Evaluation of Colchicine and Ticagrelor in Preventing Recurrent Ischemic Stroke in Patients with Atherosclerosis: A Randomized Controlled Trial

Trial ID: 2024-513669-38-00
Protocol: APHP211055
Sponsor: Assistance Publique Hopitaux De Paris

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Diseases & Conditions

Ischaemic stroke

Objectives

The primary objective of the study is to evaluate the long-term efficacy of low-dose **colchicine** and **ticagrelor** 90 mg b.i.d. in reducing a composite primary outcome cluster of recurrent major vascular events. This is clinically relevant as it aims to prevent further vascular complications in patients who have experienced an ischemic stroke due to atherosclerosis, thereby potentially reducing morbidity and mortality associated with recurrent vascular events.

Secondary objectives include evaluating the efficacy on each individual component of the composite outcome and total death. This will provide a more detailed understanding of how each treatment component contributes to the overall therapeutic effect, offering insights into the specific benefits of the treatment regimen.

Participants

The clinical trial involves participants diagnosed with **ischemic stroke**, transient ischemic attack (TIA), cardiac disease, atherosclerosis, myocardial infarction, coronary syndrome, or cerebral infarction. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a Rankin score of less than 4, indicating they have some level of independence in daily activities. The trial does not include a vulnerable population. Participants must have a documented history of atherosclerotic stenosis or symptomatic coronary artery disease, and they should not have a clear indication for colchicine treatment for conditions such as gout or Mediterranean fever. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity. The selection criteria ensure that participants are medically stable and have a documented need for long-term antiplatelet therapy, without a clear indication for oral anticoagulants. All participants must provide informed consent and have a social security number.

Plans and Procedures

The clinical trial is designed to evaluate the long-term efficacy of low-dose **colchicine** and **ticagrelor** 90 mg b.i.d. in reducing a composite primary outcome cluster of recurrent major vascular events in patients with ischemic stroke due to atherosclerosis. This study is a randomized, double-blind, controlled trial with an estimated duration of 60 months, commencing on May 17, 2023, and concluding on May 17, 2028. Participants will be randomly assigned to receive either the investigational treatment or a control, with neither the participants nor the investigators aware of the group assignments, ensuring the double-blind nature of the trial.

The trial will include several study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as documented cerebral infarction, age, and medical history. Participants must have a cerebral infarction proven by neuro-imaging and meet other specific inclusion criteria, such as documented atherosclerotic stenosis or a history of symptomatic coronary artery disease. Follow-up visits will occur at regular intervals to monitor the participants' health status, adherence to the treatment regimen, and any adverse events. The end-of-study visit will evaluate the primary and secondary endpoints, including the occurrence of nonfatal ischemic or hemorrhagic strokes, myocardial infarctions, and vascular deaths.

Participant involvement is expected to last the entire duration of the trial, approximately 60 months, unless early termination is warranted. Conditions that may lead to early termination include significant adverse events, non-compliance with the study protocol, or withdrawal of consent. The primary endpoint is a composite of nonfatal ischemic stroke, nonfatal hemorrhagic stroke, nonfatal myocardial infarction, urgent coronary or carotid revascularization following new symptoms, and vascular death, including sudden death during the study. Secondary endpoints include recurrent fatal and nonfatal ischemic strokes, myocardial infarctions, and any stroke or transient ischemic attack during the study period.

Treatment

The clinical trial involves the administration of several **experimental medications**. **Acetylsalicylic acid** is provided in tablet form, with a maximum daily dose of 300 mg and a total maximum dose of 540 g over a treatment period of 60 days. The route of administration is oral, and the medication is not a paediatric formulation. The chemical origin of the active substance is confirmed, and the product is identified by the code SUB12730MIG.

**Colchicine**, marketed as Colchicine Opocalcium 1 mg, is administered in a tablet form known as "comprimé sécable." The maximum daily dose is 0.5 mg, with a total maximum dose of 900 mg over the same 60-day treatment period. This medication is also administered orally and is not intended for paediatric use. The chemical origin of colchicine is verified, and it is identified by the code PRD2447366.

**Ticagrelor**, available as Brilique 90 mg film-coated tablets, is administered with a maximum daily dose of 180 mg and a total maximum dose of 324 g over 60 days. The administration route is oral, and the formulation is not paediatric. The chemical origin of ticagrelor is confirmed, and it is identified by the code PRD3534514.

Additionally, **D,L-lysine acetylsalicylate** is provided as an oral solution in sachet form, marketed as Kardegic 300 mg. The maximum daily dose is 300 mg, with a total maximum dose of 540 g over the treatment period of 60 days. The administration is oral, and the formulation is not paediatric. The chemical origin of the active substance is confirmed, and it is identified by the code PRD431929.

All medications are administered orally, and participant compliance is monitored throughout the trial. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The focus is on evaluating the efficacy of these medications in preventing ischemic stroke in patients with atherosclerosis.

Efficacy

The efficacy of the clinical trial will be assessed by evaluating the impact of low-dose colchicine and ticagrelor 90 mg b.i.d. on reducing a composite primary outcome cluster of recurrent major vascular events in patients with ischemic stroke due to atherosclerosis. The primary endpoints for efficacy evaluation include a composite of nonfatal ischemic stroke, nonfatal hemorrhagic stroke, undetermined stroke, nonfatal myocardial infarction, urgent coronary or carotid revascularization following new symptoms, and vascular death, including sudden death, during the study period of 36 to 60 months.

Secondary endpoints will further assess efficacy by measuring recurrent fatal and nonfatal ischemic strokes, urgent carotid revascularization following a new transient ischemic attack with negative neuro-imaging, fatal and nonfatal myocardial infarction, urgent coronary revascularization following a new acute coronary syndrome, vascular death, any stroke, any stroke or transient ischemic attack (TIA), major coronary events, any coronary endpoints, any death, fatal and non-fatal stroke with a modified Rankin Scale (mRS) score greater than 1, all revascularization procedures, and carotid revascularization during the study.

Inclusion and Exclusion Criteria

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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)
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)
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)
Pregnancy test for women of childbearing potential

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Exclusion Criteria

Hypersensitivity to colchicine or any of the excipients.
Anticipated concomitant oral or intravenous therapy with strong CYP3A4 inhibitors 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]
Symptomatic hemorrhagic stroke (the mere presence of asymptomatic cerebral hemosiderin deposits –so called “microbleedings”
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
Patients participating in another pharmaco therapeutic program with an experimental therapy that is known to affect colchicine therapy.
Leukopenia <3000UI/μl
Major digestive disorders (chronic diarrhea, inflammatory disease of the digestive tract as uncontrolled ulcerative colitis or active Crohn disease)
Patients with severe renal impairment (creatinine clearance < 30 ml/min)
Patients with severe hepatic impairment (Prothrombin Time < 50%),
Immunosuppression (all immunosuppressive treatments are forbidden, except for inhaled form corticosteroids),, medullary aplasia
Active chronic inflammatory disease with chronically elevated blood CRP/hsCRP levels (as in lupus or Horton's disease; patients with asthma or COPD are eligible),
Chronic active infection (e.g. tuberculosis). HIV is accepted if treatments taken do not interact with experimental treatments,
Evolving cancer with a life expectancy less than 3 years,
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 (oral or intravenous) or NSAIDs (or repeated high-dose intake for less than 7 days).
Prohibited treatments: All treatments contraindicated during the use of colchicine for a few clinical cases, such as chronic inflammatory diseases and chronic infectious diseases, we will ask the coordinating investigator to validate the patient's eligibility.