Clinical trial NCT06308952: Atorvastatin Pretreatment in Cerebrovascular Events (APICES) After Flow Diverter Implantation
Official title: Atorvastatin Pretreatment in Cerebrovascular Events (APICES) After Flow Diverter Implantation: Protocol of a Multicenter, Randomized, Double-blind, Placebo-controlled Clinical Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Cerebrovascular Event
Stent Stenosis
Ischemic Stroke
Hemorrhagic Stroke
Stent Thrombosis
Death, Brain
Endothelial Dysfunction
Keywords: Atorvastatin
Intracranial aneurysm
Flow-diverter devices
Stroke
Lead sponsor: Zhujiang Hospital
Sponsor class: OTHER
First posted: 2024-03-13
Enrollment: 364
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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. Investigators, other blinded investigators, subjects, and sponsors will not have access to any information regarding group assignment or related documents pertaining to the trial drug.
Primary purpose: PREVENTION

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion criteria:

1. Aged 18 to 75 years old, male or non-pregnant female;
2. UIA diagnosed by CTA, MRA, or DSA;
3. Maximal aneurysmal diameter between 3 and 25mm;
4. Understands the nature of the procedure and provision of written informed consent;
5. Indications for FD implantation with or without adjunctive coiling;
6. Is willing to return to the investigational site for follow-up according to our protocol.

Exclusion criteria:

Patients will be excluded if they meet any of the following criteria:

1. Contraindications to atorvastatin treatment or known allergy to atorvastatin;
2. Pregnancy or lactation;
3. Presence of other vascular lesions (coronary artery disease, abdominal aortic aneurysm, intracranial atherosclerotic stenosis, arteriovenous malformation, dural arteriovenous fistula, Moyamoya disease, etc.);
4. Prolonged statin therapy (≥30 days) or prior indications for atorvastatin therapy according to the Chinese guidelines for lipid management (2023) 21;
5. Ruptured aneurysms or target aneurysm received previous operative or endovascular treatment;
6. 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.);
7. Patients diagnosed with multiple intracranial aneurysms who require treatment for two or more intracranial aneurysms within a one-year period;
8. The target aneurysm is non-saccular (dissecting, fusiform, pseudo, infectious, etc.)
9. 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).
10. Patient was determined that intravenous general anesthesia or general anesthesia with tracheal intubation could not be tolerated.
11. Unwilling to be followed up or likely to have poor treatment compliance at initial screening;
12. Life expectancy less than 3 years;
13. Severe neurological deficit that renders the patient unable to live independently (modified Rankin score ≥4);
14. 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:

1. The participants voluntarily quit the trial for various reasons;
2. 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;
3. Early termination of the process based on the investigator's judgment in order to prevent development of severe complications;
4. Significant deviation in implementation, or the subject failed to comply with the scheduled protocol;
5. 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;
6. Flawed or absence of informed consents.

Primary outcomes:
measure: Efficacy endopoint
timeFrame: 1 year
Secondary outcomes:
measure: Safety endpoint
timeFrame: 1 year
Other outcomes:
Locations:
city: Guangzhou
country: China
facility: Zhujiang Hospital of Southern Medical University
state: Guangdong
Study officials:
affiliation: Southern Medical University, China
name: Chuanzhi Duan, MD
role: STUDY_DIRECTOR
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