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

NCT06337994 | Completed Phase 3

• 1 other identifier: AUH-Neurol-TBI_2024
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

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).

Conditions

Treatment of Cognitive Deficits After Traumatic Brain Injury

Keywords

Traumatic brain injury; closed head injury; cognition; memory; N-methyl-D-aspartate (NMDA)-type receptors; NMDA blocker; memantine hydrochloride

Outcome Measures

Primary Outcomes (4)

• The severity of traumatic brain injury (TBI)

  (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

  (2) Beck's Depression Inventory - II (BDI-II)

  Baseline

• The symptoms of anxiety

  (3) Hamilton Anxiety Rating Scale (HAM-A):

  baseline

• The cognitive function

  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 Outcomes (2)

• Quality of life after drug treatment

  8, 16, and 24 weeks

• Re-evaluation of the cognitive function after drug treatment

  8, 16, and 24 weeks

Study Arms (2)

Drug treatment (interventional)

ACTIVE COMPARATOR

\- 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

No intervention

NO INTERVENTION

number of participants: \>/= 40

Interventions

Memantine Hydrochloride DRUG

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.

Also known as: Active arm

Drug treatment (interventional)

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Assiut University: lead

Study Sites (1)

Assiut University, Faculty of Medicine, Hospital of Neurology, Psychiatry and Neurosurgery

Asyut, 71516, Egypt

Location

Related Publications (10)

• Bramlett HM, Dietrich WD. Long-Term Consequences of Traumatic Brain Injury: Current Status of Potential Mechanisms of Injury and Neurological Outcomes. J Neurotrauma. 2015 Dec 1;32(23):1834-48. doi: 10.1089/neu.2014.3352. Epub 2014 Dec 19.

  PMID: 25158206 BACKGROUND

• Guerriero RM, Giza CC, Rotenberg A. Glutamate and GABA imbalance following traumatic brain injury. Curr Neurol Neurosci Rep. 2015 May;15(5):27. doi: 10.1007/s11910-015-0545-1.

  PMID: 25796572 BACKGROUND

• Effgen GB, Morrison B 3rd. Memantine Reduced Cell Death, Astrogliosis, and Functional Deficits in an in vitro Model of Repetitive Mild Traumatic Brain Injury. J Neurotrauma. 2017 Feb 15;34(4):934-942. doi: 10.1089/neu.2016.4528. Epub 2016 Aug 8.

  PMID: 27450515 BACKGROUND

• Chamoun R, Suki D, Gopinath SP, Goodman JC, Robertson C. Role of extracellular glutamate measured by cerebral microdialysis in severe traumatic brain injury. J Neurosurg. 2010 Sep;113(3):564-70. doi: 10.3171/2009.12.JNS09689.

  PMID: 20113156 BACKGROUND

• Girouard H, Wang G, Gallo EF, Anrather J, Zhou P, Pickel VM, Iadecola C. NMDA receptor activation increases free radical production through nitric oxide and NOX2. J Neurosci. 2009 Feb 25;29(8):2545-52. doi: 10.1523/JNEUROSCI.0133-09.2009.

  PMID: 19244529 BACKGROUND

• Sattler R, Xiong Z, Lu WY, Hafner M, MacDonald JF, Tymianski M. Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein. Science. 1999 Jun 11;284(5421):1845-8. doi: 10.1126/science.284.5421.1845.

  PMID: 10364559 BACKGROUND

• Lipton SA. The molecular basis of memantine action in Alzheimer's disease and other neurologic disorders: low-affinity, uncompetitive antagonism. Curr Alzheimer Res. 2005 Apr;2(2):155-65. doi: 10.2174/1567205053585846.

  PMID: 15974913 BACKGROUND

• Chen HS, Wang YF, Rayudu PV, Edgecomb P, Neill JC, Segal MM, Lipton SA, Jensen FE. Neuroprotective concentrations of the N-methyl-D-aspartate open-channel blocker memantine are effective without cytoplasmic vacuolation following post-ischemic administration and do not block maze learning or long-term potentiation. Neuroscience. 1998 Oct;86(4):1121-32. doi: 10.1016/s0306-4522(98)00163-8.

  PMID: 9697119 BACKGROUND

• Dogan A, Eras MA, Rao VL, Dempsey RJ. Protective effects of memantine against ischemia-reperfusion injury in spontaneously hypertensive rats. Acta Neurochir (Wien). 1999;141(10):1107-13. doi: 10.1007/s007010050491.

  PMID: 10550658 BACKGROUND

• Mei Z, Qiu J, Alcon S, Hashim J, Rotenberg A, Sun Y, Meehan WP 3rd, Mannix R. Memantine improves outcomes after repetitive traumatic brain injury. Behav Brain Res. 2018 Mar 15;340:195-204. doi: 10.1016/j.bbr.2017.04.017. Epub 2017 Apr 13.

  PMID: 28412305 BACKGROUND

MeSH Terms

Conditions

Brain Injuries, Traumatic; Head Injuries, Closed

Interventions

Memantine

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

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

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Neurology

Model Details: parallel assignment

Study Record Dates

• First Submitted: March 23, 2024
• First Posted: March 29, 2024
• Study Start: January 1, 2024
• Primary Completion: June 1, 2024
• Study Completion: August 1, 2024
• Last Updated: August 7, 2024

Record last verified: 2024-08

Locations

EG (1)