Evaluation of Low Dose Colchicine and Ticagrelor in Prevention of Ischemic Stroke in Patients With Stroke Due to Atherosclerosis (RIISC-THETIS)
Primary Purpose
Stroke, Stroke, Ischemic, Atherosclerosis
Status
Recruiting
Phase
Phase 3
Locations
France
Study Type
Interventional
Intervention
Colchicine 0.5 MG
Ticagrelor 90mg
Aspirin 75-300mg
Sponsored by
About this trial
This is an interventional treatment trial for Stroke focused on measuring Stroke, Colchicine, Atherosclerosis, Aspirin, Ticagrelor
Eligibility Criteria
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
Sites / Locations
- URC Lariboisière-Fernand Widal-Saint LouisRecruiting
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Experimental
Experimental
Experimental
Active Comparator
Arm Label
Colchicine + Ticagrelor
Colchine + Aspirine
SOC + Ticagrelor
SOC + Aspirine
Arm Description
Outcomes
Primary Outcome Measures
Number of Participants with nonfatal ischemic stroke
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
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
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
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
- 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
Number of Participants with urgent carotid revascularization following a new transient ischemic attack with negative neuro-imaging
Number of Participants with fatal and nonfatal myocardial infarction
Number of Participants with fatal and nonfatal myocardial infarction or urgent coronary revascularization following a new acute coronary syndrome
Number of Participants with vascular death
Number of Participants with any stroke or TIA
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
Number of Participants with any coronary end-points (MI, hospitalization for recurrent ACS, coronary revascularization procedure urgent or elective, fatal coronary event)
ACS: Acute Coronary Syndrome
Number of death participant (any death)
Number of Participant with all revascularization procedures (coronary, carotid, peripheral)
Number of Participants with Carotid revascularization
Full Information
NCT ID
NCT05476991
First Posted
July 25, 2022
Last Updated
May 17, 2023
Sponsor
Assistance Publique - Hôpitaux de Paris
1. Study Identification
Unique Protocol Identification Number
NCT05476991
Brief Title
Evaluation of Low Dose Colchicine and Ticagrelor in Prevention of Ischemic Stroke in Patients With Stroke Due to Atherosclerosis
Acronym
RIISC-THETIS
Official Title
Reducing Inflammation in Ischemic Stroke With Colchicine, and Ticagrelor in High-risk Patients-extended Treatment in Ischemic Stroke
Study Type
Interventional
2. Study Status
Record Verification Date
May 2023
Overall Recruitment Status
Recruiting
Study Start Date
May 17, 2023 (Actual)
Primary Completion Date
September 1, 2027 (Anticipated)
Study Completion Date
September 1, 2027 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
REDUCING INFLAMMATION IN ISCHEMIC STROKE WITH COLCHICINE, AND TICAGRELOR IN HIGH-RISK PATIENTS-EXTENDED TREATMENT IN ISCHEMIC STROKE.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Stroke, Stroke, Ischemic, Atherosclerosis, Myocardial Infarction, Coronary Syndrome, TIA, Cardiac Disease, Cerebral Infarction
Keywords
Stroke, Colchicine, Atherosclerosis, Aspirin, Ticagrelor
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Factorial Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
2800 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Colchicine + Ticagrelor
Arm Type
Experimental
Arm Title
Colchine + Aspirine
Arm Type
Experimental
Arm Title
SOC + Ticagrelor
Arm Type
Experimental
Arm Title
SOC + Aspirine
Arm Type
Active Comparator
Intervention Type
Drug
Intervention Name(s)
Colchicine 0.5 MG
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Ticagrelor 90mg
Other Intervention Name(s)
Brilinta
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Aspirin 75-300mg
Other Intervention Name(s)
Acetylsalicylic acid
Intervention Description
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).
Primary Outcome Measure Information:
Title
Number of Participants with nonfatal ischemic stroke
Description
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".
Time Frame
36 months
Title
Number of Participants with undetermined stroke
Description
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".
Time Frame
36 months
Title
Number of Participants with nonfatal myocardial infarction
Description
Fatal or nonfatal myocardial infarction (OMS.AHA/ACC definition)
o Clinical symptoms + elevated troponin
Silent myocardial infarction following universal definition
Time Frame
36 months
Title
Number of Participants with urgent coronary or carotid revascularization following new symptoms
Description
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.
Time Frame
36 months
Title
Number of Participants with vascular death including sudden death
Description
- 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).
Time Frame
36 months
Secondary Outcome Measure Information:
Title
Number of Participants with recurrent fatal and nonfatal ischemic stroke
Time Frame
36 months
Title
Number of Participants with urgent carotid revascularization following a new transient ischemic attack with negative neuro-imaging
Time Frame
36 months
Title
Number of Participants with fatal and nonfatal myocardial infarction
Time Frame
36 months
Title
Number of Participants with fatal and nonfatal myocardial infarction or urgent coronary revascularization following a new acute coronary syndrome
Time Frame
36 months
Title
Number of Participants with vascular death
Time Frame
36 months
Title
Number of Participants with any stroke or TIA
Description
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).
Time Frame
36 months
Title
Number of Participants with major coronary events
Time Frame
36 months
Title
Number of Participants with any coronary end-points (MI, hospitalization for recurrent ACS, coronary revascularization procedure urgent or elective, fatal coronary event)
Description
ACS: Acute Coronary Syndrome
Time Frame
36 months
Title
Number of death participant (any death)
Time Frame
36 months
Title
Number of Participant with all revascularization procedures (coronary, carotid, peripheral)
Time Frame
36 months
Title
Number of Participants with Carotid revascularization
Time Frame
36 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Pierre Amarenco, Pr
Phone
140258725
Ext
+33
Email
pierre.amarenco@gmail.com
Facility Information:
Facility Name
URC Lariboisière-Fernand Widal-Saint Louis
City
Paris
ZIP/Postal Code
75010
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Brahim M Elarbi
Phone
01 40 05 43 60
Ext
+33
Email
brahim.mohamed-elarbi@aphp.fr
First Name & Middle Initial & Last Name & Degree
Pierre Amarenco, Pr
12. IPD Sharing Statement
Learn more about this trial
Evaluation of Low Dose Colchicine and Ticagrelor in Prevention of Ischemic Stroke in Patients With Stroke Due to Atherosclerosis
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