RIISC-THETIS
- Conditions
- Stroke, Ischemic, TIA, Cardiac Disease, Atherosclerosis, Myocardial Infarction, Coronary Syndrome, Cerebral Infarction
- Registration Number
- 2024-513669-38-00
- Lead Sponsor
- Assistance Publique Hopitaux De Paris
- Brief Summary
To evaluate the long-term efficacy of low dose colchicine and of ticagrelor 90 mg b.i.d. on the reduction of a composite primary outcome cluster of recurrent major vascular events
- Detailed Description
Our main hypothesis is that low-dose colchicine (0.5 mg/day) on top of best medical care, in patients with an ischemic stroke with ipsilateral atherosclerotic stenosis, will reduce the risk of major vascular events after 36-60 months of treatment as compared to no colchicine.
Our second main hypothesis, tested in 2x2 factorial design, is that ticagrelor 90 mg bid in the same patients, will reduce the long-term risk of major vascular events (after 36-60 months of treatment) as compared to aspirin 75-300 mg/day.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- Not specified
- Target Recruitment
- 2800
Cerebral infarction (CI) proven by neuro-imaging (MRI or head-CT), immediately once the neurologic deficit is stabilized (investigator judgement) if the patient was on antiplatelet agent monotherapy after the qualifying event, or after 21 days if the patient was on clopidogrel plus aspirin after the qualifying event, or after 21 to 30 days if the patient was on ticagrelor plus aspirin after the qualifying event (TIA with documented ischemic lesion (MRI or CT) in the appropriate area corresponding to the symptoms will be considered CI, following the current definition)
medical examination before the participation to the research
Under contraception in case of childbearing potential (highly effective: 1) combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation et 2) progestogen-only)
Pregnancy test for women of childbearing potential
AND documented atherosclerotic stenosis:- presence of carotid atherosclerotic stenosis (on the basis of carotid duplex, CTA, MRA, XRA – only the report will be required to document atherosclerotic disease) ipsilateral to the cerebral ischemic symptoms -OR presence of atherosclerotic stenosis of another cerebral artery (documented vertebral artery stenosis, basilar artery stenosis, other intracranial artery stenosis) ipsilateral to the ischemic area -OR presence of atherosclerotic disease of the aortic arch with a plaque ≥4mm in thickness with or without superimposed thrombus, OR a plaque <4 mm with a superimposed mobile thrombus (detected by transesophageal echocardiography or CT angiography)
OR with a history of symptomatic coronary artery disease
OR TIA lasting more 10 minutes or more (with motor symptoms or aphasia/dysarthria or visual defect), with total resolution and no brain lesion on neuro-imaging (TIA) If the patient was on antiplatelet agent monotherapy after the qualifying event, or after 21 days if the patient was on clopidogrel plus aspirin after the qualifying event, or after 21 to 30 days if the patient was on ticagrelor plus aspirin after the qualifying event - AND with ipsilateral carotid stenosis that was revascularized (endarterectomy or stenting) -OR with ipsilateral, potentially causal intracranial stenosis ≥70%
with no clear indication of colchicine treatment (gout, Mediterranean fever) and with an indication to long-term antiplatelet therapy (no clear indication to oral anticoagulant)
age equal or above 18
Rankin score less than ≤4 (ranges from 0 to 6, with 0 indicating no symptoms, 1 no disability, 2 to 3 needing some help with daily activities, 4 to 5 dependent or bedridden, and 6 death)
fully informed and signed inform consent
with social security number
Colchicine treatment needed (e.g., gout, Mediterranean fever)
Anticipated concomitant oral or intravenous therapy with strong CYP3A4 inhibitors or CYP3A4 substrates than cannot be stopped for the course of the course of this study
CI/TIA due to arterial dissection (as documented following the judgment of the investigator) or due to cardiac source of embolism without documented atherosclerotic disease (e.g., mitral stenosis or endomyocardial fibrosis, endocarditis) a patient with atrial fibrillation, or with a history of myocardial infarction, or with calcified aortic stenosis will be eligible if the above inclusion criteria are also met
Indication to long-term oral anticoagulant treatment (e.g., atrial fibrillation)
Symptomatic hemorrhagic stroke (the mere presence of asymptomatic cerebral hemosiderin deposits –so called “microbleedings” – on gradient echo imaging is not an exclusion criteria)
Active pathological bleeding
Uncontrolled hypertension (investigator judgement)
Follow-up visit impossible or anticipated bad compliance.
Intercurrent disease that may interfere with evaluation of the primary end-point or that may prevent follow-up study visits
Anticipated pregnancy at time of enrollment in the study
Breastfeeding woman
Hypersensitivity to ticagrelor or any of the excipients.
Patients participating in another pharmaco therapeutic program with an experimental therapy that is known to affect the ticagrerlor, colchicine or aspirine therapy.
Leukopenia <3000/μl
Patients with severe renal impairment (creatinine clearance < 30 ml/min)
Patients with severe hepatic impairment
Prohibited treatments: All treatments contraindicated during the use of colchicine and/or ticagrelor
Hypersensitivity to colchicine or any of the excipients.
Major digestive disorders (chronic diarrhea, inflammatory disease of the digestive tract as uncontrolled ulcerative colitis or active Crohn disease)
Immunosuppression, medullary aplasia
Active chronic inflammatory disease, chronic active infection, evolving cancer
Hemodynamic instability (need for amines for more than 24 hours, circulatory assistance)
A recent severe sepsis (7 days) or all recent acute reaches
Chronic treatment (for more than 6 months) with corticosteroids or NSAIDs (or repeated high-dose intake for less than 7 days).
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- FACTORIAL
- Primary Outcome Measures
Name Time Method Number of Participants with nonfatal ischemic stroke 36 months Sudden onset of focal neurologic symptoms related to impaired cerebral circulation. ASCOD phenotyping will be used. TIAs will not be part of strokes. However, any focal neurologic symptoms associated with positive DWI or hypodensity on the CT scan in an appropriate area in relation with these symptoms will be considered a cerebral infarction and be part of "strokes".
Number of Participants with undetermined stroke 36 months Sudden onset of focal neurologic symptoms related to impaired cerebral circulation. ASCOD phenotyping will be used. TIAs will not be part of strokes. However, any focal neurologic symptoms associated with positive DWI or hypodensity on the CT scan in an appropriate area in relation with these symptoms will be considered a cerebral infarction and be part of "strokes".
Number of Participants with nonfatal myocardial infarction 36 months * Fatal or nonfatal myocardial infarction (OMS.AHA/ACC definition)
o Clinical symptoms + elevated troponin
* Silent myocardial infarction following universal definitionNumber of Participants with urgent coronary or carotid revascularization following new symptoms 36 months Revascularization Procedure
* Coronary : Angioplasty or stenting or CABG
* Carotid : angioplasty or stenting, surgical endarterectomy
* Peripheral: angioplasty or stenting including aorta, surgical by-pass or endarterectomy of a peripheral artery.Number of Participants with vascular death including sudden death 36 months \- Vascular death
* Death due to cardiac or vascular cause
* Death due to systemic hemorrhage
* Death due to pulmonary embolism
* Sudden death: death occurring within 24 hours, unexpected in a patient in apparent healthy condition or condition that was stable or improved
* Death without documented nonvascular cause
* Fatal stroke: death occurring within 30 days of stroke onset (whether ischemic or hemorrhagic).
- Secondary Outcome Measures
Name Time Method Recurrent fatal and nonfatal ischemic stroke or urgent carotid revascularization following a new transient ischemic attack with negative neuro-imaging during the study Recurrent fatal and nonfatal ischemic stroke or urgent carotid revascularization following a new transient ischemic attack with negative neuro-imaging during the study
Recurrent fatal and nonfatal ischemic stroke during the study Recurrent fatal and nonfatal ischemic stroke during the study
Fatal and nonfatal myocardial infarction or urgent coronary revascularization following a new acute coronary syndrome during the study Fatal and nonfatal myocardial infarction or urgent coronary revascularization following a new acute coronary syndrome during the study
Fatal and nonfatal myocardial infarction during the study Fatal and nonfatal myocardial infarction during the study
Vascular death during the study Vascular death during the study
Any stroke during the study Any stroke during the study
Any stroke or TIA during the study Any stroke or TIA during the study
Major coronary events (including MI) during the study Major coronary events (including MI) during the study
Any coronary end-points (MI, hospitalization for recurrent ACS, coronary revascularization procedure urgent or elective, fatal coronary event) during the study Any coronary end-points (MI, hospitalization for recurrent ACS, coronary revascularization procedure urgent or elective, fatal coronary event) during the study
Any death during the study Any death during the study
Fatal and non-fatal stroke with mRS>1 Fatal and non-fatal stroke with mRS>1
All revascularization procedures (coronary, carotid, peripheral) during the study All revascularization procedures (coronary, carotid, peripheral) during the study
Carotid revascularization during the study Carotid revascularization during the study
Trial Locations
- Locations (1)
URC Lariboisière-Fernand Widal-Saint Louis
🇫🇷Paris, Paris, France
URC Lariboisière-Fernand Widal-Saint Louis🇫🇷Paris, Paris, France