| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Recurrent strokes in patients with atrial fibrillation who suffered an ischaemic stroke |
|
| E.1.1.1 | Medical condition in easily understood language |
| Recurrent strokes in patients with atrial fibrillation who suffered an ischaemic stroke |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| 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 main objective is to determine the net benefit of early versus late initiation of DOACs in patients with acute ischaemic stroke related to AF. Net benefit is estimated by a composite outcome that combines the outcomes of interest (recurrent ischaemic stroke and systemic embolism) to estimate efficacy and the bleeding outcomes of interest (intracerebral and extracranial major bleeding) as well as vascular death to estimate safety. |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objectives are to assess all vascular events and all-cause mortality after early initiation of DOACs in patients with acute ischaemic stroke related to AF compared to late initiation. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Written informed consent
• Age: ≥18 years
• Acute ischaemic stroke, either confirmed by MRI or CT scan (tissue based definition) or by sudden focal neurological deficit of presumed ischaemic origin that persisted beyond 24 hours and otherwise normal non-contrast CT scan. Please note: prior intravenous or endovascular treatment is allowed.
• Permanent, persistent, or paroxysmal spontaneous AF previously known or diagnosed during the index hospitalization
• Agreement of treating physician to prescribe DOACs |
|
| E.4 | Principal exclusion criteria |
• Atrial fibrillation due to reversible causes (e.g. thyrotoxicosis, pericarditis, recent surgery, myocardial infarct)
• Valvular disease requiring surgery
• Mechanical heart valve(s)
• Moderate or severe mitral stenosis. Please note that other valvular diseases and biological valves are eligible
• AF and conditions other than AF that require anticoagulation, including therapeutical dose of low-molecular-weight heparin or heparin. Please note: infratherapeutic anticoagulation at ischaemic stroke onset defined as follows is not an exclusion criteria:
o Vitamine K antagonist: International Normalized Ratio (INR) < 1.7
o Anti-IIa: thrombin time < 80 seconds and/or anti-IIa < 50 ng/ml
o Anti-Xa: anti-Xa < 50 ng/ml
• Subject who is contraindicated to DOACs
• Female who is pregnant or lactating or has a positive pregnancy test at time of admission
• Patients with serious bleeding in the last 6 months or at high risk of bleeding (e.g. active peptic ulcer disease, platelet count < 100’000/mm3 or haemoglobin < 10 g/dl or INR ≥ 1.7, documented haemorrhagic tendencies or blood dyscrasias)
• Subject currently uses or has a recent history of illicit drug(s) or abuses alcohol (defined as regular or daily consumption of more than four alcoholic drinks per day)
• Severe comorbid condition with life expectancy < 6 months
• Severe or moderate renal insufficiency as defined by creatinine clearance < 50 ml/min
• Subject who requires haemodialysis or peritoneal dialysis
• Subject with aortic dissection
• Current participation in another investigational trial
• Dual antiplatelet therapy at baseline or strong likelihood to be treated with dual antiplatelet therapy during the course of the trial
• CT or MRI evidence of haemorrhage classified as PH1 (defined as parenchymal haemorrhage = blood clots in < 30% of the infarcted area without or with slight space-occupying effect) and PH2 (defined as blood clots in > 30% of the infarcted area with a substantial space-occupying effect) independently of clinical deterioration. Please note that HI1 (defined as haemorrhagic infarct = small petechiae along the margins of the infarct) and HI2 (defined as confluent petechiae within the infarcted area but no space occupying effect) are acceptable if not associated with clinical deterioration and if the treating physician feels comfortable to treat patients with DOACs.
• CT or MRI evidence of mass effect or intra-cranial tumour (except small meningioma)
• CT or MRI evidence of cerebral vasculitis
• Endocarditis
• Evidence of severe cerebral amyloid angiopathy if MRI scan performed |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary outcome is the composite of major bleeding, recurrent ischaemic stroke, systemic embolism and/or vascular death at 30 ± 3 days after randomisation. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 30 ± 3 days after randomisation. |
|
| E.5.2 | Secondary end point(s) |
• mRS at 30 ± 3 days and at 90 ± 7 days after randomisation
• Major bleeding at 30 ± 3 days and at 90 ± 7 days after randomisation as defined for the primary endpoint
• Bleeding at 30 ± 3 days and at 90 ± 7 days after randomisation defined as clinically relevant non-major bleeding, i.e. a bleeding that fulfils at least one of the following criteria but none of the criteria for major bleeding (see definition primary outcome).
o Hospital admission due to bleeding
o Physician guided medical or surgical treatment for bleeding
o Change in antithrombotic treatment (anticoagulation or antiplatelet) therapy
• Recurrence of ischaemic stroke at 30 ± 3 days and at 90 ± 7 days after randomisation as defined for the primary endpoint
• Systemic embolism at 30 ± 3 days and at 90 ± 7 days after randomisation as defined for the primary endpoint
• Vascular death at 30 ± 3 days and at 90 ± 7 days after randomisation as defined for the primary endpoint
• All-cause mortality at 90 ± 7 days after randomisation including death due to causes other than vascular events.
• Myocardial infarction at 90 ± 7 days after randomisation defined as typical symptoms and cardiac biomarker elevation (troponin I or T, creatine kinase-MB) above the upper limit of normal, new pathological Q waves in at least 2 contiguous electrocardiogram leads, or confirmation at autopsy
• Major cardiovascular events at 90 ± 7 days after randomisation defined as composite of stroke, myocardial infarct, heart failure or cardiovascular death
• If CT/MRI scan performed: Silent brain lesions at 90 ± 7 days after randomisation defined as ischaemic lesions of the brain parenchyma detected on brain MRI (≥ 3 mm and hyperintense on FLAIR/T2-weighted images) or CT ≥ 3 mm hypodense lesions (not in typical locations of prominent perivascular spaces) that do not have any outward symptoms associated with stroke (clinically “silent”), with the patient typically being unaware that they have suffered a stroke.
• Favourable outcome at 90 ± 7 days after randomisation defined as mRS ≤ 2 (mRS, ranging from 0 [no symptoms] to 6 [death]) and shift analysis adjusted to premorbid mRS
• NIHSS at 90 ± 7 days after randomisation
• Transient ischaemic attack (TIA), defined as a transient episode of neurologic dysfunction caused by focal brain, spinal cord, or retinal ischaemia without cerebral infarction on imaging at 30 ± 3 days and at 90 ± 7 days after randomisation
• Undetermined stroke (if the type of stroke cannot be determined by imaging or other means (e.g. lumbar puncture, neurosurgery, or autopsy) but is judged to fulfil the stroke definitions from section 5.1) at 30 ± 3 days and at 90 ± 7 days after randomisation
• Compliance measured at day 30 ± 3 days after randomisation |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At 30 ± 3 days and at 90 ± 7 days after randomisation |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | Yes |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 |
| The trial is open with the exception of the assessor of the endpoints, who is blinded. |
|
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Same medicinal product, but different timepoint of administration (early vs late) |
|
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 80 |
| 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 |
| Austria |
| Belgium |
| Canada |
| Finland |
| Germany |
| Greece |
| India |
| Ireland |
| Israel |
| Italy |
| Japan |
| Norway |
| Portugal |
| Slovakia |
| Switzerland |
| United Kingdom |
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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