Clinical trial NCT05503225: Colchicine Use in Intracranial Atherosclerotic Disease
Official title: Colchicine Use in Intracranial Atherosclerotic Disease - a Pilot Open-labelled Randomized Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: ICAD - Intracranial Atherosclerotic Disease
Keywords: ICAD
CVA
colchicine
Lead sponsor: Chinese University of Hong Kong
Sponsor class: OTHER
First posted: 2022-08-16
Enrollment: 72
Sex: ALL
Minimum age (years): 40
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A 1:1 recruitment ratio of treatment to control group will be recruited. A sample size of 25 patients per arm will be required, therefore a total sample size of 50 will be required. Assuming a 30% rate of lost-to-follow-up, a sample size of 72 will be required.
Primary purpose: TREATMENT

Brief summary: Intracranial atherosclerotic disease (ICAD) is a major ischaemic stroke aetiology in Asia. Influenced by genetics, lifestyle and metabolic risk factors. From the SAMMPRIS cohort, 1-year stroke recurrence risk was 13% even with intensive medical therapy.

In this pilot randomized, double-blind, placebo-controlled trial, the investigators shall recruit 44 patients with recent ischaemic stroke due to intracranial atherosclerosis (ICAD) with ≥ 50% stenosis. Patients will be randomly assigned to either low-dose colchicine (0.5mg daily) (n=22) or placebo (n=22) for 12 months. High-resolution magnetic resonance vessel wall imaging will be performed at baseline and 12 months. The primary endpoint is a composite of regression of intracranial stenosis, plaque volume, or occurrence of any major adverse cardio- or cerebrovascular events at 12 months. The investigators shall also evaluate safety endpoints including diarrhea, marrow suppression, infections, neuromuscular dysfunction.

No studies had focused on the use of colchicine in patients with ICAD, which is highly prevalent in Asia. Results from this pilot trial will provide an important basis for a larger-scale main trial in the future.

Detailed description: Background:

Intracranial atherosclerotic disease (ICAD) is a major ischaemic stroke aetiology in Asia. Influenced by genetics, lifestyle and metabolic risk factors, over 40% of ischaemic strokes were related to ICAD in China. ICAD also predicted high risk of recurrence compared to other stroke aetiologies. From the SAMMPRIS cohort, 1-year stroke recurrence risk was 13% even with intensive medical therapy. While up-front endovascular intervention resulted in unacceptably high peri-procedural stroke risk of 20%-36%, minimal advances in medical therapy targeting ICAD had been made.

Literature clinical findings were supported by coronary plaque-imaging studies performed in human and animal models, which showed coronary plaque regression in patients with recent acute coronary syndrome and reduction in abdominal-aortic plaque inflammation in a rabbit-model. In parallel, under intensive medical therapy, ICAD plaque regression could be seen in 49% of patients. Nevertheless, recurrent stroke rate still exceeded 10% despite treatment targets of blood pressure ≤140/90, HbA1c ≤6.5%, and low-density lipoprotein (LDL) ≤1.8mmol/L in our previous cohort. There is a need to further reduce plaque growth, thrombogenicity and haemodynamic compromise by intensifying anti-atherosclerotic therapy. An updated meta-analysis showed that colchicine use in patients with high cardiovascular risk was associated with lower stroke incidence (12). However, no studies had focused on the use of colchicine in patients with ICAD, which is highly prevalent in Asia.

Objective:

In this pilot randomized, double-blind, placebo-controlled trial, the investigators aim to elucidate the efficacy and safety of low-dose colchicine (0.5mg daily) in patients with symptomatic intracranial atherosclerotic disease. The investigators hypothesize that low-dose colchicine in addition to intensive medical therapy, compared to intensive medical therapy alone, may result in more plaque regression in patients with symptomatic ICAD. Results from this pilot trial will provide an important basis for a larger-scale main trial in the future.

Methods:

In this pilot randomized, double-blind, placebo-controlled trial, the investigators shall recruit 44 patients with recent ischaemic stroke due to intracranial atherosclerosis (ICAD) with ≥ 50% stenosis. Patients will be randomly assigned to either low-dose colchicine (0.5mg daily) (n=22) or placebo (n=22) for 12 months. High-resolution magnetic resonance vessel wall imaging will be performed at baseline and 12 months. The primary endpoint is a composite of regression of intracranial stenosis, plaque volume, or occurrence of any major adverse cardio- or cerebrovascular events at 12 months. The investigators shall also evaluate safety endpoints including diarrhea, marrow suppression, infections, neuromuscular dysfunction.

Significance:

No studies had focused on the use of colchicine in patients with ICAD, which is highly prevalent in Asia. Results from this pilot trial will provide an important basis for a larger-scale main trial in the future.

Eligibility criteria: Inclusion Criteria

1. Chinese patients aged 40-80 years old
2. Patients with symptomatic ICAD of ≥ 50% stenosis in middle cerebral arteries, basilar artery. Degree of stenosis will be quantified by computer tomographic angiography (CTA), magnetic resonance imaging (MRI) or digital subtraction angiography (DSA) by the WASID method (13). Symptomatic ICAD is defined as ischemic stroke or transient ischemic attack with clinical or radiological signs correspond to the vascular territory supplied by the disease vessel.
3. Patients with first-ever ischaemic stroke within 8 weeks of recruitment

Exclusion Criteria

1. Patients who are unable to provide an informed consent
2. Patients who are contraindicated to contrast MRI scans, e.g. non-MRI compatible pacemaker, claustrophobia, known gadolinium-based contrast allergy, estimated glomerular filtration rate \< 30mL/min/1.73m2, etc.
3. Patients who have absolute or relative contraindications to colchicine therapy, e.g. colchicine allergy, neuromuscular disorders, haematological diseases, chronic diarrhea, estimated glomerular filtration rate \< 30mL/min/1.73m2, chronic liver disease, etc.
4. Patients with intracranial stenosis not due to atherosclerosis, e.g. vasculitis, vasospasm, Moyamoya disease, etc.
5. Pregnancy
6. Patients with elevated creatine kinase level at randomisation stage of study.
7. Recurrent gouty arthritis that requires colchicine for \> 3 months per year;
8. Inflammatory bowel disease or chronic diarrhea;
9. Neuromuscular disease or a nontransient creatine kinase level that was greater than three times the upper limit of the normal range (unless due to infarction) for \> 3 months;
10. Clinically significant nontransient hematologic abnormalities with hemoglobin \<10g/dL, white blood cell \< 4x10\^9, or platelet \< 100x10\^9/L for \> 3 months;
11. Alcoholism;
12. Long term systemic glucocorticoid therapy

Primary outcomes:
measure: Regression of intracranial stenosis
timeFrame: at 12 months
measure: Regression of plaque volume
timeFrame: at 12 months
measure: Major adverse cardio- or cerebrovascular events (MACE)
timeFrame: at 12 months
Secondary outcomes:
measure: Longitudinal changes in ICAD stenosis
timeFrame: at 12 months
measure: Longitudinal changes in plaque volume
timeFrame: at 1,3,6,9,12 months
measure: Longitudinal changes in resolution of plaque enhancement
timeFrame: at 1,3,6,9,12 months
measure: Longitudinal changes in white matter hyperintensity volume
timeFrame: at 12 months
measure: Longitudinal changes in number of silent lacunes
timeFrame: at 12 months
measure: Longitudinal changes in cognitive ability
timeFrame: at 1,3,6,9,12 months
Other outcomes:
Locations:
city: Hong Kong
country: Hong Kong
facility: Chinese University of Hong Kong
Study officials:
References: