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

Traumatic brain injury (TBI) can trigger biological changes that continue after the initial injury. One such change is blood-brain barrier dysfunction (BBBD). The blood-brain barrier normally regulates the movement of substances between the bloodstream and brain tissue. When this barrier is disrupted, it may contribute to brain swelling, inflammation, altered neuronal activity, and problems with cognition, mood, and neurological recovery.

BBBD is a promising treatment target because it can be measured non-invasively using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). DCE-MRI is an established technique that provides quantitative measures of abnormal movement of contrast agent from the blood into brain tissue. This allows researchers to study whether a treatment engages its intended biological target, rather than relying only on symptoms or functional assessments.

Memantine is a low-to-moderate affinity, non-competitive N-methyl-D-aspartate receptor antagonist. It is approved for the symptomatic treatment of moderate to severe Alzheimer's disease but is not approved for treating TBI. Excessive activation of N-methyl-D-aspartate receptors may contribute to harmful changes in neuronal and blood-brain barrier function after TBI. In preclinical research conducted by our group, memantine inhibited cortical spreading depolarizations, lowered blood-brain barrier dysfunction, and preserved neurological function after repetitive mild TBI. Human evidence for memantine in acute TBI remains limited, so a carefully monitored pilot trial is needed before conducting a definitive efficacy trial.

This is a single-centre, prospective, randomized, three-parallel-arm safety and feasibility (pilot) trial at the Halifax Infirmary, QEII Health Sciences Centre in Nova Scotia, Canada. Participants will be allocated in a 1:1:1 ratio to memantine 20 mg per day, memantine 30 mg per day, or usual clinical care without study drug. Treatment will begin early after hospital admission and continue for three months. Memantine will be increased gradually, no more often than weekly, until the assigned target dose is reached, as tolerated. If a participant cannot tolerate a dose increase, the study drug may be reduced, temporarily interrupted, maintained at the highest tolerated dose, or stopped according to the study's safety procedures.

The two memantine doses were selected to support dose selection for a future trial. The 20 mg daily dose corresponds to an established clinical maintenance dose. The 30 mg daily dose will test whether a modestly higher exposure is feasible and tolerable in adults with TBI and whether it may produce greater engagement of the proposed biological target.

The study is open-label because participants assigned to usual care will not receive a placebo and the active treatment groups require visible dose titration. Several safeguards will reduce the risk of bias. The randomization sequence will be concealed until enrollment is complete. Brain imaging will be processed centrally without knowledge of treatment allocation. Other assessments will be standardized and conducted without knowledge of treatment allocation when practicable. Statistical datasets will use coded treatment groups.

The trial's central mechanistic question is whether DCE-MRI can provide a reliable measure of change in abnormal blood-brain barrier permeability after TBI and detect a preliminary dose-specific treatment signal. Additional clinical, neuropsychological, electrophysiological, and participant-reported information will help researchers understand the feasibility and burden of the assessment plan and explore relationships between biological changes and recovery. These analyses are exploratory.

This pilot is designed primarily to assess feasibility, safety, and tolerability. It is not large enough to establish whether memantine improves clinical recovery. The study will determine whether participants can be enrolled and begin treatment within the required period, whether assigned doses can be reached and maintained, whether medication use and follow-up are acceptable, and whether usable imaging and assessment data can be collected consistently.

Safety monitoring will include adverse events, serious adverse events, dose changes, treatment interruptions, and discontinuations. An independent Data and Safety Monitoring Committee will review unblinded safety and treatment-exposure information at planned intervals and after any prespecified safety trigger.

The results will be considered together using prespecified progression criteria. They will inform whether a larger multicentre randomized trial is practical, which memantine dose should be taken forward, how many participants and sites would be needed, and how imaging and clinical assessments should be used in that trial. Any differences between groups in this pilot will be reported as preliminary estimates with measures of uncertainty, not as proof of treatment benefit.

By linking an intervention to a measurable biological process, this study uses a mechanism-directed and biomarker-guided approach to TBI treatment development. If the pilot shows that the treatment and research procedures are safe and workable, it will provide the foundation for a definitive trial testing whether early treatment of blood-brain barrier dysfunction can improve outcomes after TBI.