RIISC-THETIS: Evaluation of Low Dose Colchicine and Ticagrelor in Prevention of Ischemic Stroke in Patients With Stroke Due to Atherosclerosis

Sponsor

Assistance Publique - Hôpitaux de Paris (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05476991

Collaborator

(none)

2,800

Enrollment

Location

Arms

Anticipated Duration (Months)

46.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

REDUCING INFLAMMATION IN ISCHEMIC STROKE WITH COLCHICINE, AND TICAGRELOR IN HIGH-RISK PATIENTS-EXTENDED TREATMENT IN ISCHEMIC STROKE.

Condition or Disease	Intervention/Treatment	Phase
Stroke Stroke, Ischemic Atherosclerosis Myocardial Infarction Coronary Syndrome TIA Cardiac Disease Cerebral Infarction	Drug: Colchicine 0.5 MG Drug: Ticagrelor 90mg Drug: Aspirin 75-300mg	Phase 3

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

2800 participants

Allocation:

Randomized

Intervention Model:

Factorial Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Reducing Inflammation in Ischemic Stroke With Colchicine, and Ticagrelor in High-risk Patients-extended Treatment in Ischemic Stroke

Anticipated Study Start Date :

Sep 1, 2022

Anticipated Primary Completion Date :

Sep 1, 2027

Anticipated Study Completion Date :

Sep 1, 2027

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Colchicine + Ticagrelor	Drug: Colchicine 0.5 MG Colchicine is a medication used to treat gout and Behçet's disease. In gout, it is less preferred to NSAIDs or steroids. Other uses for colchicine include the management of pericarditis and familial Mediterranean fever. Drug: Ticagrelor 90mg Ticagrelor, sold under the brand name Brilinta among others, is a medication used for the prevention of stroke, heart attack and other events in people with acute coronary syndrome, meaning problems with blood supply in the coronary arteries. It acts as a platelet aggregation inhibitor by antagonising the P2Y 12 receptor. Other Names: Brilinta
Experimental: Colchine + Aspirine	Drug: Colchicine 0.5 MG Colchicine is a medication used to treat gout and Behçet's disease. In gout, it is less preferred to NSAIDs or steroids. Other uses for colchicine include the management of pericarditis and familial Mediterranean fever. Drug: Aspirin 75-300mg Also known as Aspirin, acetylsalicylic acid (ASA) is a commonly used drug for the treatment of pain and fever due to various causes. Acetylsalicylic acid has both anti-inflammatory and antipyretic effects. This drug also inhibits platelet aggregation and is used in the prevention of blood clots stroke, and myocardial infarction (MI). Other Names: Acetylsalicylic acid
Experimental: SOC + Ticagrelor	Drug: Ticagrelor 90mg Ticagrelor, sold under the brand name Brilinta among others, is a medication used for the prevention of stroke, heart attack and other events in people with acute coronary syndrome, meaning problems with blood supply in the coronary arteries. It acts as a platelet aggregation inhibitor by antagonising the P2Y 12 receptor. Other Names: Brilinta
Active Comparator: SOC + Aspirine	Drug: Aspirin 75-300mg Also known as Aspirin, acetylsalicylic acid (ASA) is a commonly used drug for the treatment of pain and fever due to various causes. Acetylsalicylic acid has both anti-inflammatory and antipyretic effects. This drug also inhibits platelet aggregation and is used in the prevention of blood clots stroke, and myocardial infarction (MI). Other Names: Acetylsalicylic acid

Outcome Measures

Primary Outcome Measures

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 definition
Number 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

Number of Participants with recurrent fatal and nonfatal ischemic stroke [36 months]
Number of Participants with urgent carotid revascularization following a new transient ischemic attack with negative neuro-imaging [36 months]
Number of Participants with fatal and nonfatal myocardial infarction [36 months]
Number of Participants with fatal and nonfatal myocardial infarction or urgent coronary revascularization following a new acute coronary syndrome [36 months]
Number of Participants with vascular death [36 months]
Number of Participants with any stroke or TIA [36 months]
A TIA is defined by sudden onset of neurologic symptoms presumed of ischemic origin, with total resolution, being clearly related to focal cerebral or retinal involvement, and with negative neuro-imaging in the cerebral area corresponding to the symptoms. TIA diagnosis must be confirmed by a neurologist, based on clinical and negative neuro-imaging evaluation (MRI with DWI is recommended).
Number of Participants with major coronary events [36 months]
Number of Participants with any coronary end-points (MI, hospitalization for recurrent ACS, coronary revascularization procedure urgent or elective, fatal coronary event) [36 months]
ACS: Acute Coronary Syndrome
Number of death participant (any death) [36 months]
Number of Participant with all revascularization procedures (coronary, carotid, peripheral) [36 months]
Number of Participants with Carotid revascularization [36 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion criteria:

Patient with:

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)
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 (stenosis defined by luminal narrowing ≥30%, judgement of the investigator)
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 (stenosis defined by luminal narrowing ≥30%, judgement of the investigator)
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)
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.
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).

Exclusion Criteria:

Colchicine treatment needed (e.g., gout)
Hypersensitivity to ticagrelor or any of the excipients.
Anticipated concomitant oral or intravenous therapy with strong CYP3A4 inhibitors or CYP3A4 substrates than cannot be stopped for 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 a history of myocardial infarction, or with calcified aortic stenosis will be eligible if the above inclusion criteria are also met]
Oral anticoagulant indicated (e.g., atrial fibrillation)
Symptomatic hemorrhagic stroke (the mere presence of asymptomatic cerebral microbleeding -or hemosiderin deposit - 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 (e.g., severe hepatic failure, severe renal impairment, cancer).
Anticipated pregnancy at time of enrollment in the study
Participation to another clinical trial
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