RIISC-THETIS

Phase 3

Recruiting

Conditions: Stroke, Ischemic, TIA, Cardiac Disease, Atherosclerosis, Myocardial Infarction, Coronary Syndrome, Cerebral Infarction

Interventions: Drug: Colchicine 0.5 MG
Drug: Aspirin 75-300mg
Drug: Ticagrelor 90mg

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: Ongoing, recruiting

Sex: Not specified

Target Recruitment: 2800

Inclusion Criteria

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

Exclusion Criteria

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

Arm && Interventions

Group	Intervention	Description
Colchine + Aspirine	Aspirin 75-300mg	-
SOC + Aspirine	Aspirin 75-300mg	-
Colchine + Aspirine	Colchicine 0.5 MG	-
Colchicine + Ticagrelor	Colchicine 0.5 MG	-
Colchicine + Ticagrelor	Ticagrelor 90mg	-
SOC + Ticagrelor	Ticagrelor 90mg	-

Primary Outcome Measures

Name	Time	Method
Composite of: nonfatal ischemic stroke or nonfatal hemorrhagic stroke or undetermined stroke, nonfatal myocardial infarction, urgent coronary or carotid revascularization following new symptoms, and vascular death including sudden death during the study (from 36 to 60 months)		Composite of: nonfatal ischemic stroke or nonfatal hemorrhagic stroke or undetermined stroke, nonfatal myocardial infarction, urgent coronary or carotid revascularization following new symptoms, and vascular death including sudden death during the study (from 36 to 60 months)

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 (43): Centre Hospitalier De Versailles
🇫🇷
Le Chesnay Rocquencourt, France
Centre Hospitalier Eure-Seine
🇫🇷
Evreux, France
Centre Hospitalier Universitaire Grenoble Alpes
🇫🇷
Grenoble Cedex 9, France
Hopital Prive Clairval
🇫🇷
Marseille, France
Centre Hospitalier Universitaire De Lille
🇫🇷
Lille Cedex, France
Centre Hospitalier Universitaire De Toulouse
🇫🇷
Toulouse, France
Centre Hospitalier Intercommunal De Mont De Marsan Et Du Pays Des Sources
🇫🇷
Mont-De-Marsan Cedex, France
Centre Hospitalier General
🇫🇷
Gonesse, France
Centre Hospitalier Universitaire De Dijon
🇫🇷
Dijon, France
Centre Hospitalier William Morey
🇫🇷
Chalon Sur Saone Cedex, France
Scroll for more (33 remaining)
Centre Hospitalier De Versailles
🇫🇷Le Chesnay Rocquencourt, France
Fernando Pico
Site contact
+33130639517
FPico@ch-versailles.fr