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

NCT07867210 | Not Yet Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: MEND-TBI-2026
• Study Type: interventional
• Target: 45
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Traumatic Brain Injury; Mild Traumatic Brain Injury; Moderate Traumatic Brain Injury (TBI); TBI

Keywords

TBI; Traumatic Brain Injury; Blood-Brain Barrier; Neurovascular; Memantine; DCE-MRI; Dynamic Contrast-Enhanced MRI; NMDA- Receptor

Outcome Measures

Primary Outcomes (1)

• Number of Participants Randomized

  The total number of participants randomized during the recruitment period. The prespecified feasibility target is 45 participants randomized within 24 months.

  From study opening through 24 months

Other Outcomes (10)

• Recruitment Rate

  From study opening through 24 months

• Proportion of Eligible Participants Randomized

  From study opening through completion of the 24-month recruitment period

• Participant Retention at the 3-Month Visit

  3 months after randomization

Study Arms (3)

Memantine 20mg/day

ACTIVE COMPARATOR

Participants assigned to this arm will receive usual clinical care plus memantine for three months. Memantine will start at 5 mg once daily and increase no more frequently than once per week, as tolerated, to 5 mg twice daily, then 10 mg in the morning and 5 mg in the evening, and finally the target dose of 10 mg twice daily (20 mg/day). Participants who cannot tolerate a dose increase may remain at the highest tolerated dose or have the study drug temporarily reduced, interrupted, or discontinued according to the study's safety procedures. Memantine will be taken orally or, when already clinically indicated, administered through a nasogastric or orogastric tube.

Drug: Memantine

Memantine 30mg/day

ACTIVE COMPARATOR

Participants assigned to this arm will receive usual clinical care plus memantine for three months. Memantine will start at 5 mg once daily and increase no more frequently than once per week, as tolerated, to 5 mg twice daily, then 10 mg in the morning and 5 mg in the evening, 10 mg twice daily, 15 mg in the morning and 10 mg in the evening, and finally the target dose of 15 mg twice daily (30 mg/day). Participants who cannot tolerate a dose increase may remain at the highest tolerated dose or have the study drug temporarily reduced, interrupted, or discontinued according to the study's safety procedures. Memantine will be taken orally or, when already clinically indicated, administered through a nasogastric or orogastric tube.

Drug: Memantine

Usual Clinical Care Without Study Drug

NO INTERVENTION

Participants assigned to this arm will receive usual clinical care for traumatic brain injury. They will not receive memantine, placebo, or another study drug. Participants will complete the same scheduled study assessments and follow-up as participants in the memantine arms.

Interventions

Memantine DRUG

Memantine is a low-to-moderate affinity, non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. It is approved for the symptomatic treatment of moderate to severe Alzheimer's disease but is not approved for the treatment of traumatic brain injury. By limiting excessive NMDA receptor activity, memantine may reduce processes associated with cortical spreading depolarization and blood-brain barrier dysfunction after traumatic brain injury (as has been evidenced in animal models).

Memantine 20mg/day; Memantine 30mg/day

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18 or older
• Acute non-penetrating TBI requiring hospital admission
• Admission GCS 9-15
• Injury within 24 hours of presentation
• Enrolment within 72 hours of admissions
• Ability to undergo dynamic contrast-enhanced MRI
• Participant or Legally Authorized Representative consent

You may not qualify if:

• Currently pregnant or currently breastfeeding
• Current incarceration or custody
• Continuous use of an NMDA-R antagonist for at least 30 days before enrolment
• Documented allergy or intolerance to NMDA-R antagonists prior to injury
• Renal dysfunction (Creatinine Clearance (CrCl) or estimate Glomerular Filtration Rate (eGFR) \<60 mL/minute/1.73 m2)

Sponsors & Collaborators

• Nova Scotia Health Authority: lead

Study Sites (1)

Halifax Infirmary, QEII Health Sciences Centre

Halifax, Nova Scotia, B3H 3A6, Canada

Location

Related Publications (6)

• 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.

  PMID: 40583186 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.

  PMID: 38091390 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.

  PMID: 38886512 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.

  PMID: 34927674 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.

  PMID: 32464655 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.

  PMID: 34657268 BACKGROUND

MeSH Terms

Conditions

Brain Injuries, Traumatic; Brain Concussion

Interventions

Memantine

Condition Hierarchy (Ancestors)

Brain Injuries; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Wounds and Injuries; Head Injuries, Closed; Wounds, Nonpenetrating

Intervention Hierarchy (Ancestors)

Amantadine; Adamantane; Bridged-Ring Compounds; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Study Officials

• Mark A MacLean, MD MSc FRCSC

  Nova Scotia Health, Dalhousie University

  PRINCIPAL INVESTIGATOR

• Alon Friedman, MD PhD

  Dalhousie University

  STUDY DIRECTOR

• David B Clarke, MDCM PhD

  Nova Scotia Health, Dalhousie University

  STUDY DIRECTOR

• Ellen Parker, MD PhD

  Nova Scotia Health, Dalhousie University

  STUDY DIRECTOR

Central Study Contacts

Mark A MacLean, MD MSc FRCSC

CONTACT

902-240-5404; mark.maclean@dal.ca

Ellen Parker, MD PhD

CONTACT

ep@dal.ca

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor, Division of Neurosurgery, Nova Scotia Health Authority

Model Details: Participants will be randomized in a 1:1:1 ratio to one of three parallel groups: memantine 20 mg per day, memantine 30 mg per day, or usual clinical care without study drug. Participants will remain in their assigned group for the three-month treatment period; there is no crossover between groups.

Study Record Dates

• First Submitted: October 5, 2026
• First Posted: October 9, 2026
• Study Start (Estimated): June 1, 2027
• Primary Completion (Estimated): September 1, 2029
• Study Completion (Estimated): March 1, 2030
• Last Updated: October 9, 2026

Record last verified: 2026-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: Beginning 12 months after publication of the primary study results and ending 5 years after the data become available.
• Access Criteria: Qualified researchers whose proposed use has a scientifically sound purpose may request access to the data. Approved researchers will receive de-identified individual participant data underlying the results reported in the primary publication, together with a data dictionary and the available supporting documents. Requests must include a research proposal and statistical analysis plan and will be reviewed by the study investigator or a designated review committee. Research ethics approval may be required, as applicable. Before receiving the data, researchers must sign a data-use agreement addressing confidentiality, secure storage, permitted uses, publication, and data destruction. Approved data will be transferred through a secure institutional mechanism.

Locations

CA (1)