| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Patients with embolic stroke of undetermined source and at least on
risk factor for cardiac embolism |
|
| E.1.1.1 | Medical condition in easily understood language |
Patients with embolic stroke of undetermined source and at least on
risk factor for cardiac embolism |
|
| 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 primary endpoint will be the occurrence of at least one new
ischemic lesion identified by magnetic resonance imaging (axial
T2-weighted fluid attenuated inversion recovery MRI (FLAIR) and/
or axial diffusion weighted MRI (DWI)) at 12 months when compared
to the baseline MRI (FLAIR, DWI) obtained at the time of
study drug initiation. MRI at 12 months will be directly compared
with the baseline MRI to assess for new ischemic lesions |
|
| E.2.2 | Secondary objectives of the trial |
Combination of recurrent ischaemic stroke, hemorrhagic stroke,
systemic embolism
• Combination of major adverse cardiovascular events (MACE)
including recurrent stroke, myocardial infarction and cardiovascular
death.
• Combination of major and clinically relevant non-major bleedings
defined according to ISTH criteria |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Must be ≥ 18 years at the time of signing the informed consent.
• ESUS must be defined according to following criteria:
- Stroke detected by CT or MRI that is not lacunar
- Absence of extracranial or intracranial atherosclerosis causing
≥50% luminal stenosis (according to NASCET) in arteries
supplying the area of ischaemia
- No major-risk cardioembolic source of embolism [Permanent
or paroxysmal atrial fibrillation, sustained atrial flutter, intracardiac
thrombus, prosthetic (mechanical) cardiac valve,
atrial myxoma or other cardiac tumors, moderate or severe
mitral stenosis, recent (<4weeks) myocardial infarction defined
as angiographically confirmed MI, left ventricular ejection
fraction less than 30%, valvular vegetations, or infective
endocarditis]
- No other specific cause of stroke identified (e.g., arteritis, dissection,
migraine/vasospasm, drug misuse)
• * At least one of the following non-major but suggestive risk factors
for cardiac embolism:
- LA size >45mm (parasternal axis)
- spontaneous echo contrast in LAA
- LAA flow velocity <=0.2m/s
- atrial high rate episodes
- CHA2DS2-Vasc score >=4
- persistent foramen ovale
• Planned ECG daily monitoring (non-invasive or invasive, initiation
within 28 days after randomization index stroke) or pre-existing
event recorder
• Understand and voluntarily sign an informed consent document
prior to any study related assessments/procedures.
• Able to adhere to the study visit schedule and other protocol requirements.
• Women of childbearing potential (WOCBP) must be using an adequate
method of contraception to avoid pregnancy throughout
the treatment period of the study or for 2 weeks after the last
dose of study medication, whichever is longer, in such a manner
that the risk of pregnancy is minimized. |
|
| E.4 | Principal exclusion criteria |
History of hypersensitivity to the investigational medicinal product
or to any drug with similar chemical structure or to any excipient
present in the pharmaceutical form of the investigational medicinal
product.
• Participation in other clinical interventional trials or observation period
of competing interventional trials.
• Diagnosis of haemorrhage or other pathology, such as vascular
malformation, tumor, abscess or other major non-ischaemic brain
disease, on baseline head CT or MRI scan
• Clear indication for anticoagulation (atrial fibrillation, mechanical
cardiac valves, deep venous thrombosis, pulmonary embolism or
known hypercoagulable state)
• Inability to control following risk factors for Hemorrhagic Transformation
of fresh cerebral Infarction (HTI) during index hospital stay
(i.e. within seven days after index stroke): presence of HTI at the
time of anticoagulation, blood pressure >160 mmHg systolic, abnormal
blood glucose (fasting glucose level >126 mg/dL or glucose
level >200 mg/dL postprandial and low platelet count (less
than 100 x 10^9/L)
• Clear indication for dual antiplatelet therapy (e.g. Aspirin® plus
Clopidogrel, Aspirin® plus Prasugrel, Aspirin® plus Ticagrelor or
Aspirin® plus Dipyridamole)
• Clear stroke-/non-stroke-indication for concomitant long-term therapy
with antiplatelets (e.g. acetylsalicylic acid (ASA), Clopidogrel,
or Prasugrel) or with non-steroidal anti-inflammatory drugs
(NSAID).
• Concomitant systemic therapy with strong inhibitors of cytochrome
P450 3A4 (CYP3A4) and P-glycoprotein (P-gp), i.e. azole-antimycotics
(e.g. ketoconazole, itrakonazole, voriconazole and
posaconazole) and human immunodeficiency virus (HIV)-protease
inhibitors.
• Contraindication to investigational medications
• Planned or likely therapy with fibrinolytic agents within 48 hours of
first study medication
• History of intracranial, intraocular, spinal, retroperitoneal or atraumatic
intra-articular bleeding
• Gastrointestinal bleed or major surgery within 3 months
• Planned or likely revascularization (any angioplasty or vascular
surgery) within the next 3 months
• TIA or minor stroke induced by angiography or surgery
• Severe non-cardiovascular comorbidity with life expectancy <3
months
• Anemia (hemoglobin level less than 100 g/L)
• Women of childbearing age not practicing reliable contraception
who do not have documented negative pregnancy test result
• Severe renal failure, defined as Creatinine Clearance (CrCl, Cockroft-
Gault) <15ml/min
• Severe hepatic insufficiency (Child-Pugh score B to C),
• Active liver disease, including but not limited to
• a. Persistent ALT, AST, AP greater than twice the upper limit of
the normal range
• b. Active hepatitis A
• c. Active hepatitis C (positive HCV RNA)
• d. Active hepatitis B (HBs antigen +, anti HBc IgM +)
• Hep B/C serology testing only upon suspicion of active
disease
Contraindications against performance of MRI (pacemaker/ICD),
previous implantation non-MRI capable protheses
• Patients considered unreliable by the investigator, or having a life
expectancy less than the expected duration of the trial because of
concomitant disease, or having any condition which, in the opinion
of the investigator, would not allow safe participation in the study
(e.g., drug addiction, alcohol abuse)
• Pregnancy, breast feeding and ineffective contraception is present |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint will be the occurrence of at least one new
ischemic lesion identified by magnetic resonance imaging (axial
T2-weighted fluid attenuated inversion recovery MRI (FLAIR) and/
or axial diffusion weighted MRI (DWI)) at 12 months when
compared to the baseline MRI (FLAIR, DWI) obtained at the time
of study drug initiation. MRI at 12 months will be directly compared
with the baseline MRI to assess for new ischemic lesions |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Combination of recurrent ischaemic stroke, hemorrhagic stroke,
systemic embolism
• Combination of major adverse cardiovascular events (MACE)
including recurrent stroke, myocardial infarction and cardiovascular
death.
• Combination of major and clinically relevant non-major bleedings
defined according to ISTH criteria |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | 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) | 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 | 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 |
|
| 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 | 13 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
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