2024 Volume 10 Pages 11-14
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic small vessel disease leading to recurrent strokes and cognitive decline. Stroke prevention is essential in CADASIL patients, since recurrent strokes determine the prognosis. However, there is no proven treatment for stroke prevention in CADASIL, although antiplatelet therapy is commonly used. Previous studies indicated reduced cerebral blood flow and impaired vasoreactivity in CADASIL patients, contributing to disease progression. Lomerizine hydrochloride is a calcium channel blocker approved in Japan for migraine prophylaxis. It has been reported to selectively inhibit cerebral artery contraction, increase cerebral blood flow, and exhibit neuroprotective effects. Therefore, lomerizine is a potential therapeutic agent for CADASIL patients. Preliminary data suggest the efficacy of lomerizine for preventing recurrent strokes in such patients. The LOMCAD trial, a multicenter, prospective, single-arm clinical trial comparing historical controls, designed to evaluate the efficacy of lomerizine to prevent recurrent ischemic events in CADASIL patients with recent histories of cerebral ischemic events, is currently underway. The results of this ongoing study are anticipated.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic cerebral small vessel disease caused by mutation in the NOTCH3 gene1). The typical disease course is characterized by a history of migraine in patients in their 20s to 30s, recurrent subcortical strokes and white matter lesions in the 40s to 50s, eventually leading to gait disturbance, cognitive impairment, and death in the 60s to 70s2,3). In the clinical course, recurrent strokes lead to physical disabilities and cognitive impairment, making it difficult to continue working and necessitating nursing care. This not only represents a marked setback for the affected patients and their families but also constitutes a substantial societal loss. Therefore, stroke prevention is essential in CADASIL patients, since recurrent strokes determine the prognosis. In general, antiplatelet therapy is used to prevent stroke in the presence of cerebral small vessel disease. Therefore, CADASIL patients are also treated with antiplatelet therapy for stroke prevention. However, there is no evidence supporting the efficacy of antiplatelet therapy in CADASIL patients4,5). In fact, most CADASIL patients experience recurrent strokes even on receiving antiplatelet therapy. Furthermore, antiplatelet therapy increases the risk of intracerebral hemorrhage due to the vessel fragility in CADASIL patients. Thus, the development of effective alternative strategies other than antithrombotic drug for stroke prevention in CADASIL patients is urgently needed. In this review, we highlight a potential stroke-preventive effect of lomerizine hydrochloride (lomerizine) in CADASIL patients.
CADASIL arteriopathy is characterized by the loss of vascular smooth muscle cells and thickening of vascular walls, leading to impairment of the vascular function and reduced cerebral blood flow (CBF)3). Several previous studies showed that CADASIL patients exhibited reduced CBF and impaired cerebral vasoreactivity (CVR) in response to carbon dioxide or acetazolamide in white matter even in early disease stages compared with controls6–8). Furthermore, impaired CVR may also be associated with disease progression. Lower CVR at the baseline was associated with a greater increase in white matter hyperintensities9). We also demonstrated that CVR by acetazolamide in the thalamus was significantly lower in CADASIL patients with symptomatic stroke, which implies advanced CADASIL, than in those without symptomatic stroke10). Thus, chronic subcortical ischemia by cerebral hypoperfusion and impaired CVR based on CADASIL arteriopathy may play primary roles in the progression of recurrent subcortical strokes and microstructural alterations leading to cognitive decline. Therefore, an increase of cerebral perfusion by utilizing pharmacological vasodilation may be a potential therapeutic target in CADASIL.
Lomerizine is a calcium channel blocker which can cross the blood brain barrier. In Japan, it has been approved for the prophylaxis of migraine since 1999. It has been reported that lomerizine selectively inhibits cerebral artery contraction and increases CBF without causing systemic hypotension11,12). In addition, previous animal studies showed that it had a neuroprotective effect against experimental ischemia and hypoxia13,14). Therefore, lomerizine may be a promising agent for stroke prevention in CADASIL patients showing reduced CBF and impaired CVR. In 2009, we reported the first case of a 64-year-old female that suggested the efficacy of lomerizine in CADASIL15). During a 2-year lomerizine administration period, she could maintain her cognitive function with an improvement of CBF. Furthermore, she showed no recurrent stroke during those 2 years, although she experienced 2 ischemic events during the 4-month period prior to lomerizine administration. Thereafter, other case reports from Japan also presented CADASIL patients with symptomatic ischemic stroke who experienced no recurrent stroke for a number of years after the initiation of lomerizine, and suggested the efficacy of lomerizine to prevent recurrent stroke in CADASIL patients16–18). Thus, we conducted a pilot study to elucidate the long-term impact of lomerizine on preventing stroke events among CADASIL patients anticipating its potential efficacy19). This was an open-labeled clinical trial involving 30 adult CADASIL patients who were administered lomerizine at a dosage of 10 mg per day. The study assessed the number of symptomatic stroke events over a 2-year period following the initiation of lomerizine treatment, comparing with those observed in the preceding 2 years prior to the intervention. The efficacy of lomerizine to prevent strokes was evaluated based on the incidence rate ratio (IR), which was calculated with the Mantel-Haenszel method. Among the 30 CADASIL patients, 15 patients had a history of symptomatic stroke events at any time before the initiation of lomerizine, and 10 patients experienced symptomatic stroke events in the preceding 2 years prior to the initiation. The study results are shown in Fig. 1. In the analysis of all 30 study patients (Group 1), IR by lomerizine was 0.46 (95% confidence interval [CI], 0.19–1.12), but it did not reach significance. However, lomerizine significantly reduced subsequent symptomatic stroke events in the 15 patients with a history of symptomatic stroke events (Group 2) (IR 0.33 [95%CI: 0.12–0.94]). Especially, lomerizine led to an 83% reduction of recurrent strokes in patients with a history of symptomatic stroke events in the 2 years prior to the initiation of treatment. (Group 3) (IR 0.17 [95%CI, 0.04–0.67]). These results suggested the potential efficacy of lomerizine for secondary stroke prevention in CADASIL patients. Regarding the current status of stroke prevention strategies for CADASIL in Japan, a nationwide survey of 88 CADASIL patients in 2016 revealed that 43% of patients were treated with lomerizine and 75% underwent anti-platelet therapy for stroke prevention20). Thus, it was revealed that lomerizine is widely administered for patients with CADASIL in routine clinical practice in Japan as off-label use.
Given the data suggesting the efficacy of lomerizine, a further interventional trial is warranted to provide supporting evidence for the long-term benefits of lomerizine for stroke prevention in CADASIL patients. However, it is difficult to recruit a sufficient number of participants for a double-blind trial because it is a rare disease21). Therefore, we are currently conducting the LOMCAD trial (jRCTs051220072; https://jrct.niph.go.jp/en-latest-detail/jRCTs051220072), a multicenter, prospective, single-arm clinical trial comparing historical controls, designed to evaluate the efficacy of lomerizine to prevent the recurrence of cerebral ischemic events in CADASIL patients. From the results of our previous pilot study, lomerizine may be more effective in CADASIL patients with recent stroke events, who have a higher risk of recurrent stroke19). Therefore, we enrolled CADASIL patients who had experienced 2 or more cerebral ischemic events within the past two years in the LOMCAD trial. Cerebral ischemic events are defined as symptomatic ischemic stroke, transient ischemic attack, or an asymptomatic acute ischemic lesion detected by diffusion-weighted imaging. Detailed eligibility criteria are shown in Fig. 2. The study treatment is 5-mg lomerizine hydrochloride tablets taken orally twice daily. Concomitant use of a single antithrombotic drug with lomerizine is permitted. The primary endpoint is symptomatic cerebral ischemic events during the 24 months after the start of treatment. The secondary end points are the number of symptomatic cerebral ischemic events, any cerebral ischemic events and changes modified Rankin Scale in during the 24 months after the start of study treatment. For analysis of the primary endpoint and sample size calculation, we use data from historical CADASIL cohorts treated with or without lomerizine in our institute. Regarding our historical data of CADASIL patients who showed 2 or more cerebral ischemic events within the past two years, event-free rates of symptomatic cerebral ischemic events in the following 2 years without lomerizine were 36%, whereas those in the 2 years with lomerizine were 63%. Utilizing these data, Bayesian sample size calculation based on the prior predictive distribution yielded a sample size requirement of 20 cases. We started to enroll study patients in August 2022 and terminated the enrollment at the end of November 2023. Consequently, a total of 24 CADASIL patients were enrolled in the LOMCAD study. We are now following the study patients for the 2 years after the initiation of lomerizine.
Stroke prevention is essential for the prevention of disabilities in CADASIL patients. Lomerizine may be a promising agent for stroke prevention by increasing CBF in white matter and exhibiting a neuroprotective effect. Preliminary data suggest the efficacy of lomerizine to prevent recurrent strokes in CADASIL patients. The LOMCAD trial, a multicenter, prospective, single-arm clinical trial comparing historical controls, designed to evaluate the efficacy of lomerizine to prevent recurrent ischemic events in CADASIL patients with recent histories of cerebral ischemic events, is currently underway. The results of this ongoing study will be unveiled in 2026.
This work was supported by the Japan Agency for Medical Research and Development (AMED) [23lk0201157h0002] under its FY2022 “Project Promoting Clinical Trials for Development of New Drugs”.
The authors have no conflicts of interest.
