Efficacy of Butylphthalide on Symptomatic Atherosclerotic Stenosis in Middle Cerebral Artery

Overview

Ischemic stroke with high incidence, mortality, disability and recurrence rate, has become the leading threat to the health worldwide. Intracranial atherosclerotic stenosis (ICAS) is commonly associated with ischemic stroke, especially in Chinese residents. Patients with severe ICAS are subject to a very high risk of recurrent stroke events, despite best medical therapy available. Unstable or complex atherosclerotic plaques can lead to plaque ruptures and distal embolisms, thereby increasing the risk of ischemic stroke recurrence. Studies have shown that activation of inflammatory states may play a driving role in the formation and development of atherosclerosis. So far, it remains unclear which are the best treatments for this condition, especially for high-risk patients. Dl-3-n-butylphthalide (NBP) is a Class I novel drug independently developed in China and was officially approved for use in acute ischemic stroke. Preclinical data showed that NBP can act multiple effects of anti-inflammation, antioxidation and anti-apoptosis by suppressing pro-inflammatory factors and upregulating the expression of anti-inflammatory factors. It is still undetermined whether combined therapy with NBP could enhance the curative effect of intracranial atherosclerosis. The primary purpose of this trial is to evaluate the efficacy of butylphthalide in reducing the degree of arterial stenosis and stabilizing plaques in patients with severe symptomatic middle cerebral artery stenosis.

The SICAS trial is a prospective, randomized, double-blinded, placebo- controlled, multiple-center trial to evaluate the efficacy of butylphthalide in the reduction of symptomatic atherosclerotic stenosis of middle cerebral artery in acute ischemic stroke patients. A total of approximately 140 patients within 7 days of symptom onset of acute ischemic stroke or transient ischemic attack (TIA) will be enrolled. The participants fulfilling the inclusion criteria will be randomized 1:1 into two groups: 1) the Butylphthalide group will receive Butylphthalide Sodium Chloride injection (100ml, twice/day) for the initial 10±3 days, followed by oral Butylphthalide soft capsules (0.2g, triple/day) from day 11±3 to day 180. 2) the Placebo group will receive Butylphthalide Placebo injection (100ml, twice/day) for the initial 10±3 days, followed by oral Butylphthalide Placebo soft capsules (0.2g, triple/day) from day 11±3 to day 180. The study consists of four visits including the day of randomization, day 10±3 when the injection therapy is done, and 90 and 180 days when the oral therapy is finished. The primary end point is the change in degree of atherosclerotic stenosis in the symptomatic middle cerebral artery at 180 days. The atherosclerotic stenosis is evaluated by high-resolution MRI vessel-wall imaging technique. The second end point are rate of recurrence of ischemic stroke or TIA in the qualifying artery within 180 days, the changes in plaque volumes, hemorrhage and enhancement volumes of atherosclerotic plaque in the symptomatic middle cerebral artery, National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), change in cerebral perfusion and concentrations of serum lipid profiles within 180 days.