E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
High risk atrial fibrillation patients with previous intracranial hemorrhage |
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E.1.1.1 | Medical condition in easily understood language |
Abnormal heart rhythm with a risk of blood clot formation and stroke in patients with previous bleeding in the head. |
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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 | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10018985 |
E.1.2 | Term | Haemorrhage intracranial |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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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.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine whether edoxaban (60/30 mg daily) compared to non-anticoagulant medical therapy (either no antithrombotic therapy or antiplatelet monotherapy) reduces the risk of stroke (composite of ischemic, hemorrhagic and unspecified stroke) in high-risk atrial fibrillation (CHA2DS2-VASc score ≥2) patients with previous intracranial hemorrhage. |
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E.2.2 | Secondary objectives of the trial |
i) To assess whether edoxaban (60/30 mg daily) compared to non-anticoagulant medical therapy (either no antithrombotic therapy or antiplatelet monotherapy) reduces the risk of cardiovascular death in high-risk atrial fibrillation participants with previous intracranial hemorrhage.
ii) To assess whether edoxaban (60/30 mg daily) is associated with increased risk of major hemorrhage compared to standard of care (either no antithrombotic therapy or antiplatelet monotherapy).
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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 |
Title: MRI Substudy (please refer to Appendix 2 of the ENRICH-AF protocol (global) for further details) Date: 2019August19 Version: 1.0
The substudy aims to investigate the potential for treatment effect modification with baseline MRI markers of advanced cerebral small vessel disease, including cerebral microbleeds and cortical superficial siderosis, for the primary outcome of stroke and safety outcome of recurrent intracranial hemorrhage. This substudy will be launched at select global participating centers by the end of 1st quarter of 2020 and will continue in unison until study termination of the broader ENRICH-AF trial. An estimated 600-800 participants will be enrolled in this substudy.
An MRI will be obtained for each participant before randomization, unless contraindications exist (i.e. pacemakers, ineligible metallic foreign bodies or implantable hardware, extreme claustrophobia unmitigated by light sedation, etc.). Mandated MRI sequences including T2*-gradient echo or susceptibility weighted sequences, diffusion-weighted imaging, T1-weighted, T2-weighted, and FLAIR. Study-related MRIs must be obtained following informed consent and prior to randomization. T2*-gradient echo or susceptibility weighted sequences should be prioritized as the initial sequence during acquisition, followed by FLAIR, T1-weighted, diffusion-weighted imaging and T2-weighted sequences. |
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E.3 | Principal inclusion criteria |
1. Written informed consent provided 2. Age ≥45 years, at the time of signing the informed consent 3. Previous intracranial hemorrhage (symptomatic, spontaneous and non-traumatic intraparenchymal, intraventricular, and/or cSAH, and symptomatic spontaneous or non-penetrating traumatic subdural hemorrhages) on or off antithrombotic therapy (Table 2) 4. Documented atrial fibrillation (paroxysmal, persistent, permanent) 5. CHA2DS2-VASc score ≥2 |
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E.4 | Principal exclusion criteria |
1. Recent intracranial hemorrhage (within 14 days) 2. Secondary macrovascular, neoplastic or infectious causes of intracranial hemorrhage (except for antithrombotic treatment or non-penetrating traumatic subdural hemorrhages) 3. Traumatic or aneurysmal cSAH 4. Need for ongoing oral anticoagulant therapy for indication other than AF (e.g. mechanical heart valve, venous thromboembolic disease) 5. Need for ongoing antiplatelet therapy for indication where edoxaban would not be a suitable substitute 6. Plans for left atrial appendage occlusion 7. Estimated creatinine clearance (CrCl) < 15 mL/min or other creatinine clearance following local product monograph (Canada < 30mL/min) 8. Platelet count less than 100,000mm3 at enrollment or other bleeding diathesis 9. Persistent, uncontrolled hypertension (systolic BP averaging >150 mmHg) 10. Chronic use of NSAID 11. Clinically significant active bleeding, including gastrointestinal bleeding 12. Lesions or conditions at increased risk of clinically significant bleeding, e.g. active peptic ulcer disease with recent bleeding, patients with spontaneous or acquired impairment of hemostasis 13. Antiphospholipid antibody syndrome 14. Hepatic disease associated with coagulopathy and clinically relevant bleeding risk 15. Known hypersensitivity to edoxaban 16. Estimated inability to adhere to study procedures 17. Pregnancy or breastfeeding 18. Estimated life expectancy < 6 months at the time of enrollment 19. Close affiliation with the investigational site; e.g. a close relative for the investigator, dependent person (e.g., employee or student of the investigational site)
* Post menopausal female subjects must be amenorrheic for ≥12 months prior to screening or ≥6 weeks post-surgical bilateral oophorectomy (with or without hysterectomy) prior to screening. Women of childbearing potential must have negative serum pregnancy test within 7 days prior to randomization or urine pregnancy testing within 24 hours of randomization. Heterosexually active women of childbearing potential must use highly effective methods of contraception for 32 days after discontinuation (duration of study drug plus 30 days duration of one ovulatory cycle).
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy end point is stroke (composite of ischemic, hemorrhagic and unspecified).
The primary safety endpoint is major hemorrhage as defined by the International Society on Thrombosis and Haemostasis (ISTH) criteria
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Participants will be followed every 6 months until the common study end date. This trial is event driven to accrue 123 primary events, anticipated one year after the end of the recruitment. Follow up is anticipated to be an average of 24 months per participant (range 1 to 3 years). |
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E.5.2 | Secondary end point(s) |
The secondary efficacy end points are: 1. Ischemic stroke 2. Cardiovascular death 3. Hemorrhagic stroke 4. Disabling/fatal stroke 5. Composite of all stroke, myocardial infarction, systemic thromboembolism or all-cause death 6. Net clinical benefit (composite of stroke, myocardial infarction, cardiovascular death, fatal bleeding, and symptomatic bleeding into a critical organ or area) 7. Modified Rankin scale (mRS) at 12 months
The secondary safety end point(s) are: 1. All intracranial hemorrhage (intracerebral hemorrhage, intraventricular hemorrhage, subdural hematoma, subarachnoid hemorrhage) 2. Fatal intracranial hemorrhage 3. Subdural hemorrhage 4. Hospitalization for any cause
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timepoints of evaluation will be every 6 months until the common study end date. Follow up is anticipated to be an average of 24 months per participant (range 1 to 3 years). |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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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 | 30 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 159 |
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 |
Canada |
China |
Egypt |
India |
Korea, Republic of |
Nepal |
Taiwan |
United States |
Austria |
Poland |
Spain |
Switzerland |
Czechia |
Germany |
Greece |
Italy |
Belgium |
Norway |
Portugal |
Slovakia |
United Kingdom |
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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
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 15 |
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 | 15 |