Atorvastatin Pretreatment in Cerebrovascular Events (APICES) After Flow Diverter Implantation: Protocol of a Multicenter, Randomized, Double-blind, Placebo-controlled Clinical Trial
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 发起方
- 入组人数
- 354
- 试验地点
- 1
- 主要终点
- Efficacy endopoint
研究概览
简要总结
APICES trial is an investigator-initiated, multicenter, multicenter, randomized, double-blind, placebo-controlled clinical trial that plans to enroll 396 patients with a 1-year follow-up, including a neurovascular imaging examination [digital subtraction angiography (DSA), CT angiography (CTA) or magnetic resonance angiography (MRA)] at 6 months after index treatment. It was designed in compliance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. The study was approved by the Ethics Committee of Zhujiang Hospital of South Medical University (2024-KY-032-02) and registered at ClinicalTrials.gov (NCT06308952). The participants will be recruited from twelve advanced stroke centers in China.
详细描述
Aneurysmal subarachnoid hemorrhage (aSAH) is a disastrous subtype of stroke, which is associated with high mortality and morbidity. With the advancement of endovascular techniques, flow diverter (FD) devices have emerged as a preventive treatment for unruptured intracranial aneurysms (UIAs). Although a series of studies have demonstrated that FDs can achieve high rates of aneurysmal occlusion, the safety of FDs remains a concern, with a non-negligible risk of complications (5%-12%). Furthermore, previously published studies have also confirmed that FDs have a significantly higher rate of in-stent stenosis (ISS) compared with conventional stents, which remains a clinical issue requiring attention and resolution. However, there are currently no guideline recommendations or clinical evidence available on how to prevent complications in patients with IA after undergoing FD implantation, apart from conventional dual antiplatelet therapy.
Elevated low-density lipoprotein cholesterol (LDLC) levels increase the risk of vascular events. Lipid-lowing treatment with β-Hydroxy β-methylglutaryl-CoA reductase inhibitors (such as statins) is a cornerstone in avoiding such events. Several studies indicate that the advantages of statins could surpass their traditional role in lowering cholesterol levels, encompassing a range of additional benefits known as pleiotropic effects. Those multiple effects include anti-inflammatory function, vasodilation, anticoagulation, platelet inhibition, and antioxidants. Although the clinical benefit of statin pretreatment has been clarified in carotid artery stenting, percutaneous coronary intervention, and abdominal aortic aneurysm repair, its effect on endovascular treatment of UIAs remains unclear.
Due to the pleiotropic benefits beyond lipid lowering, the effect of statin pretreatment may theoretically contribute to the reduction of cerebrovascular events after FD implantation. Nevertheless, there is currently a lack of high-quality clinical evidence supporting this hypothesis. Thus, we designed the atorvastatin pretreatment in cerebrovascular events (APICES) randomized controlled trial (RCT) to explore whether statin pretreatment is superior to placebo in patients undergoing FD treatment for UIAs.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
The subject numbers and corresponding medication numbers are permanently identified and unique for each successfully randomized patient. If any patients who have been successfully randomized do not receive the trial medication or cannot be reassigned to others, their medication and medication numbers will be invalidated by the medication administrator. To ensure blinding during the trial execution, unblinded personnel responsible for administering and configuring the trial drug must sign a confidentiality agreement.
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Aged 18 to 75 years old, male or non-pregnant female;
- •UIA diagnosed by CTA, MRA, or DSA;
- •Maximal aneurysmal diameter between 3 and 25mm;
- •Understands the nature of the procedure and provision of written informed consent;
- •Indications for FD implantation with or without adjunctive coiling;
- •Is willing to return to the investigational site for follow-up according to our protocol.
排除标准
- •Patients will be excluded if they meet any of the following criteria:
- •Contraindications to atorvastatin treatment or known allergy to atorvastatin;
- •Pregnancy or lactation;
- •Presence of other vascular lesions (coronary artery disease, abdominal aortic aneurysm, intracranial atherosclerotic stenosis, arteriovenous malformation, dural arteriovenous fistula, Moyamoya disease, etc.);
- •Prolonged statin therapy (≥30 days) or prior indications for atorvastatin therapy according to the Chinese guidelines for lipid management (2023) 21;
- •Ruptured aneurysms or target aneurysm received previous operative or endovascular treatment;
- •Patient currently using drugs that interact with atorvastatin metabolism (including transporter inhibitors, cyclosporine, protease inhibitors, other lipid-lowering medications (such as fibrates, ezetimibe, pcsk9 inhibitor, etc.), antacids, erythromycin, cytochrome P450 enzyme, colchicine, etc.);
- •Patients diagnosed with multiple intracranial aneurysms who require treatment for two or more intracranial aneurysms within a one-year period;
- •The target aneurysm is non-saccular (dissecting, fusiform, pseudo, infectious, etc.)
- •Other situations that the researcher deems unsuitable for inclusion in the study (inability to receive anti-platelet or anticoagulant medication; allergy or contraindication for the use of FD alloy, history of life-threatening allergy to contrast dye, ect).
- •Patient was determined that intravenous general anesthesia or general anesthesia with tracheal intubation could not be tolerated.
- •Unwilling to be followed up or likely to have poor treatment compliance at initial screening;
- •Life expectancy less than 3 years;
- •Severe neurological deficit that renders the patient unable to live independently (modified Rankin score ≥4);
- •Enrollment in another trial.
- •Withdrawal criteria
- •In this trial, participants who have provided written informed consent but are unable to complete the entire study for any reason will be withdrawn. These circumstances include the following:
- •The participants voluntarily quit the trial for various reasons;
- •Occurrence of serious adverse events (SAEs). The study may be terminated by the participants, principal investigators, ethics committee, sponsor, or regulatory authorities based on ethical considerations;
- •Early termination of the process based on the investigator's judgment in order to prevent development of severe complications;
- •Significant deviation in implementation, or the subject failed to comply with the scheduled protocol;
- •Miss the follow-up due to changes in working/living places, or fortuitous accident (traffic accident, bone fracture, accidental death, ect.). Thus, close follow-up should be conducted to determine their relationship with the usage of FD and experimental drug;
- •Flawed or absence of informed consents.
研究组 & 干预措施
Control group
placebo (composed mainly of starch, Frontage Pharma, Jiangsu, China) 20mg orally once daily for 180 days
干预措施: Atorvastatin 20mg (Drug)
Experimental group
atorvastatin (Pfizer, New York, USA) 20mg orally once daily for 180 days
干预措施: Atorvastatin 20mg (Drug)
结局指标
主要结局
Efficacy endopoint
时间窗: 1 year
Patients without new-onset cerebrovascular events within 12 months: 1. Any documented stroke (clinical and imaging): hemorrhage stroke (any intracranial hemorrhage subtype confirmed by CT scan) or ischemic stroke (neurological dysfunction more than 24 hours after onset or new acute cerebral infarction lesion confirmed by imaging); 2. the incidence of significant in-stent stenosis (a narrowing of the FD diameter exceeding 50% without pre-existing significant artery stenosis detected by 12-month angiographic follow-up).
次要结局
- Safety endpoint(1 year)
研究者
Duan Chuanzhi
Professor
Zhujiang Hospital