EPOCH Trial Tests Cilostazol for Hematoma Clearance After Intracerebral Hemorrhage

A newly published protocol describes EPOCH, a phase 2b randomized trial (NCT06504576) testing whether the antiplatelet and vasodilator drug cilostazol can accelerate hematoma clearance and improve functional recovery after intracerebral hemorrhage (ICH), a condition with no established medical treatment to promote hematoma resorption. The trial design is grounded in preclinical evidence that cilostazol enhances meningeal lymphatic drainage of hematoma from the brain to the deep cervical lymph nodes.¹

EPOCH is a single-center, prospective, randomized, open-label, blinded-endpoint (PROBE) trial being conducted at National Taiwan University Hospital. The study was registered in March 2024, and enrollment began in 2025, with the first participant enrolled on June 16, 2025; recruitment is ongoing.^1,2

ICH carries a mortality rate of 40% in the first month and 45% at 1 year, and more than 80% of patients develop long-term functional dependency. Current management relies mainly on supportive care, including blood pressure control and correction of coagulopathy, while surgical hematoma evacuation has shown benefit only in lobar ICH. “Despite decades of research, therapeutic options to target secondary brain injury and hematoma clearance remain quite limited,” Hsieh, Tsai, and colleagues wrote in the protocol paper.¹

Rationale for cilostazol

Cilostazol is an FDA-approved phosphodiesterase-3 inhibitor already used for intermittent claudication and as secondary prevention after transient ischemic attack or noncardioembolic stroke, where it acts as an antiplatelet and vasodilatory agent by raising intracellular cyclic AMP. In the investigators' own earlier experimental ICH model, cilostazol enhanced meningeal lymphatic function and promoted clearance of hematoma from the brain parenchyma to the deep cervical lymph nodes, providing the mechanistic basis for testing the drug in this trial.

The dose selected for EPOCH, 50 mg orally twice daily, was based on prior preclinical dose-ranging work in a mouse ICH model using doses approximating 0.8, 1.6, and 3.2 mg/kg in human-equivalent terms, in which hematoma resorption increased at higher doses. Preclinical safety testing found that neither pretreatment nor post-treatment with the highest dose increased hematoma size despite cilostazol's antiplatelet activity, supporting selection of the 100-mg daily dose for this trial.

Trial design and population

Eligible participants are adults ages 18 to 80 years with ICH located in the basal ganglia or thalamus, an ICH score of 3 or less, a hematoma volume no greater than 15 mL, and hospital admission within 24 hours of symptom onset. The published abstract lists the eligible age range as 18 to 80 years, though the inclusion criteria table in the same protocol specifies a minimum age of 20 years; that discrepancy is present in the published article itself.

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Exclusion criteria include imaging findings associated with higher bleeding risk, such as a CT angiography spot sign or irregular hematoma border, lobar ICH location, contraindications to cilostazol such as heart failure or recent myocardial infarction, poor blood pressure control, and use of an oral antiplatelet or anticoagulant at the time of ICH.

Eligible participants are randomized 1:1, using a block randomization method with blocks of 4, to receive oral cilostazol 50 mg twice daily from day 2 through day 16 after ICH in addition to standard medical care, or standard medical care alone. The trial is open-label, meaning participants and treating investigators know the treatment assignment, but it uses a PROBE design in which the neurologists or neurosurgeons performing NIHSS and modified Rankin Scale assessments, as well as the neuroradiologists evaluating imaging, are blinded to treatment allocation.

End points and safety oversight

The primary efficacy end point is the absolute change in hematoma volume between day 1 and day 16 after ICH, with the presence of hematoma expansion serving as the primary safety end point. Secondary end points include change in NIHSS score at 16, 30, and 90 days; the proportions of participants achieving modified Rankin Scale scores of 0 to 1 and 0 to 2 at 30 and 90 days; hematoma resorption ratio; perihematomal edema volume; and time to maximal cervical lymph node intensity on dynamic contrast-enhanced MRI, a novel imaging measure of meningeal lymphatic drainage function.

Brain and neck MRI will be performed at day 16 (plus or minus 2 days) to localize the deep cervical lymph nodes and assess drainage kinetics using gadolinium-based contrast, with images analyzed using 3D Slicer software. The trial is designed to enroll an estimated 72 to 108 participants over approximately 3 years, based on regional recruitment feasibility rather than a formal effect-size-driven calculation; the investigators state this sample size would provide approximately 80% power to detect a moderate effect size (Cohen d, 0.55 to 0.65) in the primary end point, using a predefined minimal clinically relevant threshold of a 10% relative reduction in hematoma growth compared with standard care.

An independent data and safety monitoring board will review the trial every 6 months, with recruitment suspension triggered if adverse events or serious adverse events occur in more than 10% of enrolled participants, and immediate trial termination required if a participant death is directly attributable to a serious adverse reaction to cilostazol. "The EPOCH trial holds promise as a pioneering endeavor to explore the potential of cilostazol to promote hematoma clearance and improve the outcomes of participants who have suffered spontaneous ICH," the authors wrote, noting that a positive signal of safety and efficacy would support advancing to a large, multicenter phase 3 randomized trial.¹

REFERENCES
1. Hsieh YC, Tsai LK, Jeng JS, et al. Effect of cilostazol for promoting hematoma clearance after intracerebral hemorrhage: study protocol for a randomized clinical trial. Neurol Open Access. 2026;2:e000143. doi:10.1212/WN9.0000000000000143
2. Cilostazol for hematoma clearance in intracerebral hemorrhage (EPOCH). ClinicalTrials.gov identifier: NCT06504576. Accessed September 16, 2026. https://clinicaltrials.gov/study/NCT06504576