Chronic Subdural Hematoma
Conditions
Keywords
bevacizumab, middle meningeal artery embolization, intra-arterial chemotherapy, VEGF
Brief summary
This is a Phase 1, open-label, single-center, dose-escalation study evaluating the safety and tolerability of intra-arterial bevacizumab (IA-BEV) given as an adjunct to middle meningeal artery embolization (MMAE) in adults with non-surgical chronic subdural hematoma (cSDH). Up to 18 participants who are already scheduled to undergo MMAE as standard of care will receive a single dose of bevacizumab, delivered directly into the middle meningeal artery immediately before embolization, during the same procedure. Three dose levels (2.0, 3.5, and 5.0 mg/kg) will be tested using a standard 3+3 dose-escalation design to identify the maximum tolerated dose. The study will also collect imaging and blood biomarker data to help understand which patients may benefit most from this combined treatment approach.
Detailed description
Chronic subdural hematoma (cSDH) is a common and growing neurological condition, particularly in older adults, and standard surgical treatment carries meaningful perioperative risk. Middle meningeal artery embolization (MMAE) has emerged as an effective standalone or adjunctive treatment, but a meaningful proportion of patients do not achieve adequate hematoma resolution with embolization alone. Vascular endothelial growth factor (VEGF)-driven angiogenesis within the hematoma membrane is believed to underlie continued hematoma growth and treatment failure. Bevacizumab, an anti-VEGF monoclonal antibody, may interrupt this process when delivered directly into the middle meningeal artery at the time of embolization. This study will enroll up to 18 adults undergoing MMAE as standard of care, assigning them to one of three sequential dose cohorts (2.0, 3.5, or 5.0 mg/kg) of intra-arterial bevacizumab using a 3+3 dose-escalation design. The primary objective is to characterize the safety and tolerability of IA-BEV and identify a maximum tolerated dose. Secondary objectives include volumetric hematoma response, functional and neurological outcomes, and clinical event rates through 180 days. Exploratory objectives include correlating treatment response with Nakaguchi radiographic subtype, dual-energy CT membrane imaging biomarkers, and VEGF concentrations sampled from the middle meningeal artery at the time of the procedure.
Interventions
DRUGBevacizumab (intra-arterial)
Single intra-arterial infusion of bevacizumab (reference product or FDA-approved biosimilar) at 2.0, 3.5, or 5.0 mg/kg, delivered via microcatheter into the middle meningeal artery over 5-10 minutes, immediately before MMAE.
Sponsors
Dheeraj Gandhi
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Sequential 3+3 dose-escalation cohorts (not separate arms)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Age 18-85 years * Scheduled to undergo MMAE as standard of care for cSDH, no concurrent surgical evacuation planned (prior surgery for the target cSDH allowed if ≥14 days elapsed) * Radiographically confirmed cSDH meeting specified unilateral/bilateral density criteria * cSDH volume 20-100 cc * Midline shift \<8 mm * Markwalder Grade 1 or 2 * Subject or LAR able to provide written informed consent
Exclusion criteria
* Requires immediate/urgent surgical evacuation * Prior large craniotomy, membranectomy, or MMAE for the current target cSDH * Life expectancy \<1 year * Uncontrolled bleeding disorder (INR \>1.7, aPTT \>35s, platelets \<100,000/μL) * Concurrent intracranial hemorrhage outside the target subdural space * Persistent neurological deficit from another acute/chronic neurological condition * Pregnancy or lactation * Known/suspected intracranial neoplasm or mass lesion * Active alcohol/substance use disorder within 12 months * Baseline mRS ≥3 * Uncontrolled severe hypertension (SBP \>220 or DBP \>120, or IV antihypertensive need within 24h pre-procedure) * Thromboembolic event within 6 months (DVT, PE, TIA, stroke) * Contraindication to VTE prophylaxis * eGFR \<60 mL/min/1.73m² or acute kidney injury at screening * Known hypersensitivity to bevacizumab or its components
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of dose-limiting toxicities | 30 Days of Treatment | Incidence of dose-limiting toxicities probably or definitely related to IA-BEV |
| Incidence of SAE's | 30 Days of Study Treatment | Incidence of dose-limiting toxicities (DLTs) and serious adverse events (SAEs) probably or definitely related to IA-BEV |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of acute neurological worsening | Within 24 hours post-procedure | Incidence of acute neurological worsening (≥2-point NIHSS increase, NIHSS motor sub-score increase, or GCS decline) |
| Volumetric change in cSDH size | 30, 90, and 180 days | Volumetric change in cSDH size on serial neuroimaging |
| Rates of surgical rescue, unplanned hospitalization, neurological death, and all-cause mortality | Through 6 months | — |
| Functional status | 30, 90, and 180 days | As assessed using modified Rankin Scale (mRS) |
| Neurological Status | 30 and 180 days | Neurological deficit is assessed using the National Institutes of Health Stroke Scale (NIHSS), a scale ranging from 0 to 42, with higher scores indicating more severe neurological impairment (worse outcome) |
| Adverse events attributable to the MMAE procedure itself | through study completion, an average of 1 year | — |
| Health-Related Quality of Life | 30, 90, 180 Days | As measured by the 36-Item Short Form Health Survey (SF-36) |
Contacts
CONTACTKaitlyn Henry, MS
CONTACTNajme Hosseini, MD
Outcome results
None listed