Effect of Lomerizine Hydrochloride on Preventing Recurrence of Cerebral Ischemic Events in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (LOMCAD)

Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebral small vessel disease caused by mutations in NOTCH3. CADASIL patients experienced recurrent strokes in middle age, resulting in development of dementia. To prevent disease progression, avoidance of recurrent subcortical stroke is crucial in managing CADASIL. However, CADASIL is resistant to antiplatelet therapy used in stroke prevention and no effective treatment strategies have yet to be established.Lomerizine hydrochloride is a calcium channel blocker that selectively inhibits cerebral vasoconstriction and is approved for prevention of migraine in Japan. We reported a CADASIL case in which cognitive impairment and cerebral hypoperfusion improved during lomerizine administration1). Furthermore, we demonstrated that lomerizine may provide significant benefits in stroke prevention in a single center observational study of 30 CADASIL subjects, particularly in those who have had ischemic stroke in the 2 years prior to taking the drug2).We are currently conducting the LOMCAD trial (jRCTs051220072), a multicenter, prospective, single-arm clinical trial designed to evaluate the efficacy of lomerizine in preventing recurrent ischemic events in CADASIL subjects who had at least two cerebral ischemic events within the past two years, compared to historical controls. The target number of enrolled cases is 20 (single group) and the enrollment period is from August 2022 to November 2023. The study treatment period is 24 months. The primary endpoint is symptomatic cerebral ischemic events during the 24 months after the start of study treatment. Secondary endpoints are ① Number of symptomatic cerebral ischemic events, ② All cerebral ischemic events, ③Changes in modified Rankin.Our previous observational study showed that of the subjects who had 2 episodes of symptomatic cerebral infarction, transient ischemic attack, or asymptomatic acute ischemic foci during the 2 years without lomerizine hydrochloride, symptomatic cerebral ischemic events were observed in the 64%. In the analysis the prior distribution was set to Beta (2.5, 1.5). In this clinical study, a Bayesian sample size design based on a prior predictive distribution was used. Seventeen cases are needed to achieve a probability of effectiveness if the treatment is determined as effective.