Memantine Targeting Neurovascular Dysfunction After Mild and Moderate Traumatic Brain Injury (MEND)

Summary

The goal of this pilot clinical trial is to learn whether memantine can be given safely and successfully to adults in hospital with a mild or moderate traumatic brain injury (TBI). Memantine is approved to treat Alzheimer's disease, but it is not approved to treat TBI. The study will also test whether brain scans and other assessments are suitable for a larger trial. TBI can damage the blood-brain barrier. This protective lining controls what can pass from the bloodstream into the brain. Researchers can measure this damage with a specialized magnetic resonance imaging (MRI) scan using contrast dye. The main questions are: * Can participants start memantine soon after their injury and take it for three months? * How safe and tolerable are daily memantine doses of 20 mg and 30 mg? * Can MRI scans measure changes in the blood-brain barrier from the start of the study to three months? * Can researchers complete the study visits and collect enough information to plan a larger trial? The study will include 45 adults admitted to the Halifax Infirmary in Nova Scotia, Canada, with a non-penetrating mild or moderate TBI. A computer will assign each participant by chance to one of three groups. One group will receive 20 mg of memantine per day. Another group will receive 30 mg per day. The third group will receive usual care without memantine. The memantine dose will increase gradually based on how well each participant tolerates it. Participants will: * Receive usual care, with or without memantine for three months; * Have specialized MRI scans near the start of the study and at three months; * Have recordings of brain activity near the start, at three months, and at six months; and * Complete tests and questionnaires about symptoms, memory, attention, mood, daily function, disability, and quality of life. Researchers will compare the groups to look for differences in blood-brain barrier changes, side effects, and recovery measures. Because this is a small pilot study, it is not designed to prove that memantine improves recovery. Its results will instead help researchers choose a dose, assess safety of drug delivery, and design a larger trial.

Timeline

Start

2027-06

Primary completion

2029-09

Completion

2030-03

Publications

• Background Muradov JH, Reid H, Parker E, Phinney J, Clarke DB, Friedman A, MacLean MA. N-Methyl-D-Aspartate receptor antagonist treatment in traumatic brain injury: a systematic review of the clinical studies. Expert Rev Neurother. 2025 Aug;25(8):991-1006. doi: 10.1080/14737175.2025.2524102. Epub 2025 Jun 29.
• Background MacLean MA, Muradov JH, Greene R, Van Hameren G, Clarke DB, Dreier JP, Okonkwo DO, Friedman A. Memantine inhibits cortical spreading depolarization and improves neurovascular function following repetitive traumatic brain injury. Sci Adv. 2023 Dec 15;9(50):eadj2417. doi: 10.1126/sciadv.adj2417. Epub 2023 Dec 13.
• Background van Hameren G, Aboghazleh R, Parker E, Dreier JP, Kaufer D, Friedman A. From spreading depolarization to blood-brain barrier dysfunction: navigating traumatic brain injury for novel diagnosis and therapy. Nat Rev Neurol. 2024 Jul;20(7):408-425. doi: 10.1038/s41582-024-00973-9. Epub 2024 Jun 17.
• Background Parker E, Aboghazleh R, Mumby G, Veksler R, Ofer J, Newton J, Smith R, Kamintsky L, Jones CMA, O'Keeffe E, Kelly E, Doelle K, Roach I, Yang LT, Moradi P, Lin JM, Gleason AJ, Atkinson C, Bowen C, Brewer KD, Doherty CP, Campbell M, Clarke DB, van Hameren G, Kaufer D, Friedman A. Concussion susceptibility is mediated by spreading depolarization-induced neurovascular dysfunction. Brain. 2022 Jun 30;145(6):2049-2063. doi: 10.1093/brain/awab450.
• Background Veksler R, Vazana U, Serlin Y, Prager O, Ofer J, Shemen N, Fisher AM, Minaeva O, Hua N, Saar-Ashkenazy R, Benou I, Riklin-Raviv T, Parker E, Mumby G, Kamintsky L, Beyea S, Bowen CV, Shelef I, O'Keeffe E, Campbell M, Kaufer D, Goldstein LE, Friedman A. Slow blood-to-brain transport underlies enduring barrier dysfunction in American football players. Brain. 2020 Jun 1;143(6):1826-1842. doi: 10.1093/brain/awaa140.
• Background Reinhart KM, Humphrey A, Brennan KC, Carlson AP, Shuttleworth CW. Memantine Improves Recovery After Spreading Depolarization in Brain Slices and can be Considered for Future Clinical Trials. Neurocrit Care. 2021 Oct;35(Suppl 2):135-145. doi: 10.1007/s12028-021-01351-9. Epub 2021 Oct 17.

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