Efficacy of Butylphthalide on Symptomatic Atherosclerotic Stenosis in Middle Cerebral Artery (SICAS)

Efficacy of Butylphthalide on Symptomatic Atherosclerotic Stenosis in Middle Cerebral Artery (SICAS): a Prospective, Randomized, Double-blinded, Placebo-controlled, Multiple-center Trial.

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Ischemic Stroke, Acute; Intracranial Atherosclerosis
• Intervention / Treatment: Drug: Butylphthalide; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 140
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Shihui Xing; Phone Number: +8613602755395; Email: xingshih@mail.sysu.edu.cn
• Study Contact Backup: Name: Jinsheng Zeng; Phone Number: +8613322800657; Email: zengjs@pub.guangzhou.gd.cn

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510080
      • The First Affiliated Hospital, Sun Yat-sen University
      • Contact: Shihui Xing; Phone Number: +8613602755395; Email: xingshih@mail.sysu.edu.cn
      • Contact: Jinsheng Zeng; Phone Number: +8613322800657; Email: zengjs@pub.guangzhou.gd.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Female or male aged 55-75 years;
2. At least one of the following risk factors of atherosclerosis: hypertension, diabetes, hypercholesterolemia, or smoking;
3. Symptomatic atherosclerotic stenosis in middle cerebral artery: large artery atherosclerotic cerebral infarction or TIA within 7 days of onset; 70%-99% stenosis of the responsible middle cerebral artery [M1] confirmed by high-resolution MRI examination (referred to Warfarin-Aspirin Symptomatic Intracranial Disease standard); new-onset infarction confirmed by diffusion weighted imaging (DWI) or TIA symptoms in the territory of the responsible artery supply;
4. NIHSS ≤ 20;
5. mRS ≤ 2 at randomization (pre-morbid historical assessment);
6. Participants understand the purpose of the study and have signed informed consent form.

Exclusion Criteria:

1. Presence of intracranial hemorrhage or other pathological brain diseases;
2. Plan to or have performed intravenous thrombolysis or mechanical thrombectomy therapy;
3. Unable to undergo MRI examination;
4. Use Butylphthalide during onset between randomization;
5. Suspect of cardiac embolism, such as atrial fibrillation, artificial heart valves, endocarditis, etc;
6. Contraindications for the use of clopidogrel or aspirin;
7. Known allergy history of celery or butylphthalide;
8. Severe liver dysfunction (aspartate aminotransferase or alanine transaminase > 2 times normal upper limit) or severe renal dysfunction (creatinine value > 1.5 times normal upper limit), heart failure, asthma, etc;
9. History of intracranial hemorrhage, coagulation disorders, systemic bleeding, thrombocytopenia, or other hematological disorders;
10. Plan to perform other surgical procedures or interventional treatments that may require termination of investigational drug use;
11. Severe non-cerebrovascular diseases with an expected survival time less than 3 months;
12. Actively participating in another drug or device trial;
13. Use any drugs with the same or similar mechanism as Butylphthalide during the follow-up period;
14. Unsuitable for this trial from the opinion of the investigators.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Butylphthalide; 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) for day 11±3 to day 180.	Drug: Butylphthalide; Butylphthalide Sodium Chloride injection for 10±3 days, oral Butylphthalide soft capsules for day 11±3 to day 180.; Other Names: DL-3-n-butylphthalide
Placebo Comparator: Placebo; 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) for day 11±3 to day 180.	Drug: Placebo; Butylphthalide Placebo injection for 10±3 days, oral Butylphthalide Placebo soft capsules for day 11±3 to day 180.; Other Names: Blank

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in stenosis degree in the responsible artery	Intracranial atherosclerosis is evaluated by high-resolution MRI vessel-wall imaging technique.	180 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stroke recurrence	Rate of new-onset ischemic stroke or TIA in the territory of the symptomatic middle cerebral artery within 180 days.	180 days
Change in plaque volumes the responsible artery	Change in plaque volumes in the symptomatic middle cerebral artery at 90 days and 180 days.	90 days, 180 days
Changes in hemorrhage and enhancement volumes of atherosclerotic plaque in the responsible artery	Changes in hemorrhage and enhancement volumes of atherosclerotic plaque in the symptomatic middle cerebral artery at 90 days and 180 days.	90 days, 180 days
Changes in National Institutes of Health Stroke Scale (NIHSS)	National Institutes of Health Stroke Scale (NIHSS, range: 0 - 42) at baseline and discharge.	10±3 days
Proportion of patients with modified Rankin Scale score (mRS) 0-2	Proportion of patients with modified Rankin Scale score (mRS) 0-2 at 90 days and 180 days.	90 days, 180 days
Change in the value of cerebral blood flow (CBF) in the responsible artery territory	Qualitative analysis of regional cerebral blood flow (CBF) in arterial spin labeling sequence in the territory of the symptomatic middle cerebral artery at baseline, 90 days and 180 days.	90 days, 180 days
Change in concentrations of serum lipid profiles	Concentrations of total cholesterol, serum triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol at baseline, discharge, 90 days and 180 days.	10±3 days, 90 days, 180 days

Collaborators and Investigators

• Sponsor: First Affiliated Hospital, Sun Yat-Sen University
• Investigators: Principal Investigator: Jinsheng Zeng, First Affiliated Hospital, Sun Yat-Sen University

Study record dates

Study Major Dates

• Study Start (Estimated): March 15, 2024
• Primary Completion (Estimated): May 31, 2026
• Study Completion (Estimated): August 31, 2026

Study Registration Dates

• First Submitted: March 11, 2024
• First Submitted That Met QC Criteria: March 19, 2024
• First Posted (Actual): March 26, 2024

Study Record Updates

• Last Update Posted (Actual): March 26, 2024
• Last Update Submitted That Met QC Criteria: March 19, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: stroke; middle cerebral artery; atherosclerotic stenosis; dl-3-n-Butylphthalide
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Pathological Conditions, Anatomical; Intracranial Arterial Diseases; Stroke; Ischemic Stroke; Constriction, Pathologic; Atherosclerosis; Intracranial Arteriosclerosis; Physiological Effects of Drugs; Platelet Aggregation Inhibitors; Neuroprotective Agents; Protective Agents; 3-n-butylphthalide
• Other Study ID Numbers: SICAS

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No