The goal of this clinical trial is to determine whether a watchful waiting strategy with imaging surveillance is superior to immediate aneurysm treatment in adults with incidentally discovered unruptured intracranial aneurysms (UIAs). The main questions it aims to answer are: * Does watchful waiting reduce the risk of clinically significant neurological disability compared with immediate treatment? * How do the two strategies compare in terms of aneurysm rupture, treatment-related complications, quality of life, anatomical outcomes, and healthcare costs? Researchers will compare two management strategies: * Immediate selective treatment of the aneurysm (endovascular or neurosurgical treatment according to standard practice). * Watchful waiting with regular clinical and imaging follow-up and no initial aneurysm treatment. Participants will: * Be randomly assigned to either immediate treatment or watchful waiting. * Undergo routine clinical assessments and annual brain imaging for at least 42 months. * Complete quality-of-life questionnaires (EQ-5D-5L) at baseline and annually during follow-up. * Participate in annual telephone follow-up assessments, including evaluation of functional outcome using the modified Rankin Scale (mRS). * Undergo a blood or urine pregnancy test at enrollment if they are women of childbearing potential. The study includes adults aged 35 years or older with incidentally discovered, non-infectious, intradural saccular UIAs measuring between 2.0 mm and 7.9 mm and no history of subarachnoid hemorrhage. The primary objective is to compare the impact of the two management strategies on neurological dependency during follow-up.
Over the past two decades, the development of non-invasive cerebral vascular imaging and the ageing of the Western population have contributed to the diagnosis of an increasing number of fortuitous unruptured intracranial aneurysms (UIAs), of which approximately 80% measure less than 8 mm in diameter. Neuroradiology and neurosurgery teams have long considered that these UIAs should be treated to protect patients from the risk of subarachnoid haemorrhage (SAH). The medical community is currently deeply divided regarding the management of these incidentally discovered lesions, with some teams advocating systematic treatment, while others favor radiological surveillance. This divergence reflects a significant degree of uncertainty, thereby justifying the undertaking of a prospective randomized study comparing treatment strategies with surveillance. The STAF study is designed to evaluate whether a conservative management strategy based on watchful waiting and imaging surveillance is superior to immediate aneurysm treatment with regard to long-term neurological outcomes. The study hypothesis is that patients undergoing immediate aneurysm treatment will experience a higher rate of clinically significant neurological disability than patients managed conservatively. Clinically significant disability is defined as a modified Rankin Scale (mRS) score ≥2 persisting for more than 90 days. STAF is a prospective, national, multicenter, randomized, open-label, parallel-group trial with adjudication of events ("Prospective Randomized Open-label Blinded Endpoint" PROBE study design). Approximately 7 to 10 neuroradiology and neurosurgery centers across France will participate and recrute in the study. This study enrolls adult participants with incidentally discovered UIAs. Following incidental aneurysm detection during routine clinical care, patients will be referred to an interventional neuroradiologist or neurosurgeon. During the screening visit, aneurysm characteristics and eligibility criteria will be assessed, and study information will be provided. Eligible patients will return for an inclusion visit within three months, during which eligibility will be confirmed, written informed consent obtained, and randomization performed. Randomization will be conducted through an Interactive Web Response System (IWRS) using a 1:1 allocation ratio between the two study groups. Randomization will be stratified by participating center, age category (35-55 years versus 56-75 years), and aneurysm size (\<5 mm versus ≥5 mm). Participants randomized to the intervention strategy will undergo selective aneurysm treatment according to standard clinical practice, including either endovascular or neurosurgical treatment as determined by the treating physicians. Participants randomized to the watchful waiting strategy will receive no initial selective aneurysm treatment. All participants will be followed according to routine clinical practice, including annual consultation visits and cerebral imaging performed in accordance with current American Heart Association/American Stroke Association recommendations. To ensure regular assessment of functional status from screening to the end-of-study visit, participants will also be contacted annually by a brief telephone follow-up, scheduled approximately 6 months after their previous on-site visit. All randomized patients will be followed for a minimum of 3,5 years (i.e. 42 months for the last included patients) to a maximum of 6,5 years (i.e. 78 months for the first included patients) with a mean follow-up of 5 years. Because of the prolonged follow-up period and the possibility of clinical events unrelated to aneurysm disease or treatment, all major study outcomes will be independently adjudicated to determine whether they are related or unrelated to aneurysm progression or treatment. The primary objective is to compare the effect of immediate aneurysm treatment versus watchful waiting on neurological dependency during follow-up. Secondary objectives include comparison of subarachnoid hemorrhage rates, evaluation of the safety, assessment of treated aneurysm anatomical outcomes through imaging review and economic evaluation of the two management strategies.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
600
Participants undergo active surveillance of incidentally discovered unruptured intracranial aneurysms without initial preventive treatment. Management includes routine neurological follow-up and brain annual imaging according to routine clinical practice. Imaging consists of a 3D Time-of-Flight Magnetic Resonance Imaging (TOF MRI) sequence (or contrast-free CT (Computed-Tomography) and CT angiography of the circle of Willis in case of contraindications, and catheter angiogram with 3D if needed). Treatment will only be considered in the presence of predefined criteria suggestive of increased aneurysm related risk (e.g., aneurysm growth or clinical deterioration).
Participants undergo immediate preventive treatment of the unruptured intracranial aneurysm according to standard clinical practice. Treatment modalities include endovascular procedures (e.g., coiling, stent-assisted coiling, flow diversion) or neurosurgical clipping, as determined by the treating physician. For patients with multiple aneurysms (≤7.9 mm), the operating investigator chooses at least one aneurysm to treat, while the treatment of any additional aneurysms is at the discretion of the team. Subsequent follow-up is performed according to standard clinical care (radiological follow-up at least annually, using the technique deemed most appropriate by the team). In case of recanalization, the choice and technique for additional treatment are left to the discretion of the team.
Service de Neuroradiologie - Hôpital Lariboisière - APHP Nord
Paris, Île-de-France Region, France
Occurrence of a clinically significant event
The primary outcome is the occurrence of a clinically significant event during follow-up (minimum duration 3.5 years - maximum 6.5 years, mean duration of 5 years). A clinically significant event is defined as the occurrence of a functional disability with a modified Rankin Scale (mRS) score ≥ 2, persisting for more than 90 days, attributable to the natural history of the aneurysm or to its preventive treatment, as adjudicated by an independent committee.
Time frame: From randomization until the occurrence of a mRS score ≥ 2, assessed up to 90 days after occurence by an independent neurologist, blinded to treatment allocation
Distribution of modified Rankin Scale
During follow-up, the mRS score is systematically collected by the investigator at each scheduled study visit and through telephone follow-up ensuring regular assessment of functional status from screening to the end-of-study visit. In order to ensure an independent evaluation of the primary endpoint, predefined mRS assessments will be performed by an independent neurologist, blinded to treatment allocation, at key time points (inclusion or screening visit, at hospital discharge , at the end of the study, and finally in case of functional deterioration identified by the investigator (mRS ≥ 2). The mRS is a widely used scale to measure the degree of disability or dependence in daily activities in patients with neurological or other causes of disability. There are 6 grades of disability from 0 (minimum value i.e. "the patient has no residual symptoms") to 6 (maximum value i.e. "The patient has expired (during the hospital stay or after discharge from the hospital").
Time frame: Through study completion, an average of 5 years
Occurrence of a transient modified Rankin Scale ≥ 3
Occurrence of a transient modified Rankin Scale (mRS) ≥ 3 (disease or treatment-related as judged by an independent committee) during the follow-up period. The mRS is a widely used scale to measure the degree of disability or dependence in daily activities in patients with neurological or other causes of disability. There are 6 grades of disability from 0 (minimum value i.e. "the patient has no residual symptoms") to 6 (maximum value i.e. "The patient has expired (during the hospital stay or after discharge from the hospital"). Grade 3 is for "The patient has moderate disability; requiring some external help but able to walk without the assistance of another individual."
Time frame: Up to the occurrence of a mRS score ≥ 3, assessed by an investigator
SAH occurrence
The rate of subarachnoid haemorrhage (SAH) is evaluated through cerebral imaging in both arms during follow-up.
Time frame: Through study completion, an average of 5 years
Rupture rate
The rupture rate per aneurysm and per year will be calculated in both groups
Time frame: Through study completion, an average of 5 years
Iatrogenic complications
To measure morbidity/mortality of endovascular treatment,all iatrogenic complications will be reviewed by the endpoint adjudication committee to assure quality control on a case-by-case basis. An iatrogenic complication is a treatment-related adverse event following aneurysm intervention, not related to the aneurysm's natural history. Treatment-related mortality or morbidity is defined as any event following endovascular procedure, open surgery, or due to complication of adjunct treatment to endovascular procedure.
Time frame: Through study completion, an average of 5 years
Rate of Unruptured Intracranial Aneurysms-related (UIA) Adverse Events
The rate of novel UIA-related adverse events in both arms during follow-up.
Time frame: Through study completion, an average of 5 years
Classification of treated aneurysms
Classification of treated aneurysms in each study arm according to the Roy-Raymond scale revised in 2020 at the final imaging assessment (centralized Core Lab reading): complete occlusion, neck remnant, residual aneurysm, or neo-pouch formation.
Time frame: through study completion, an average of 5 years
Economic evaluation (cost-utility analysis)
Evaluation of the incremental cost-utility ratio, estimated as the difference in costs divided by the difference in QALYs (Quality-Adjusted Life Years), calculated as the patient-level utility values derived from the Quality of life (EQ5D5L) (at the inclusion visit, during hospitalization, at 9 months, 18 months, 30 months, and 42 months), multiplied by the time intervals, between the two strategies.
Time frame: From inclusion visit until 42 months visit
Economic evaluation (cost-effectiveness analysis)
Evaluation of the incremental cost-effectiveness ratio, estimated as the difference in costs divided by the difference in the rate of 3,5-year adverse events (composite endpoint of mortality and major events) between the two strategies. The cost-effectiveness outcome is measured using the incremental cost-effectiveness ratio (ICER), defined as the difference in the rate of 3,5-year adverse events (composite endpoint of mortality and major events) between the two strategies. Costs include hospitalization, diagnostic tests, medications, outpatient visits, and other healthcare resource utilization collected prospectively during follow-up.
Time frame: From inclusion visit until 42 months visit
Non-aneurysm-related death
Non-aneurysm-related death during follow-up.
Time frame: Through study completion, an average of 5 years
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.