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CHANCE-3

Q: What were the key findings of the CHANCE-3 trial?

Low-dose colchicine initiated within 24 hours of minor-to-moderate non-cardioembolic stroke or high-risk TIA with elevated hs-CRP did not reduce 90-day stroke risk compared with placebo, and had a similar safety profile regarding serious adverse events.

Colchicine in patients with acute ischaemic stroke or transient ischaemic attack (CHANCE-3): multicentre, double blind, randomised, placebo controlled trial

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Year of Publication: 2024

Authors: Jiejie Li, Xia Meng, Fu-Dong Shi, ..., Yongjun Wang; on behalf of the CHANCE-3 Investigators

Journal: BMJ

Citation: BMJ 2024;385:e079061

Link: http://dx.doi.org/10.1136/bmj-2023-079061

PDF: https://www.bmj.com/content/bmj/385/bmj-2023-079061.full.pdf

Clinical Question

To assess the efficacy and safety of low-dose colchicine versus placebo for reducing the risk of subsequent stroke within 90 days among patients with acute high-risk non-cardioembolic ischaemic stroke or transient ischaemic attack and evidence of inflammation (high-sensitivity C-reactive protein ≥2 mg/L).

Study Overview

Objective

Low-dose colchicine to reduce the risk of subsequent stroke in patients with acute minor-to-moderate non-cardioembolic ischemic stroke or TIA and evidence of inflammation (CRP ≥2 mg/L).

Study Summary

Recurrent stroke within 90 days: 6.3% colchicine (264/4176) vs 6.5% placebo (270/4167) (HR 0.98, 95% CI 0.83–1.16; P=0.79) — non-significant
Diarrhoea more common with colchicine (1.7% vs 0.7%, P<0.001); no increase in serious adverse events (2.2% vs 2.1%, P=0.83)
Exploratory age subgroup: patients <65y trended toward benefit, ≥65y toward harm (crude interaction P=0.02, unadjusted)

Intervention

Low-dose colchicine (0.5 mg twice daily for 3 days, then 0.5 mg daily) or a matching placebo, administered for 90 days in addition to standard secondary prevention therapy.

Bottom Line

Low-dose colchicine initiated within 24 hours of minor-to-moderate non-cardioembolic stroke or high-risk TIA with elevated hs-CRP did not reduce 90-day stroke risk compared with placebo, and had a similar safety profile regarding serious adverse events.

        Major Points
        CHANCE-3 was a multicenter, double-blind RCT enrolling 8343 patients with non-cardioembolic stroke or TIA and hs-CRP ≥2 mg/L across 244 hospitals in China.
Colchicine was started within 24 hours of symptom onset and continued for 90 days.
There was no difference in 90-day stroke recurrence between colchicine and placebo (6.3% vs 6.5%, HR 0.98; P=0.79).
Serious adverse event rates were similar between groups; mild diarrhea and abnormal liver function were more frequent with colchicine.
Subgroup analyses were exploratory; crude interaction was nominally significant for age (P=0.02, <65y trended toward benefit) and for symptomatic intracranial artery stenosis (P=0.03), but not adjusted for multiple testing.

      

Design

Study Type: Multicentre, double blind, randomised, placebo controlled trial

Randomization: 1

Blinding: Double-blind (patients, caregivers, and outcome assessors masked to allocation)

Enrollment Period: August 11, 2022, to April 13, 2023

Follow-up Duration: 90 days

Centers: 244

Countries: China

Sample Size: 8343

Analysis: Intention-to-treat; primary endpoint analyzed with shared frailty Cox model to account for site-level clustering

Inclusion Criteria

Age ≥40 years
Acute non-cardioembolic ischaemic stroke (NIHSS ≤5) or high-risk TIA (ABCD² score ≥4)
hs-CRP ≥2 mg/L at baseline
Symptom onset within 24 hours
Eligible for trial drug administration within 24 hours

Exclusion Criteria

Presumed cardioembolic stroke (e.g., atrial fibrillation, prosthetic valve)
Inflammatory bowel disease or chronic diarrhoea
Symptomatic peripheral neuropathy or pre-existing progressive neuromuscular disease
Non-transient creatine kinase >3× ULN
Creatinine >1.5× ULN or eGFR <50 mL/min
Severe hepatic disease
Clinically significant non-transient haematological abnormalities
Acute infection (respiratory, urinary, or gastrointestinal) or current/planned oral or IV anti-infective treatment for any other infection
Current or planned long-term use of systemic glucocorticoids
Planned use of medications that may interact with colchicine

Baseline Characteristics

Characteristic	Control	Active
Group	Placebo (n=4167)	Colchicine (n=4176)
Age, median (IQR), years	66.4 (58.3–73.2)	66.3 (58.2–73.1)
Female, n (%)	1589 (38.1%)	1544 (37.0%)
Qualifying event - Ischaemic stroke, n (%)	3693 (88.6%)	3718 (89.0%)
Median hs-CRP, mg/L (IQR)	4.7 (2.9–9.3)	4.9 (3.0–9.8)
Median time to randomisation, h (IQR)	14.5 (9.2–20.5)	14.8 (8.9–20.7)

Arms

Field	Control	Colchicine
Intervention	Matching placebo, 0.5 mg twice daily on days 1–3, then once daily on days 4–90	Colchicine 0.5 mg twice daily on days 1–3, then once daily on days 4–90
Duration	90 days	90 days

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Any new stroke (ischaemic or haemorrhagic) within 90 days	Primary	6.5% (270/4167)	6.3% (264/4176)	0.98	0.79
Composite vascular event (stroke, TIA, MI, or vascular death)	Secondary	7.4% (309/4167)	7.1% (298/4176)	HR 0.96 (95% CI 0.82–1.13)	0.64
Ischaemic stroke	Secondary	6.3% (263/4167)	6.2% (257/4176)	HR 0.98 (95% CI 0.82–1.16)	0.79
Stroke or TIA	Secondary	7.0% (290/4167)	6.8% (284/4176)	HR 0.98 (95% CI 0.83–1.15)	0.79
Ordinal stroke or TIA severity (six-level scale)	Secondary	—	—	COR 1.03 (95% CI 0.88–1.21)	0.74
Modified Rankin Scale score >1 at 90 days	Secondary	10.6% (440/4167)	10.4% (435/4176)	OR 0.99 (95% CI 0.86–1.14)	0.86
Primary Safety Outcome: Any serious adverse event	Adverse	2.1% (88/4167)	2.2% (91/4176)		0.83
Death (all-cause)	Adverse	1.1% (45/4167)	0.8% (34/4176)		0.21
Cardiovascular death	Adverse	0.7% (27/4167)	0.5% (19/4176)		0.23
Any adverse event	Adverse	21.3% (888/4167)	21.8% (910/4176)		0.59
Gastrointestinal event	Adverse	3.6% (150/4167)	4.1% (173/4176)		0.20
Diarrhoea	Adverse	0.7% (30/4167)	1.7% (71/4176)		<0.001
Flatulence	Adverse	0.2% (10/4167)	0.5% (21/4176)		0.05
Constipation	Adverse	1.1% (45/4167)	0.7% (30/4176)		0.08
Abnormal hepatic function (ALT/AST ≥3× ULN)	Adverse	0.1% (3/4167)	0.3% (12/4176)		0.03
Myopathy	Adverse	0 (0.0%)	0 (0.0%)		—

Subgroup Analysis

Prespecified subgroup analyses were exploratory (crude P values, unadjusted for multiple testing). Age interaction was nominally significant (P=0.02 dichotomised at 65y; P=0.018 continuous): patients <65y trended toward benefit with colchicine (HR 0.79, 95% CI 0.61–1.02) whereas ≥65y trended toward harm (HR 1.16, 95% CI 0.92–1.46). Symptomatic intracranial artery stenosis also showed a nominally significant interaction (P=0.03). No other prespecified subgroup (sex, BMI, hypertension, diabetes, prior stroke/TIA, hs-CRP <4.8 vs ≥4.8, etc.) showed a significant interaction.

Criticisms

Biologic effect of colchicine on inflammation could not be assessed due to lack of follow-up hs-CRP levels.
Short treatment duration may miss long-term effects.
Trial conducted exclusively in China, limiting global generalizability.
Limited post-randomization cardiac monitoring may underestimate cardioembolic stroke misclassification.

Funding

National Key Research and Development Program of China, National Natural Science Foundation of China, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, and Capital's Funds for Health Improvement and Research. Trial drugs and matching placebo were provided free of charge by Kunming Pharmaceuticals, which had no role in trial design, conduct, data analysis, or manuscript preparation.

Based on: CHANCE-3 (BMJ, 2024)