Colchicine in High-risk Patients With Acute Minor-to-moderate Ischemic Stroke or Transient Ischemic Attack (CHANCE-3)

Study Overview
=================
Brief Summary
-----------------
This study is a multicentre, randomized, double-blind, placebo-controlled, investigator-sponsored study that aims to investigate the efficacy of colchicine in preventing recurrent stroke in the patients with acute minor-to-moderate ischemic stroke or TIA and a hsCRP level of ≥2mg/L.

Detailed Description
-----------------
This is a multicentre, randomized, double-blind, placebo-controlled trial that aims to investigate the efficacy of colchicine in preventing recurrent stroke in the patients with acute minor-to-moderate ischemic stroke or TIA and a hsCRP level of ≥2mg/L. Patients who were eligible to the inclusion criteria and ineligible to the exclusion criteria will be randomly assigned into two groups by a 1:1 ratio. Patients in one arm will receive colchicine initiated with a dose of 1mg per day on days 1 through 3, and continuing with 0.5 mg per day on days 4 through 90, and those in the other arm will receive an equivalent placebo drug. Study visits will be performed on the day of randomization, at discharge, at day 90 and at 1 year. The primary outcome was stroke (ischemic or hemorrhagic) during 90 days of follow-up in an intention-to treat analysis.

Official Title
-----------------
Colchicine in High-risk Patients With Acute Minor-to-moderate Ischemic Stroke or Transient Ischemic Attack (CHANCE-3)

Conditions
-----------------
TIA, Ischemic Stroke

Intervention / Treatment
-----------------
* Drug: Colchicine
* Drug: Placebo colchicine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 40 years or older than 40 years； Acute cerebral ischemic event due to： Acute minor-to-moderate ischemic stroke (NIHSS≤5 at the time of randomization) or TIA with moderate-to-high risk of stroke (ABCD2 score ≥ 4 at the time of randomization)； With a hsCRP level of ≥2mg/L at randomization; Can be treated with study drug within 24 hours of symptoms onset*(*Symptom onset is defined by the last seen normal principle)； Informed consent signed. Exclusion Criteria: Malformation, tumor, abscess or other major non-ischemic brain disease (e.g., multiple sclerosis) on baseline head CT or MRI. Isolated or pure sensory symptoms (e.g., numbness), isolated visual changes, or isolated dizziness/vertigo without evidence of acute infarction on baseline head CT or MRI. Iatrogenic causes (angioplasty or surgery) of stroke or TIA. Presumed cardiac source of embolus, such as atrial fibrillation or prosthetic cardiac valve). A score of ≥ 2 on the modified Rankin scale immediately before the occurrence of the index event. Usage of colchicine within 30 days before randomization or planning to take colchicine therapy for other indications. Known allergy or sensitivity or intolerance to colchicine. Inflammatory bowel disease (Crohn's or ulcerative colitis) or chronic diarrhea. Symptomatic peripheral neuropathy or pre-existing progressive neuromuscular disease or with creatine kinase (CK) level > 3 times the upper limit of normal as measured within the past 30 days and determined to be non-transient through repeat testing. A history of cirrhosis, chronic active hepatitis or severe hepatic disease. Impaired hepatic (ALT or AST > twice the upper limit of normal range) or kidney (creatinine exceeding 1.5 times of the upper limit of normal range or eGFR less than 50 ml/min) function at randomization. Anemia (haemoglobin <10g/dL), thrombocytopenia (platelet count <100×109/L) or leucopenia (white blood cell <3×109/L) at randomization. In the acute phase of respiratory tract infection, urinary tract infection, and gastro-enteritis, or currently using or planning to receive oral or intravenous anti-infective therapy for any other infection. Currently using or planning to begin long-term (>7 days) systemic anti-inflammatory drugs (NSAIDs except for aspirin, oral or intravenous steroid therapy) during the study. Planning to use moderate or strong CYP3A4 inhibitors (clarithromycin, erythromycin, telithromycin, other macrolide antibiotics, ketoconazole, itraconazole, voriconazole, ritonavir, atazanavir, indinavir, other HIV protease inhibitors, verapamil, diltiazem, quinidine, digoxin, disulfiram, etc) or P-gp inhibitors (cyclosporine) at randomization. Planned surgery or interventional treatment requiring cessation of the study drug during the study. Participating in another clinical trial with an investigational drug or device concurrently or during the last 30 days. Women of childbearing age who were not practicing reliable contraception and did not have a documented negative pregnancy test or severe noncardiovascular coexisting condition. Severe non-cardiovascular comorbidity with a life expectancy of less than 3 months. With a history of clinically significant drug or alcohol abuse. Inability to understand and/or follow research procedures due to mental, cognitive, or emotional disorders, or to be an unsuitable candidate for the study for any other considered by the investigator.

Ages Eligible for Study
-----------------
Minimum Age: 40 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Colchicine Group<br>Patients in this arm will receive colchicine for 90 days in addition to standard medical care | Drug: Colchicine<br>* Oral colchicine will be initiated with a dose of 1mg per day (one tablet of 0.5mg initially followed by another tablet of 0.5 mg at least four hours later) on days 1 through 3, and continuing with 0.5 mg (one tablet) per day on days 4 through 90.<br>|
| Placebo Comparator: Placebo Colchicine Group<br>Patients in this arm will receive placebo colchicine for 90 days in addition to standard medical care | Drug: Placebo colchicine<br>* Oral placebo colchicine will be initiated with a dose of 1mg per day (one tablet of 0.5mg initially followed by another tablet of 0.5 mg at least four hours later) on days 1 through 3, and continuing with 0.5 mg (one tablet) per day on days 4 through 90.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Any new stroke events | Incidence of any new ischemic or hemorrhagic stroke | any time within 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| New vascular events | Incidence of any new vascular events, including ischemic stroke, hemorrhagic stroke, TIA, myocardial infarction and vascular death | any time within 90 days | 
| New ischemic stroke | Incidence of any new ischemic stroke | any time within 90 days | 
| Poor functional outcome | Rate of poor functional outcome defined as a Modified Rankin Scale score of >1 (Modified Rankin Scale score ranges from 0 (no symptoms) to 6 (death) and higher score means worse outcome) | at 90 days after randomization | 
| New stroke and TIA | Incidence of any new stroke and TIA | any time within 90 days | 
| Severity of recurrent stroke and TIA | Severity is measured using a six-level ordered categorical scale that incorporates the mRS: fatal stroke [mRS 6]/severe non-fatal stroke [mRS 4 or 5]/moderate stroke [mRS 2 or 3]/mild stroke [mRS 0 or 1]/TIA/no stroke-TIA | within 90 days after randomization |