. Subjects receiving antiretroviral therapy for human immunodeficiency virus (HIV) infection or likely to receive such therapy during the study;
15. Subjects with hemoglobin < 10 g/dL or platelet count < 100,000 cells/μL or white blood cell count (WBC) < 3000 cells/μL;
16. Subjects with pre-planned invasive procedures (other than routine endoscopy) or surgeries in which bleeding is anticipated during the study period;
17. 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;
18. Subjects previously randomized in a DU-176b study;
19. Females of childbearing potential including including the following:
• Females with a history of tubal ligation;
• Females less than 2 years postmenopausal;
20. 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);
• Concurrent treatment with anti-cancer therapy (drug and/or radiation);
• Significant active concurrent medical illness or infection;
• Life expectancy < 12 months;
21. 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);
22. Subjects with a known drug or alcohol dependence within the past 12 months as judged by the Investigator.
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| 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 |
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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 | 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 |
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| 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.8.3 |
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 | 15 |
| 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 | 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 | 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 |
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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 | 3 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
| 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 |
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