Steroid Avoidance, Dexamethasone, and RAGE Inhibition for Perioperative Cerebral Edema Management in High-Grade Gliomas

The purpose of this study is to learn whether two alternatives to standard steroid treatment can safely control swelling around a brain tumor after surgery. The study will compare three approaches by placing participants in one of three study groups: standard dexamethasone (a steroid), no routine steroid treatment, and azeliragon, a study drug that may reduce brain swelling through a different pathway. Researchers want to determine whether these alternatives can control swelling while reducing some of the side effects associated with steroid use. Participants in this study will be randomly assigned to one of three study groups. Participants will undergo their planned brain tumor surgery and receive the treatment assigned to their group. Study procedures are the same as their routine care and include physical and neurological examinations, blood tests, MRI scans, review of medical records, and collection of tumor tissue removed during surgery (optional). Most study visits will occur during routine medical care. Participants will be followed for approximately 24 months after surgery.

Inclusion Criteria: Age ≥18 years at the time of screening * Newly diagnosed supratentorial tumor with imaging characteristics consistent with high-grade glioma * Candidate for craniotomy with planned resection of more than 50% of the contrast-enhancing tumor * Midline shift ≤10 mm on preoperative imaging * Limited pre-enrollment corticosteroid exposure (≤10 mg dexamethasone total and no chronic steroid use within 30 days) * Karnofsky Performance Status ≥60 * Adequate organ function to undergo surgery and postoperative care as determined by the investigator * Ability to provide informed consent and comply with study procedures * Agreement to use effective contraception, when applicable Exclusion Criteria: * Participants meeting any of the following will be excluded: * Imaging or clinical features highly suggestive of primary CNS lymphoma or metastatic disease * Posterior fossa tumors or lesions associated with high risk of brainstem compression * Leptomeningeal or widely disseminated disease * Clinical conditions requiring immediate corticosteroid therapy * Prior exposure to high-dose corticosteroids (\>10 mg dexamethasone) or chronic steroid use within 30 days * Active systemic illness that increases surgical risk, including uncontrolled infection, coagulopathy, or severe cardiopulmonary disease * Pregnancy or breastfeeding * Known immunodeficiency or chronic infection requiring immunosuppressive therapy * Use of investigational agents within 30 days or concurrent use of immunosuppressive medications not permitted by protocol * Known hypersensitivity to azeliragon * Inability to undergo MRI due to contraindications such as incompatible implants or severe claustrophobia * Life expectancy less than 3 months as determined by the investigator * Participation in another interventional clinical trial prior to initiation of standard adjuvant therapy Vulnerable Populations: This study will not enroll children, pregnant or breastfeeding individuals, or prisoners. Individuals with impaired decision-making capacity may be enrolled only when a legally authorized representative is available to provide consent in accordance with institutional and regulatory requirements.