Official Title: “Double-Blind Cross-Over Study of the Effect of Namenda on Short Term Memory and Attention in Patients With Mild to Moderate Traumatic Brain Injury, Protocol NAM-MD-44”

The purpose of this study is to determine whether memantine (Namenda) improves memory and attention in patients with mild to moderate traumatic brain injury.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Investigator, Outcomes Assessor), Placebo Control, Crossover Assignment, Efficacy Study

Study Primary Completion Date: September 2009

Background and significance:

Each year in the United States approximately 1.5 million people sustain a traumatic brain injury (TBI) and of these approximately 80-90,000 result in long-term or lifelong disability.

An estimated 5.3 million people are currently living with a disability due to TBI. The CDC estimated that about 75% (1.1 million) of the reported TBIs are concussions or other forms of mild TBIs (MTBI). However, the incidence of MTBI has been vastly underestimated according to a CDC Report to Congress.

The long term problem associated with MTBI is primarily memory impairment. Memory impairment resulting form MTBI is not likely to improve with time beyond the initial stabilizing period of about one year post-injury. Dementia from Alzheimer's Disease produces cognitive problems that are similar to those experienced by patients with mild to moderate traumatic brain injury. The efficacy of Namenda for treatment of cognitive problems due to Alzheimer's Dementia suggests it may have efficacy for treatment of short term memory and attention deficits in patients with mild to moderate traumatic brain injury.

Overall Design and Plan of Study:

Twenty post-TBI patients whose TBI occurred at least 1 year prior to beginning the study will be recruited for this pilot study. Patients who meet screening criteria will have cognitive abilities assessed at baseline and at subsequent visits while taking Namenda or placebo.

Patients will be randomly assigned to begin either Namenda or placebo and will then crossover to the alternate treatment. Each patient will participate in the study for a total of 32 to 34 weeks. Patients completing the study will have 10 total visits and 6 visits at which a cognitive test battery will be administered. This will include 24 weeks of study drug treatment (12 weeks of Namenda and 12 weeks of placebo) and two 4-week washout periods.

Patients will be titrated up to 20 mg of Namenda per day. Namenda and placebo will be provided by Forest Laboratories Inc.

Cognitive screening criteria will include a Mini-Mental State Exam (MMSE) score of 20-27 and a Galveston Orientation and Amnesia Test (GOAT) score of at least 75.

The cognitive test battery measurements will be made at the first baseline before Namenda or placebo administration (week 0), and at weeks 6, & 12 after Namenda or placebo administration. After washout for 4 weeks, the second baseline (week 16) will be assessed, and the cognitive test battery will be administered again at weeks 22 & 28 after Namenda or placebo administration.

The cognitive test battery used to assess efficacy will utilize the following tests;

Verbal Memory: Hopkins Verbal Learning Test Revised (HVLT-R). Visual Memory: Brief Visuo-Spatial Memory Test Revised (BVMT-R). Speed of processing: Trail Making Test Part A.

Attention: Trail Making Test Part B. Memory/processing speed: Symbol Digit Modality Test (SDMT).

The primary endpoints for cognitive assessment will be the HVLT-R and the BVMT-R. The 6 different forms of the HVLT-R and BVMT-R will be administered at each of the 6 cognitive test battery assessments. The sequence of forms administered will be randomized. The other listed cognitive tests will be considered secondary endpoints. An additional secondary efficacy endpoint will be the Physicians Global Impression of Change which will be recorded with the same visit frequency as other cognitive tests.

In addition to the neuropsychological tests, patients will have physical examinations, electrocardiograms, and laboratory tests of blood and urine.

Safety and tolerability will be monitored by clinical assessment, reporting of adverse events, and laboratory values. Patient health will be assessed at clinic visits every 3-4 weeks throughout the study. Serum pregnancy (for females of child bearing potential) will be completed at screening and at weeks 12 and 28. Urine pregnancy tests will be completed at baseline (week 0) and weeks 16 & 32. A Safety Officer will be utilized as the primary means of monitoring safety of the study. The Safety Officer will be a physician not associated with the study in any other capacity. The Safety Officer will be given periodic reports of clinical assessments, laboratory values, and adverse events.

Intervention(s) in this Clinical Trial

• Drug: memantine
  • After randomization of the subject, subjects will be titrated up to 20 mg of memantine or placebo (provided by Forest Laboratories) per day. Memantine and placebo are provided as 5 mg tablets. Subjects will be started at 5 mg per day. The dose will be increased by 5 mg increments to 10 mg per day (5 mg twice per day), 15 mg per day (5 mg and 10 mg as separate doses) and 20 mg per day (10 mg twice per day). The minimum interval between dose increases will be one week. Subjects will take memantine or placebo for 12 weeks during each part of the crossover study. Subjects are randomized to begin either memantine or placebo in each arm of the study, arm AB or arm BA. Study personnel are blinded to A and B treatment identity.
• Drug: memantine
  • Subjects will have the same dosage regimen for memantine or placebo as listed above. In arm BA, subjects will start with treatment B and crossover to treatment A.

Arms, Groups and Cohorts in this Clinical Trial

• Other: AB
  • Subjects begin with treatment A and crossover to treatment B.
• Other: BA
  • Subjects begin with treatment B and crossover to treatment A.

Primary Measures

• Improvements from baseline scores after 6 and 12 weeks of memantine compared to placebo on the Hopkins Verbal Learning Test Revised (HVLT-R).
  • Time Frame: baseline, 6 weeks, and 12 weeks after beginning Namenda or placebo
    Safety Issue?: No
• Improvements from baseline scores after 6 and 12 weeks of memantine compared to placebo on the Brief Visuo-Spatial Memory Test Revised (BVLT-R).
  • Time Frame: baseline, 6 weeks, 12 weeks after beginning Namenda or placebo
    Safety Issue?: No

Secondary Measures

• Improvements from baseline scores after 6 and 12 weeks of memantine compared to placebo on the Trail Making Test Part A and Part B.
  • Time Frame: baseline, 6 weeks, 12 weeks
    Safety Issue?: No
• Improvements from baseline scores after 6 and 12 weeks of memantine compared to placebo on the Symbol Digit Modality Test.
  • Time Frame: baseline, 6 weeks, 12 weeks
    Safety Issue?: No

Inclusion Criteria:

• 1. Patients will have persistent memory and attention deficits due to a closed traumatic brain injury not less than one year prior to entrance in the study.
• 2. Meet or exceed American Congress of Rehabilitation Medicine (ACRM) criteria for mild
• TBI.
• 3. Mini-Mental State Exam (MMSE) score of 20-27.
• 4. Galveston Orientation and Amnesia Test (GOAT) score of at least 75.
• 5. Be of sufficient cognitive ability to complete neuropsychological tests.
• 6. Male or female, 18-50 years of age.
• 7. Females of childbearing potential must use acceptable means of birth control and have a negative screening b-HCG pregnancy test. Acceptable birth control includes hormonal birth control (such as oral birth control pills, implanted or injected contraceptives), an intrauterine device (IUD), surgical sterilization (such as tubal ligation or hysterectomy), a spermicide with barrier methods (condoms or diaphragm), or a partner who has had a vasectomy.
• 8. Patients taking donepezil (Aricept) or rivastigmine (Exelon) must be at a steady state dose for a minimum of six months.
• 9. Patients taking any other medication(s) affecting cognition must be at a steady state dose for a minimum of two months.
• 10. Able to provide written informed consent.
• 11. Able to read, write, and speak in English.
• 12. Willing and able to comply with the physician's instructions for all aspects of the study.

Exclusion Criteria:

• 1. Patients must not have any medical or psychiatric disorder that in the opinion of the PI would interfere with or bias the assessment of efficacy or place their health at risk when placed on the memantine (Namenda) regimen.
• 2. Patients with a history of seizure are excluded.
• 3. Patients with a history of severe renal insufficiency are excluded.
• 4. Patients must not have taken any experimental drug within the last 30 days prior to entering the protocol.
• 5. Patients must not have taken any drug known to have major organ system toxicity within the last 30 days prior to entering the protocol.
• 6. Women who are pregnant, nursing, or intend to become pregnant during the study are excluded.
• 7. Patients with a penetrating TBI are excluded.
• 8. Patients whose screening laboratory values are 1.5 times greater than ULN are excluded.
• 9. Patients with systolic blood pressure greater than 180 mm Hg or less than 90 mm Hg or diastolic blood pressure greater than 105 mm Hg or less than 50 mm Hg at the screening visit are excluded.
• 10. Concomitant use of amantadine (Symmetrel) is prohibited and a washout period of 4 weeks is required before study entry.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 50 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: University of Missouri-Columbia

Overall Clinical Trial Officials and Contacts

S. Jon Rupright, D.O. Principal Investigator Associate Professer, Clinical Physical Medicine & Rehabilitation, School of Medicine, University of Missouri-Columbia  

Overall Contact: Fred Murdock, Ph.D. 573-884-5217 murdockf@health.missouri.edu

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00462228

Study ID Number: NAM-MD-44

ClinicalTrials.gov Identifier: NCT00462228

Health Authority: United States: Institutional Review Board