Colchicine for the Prevention of Vascular Events After an Acute Intracerebral Hemorrhage: A Placebo-Controlled Trial

Abstract

BACKGROUND:

There is a need for novel treatments that lower the risk of major adverse cardiovascular events and secondary inflammatory brain injury after an intracerebral hemorrhage (ICH).

METHODS:

We performed a double-blind, placebo-controlled, pilot randomized clinical trial at 11 centers across Canada to determine the feasibility of testing colchicine after an acute ICH. We recruited adults presenting within 48 hours of ICH onset with vascular neuroimaging evidence or risk factors for atherosclerosis. Participants were randomized to oral colchicine 0.5 mg daily or placebo and followed to a common study termination date. The primary feasibility outcome was the recruitment rate (participants/center per year). Secondary feasibility outcomes included retention of participants at 6 months and medication adherence at 12 months. This trial is registered (URL: https://www.clinicaltrials.gov; Unique identifier: NCT05159219).

RESULTS:

Between August 2022 and March 2024, 52 participants were allocated to colchicine 0.5 mg daily and 48 participants to placebo daily. Participants were, on average, 68 years old, and 60% were male. The mean time from ICH onset to randomization was 35 hours. The average recruitment rate was 8.9 participants/site per year. Retention at 6 months was 92% (colchicine 91% versus placebo 93%). Following randomization, 14 participants (27%) in the colchicine group and 13 participants (27%) in the placebo group permanently discontinued the study drug. Excluding participants who died or permanently discontinued the study intervention, 12-month medication adherence was 97%, with similar rates between the colchicine and placebo groups (100% versus 93%). We detected no difference in predefined exploratory efficacy or safety end points between the 2 groups over the median follow-up time of 364 days.

CONCLUSIONS:

It is feasible to test low-dose colchicine after an acute ICH. Future randomized clinical trials should account for the high rates of early permanent study drug discontinuation in this patient population.

REGISTRATION:

URL: https://www.clinicaltrials.gov; Unique identifier: NCT05159219.

Thromboinflammation is believed to worsen neurological outcomes and contribute to ischemic vascular events in patients with small vessel disease, including intracerebral hemorrhage (ICH). The management of patients with ICH is challenging and requires balancing the benefit of ischemic vascular preventive treatments against any possible increase in bleeding risk.¹ ICH survivors have a constant risk of rebleeding, with the annual rate of ICH recurrence ranging from 1.3% to 7.4%.² Because of their preexisting vascular risk factors and comorbidities, ICH survivors are at considerably higher risk of major adverse cardiovascular events (MACE),^3–5 which is further aggravated by the cessation of antithrombotic medications for significant periods after ICH.⁶ These findings highlight the need for novel treatments that lower the high vascular risk over the long term in ICH survivors, particularly in the early post-ICH period when patients are not receiving antithrombotic medications.

Randomized-controlled clinical trials (RCTs) have established that colchicine reduces the risk of MACE (risk ratio, 0.73 [95% CI, 0.65–0.90]) and ischemic stroke (risk ratio, 0.73 [95% CI, 0.58–0.90]) in patients with a history of coronary artery disease, with no increase in ICH risk.⁷ Results from an observational study further suggest that patients with diabetes receiving colchicine treatment have lower risks of stroke, with the risk reduction for both ischemic and hemorrhagic stroke being proportionate to the duration of colchicine use.⁸ In an experimental murine collagenase-induced ICH model, we provided proof of concept for the safety of oral colchicine after ICH, detecting no increase in hematoma volume and less perihematomal brain inflammation at a scaled dose equivalent to the 0.5 mg daily that was used in trials testing colchicine in patients with coronary artery disease, when compared with placebo.⁹

We initiated the CoVasc-ICH trial (Colchicine for the Prevention of Vascular Events After an Acute Intracerebral Hemorrhage) to determine the feasibility of testing colchicine for reducing the risk of MACE and secondary inflammatory brain injury following an acute spontaneous ICH.

Methods

Study Design

CoVasc-ICH was an investigator-initiated, double-blind, placebo-controlled, randomized, phase II clinical trial performed in 11 academic stroke centers across Canada. A list of participating institutions, investigators and collaborators is provided in the Supplemental Material. The trial protocol (Revised 1.0; 2022-02-02) was approved by Health Canada and the Research Ethics Committees of the participating institutions. The trial was funded by competitive grants from the Canadian Institutes of Health Research and the Population Health Research Institute. The trial’s sponsor and coordinating center were the Population Health Research Institute. Data, analytic methods, and study materials may be available upon request to the sponsor.

Participants

We included adult (≥18 years) patients presenting with spontaneous intracerebral hemorrhage within 48 hours of symptom onset and meeting criteria for atherosclerosis on the basis of at least one of the following severity categories: (1) history of symptomatic coronary, peripheral, or carotid artery disease (severe atherosclerotic vascular disease); (2) visualized extracranial cervical/intracranial atherosclerotic disease causing any degree of stenosis/occlusion or the presence of aortic arch plaque with maximum thickness ≥1 mm (moderate atherosclerotic vascular disease); or (3) 2 or more risk factors, including age ≥60 years, hypertension, dyslipidemia, diabetes, chronic kidney disease (estimated glomerular filtration rate=15–50 mL/min), history of ischemic stroke or current smoking (mild atherosclerotic vascular disease).

We excluded adults with secondary causes of ICH (relating to trauma, macrovascular anomalies, neoplasms, or bleeding diathesis), inflammatory bowel disease or chronic diarrhea, cirrhosis or severe hepatic dysfunction, renal insufficiency (estimated glomerular filtration rate <15 mL/min), or an estimated life expectancy <6 months at the time of enrollment. We also excluded adults with a known allergy or sensitivity to colchicine, a strong indication for colchicine (where assignment to placebo was deemed unacceptable), or those who were on concurrent treatment with strong CYP3A4 inhibitors (atazanavir, clarithromycin, darunavir/ritonavir, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, tipranavir/ritonavir) or P-gp inhibitors (cyclosporine, ranolazine). We finally excluded adults who were pregnant or breastfeeding, those who reported an inability to adhere to study procedures, or those who had a close affiliation with the investigational site. Patients with a history of organ transplantation were not excluded.

Patients satisfying the aforementioned inclusion and exclusion criteria provided written informed consent before enrollment. When the patient did not have capacity at the time of the screening visit, written consent was obtained from a substitute decision-maker (their nearest relative or legally authorized representative).

Randomization and Masking

Investigators supplied information about participants’ demographics, the severity of underlying atherosclerotic vascular disease (mild, moderate, or severe as per the definitions above), and confirmed the absence of any exclusion criterion, as listed above, into an interactive web-response randomization system. Randomization was conducted centrally via a secure web client using random permuted blocks. Randomization was stratified by center and the severity of underlying atherosclerotic vascular disease (mild, moderate, or severe) to account for potential differences in the patient population and cointerventions. Colchicine and placebo tablets were identical in appearance. Investigators, site staff, and participants were masked to treatment assignment during the trial until the last participant completed 6 months of follow-up and the database was locked.

Procedures

Participants were randomly assigned within 48 hours of symptom onset to a daily tablet of colchicine 0.5 mg or a daily tablet of placebo. The study drug (colchicine or placebo) was started immediately after randomization and continued once daily for the duration of the trial. In the event of a temporary interruption of the study drug for any reason, the study drug was restarted as soon as medically justified in the opinion of the investigator. There was no predefined maximum limit for temporary treatment interruption. All participants were followed for up to 6 months after the end of recruitment to a common termination date. Follow-up visits were performed in person or over the telephone in the first 3 months after randomization and then every 6 months until the common termination date. At each study visit, investigators assessed participants for their adherence to the study drug, screened for the occurrence of study end points and adverse events, and reviewed laboratory test results when available.

Monitoring included central statistical and data monitoring of the trial, to ensure data quality and participant safety. Recruitment, participant demographics, study drug adherence, and safety outcomes were reviewed every 6 months by an independent data safety monitoring board, as listed in the Supplemental Material. Before database lock, all data in the web-based case report forms underwent completeness, range, consistency, validation, and logic checks.

Outcomes

The primary feasibility outcome was the recruitment rate, with a target of ≈10 participants per site per year. The decision to proceed to a full-scale trial was based on prespecified recruitment rate thresholds as outlined in Table S1. Secondary feasibility outcomes included refusal rates, participant retention, and medication adherence. Determinants of success for participant retention (target of 90% at 6 months) and medication adherence (target of 75% at 12 months) were predefined. Adherence to medication was defined as taking 80% to 125% of the scheduled dose as reported by participants or caregivers at each study visit, excluding those who died or permanently discontinued the study medication before the visit. As it was not feasible for all sites to consistently keep screening logs, we were not able to reliably estimate refusal rates; therefore, those rates are not provided.

As exploratory efficacy end points, we collected time to first MACE occurring from randomization to the end of the study, consisting of any stroke, myocardial infarction, revascularization procedures for coronary, carotid, or peripheral arterial disease, resuscitated cardiac arrest or cardiovascular death. We also evaluated functional outcomes at 3, 6, and 12 months after randomization with the modified Rankin Scale (mRS) and the rate of dependency at 6 months after randomization, defined as mRS scores between 3 and 5. As exploratory safety end points we evaluated the occurrence of major gastrointestinal adverse reactions, systemic infection, neutropenia, myotoxicity, symptomatic hematoma expansion, intracranial hemorrhage, major hemorrhage, renal failure, all-cause mortality, or hospitalization for any reason occurring from randomization to the end of the study. Definitions of exploratory efficacy and safety end points are provided in the protocol Supplemental Material. All adverse and outcome events were first reviewed by a blinded consultant neurologist at the trial coordinating center (A.S.) to ensure appropriate and complete reporting. All outcome events were then externally reviewed by an adjudication committee (Supplemental Material) blinded to participant characteristics and treatment allocation.

Statistical Analysis

The sample size of 100 participants was a prespecified convenience sample size to obtain the requisite data on recruitment rates, operational feasibility, and incidence rates to refine our calculations for an international, phase III RCT. Analyses were performed including all randomized participants within the treatment groups to which they were randomized, regardless of the treatment received or duration of trial participation (intention-to-treat population). Baseline characteristics are summarized using mean (±SDs) or medians with interquartile ranges for continuous variables, as appropriate, and counts and percentages for categorical variables. No statistical testing was performed to compare patient characteristics.

Recruitment rate was calculated as the total number of randomizations divided by the number of sites and by the period each site was active for enrollment. Retention rate was calculated by dividing the number of randomized participants who had not withdrawn consent at the time of the due visit by the total number of randomized participants at that time. Medication adherence rate was calculated as the percentage of participants reporting that they were on study medication at the time of the due visit, excluding those who died or permanently discontinued the study intervention before the due visit.

For the exploratory composite end point of time to first MACE and its individual components we estimated the treatment effect, as measured by the hazard ratio and corresponding 95% CI derived from a Cox proportional hazards model including treatment group as the only covariate. The plausibility of the proportional hazards assumption was assessed by visually examining the plots of the log(-log[survival]) versus time for evidence of nonparallelism. The consistency of treatment effects on the composite of MACE was explored in prespecified subgroups, including age (<65, ≥65 years), sex (male, female), race/ethnicity (White only, other), qualifying intracerebral hemorrhage (lobar, nonlobar), and severity of atherosclerotic disease (mild, moderate, severe). For the subgroup analyses, we tested for interactions in the Cox regression model and evaluated the treatment effect.

We used logistic regression to compare the probability of functional dependency at 6 months between the colchicine and placebo groups and reported the respective odds ratio (OR) and accompanying 95% CI. Differences in distributions of mRS scores between colchicine and placebo groups were assessed with ordinal regression (shift analysis) and reported with common ORs and 95% CIs, both unadjusted and after adjustment for participant’s baseline National Institutes of Health Stroke Scale scores and age at randomization.

The effect of the study treatment on each of the safety outcomes was assessed by comparing the total number of participants with reported outcomes at the end of the study in the colchicine and placebo groups using the χ² test.

All analyses were conducted by the study’s statistician (A.W.) using SAS, version 9.4. Two-sided hypothesis tests with a 5% significance level were used. This trial is registered with ClinicalTrials.gov (NCT05159219) and is now completed.

Role of the Funding Source

The funders of this study had no role in study design, data collection, data analysis, data interpretation, writing, or the decision to publish.

Results

Between August 4, 2022, and March 20, 2024, 100 participants from 11 centers in Canada consented to participate in the study. Information on cumulative recruitment and by site is available in Figure S1 and Table S2, respectively. Following randomization, 52 participants were allocated to receive colchicine 0.5 mg daily and 48 participants to receive placebo daily. End-of-study visits were performed 6 months after randomization of the last participant, between September 20, 2024, and October 20, 2024. The median follow-up time for all participants was 364 days (interquartile range, 225.5–550). During the follow-up period, no participant was lost to follow-up, while 1 participant in each group withdrew consent (Figure 1).

Figure 1.

Trial flowchart.

Baseline characteristics were well balanced between the treatment groups (Table 1). Participants were, on average, 68 years old, ≈60% were male, two-thirds were White, and 23% were Asian. One in 4 participants had a lobar ICH. More than 70% of the participants had an ICH volume of <30 cm³, and 26% had an associated intraventricular hemorrhage. In the colchicine group, 42 (81%), 7 (14%), and 3 (6%) participants had ICH volumes <30 cm³, 30–60 cm³, and >60 cm³, respectively; the corresponding values in the placebo group were 31 (65%), 12 (25%), and 5 (10%). The mean time from ICH onset to randomization was 35 hours.

Table 1.

Baseline Characteristics

More than half of the participants were classified by investigators to be in the mild atherosclerotic vascular disease group (58% in the colchicine group versus 54% in the placebo group), around 30% were in the moderate atherosclerotic vascular disease group (27% in the colchicine group versus 35% in the placebo group), and 13% were in the severe atherosclerotic vascular disease group (15% in the colchicine group versus 10% in the placebo group). A quarter of the participants were on antiplatelet therapy before ICH onset. A history of coronary disease was reported in 17%, peripheral arterial disease in 3%, and prior ischemic stroke or transient ischemic attack in 11%. A diagnosis of hypertension and diabetes was prevalent in 88% and 33% of the participants at randomization, respectively. Current tobacco and alcohol use were reported in 13% and 45% of the participants, respectively. A detailed overview of the medical history and medications at the onset of the index event is provided in Table S3.

The average recruitment rate was 8.9 participants per site per year, with 4 of the participating sites exceeding the target of an average of 10 participants per year (Table S2). No sites stopped enrolling before the end of the trial. Retention of participants at 6 months was 92%, with similar rates between the colchicine and placebo groups (91% versus 93%). The overall visit adherence was 92%, with a total of 414 visits performed out of the expected 452 total visits over the trial’s duration (Table S4). Following randomization, a total of 27 participants permanently discontinued the study drug, 14 (27%) in the colchicine group and 13 (27%) in the placebo group. The median time from randomization to study drug discontinuation was 61 days, with no significant difference between the colchicine (64 days, interquartile range, 32–171) and placebo (49 days, interquartile range, 14–186) groups. Cumulative permanent drug discontinuation, overall and by study visit, between the 2 groups is outlined in Figure S2 and Table S5. Medication adherence was 97% at 12 months, with similar rates between the colchicine and placebo groups (100% versus 93%). Medication adherence across study visits is presented in Table S6. Overall study drug adherence was similar between the colchicine (98%) and placebo (96%) groups. The rates of antithrombotic use throughout the course of the trial are presented in Figure S3. Although 29 of 100 participants (29%) reported use of antithrombotics (antiplatelet or anticoagulant) within 2 weeks before randomization, reported use of antithrombotics was 14% at both 3 and 6 months. There was a numerical difference in the overall use of antithrombotics after randomization between the colchicine and placebo groups (13.5% versus 22.9%), which did not reach statistical significance (P=0.219).

During follow-up, 6 participants (11%) allocated to colchicine treatment and 5 participants (10%) allocated to placebo had an incident MACE (hazard ratio, 1.22 [95% CI, 0.37–4.01]), mainly attributed to early cardiovascular death in 6 participants in the colchicine group and 4 participants in the placebo group (11% versus 8%; hazard ratio, 1.53 [95% CI, 0.43–5.43]). There were no incident ischemic or undefined strokes, myocardial infarction, revascularization procedures, or resuscitated cardiac arrests in either group during follow-up. No hemorrhagic strokes were reported in the colchicine arm, while 2 participants in the placebo group (4%) had hemorrhagic stroke recurrence (Table 2). We found no evidence of heterogeneity in the effects of colchicine on the risk of MACE in prespecified exploratory subgroup analyses (Figure S4). Rates of dependency at 6 months were similar between the colchicine and placebo groups (32% versus 29%; OR, 1.11 [95% CI, 0.45–2.76]). No differences were detected in the distribution of the mRS scores between the 2 groups at 3 months (unadjusted common OR, 0.98 [95% CI, 0.48–2.00]; adjusted common OR, 1.06 [95% CI, 0.50–2.25]), 6 months (unadjusted common OR, 1.24 [95% CI, 0.59–2.59]; adjusted common OR, 1.44 [95% CI, 0.66–3.14]), or 12 months (unadjusted common OR, 0.85 [95% CI, 0.31–2.32]; adjusted common OR, 0.80 [95% CI, 0.27–2.33]; Figure 2). The distribution of the mRS scores between the 2 groups at 18 months and at the end of the study is presented in Figures S5 and S6, respectively.

Table 2.

Exploratory Efficacy Outcomes

Figure 2.

Distribution of modified Rankin Scale scores between colchicine and placebo groups. Timepoints at (A) 3 months, (B) 6 months, and (C) 12 months.

We detected no difference in the incidence of predefined safety end points between the 2 arms (Table 3). Summaries of the primary cause of death and serious adverse events by treatment group are provided in Tables S7 and S8, respectively.

Table 3.

Safety Outcomes

Discussion

We demonstrated that it is feasible to conduct a multicenter RCT of low-dose colchicine after an acute ICH, with an average recruitment of ≈9 participants per site per year and retention of more than 90% of participants over a year follow-up. Although the rate of early permanent discontinuation of study drug was high, participants who continued on the study medication were highly adherent during follow-up. We identified no major safety concerns with colchicine treatment used shortly after acute ICH, when compared with placebo. These findings support further investigating low-dose colchicine after acute ICH to reduce the risk of vascular events and improve functional outcomes within the setting of phase III RCTs powered for efficacy.

Our average recruitment rate narrowly missed the predefined feasibility target of 10 participants per site per year, but did meet our predefined threshold for probable likelihood of feasibility of 8 participants per site per year (Table S1). Ten participants per site per year was selected as a feasibility benchmark based on the estimated number of participants required to enroll ≈1678 participants in a phase III clinical trial, assuming a 24-month recruitment period and that activating <100 sites globally for the phase III trial would be feasible. The phase III CoVasc-ICH2 trial (URL: https://www.clinicaltrials.gov; Unique identifier: NCT06587737) has a re-estimated target sample size of 1125 participants on the basis of a hierarchical composite end point combining MACE with dependency on the mRS to capture the potential effects of colchicine in reducing both MACE and secondary inflammatory brain injury within a single primary efficacy end point. Based on a recruitment rate of 8.9 participants per site per year over 2 years, at least 65 sites will need to be activated for CoVasc-ICH2, which is an achievable and realistic target for our international ICH trials network established through the ANNEXA-i (Andexanet Alfa in Acute Intracranial Hemorrhage in Patients Receiving an Oral Factor Xa Inhibitor; 131 sites in 23 countries)¹⁰ and ENRICH-AF (Edoxaban for Intracranial Hemorrhage Survivors With Atrial Dibrillation; URL: https://www.clinicaltrials.gov; Unique identifier: NCT03950076; 240 sites in 20 countries) trials.

The permanent drug discontinuation rate of 27% over a median follow-up of approximately 1 year in CoVasc-ICH was higher than expected, and exceeds the discontinuation rates in clinical trials assessing low-dose colchicine in patients with coronary artery disease or after noncardiac surgery.^11–15 The discontinuation rate of low-dose colchicine following an ischemic stroke in the CONVINCE trial (Colchicine for the Prevention of Vascular Inflammation in Noncardioembolic Stroke) was 21% over a median follow-up duration of 33.6 months.¹⁶ Patients in CONVINCE were enrolled between 72 hours and 28 days from the onset of stroke symptoms compared with CoVasc-ICH, enrolling participants within 48 hours from symptoms onset. The risk of permanent discontinuation in CoVasc-ICH was frontloaded with 63% of the permanent discontinuations happening within the first 3 months from randomization and 82% by the first 6 months. More than half of the participants (52%) reported burden of treatment as the reason for discontinuation, followed by adverse events (26%), palliation (15%), and withdrawal from the study for other reasons (7%). Discontinuation rates, reasons for discontinuation, and trends over time were comparable between participants allocated to colchicine or placebo. Early treatment discontinuation in patients with ICH has been more frequently reported among those individuals with severe neurological injury and poor prognosis.¹⁷

One in 10 participants in CoVasc-ICH experienced cardiovascular death over the median 1-year follow-up, which is much higher than the 7.8% rate of cardiovascular death over a 2-year follow-up reported in the RESTART (Restart or Stop Antithrombotics Randomized Trial).¹⁸ The vast majority of cardiovascular deaths occurred in the first 2 months from randomization in CoVasc-ICH. Although the RESTART trial allowed enrollment of participants to occur as soon as 24 hours post-ICH, the median time from ICH onset to randomization was 76 days, while the median time from ICH onset to enrollment in CoVasc-ICH was just 35 hours. In post hoc, exploratory analyses, we found that participants in CoVasc-ICH with higher ICH scores¹⁹ or increased ICH volume at baseline had higher rates of both permanent drug discontinuation and early cardiovascular death. To mitigate the risks of early permanent discontinuation and early cardiovascular mortality in CoVasc-ICH2, we will be excluding patients with severe ICH, defined as an ICH score of 3 or higher, or with a Glasgow Coma Scale score of <8, patients on mechanical ventilation at the time of consent, or an ICH volume of more than 40 mL on the most recent brain imaging before consent. Using the aforementioned exclusion criteria, we have estimated that 13 participants in CoVasc-ICH (13%) would have been excluded from participation.

By recruiting participants shortly after ICH onset, we aim to address the unmet need for treatment options that can lower the early high risk of MACE in ICH survivors when the vast majority of patients are not receiving antithrombotic medications and provide the best chance to mitigate secondary brain injury from thromboinflammation.²⁰ We detected no signal of major safety concerns when colchicine was started within 48 hours of ICH onset. The low dose of colchicine (0.5 mg daily) that was used in CoVasc-ICH has been evaluated in over 11 816 patients with coronary artery disease enrolled in RCTs and was not associated with increased risk of hospitalization due to infection or major gastrointestinal side effects.⁷ Long-term low-dose colchicine has not been found to increase the risk of cancer, sepsis, cytopenia, myotoxicity, or changes in renal function.^21,22 Despite suggested pleiotropic antiplatelet properties of colchicine in vitro,²³ we detected no increase in the risk of hematoma expansion, recurrent ICH, or major hemorrhage with colchicine, which is consistent with bleeding outcomes from previous RCTs^12–16 and the findings from our experimental animal model.⁹

CoVasc-ICH is the first RCT evaluating the use of low-dose colchicine in patients with ICH. The study used placebo, reducing the risk of potential biases from patients and investigators. Despite the novelty and strengths of the study, some limitations need to be acknowledged. CoVasc-ICH is a pilot study designed to evaluate the feasibility of a phase III trial and therefore all analyses of efficacy and safety end points were underpowered and exploratory in nature. Given the wide CIs around the effect estimates, the possibility of benefit or harm from low-dose colchicine cannot be excluded. The potential of low-dose colchicine to reduce the risk of MACE and improve the functional outcomes of ICH survivors needs to be evaluated in adequately powered phase III trials. It also needs to be noted that the feasibility metrics in CoVasc-ICH (recruitment, adherence, retention) may not scale linearly when expanding from a national to an international RCT including countries with differences in healthcare and research infrastructure.²⁴ Specifically, for adherence to medication, it needs to be highlighted that it was assessed using a self-reported measure, which is practical and inexpensive to administer but may not be as accurate when compared with more objective approaches, such as pill counts. Moreover, adherence was assessed among participants who remained on study medication at each scheduled visit, excluding those who had died or permanently discontinued treatment before that visit. This approach is consistent with the conceptualization of adherence as implementation of the prescribed regimen among participants with ongoing treatment exposure and has been used in large randomized trials.²⁵ Finally, it should be noted that, compared with the general population of Canada, there was an overrepresentation of the Asian population in CoVasc-ICH, likely attributed to the higher risks of ICH and atherosclerotic disease in this population.^26–28

CoVasc-ICH has established the feasibility of testing colchicine after an acute ICH, uncovering high rates of early permanent study drug discontinuation and cardiovascular mortality in this frail patient population. These findings inform the forthcoming international phase III RCT CoVasc-ICH2 (URL: https://www.clinicaltrials.gov; Unique identifier: NCT06587737), testing the long-term use of colchicine to reduce the cardiovascular events and functional disability after an acute ICH by excluding patients with severe ICH, and the ongoing INTERACT 5 (The Fifth Intensive Preventing Secondary Injury in Acute Cerebral Haemorrhage Trial Within ACT-GLOBAL; URL: https://www.clinicaltrials.gov; Unique identifier: NCT06763055), evaluating 6-month colchicine use to improve functional outcomes after an acute ICH.

ARTICLE INFORMATION

Acknowledgments

Dr Katsanos holds a Career Award from the Heart & Stroke Foundation of Canada (HSFC). Dr Yu holds a Canada Research Chair (Tier 2) in data-driven design of stroke systems. Dr Field holds the Sauder Family/Heart and Stroke Professorship of Stroke Research at the University of British Columbia. Dr Gioia holds a Junior 1 Researcher Salary Award from the Fonds de recherche du Québec–Santé (FRQS).

Disclosures

Dr Katsanos reports grants from the Heart and Stroke Foundation of Canada; grants from the Canadian Institutes of Health Research; and compensation from Diamedica, Inc, for consultant services. Dr Ng reports compensation from AbbVie, Inc, for end point review committee services and compensation from Hamilton Health Sciences for other services. Dr Field reports compensation from the Canadian Medical Protective Association for expert witness services; service as a board member for Destine Health; service as a board member for Vancouver General Hospital Foundation; compensation from Boston Scientific Corporation for consultant services; and compensation from Bayer for consultant services. Dr Yu reports grants from Canada Research Chairs; grants from Brain Canada Foundation; grants from the Canadian Institutes of Health Research; and grants from the Heart and Stroke Foundation of Canada. Dr Gioia reports grants from the Fonds de recherche du Québec–Santé; compensation from the Bayer for consultant services; compensation from Servier Pharmaceuticals LLC for consultant services; compensation from Heart and Stroke Foundation of Canada for other services; and grants from AstraZeneca Canada. Dr Dowlatshahi reports grants from the Canadian Institutes of Health Research. Dr Shoamanesh reports grants from Octapharma USA, Inc; grants from Javelin Medical to other; grants from Daiichi Sankyo Company; a patent for the treatment of intracranial hemorrhage; compensation from VarmX for consultant services; grants from the National Institutes of Health; grants from the Canadian Institutes of Health Research; compensation from Bayer for consultant services; compensation from AstraZeneca for consultant services; grants from the Heart and Stroke Foundation of Canada; compensation from Alnylam Pharmaceuticals for data and safety monitoring services; grants from Bayer to other; a patent for methods of preventing symptomatic ischemic stroke; grants from AstraZeneca; employment by McMaster University; grants from the Canadian Institutes of Health Research; compensation from Takeda Pharmaceutical Company for consultant services; compensation from Bayer for data and safety monitoring services; compensation from Daiichi Sankyo Company for consultant services; grants from Bayer; and grants from Servier Affaires Medicales. The other authors report no conflicts.

Supplemental Material

Investigators and Collaborators at Participating Sites

Data Safety Monitoring Board (DSMB)

Adjudication Committee

Tables S1–S8

Figures S1–S6

CONSORT Checklist

Protocol

Funding Statement

CoVasc-ICH (Colchicine for the Prevention of Vascular Events After an Acute Intracerebral Hemorrhage) was funded by the Canadian Institutes of Health Research and the Population Health Research Institute.