A Phase 2 interventional study of Memantine in Traumatic Brain Injury, Mild Traumatic Brain Injury and Moderate Traumatic Brain Injury (TBI), sponsored by Nova Scotia Health Authority. Not yet recruiting at 1 site in Canada. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-10-09.
Sponsored by Nova Scotia Health Authority · Phase 2, Interventional, and Treatment
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:
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:
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.
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.
1,775 studies on the registry are indexed under Brain Injuries, Traumatic; 448 are open to participants now.
This study's planned enrollment of 45 is below the median of 56 across 1,133 interventional studies indexed under Brain Injuries, Traumatic.
Browse Brain Injuries, Traumatic studies →Nova Scotia Health Authority is the lead sponsor of 256 studies on the registry; 77 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
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
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
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.
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).
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.
Time frame: From study opening through 24 months
Recruitment Rate
Recruitment rate will be calculated as the total number of participants randomized divided by the number of months that recruitment is open. The planned recruitment rate is approximately 2 participants per month.
Time frame: From study opening through 24 months
Proportion of Eligible Participants Randomized
The number of eligible participants who are randomized divided by the total number of eligible participants identified during screening, multiplied by 100. The prespecified feasibility target is at least 50%.
Time frame: From study opening through completion of the 24-month recruitment period
Participant Retention at the 3-Month Visit
The number of randomized participants who complete the scheduled 3-month visit divided by the total number randomized, multiplied by 100. The prespecified feasibility target is at least 75%.
Time frame: 3 months after randomization
Assigned Memantine Target-Dose Attainment
The number of participants assigned to a memantine arm who reach their assigned target dose of 20 mg/day or 30 mg/day divided by the number of participants who receive at least one dose of memantine, multiplied by 100. The highest dose reached and reasons for not reaching the assigned target dose will also be recorded.
Time frame: From first dose through 3 months
Proportion of Planned Memantine Doses Taken
For participants assigned to a memantine arm, adherence will be calculated as the total number of study-drug doses taken divided by the total number of planned doses, multiplied by 100. Adherence will be assessed using pill counts and/or electronic adherence monitoring. The prespecified progression target is more than 80% of planned active-arm doses taken.
Time frame: From first dose through 3 months
Tolerability of Memantine Based on Treatment Modification or Discontinuation
Among participants who receive at least one dose of memantine, the number and percentage who require a dose reduction, temporary treatment interruption, or permanent discontinuation because of an adverse event or intolerance will be reported by assigned dose group.
Time frame: From first dose through 3 months
Incidence of Adverse Events and Serious Adverse Events
The number and percentage of participants experiencing one or more adverse events or serious adverse events will be reported by study arm. Events will be classified by severity, expectedness, and relationship to memantine. The type and total number of events will also be summarized.
Time frame: From randomization through 6 months
Usability of Dynamic Contrast-Enhanced MRI Scans
The number of acquired dynamic contrast-enhanced magnetic resonance imaging scans that meet prespecified acquisition and image-quality requirements for analysis divided by the total number of scans acquired, multiplied by 100. The prespecified feasibility target is more than 90% of acquired scans being usable.
Time frame: Baseline and 3 months
Change in Whole-Brain Abnormal Blood-Brain Barrier Permeability Burden
Blood-brain barrier permeability will be measured using dynamic contrast-enhanced magnetic resonance imaging. Abnormal permeability burden will be quantified as the whole-brain volume and proportion of brain tissue exceeding prespecified abnormal-permeability thresholds. Change will be calculated by comparing the baseline scan with the three-month scan.
Time frame: From baseline through 3 months
Proportion of Participants Completing the Baseline and 3-Month Outcome-Assessment Batteries
The number of randomized participants who complete the prespecified core components of both the baseline and 3-month outcome-assessment batteries divided by the total number of randomized participants eligible for those assessments, multiplied by 100. The prespecified progression target is at least 75%.
Time frame: Baseline through 3 months
Plan to share: Yes — De-identified individual participant data underlying the results reported in the primary publication will be available for sharing. This may include participant characteristics, treatment allocation and exposure, adherence, safety data, clinical and neuropsychological outcome data, and derived imaging and electrophysiological measures. A data dictionary describing the shared variables will be provided. Information that could identify participants and raw source imaging containing potentially identifying information will not be shared.
Supporting information: Study protocol, Sap, Icf, Csr, Analytic code
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Nova Scotia Health Authority