Clinical trial NCT04192955: Evaluating Oral Peri-operative Acetylsalicylic Acid in Subjects Undergoing Endovascular Coiling-only of Unruptured Brain Aneurysms
Official title: Evaluating Oral Peri-operative Acetylsalicylic Acid in Subjects Undergoing Endovascular Coiling-only of Unruptured Brain Aneurysms(EVOLVE): A Phase 3 Multicenter Randomized Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Unruptured Cerebral Aneurysm
Lead sponsor: University of Calgary
Sponsor class: OTHER
First posted: 2019-12-10
Enrollment: 440
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: This trial is a is a prospective, randomized (1:1) placebo-controlled, clinical trial with blinded endpoint assessment of 440 participants with unruptured brain aneurysm planned for endovascular treatment using coiling-only approach (primary coiling or using balloon-assistance but not stenting) to test if oral acetylsalicylic acid (325 mg/ day for a total of 5 days) is superior placebo in preventing clinical and silent strokes. The primary outcome is a clinical or silent stroke at the time of discharge assessed by clinical examination and MRI brain. Participants will return to the clinic or be contacted by phone for the end of study procedures on Day 90 to collect functional outcome data.

Detailed description: Endovascular aneurysm treatment has become the mainstay of treatment of unruptured brain aneurysms. Since the introduction of Guglielmi detachable coils in the late 1980s, thousands of procedures are performed annually worldwide. The expanding endovascular armamentarium with the use of balloon-assisted coiling, stents (either in stent-assisted coiling or flow-diversion), and unassisted coiling-only procedures made it possible to treat aneurysms of almost all intracranial locations, shapes, and sizes.

Thromboembolic complications are potential adverse events whenever catheters are introduced into the intracranial arteries. Diagnostic and interventional neurological procedures, such as diagnostic and therapeutic cerebral angiograms may lead to ischemic strokes of varying frequency and severity. Luckily, most of the thromboembolic events do not cause a clinical stroke. Instead, tiny infarction signals are seen on Diffusion-weighted magnetic resonance imaging (DWI MRI) of the brain without neurological signs or symptoms. These are often labelled as silent (or covert) strokes. These imaging surrogates have been used to compare the safety and efficacy of various endovascular procedures and techniques. In a Canadian cohort, heparin bolus during aneurysm coiling was associated with significantly less DWI load on post-coiling MRI. This supports the notion that most of these lesions are caused by thrombi, as opposed to bubbles.

There is limited direction from available guidelines regarding the use of anticoagulation or antiplatelet agents to prevent thromboembolic complications associated with endovascular treatment of brain aneurysms. This resulted in huge variability of the protocols used for anticoagulation and antiplatelet therapies before, during and after coil embolization of brain aneurysms. Most of the current practices are extrapolated from coronary literature.

Platelet inhibition is an effective strategy to minimize the rate of thromboembolism. Antiplatelet treatment has been routinely used before coronary angioplasty to reduce the risk of thromboembolic events. The different action of ASA from that of anticoagulants gives it an additive effect to heparin alone in neuro-interventional procedures. This notion is supported by observations from multiple retrospective and prospective studies.

We will perform a prospective, randomized (1:1) placebo-controlled, clinical trial with blinded endpoint assessment of 440 participants with unruptured brain aneurysm planned for endovascular treatment using coiling-only approach (primary coiling or using balloon-assistance but not stenting) to test if oral acetylsalicylic acid (325 mg/ day for a total of 5 days: 3 days prior and two days after and including the coiling procedure day) is superior placebo in preventing clinical and silent strokes. The primary outcome is a clinical or silent stroke at the time of discharge assessed by clinical examination and MRI brain.

Eligibility criteria: Inclusion Criteria:

* Unruptured intracranial aneurysm suitable for coiling-only (primary coiling or balloon-assisted) as a primary treatment.
* Functionally independent at baseline (modified Rankin scale \<3).
* Informed consent and availability of the subject for the entire study period.

Exclusion Criteria:

1. Planned complex aneurysm treatment including use of any device that requires post-operative antiplatelet therapy (stent-assisted coiling or flow-diverter device), or endovascular vessel sacrifice.
2. Dissecting or mycotic brain aneurysm.
3. Any ongoing ischemic symptoms such as transient ischemic attacks, minor strokes, or stroke-in-evolution within 2 weeks before randomization.
4. Allergy or contraindication to ASA.
5. Unable to take study drug orally for any reason.
6. Subjects already taking single or dual antiplatelet, warfarin, or any of the non-Vitamin K antagonist oral anticoagulants.
7. Subjects unable to undergo MRI imaging for any reason (e.g., severe claustrophobia or presence of metals).
8. Any other medical condition that the site investigator deems would put the subject at excessive risk by participation in the study (e.g. active bleeding, symptomatic peptic ulcer disease, liver or kidney failure, thrombocytopenia or coagulopathy) or an expected life expectancy less than one year, or that would result in an inability to collect radiological outcomes and clinical outcomes at 90 days.
9. Pregnancy or breastfeeding.
10. Prior enrollment in EVOLVE trial for another aneurysm.
11. Participation in another clinical trial of an investigational drug, device or procedure if the subject received the trial drug, device or procedure in the preceding 30 days from the anticipated coiling date.

Primary outcomes:
measure: Clinical or silent stroke
timeFrame: within 2-4 days of completion of the coiling procedure
Secondary outcomes:
measure: Symptomatic stroke
timeFrame: Day 90 following coiling.
measure: Death rate
timeFrame: within 90 days following coiling
measure: Peri-operative hemorrhagic complication
timeFrame: within 90 days following coiling
measure: Count of new DWI lesions on post-coiling MRI
timeFrame: within 2-4 days of completion of the coiling procedure
measure: Total volume of new DWI lesions on post-coiling MRI
timeFrame: within 2-4 days of completion of the coiling procedure
measure: Frequency of large (> 10 cc volume) strokes on DWI MRI
timeFrame: within 2-4 days of completion of the coiling procedure
measure: Incidence of cognitive decline on Montreal Cognitive Assessment (MoCA) from baseline to discharge.
timeFrame: within 2-4 days of completion of the coiling procedure
measure: Incidence of visible thrombus formation during the coiling procedure
timeFrame: During the procedure
Other outcomes:
Locations:
city: Calgary
country: Canada
facility: Foothills Medical Center
state: Alberta
city: Edmonton
country: Canada
facility: U of Alberta
state: Alberta
city: Halifax
country: Canada
facility: Dalhousie University
state: Nova Scotia
city: Hamilton
country: Canada
facility: McMaster University
state: Ontario
city: Toronto
country: Canada
facility: Toronto St Michael's Hospital
state: Ontario
city: Toronto
country: Canada
facility: Toronto Western Hospital
state: Ontario
city: Montréal
country: Canada
facility: McGill University
state: Quebec
city: Saskatoon
country: Canada
facility: University of Saskatchewan
state: Saskatchewan
city: Tours
country: France
facility: Centre Hospitalier Régional Universitaire de Tours
state: Centre-Val De Loire
Study officials:
affiliation: University of Calgary
name: Mohammed A Almekhlafi, MD MSc FRCPC
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Calgary
name: Mayank Goyal, MD PhD FRCPC
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Calgary
name: Linda Andersen, PhD
role: STUDY_DIRECTOR
affiliation: University of Calgary
name: Craig Doram, PEng
role: STUDY_DIRECTOR
References: