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

A Randomized Trial of 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.

Study Overview

• Status: Not yet recruiting
• Conditions: High-grade Gliomas (HGG)
• Intervention / Treatment: Drug: Dexamethasone; Drug: Azeliragon

Detailed Description

This study is a randomized Phase II trial because it is designed to evaluate the preliminary efficacy, safety, and feasibility of steroid avoidance and azeliragon as alternatives to dexamethasone for perioperative cerebral edema management in high-grade glioma. The trial uses an intermediate imaging-based efficacy endpoint, enrolls a modest sample size, and is intended to identify promising strategies for subsequent confirmation in a definitive Phase III study.

The trial compares three perioperative strategies-standard dexamethasone, complete steroid avoidance, and RAGE inhibition with azeliragon-to determine their relative safety and effectiveness in controlling cerebral edema following tumor resection. In addition to edema control, the study evaluates clinical, functional, and immunologic outcomes associated with perioperative corticosteroid exposure.

Despite widespread use, dexamethasone lacks prospective evidence defining its optimal perioperative role in glioma patients. This study addresses that gap by rigorously evaluating steroid avoidance and a mechanistically targeted alternative, with the goal of improving patient outcomes while minimizing treatment-related toxicity.

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Akshitkumar M Mistry, MD; Phone Number: 502-276-5030; Email: a.mistry@uoflhealth.org
• Study Contact Backup: Name: UofL Health Brown Cancer Center; Phone Number: 502-562-4370

Study Locations

• United States
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • UofL Health Brown Cancer Center; University of Louisville Hospital
      • Contact: UofL Health Brown Cancer Center; Phone Number: 502-562-4370
    • Louisville, Kentucky, United States, 40202
      • UofL Health Jewish Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Dexamethasone Arm; Standard dexamethasone (steroid) treatment	Drug: Dexamethasone; Potent FDA-approved corticosteroid
No Intervention: No-dexamethasone Arm; No routine dexamethasone treatment
Experimental: Azeliragon Arm; Azeliragon administered for the treatment of brain cancer and to evaluate its capability to control brain swelling around the time of surgery.	Drug: Azeliragon; orally bioavailable inhibitor of the receptor for advanced glycation endproducts (RAGE)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
change in peritumoral edema between the preoperative and postoperative period	The primary outcome is the change in peritumoral edema between the preoperative and postoperative period. Specifically, it is the ratio of postoperative to preoperative peritumoral edema volume, adjusted for extent of enhancing tumor removed. This outcome is derived from MRI-based volumetric assessment and reflects the effectiveness of each perioperative strategy in controlling cerebral edema while accounting for surgical factors	before the start of adjuvant chemo radiation (up to 6 weeks)

Collaborators and Investigators

• Sponsor: Akshitkumar MIstry
• Collaborators: James Graham Brown Cancer Center; Cantex Pharmaceuticals Inc.
• Investigators: Principal Investigator: Akshitkumar M Mistry, MD, UofL Health - Brown Cancer Center

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2026
• Primary Completion (Estimated): August 1, 2029
• Study Completion (Estimated): August 1, 2029

Study Registration Dates

• First Submitted: June 30, 2026
• First Submitted That Met QC Criteria: July 6, 2026
• First Posted (Actual): July 9, 2026

Study Record Updates

• Last Update Posted (Actual): July 9, 2026
• Last Update Submitted That Met QC Criteria: July 6, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Polycyclic Compounds; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Steroids, Fluorinated; Pregnadienetriols; Dexamethasone; azeliragon
• Other Study ID Numbers: ROID-RAGE-HGG

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: name, address, date of birth, medical history, and other information from your medical records from UofL Health and other institutions involved with this research, as well as from your other healthcare providers (which may include information about HIV status, drug, alcohol or sexually transmitted disease treatment, genetic test results, or mental health treatment)
• IPD Sharing Time Frame: Identifiable information will be maintained only as long as necessary for research, regulatory, legal, and record-retention purposes. Until all study activities have been completed.
• IPD Sharing Access Criteria: Those who provide funding to the study, outside providers, study safety monitors, government agencies, other sites in the study, data managers, and other agents and contractors used by the study team. Information may also be shared as required by law (for example, to collect or receive information for reporting child abuse or neglect, preventing or controlling disease, injury, or disability, and conducting public health surveillance, investigations or interventions.)
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No