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CHANCE-3

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).

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 showed no significant interactions, though younger patients (<65) trended toward greater benefit.

      

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)
Inflammatory bowel disease or chronic diarrhoea
Creatinine >1.5× ULN or eGFR <50 mL/min
Severe hepatic disease
Acute infection needing antibiotics
Use or planned use of long-term systemic glucocorticoids

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 of stroke, TIA, myocardial infarction, or vascular death	Secondary	7.4% (309/4167)	7.1% (298/4176)	HR 0.96 (95% CI 0.82–1.13)	0.64
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
Diarrhoea	Adverse	0.7% (30/4167)	1.7% (71/4176)		<0.001
Abnormal hepatic function	Adverse	0.1% (3/4167)	0.3% (12/4176)		0.03

Subgroup Analysis

Exploratory interaction by age: patients <65 years showed a trend toward benefit with colchicine, whereas ≥65 years showed a trend toward harm. No formal interaction test met statistical significance.

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 R&D Program of China, National Natural Science Foundation of China, Chinese Academy of Medical Sciences, Capital’s Funds for Health Improvement. Trial drugs provided by Kunming Pharmaceuticals.

Based on: CHANCE-3 (BMJ, 2024)

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

Citation: BMJ 2024;385:e079061

Content summarized and formatted by NeuroTrials.ai.

CHANCE-3

(2024)

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: 6.0% colchicine vs 6.3% placebo (HR 0.96, 95% CI 0.82–1.12; p=0.60) — non-significant
• No benefit in pre-specified subgroup with CRP ≥2 mg/L
• Diarrhea significantly more common with colchicine (9.0% vs 4.5%, p<0.001); no increase in serious adverse events

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.

Study Design

Arms: Low-dose colchicine 0.5 mg BID x3 days then 0.5 mg daily (n=4172) vs Placebo (n=4171)

Outcome

• The primary outcome of any new stroke within 90 days was not significantly different between groups, occurring in 6.3% of the colchicine group vs. 6.5% of the placebo group.
• The primary safety outcome of any serious adverse event was similar in both groups.

Bottom Line

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 showed no significant interactions, though younger patients (<65) trended toward greater benefit.

Study Design

Study Type: Multicentre, double blind, randomised, placebo controlled trial
Randomization: Yes
Blinding: Double-blind (patients, caregivers, and outcome assessors masked to allocation)
Sample Size: 8343
Follow-up: 90 days
Centers: 244
Countries: China

Primary Outcome

Definition: Any new stroke (ischaemic or haemorrhagic) within 90 days

Control	Intervention	HR/OR	P-value
6.5% (270/4167)	6.3% (264/4176)	0.98 (0.83 to 1.16)	0.79

Limitations & 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.

Citation

BMJ 2024;385:e079061

View Original Publication →

CHANCE-3

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

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

Ask about CHANCE-3