Evaluation of Bevacizumab Efficacy and Safety in Patients with Symptomatic Cerebral Arteriovenous Malformations Ineligible for Interventional Therapy

The primary objective of this study is to evaluate the 6-month efficacy of intravenous injections of **bevacizumab** at a dosage of 5 mg/kg every 14 days for a total of 3 months (6 injections) on disabling symptoms in patients with symptomatic **cerebral arteriovenous malformations** who are ineligible for interventional therapy. This is clinically relevant as it aims to provide a therapeutic option for patients who cannot undergo standard interventional treatments, potentially improving their quality of life and managing symptoms effectively.

Secondary objectives include assessing the following between the two arms (bevacizumab and placebo) from baseline (M0) to 6 months (M6):

• Improvement in cognitive impairment
• Improvement in neurological signs
• Improvement in epileptic symptoms
• Headache improvement
• Cerebral hemorrhage rate
• Change in diameter of AVM drainage veins
• Evolution of peri-AVM edema
• Rate of favorable neurological functional prognosis
• Evolution of neurological functional prognosis
• Change in quality of life
• All-cause mortality
• Changes in plasma VEGF levels
• Description of the evolution up to 12 months (M12) in each arm regarding disabling symptoms, neurological functional prognosis, quality of life, cerebral hemorrhage rate, and occurrence of adverse events

The clinical trial focuses on evaluating the efficacy of intravenous injections of **bevacizumab** in patients with symptomatic **cerebral arteriovenous malformations** who are ineligible for interventional therapy. The study population includes both male and female participants over the age of 18, with no specific upper age limit mentioned. Participants are required to have a symptomatic cerebral AVM of Spetzler and Martin grade III, IV, or V, with symptoms severe enough to potentially benefit from treatment. The trial does not involve a vulnerable population. Participants must have normal bone marrow, liver, and kidney function, and women of childbearing potential must have a negative pregnancy test and use effective contraception. The sponsor has not provided information regarding the total number of participants. The selection criteria include fluency in the French language and affiliation with a social security plan. Participants must have disabling symptoms not resulting from a previous bleeding episode and be ineligible for endovascular, neurosurgical, or radiosurgical interventions. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the efficacy and safety of **bevacizumab** in patients with symptomatic **cerebral arteriovenous malformations**. This is a Phase 4, randomized, double-blind, controlled trial. Participants will receive intravenous injections of bevacizumab at a dose of 5 mg/kg every 14 days for a total of 6 injections over a 3-month period. The trial is expected to commence on January 15, 2024, and conclude by January 14, 2027. The primary endpoint is the comparison between the two arms of the proportion of patients showing significant improvement in symptoms at 6 months. Secondary endpoints include various clinical and imaging assessments at 6 and 12 months.

Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit, or screening, will confirm eligibility based on criteria such as age, symptom severity, and ineligibility for other therapeutic interventions. Follow-up visits will occur bi-weekly during the treatment phase to administer the drug and assess safety and efficacy. An end-of-study visit will be conducted at 6 months to evaluate primary and secondary endpoints, with additional assessments at 12 months for long-term outcomes.

Participant involvement is expected to last approximately 12 months, including the treatment and follow-up periods. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or any condition that, in the investigator's opinion, warrants discontinuation for the participant's safety. The trial will adhere to rigorous ethical standards, ensuring informed consent and the protection of participant welfare throughout the study duration.

The clinical trial involves the administration of **Aybintio**, a **bevacizumab**-based medication, which is a **concentrate for solution for infusion**. The pharmaceutical form is a solution for infusion, and it is administered intravenously. The dosage is set at 5 mg/kg, with the treatment being administered every 14 days over a period of 3 months, totaling 6 injections. The maximum daily dose is 1 mg/kg, and the maximum total dose over the treatment period is 6 mg/kg. The product is manufactured by Samsung Bioepis NL B.V. and is authorized under the marketing authorization number EU/1/20/1454/001. The active substance, bevacizumab, is a protein of other origin, classified under the ATC code L01XC07.

In addition to the experimental treatment, the trial utilizes a non-experimental treatment consisting of 100 mL of **NaCl 0.9%**. This solution serves as a placebo and is administered intravenously. The pharmaceutical form and active substance details are not specified beyond its role as a placebo in the trial. The administration of NaCl 0.9% is intended to match the administration schedule of the experimental treatment to ensure blinding and consistency in the trial protocol.

The efficacy of intravenous **bevacizumab** in patients with symptomatic cerebral arteriovenous malformations will be assessed through a series of primary and secondary endpoints. The primary endpoint involves a comparison between two arms of the trial, focusing on the proportion of patients demonstrating significant improvements at 6 months. These improvements are defined as an increase of at least 5 points in the Montreal Cognitive Assessment (MoCA) score, a reduction of at least 4 points in the National Institutes of Health Stroke Scale (NIHSS) score, an improvement of at least one stage in the epilepsy balance score, or a reduction of at least 12 points on the Headache Impact Test (HIT-6) score.

Secondary endpoints will include various measures of symptom improvement and disease progression between baseline (M0) and 6 months (M6). These include changes in MoCA, NIHSS, epilepsy balance, and HIT-6 scores, as well as cerebral hemorrhage diagnosis via MRI, percentage reduction in the diameter of arteriovenous malformation (AVM) drainage veins, and evolution of peri-MAV edema on brain MRI. Additional assessments will involve the modified Rankin score (mRS), EQ-5D-5L score, all-cause mortality, and plasma VEGF concentration. Long-term efficacy will be evaluated at 12 months, with assessments of MoCA, HIT-6, NIHSS, epilepsy balance scores, mRS score, EQ-5D-5L score, and the rate of cerebral hemorrhage and adverse events.