Memantine Hydrochloride for Treatment of Cognitive Dysfunction Due to Traumatic Brain Injury

August 6, 2024 updated by: Sherifa Ahmed Hamed, Assiut University

Treatment of Post-traumatic Cognitive Dysfunction With Memantine Hydrochloride, an N-methyl-D-aspartate (NMDA)-Type Receptor Blocker: a Clinical Trial

Posttraumatic consequences are common causes of disability and long-term morbidity. They include cognitive dysfunction, seizures, headache, dizziness, fatigue, sensory deficits, neurodegeneration and psychiatric disorders (e.g. posttraumatic stress disorder, depression, anxiety, etc). Diffuse axonal injury and disruption of normal neuronal function are the most common and important pathologic features of traumatic primary closed head injury. depression, anxiety, etc). Excitotoxicity and apoptosis caused by activation of N-methyl-D-aspartate (NMDA) glutamate receptors, are two main suggested mechanisms of traumatic neuronal cell death and posttraumtic neurologic adverse consequences. Experimental and clinical studies have demonstrated that memantine hydrochloride, NMDA-type glutamate receptor antagonist, could have beneficial effect in treatment of posttraumatic cognitive dysfunction. Memantine may contribute to cognitive improvements in TBI by decreasing the synaptic 'noise' resulting from excessive NMDA receptor activation, inhibition of β-amyloid mediated toxicity and readjustment of the balance between inhibition and excitation on neuronal networks in the central nervous system (CNS).

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Posttraumatic consequences are common causes of disability and long-term morbidity. Traumatic brain injuries (TBIs) are traditionally classified into primary and secondary injuries. Primary brain injury is usually mechanically induced and occurs at the moment of injury while secondary injury is not mechanically induced, delayed from the moment of injury and may superimpose a previously injured brain by mechanical forces. Primary brain injury may be associated with focal scalp injury, skull fractures, brain contusion caused by contact (i.e. an object striking the head or the brain striking the inside of the skull) as well as diffuse axonal brain injury which is usually caused by acceleration-deceleration forces or rotational acceleration of the brain as a result of unrestricted movement of the head, shearing and tensile forces and compressive strains. Diffuse axonal injury and disruption of normal neuronal function are the most common and important pathologic features of TBI. The latter is mostly microscopic damage and is often not visible in neuroimaging. Consequences of TBI include cognitive dysfunction, seizures, headache, dizziness, fatigue, sensory deficits, neurodegeneration and psychiatric disorders (e.g. posttraumatic stress disorder, depression, anxiety, etc). Excitotoxicity and apoptosis are two main suggested mechanisms of traumatic neuronal cell death. The N-methyl-D-aspartate (NMDA) glutamate receptors are implicated in these mechanisms. Furthermore, the activation of NMDA receptors by glutamate promotes the production of reactive oxygen species (ROS) and nitric oxide (NO) which further exacerbate secondary cell injury. NMDA receptor plays a pivotal role in learning and memory. Experimental and clinical studies have demonstrated that memantine hydrochloride, NMDA-type glutamate receptor antagonist, could have beneficial effect in treatment of posttraumatic cognitive dysfunction. Memantine is an FDA-approved drug for the treatment of moderate to severe Alzheimer's disease and is also used clinically for the treatment of some patients with Parkinson's disease. Memantine is effective in blocking excessive activity of NMDA-type glutamate receptors and reduces the progression of dementia. Memantine has shown to be neuroprotective in animal models of cerebral and spinal cord ischemia and in models of TBI. Memantine may contribute to cognitive improvements in TBI by decreasing the synaptic 'noise' resulting from excessive NMDA receptor activation, inhibition of β-amyloid mediated toxicity and readjustment of the balance between inhibition and excitation on neuronal networks in the CNS. It showed beneficial effects in treating post-injury synaptic dysfunction in the neocortex, partially reversing deficits in long-term potentiation (LTP), mitigating pathologic NMDAR loss, and reducing tau phosphorylation and β-amyloid expression. Memantine spares hippocampal neurons after a single moderate/severe or repetitive TBI and normalizes LTP, β-amyloid and tau expressions, and neuroinflammation abnormalities in a repeat experimental model of TBI. In rodent studies, memantine dramatically increased adult hippocampal neurogenesis. Memantine does not have the significant negative side effects, such as hallucinations and coma of other NMDAR antagonists. High doses (≥20 mg/d) may cause non-serious side effects, e.g. dizziness, anxiety, restlessness or agitation,

Study Type

Interventional

Enrollment (Actual)

60

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Egypt
      • Assiut, Egypt, 71516
        • Assiut University, Faculty of Medicine, Hospital of Neurology, Psychiatry and Neurosurgery

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  • Adults (age: 18 - 60 years old)
  • History of primary traumatic closed head injury
  • At least 6 months after TBI
  • Mild/moderate previous TBI
  • Normal neuroimaging of the brain at the period of the study.

Exclusion Criteria:

  • Secondary injury or superimpose injury on a brain already affected by a mechanical injury
  • patients with duration of illness less than 6 months
  • History of open or severe head injuries
  • Severe neurologic consequences after TBI
  • Post traumatic seizures
  • Posttraumatic hydrocephalus'
  • Posttraumatic abnormal neuroimaging of the brain
  • History of chronic mental or neurologic disorders (e.g. comorbid schizophrenia, severe manic phase of bipolar disorder or intellectual disability).
  • Substance abuse
  • Pregnancy
  • Individuals with the following physical conditions that are described in manufacturer's package including history of epilepsy or convulsion, renal dysfunction, factors increasing urine pH and severe liver dysfunction

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
No Intervention: No intervention
number of participants: >/= 40
Active Comparator: Drug treatment (interventional)

- number of participant: >/= 60. This open-label clinical trial consisted of 24 weeks of memantine intake period, followed by 4-week (or more) post-trial observation period to monitor the drug adverse effects (e.g. sleep problems, sleepiness, sedation, anxiety, weight change and hypotension). Clinic visits will be scheduled at baseline and follow-ups after 6, 12, 18, 24 weeks of treatment initiation. Concomitant medications were essentially kept unchanged during the trial, i.e. the intake of antidepressant or antianxiologic psychotropic medications, psychotherapy to treat depressive or anxiety symptoms does not exclude participation in the study.

Memantine was added to each patient's current medication, with the initial dosage of 5 mg/day (once daily). The dosage was then increased to 10 mg/day after a week and maintained till the end of the study. In the case of intolerance to this increase, the dosage was flexibly adjusted according to the condition of the patient.
Drug: Memantine Hydrochloride
Memantine was added to each patient's current medication, with the initial dosage of 5 mg/day (once daily). The dosage was then increased to 10 mg/day after a week and maintained till the end of the study. In the case of intolerance to this increase, the dosage was flexibly adjusted according to the condition of the patient.
Other Names:
  • Active arm

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The severity of traumatic brain injury (TBI)
Time Frame: Baseline
(1) The severity of TBI at onset which was assessed according to (a) Glasgow coma scale (GCS) determined at the time of injury. (b)The duration of loss of consciousness (LOC) at the time of injury: (c) The time elapsed from injury to the moment when patients can demonstrate continuous memory of what is happening around them (i.e. orientation).
Baseline
The symptoms of depression
Time Frame: Baseline
(2) Beck's Depression Inventory - II (BDI-II)
Baseline
The symptoms of anxiety
Time Frame: baseline
(3) Hamilton Anxiety Rating Scale (HAM-A):
baseline
The cognitive function
Time Frame: baseline
The validated versions of Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) will be used to assess cognition. Each takes ~10-15 min to be administered.
baseline

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Quality of life after drug treatment
Time Frame: 8, 16, and 24 weeks
(1) The brief WHO quality of life questionnaire (WHOQOL-brief) will be used for assessment. WHO defines Quality of Life as an individual's perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns.
8, 16, and 24 weeks
Re-evaluation of the cognitive function after drug treatment
Time Frame: 8, 16, and 24 weeks
The validated versions of Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were used to assess cognition as described above.
8, 16, and 24 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Assiut University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 1, 2024

Primary Completion (Actual)

June 1, 2024

Study Completion (Actual)

August 1, 2024

Study Registration Dates

First Submitted

March 23, 2024

First Submitted That Met QC Criteria

March 23, 2024

First Posted (Actual)

March 29, 2024

Study Record Updates

Last Update Posted (Actual)

August 7, 2024

Last Update Submitted That Met QC Criteria

August 6, 2024

Last Verified

August 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • AUH-Neurol-TBI_2024

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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