Effect of Namenda on Short Term Memory and Attention in P... | NCT00462228

NCT00462228

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

No data available

No data is available for this block.

Document Section

No data available

No data is available for this block.

Derived Section

Miscellaneous Info Module

Status Module

Name	Class
Forest Laboratories	INDUSTRY

Description Module

Detailed Description

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 Centers for Disease Control (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 include a Galveston Orientation and Amnesia Test (GOAT) score of at least 75, and either a Mini-Mental State Exam (MMSE) score of 20 to 27 obtained at the screening visit, or a California Verbal Learning Test (CVLT) total score for trials 1-5 one standard deviation lower than the age matched normative score. The CVLT score for inclusion may be obtained from the medical record provided that the CVLT testing occurred one year or more post TBI and within two years of study entry.

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 VisuoSpatial 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 3-6 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.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Memantine	Experimental	Subjects will be titrated up to 20 mg of memantine per day for 12 weeks, followed by placebo for 12 weeks	Drug: Memantine
Placebo	Placebo Comparator	Subjects will be titrated up to 20 mg of placebo per day for 12 weeks, followed by memantine for 12 weeks	Drug: Placebo

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Memantine	Drug	After randomization of the subject, subjects will be titrated up to 20 mg of memantine or placebo 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.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Improvements From Baseline Scores After 6 and 12 Weeks of Memantine Compared to Placebo on the Hopkins Verbal Learning Test Revised (HVLT-R) Total Recall Learning Scores.	HVLT-R Learning Scores provide a brief assessment of immediate recall, delayed recall and delayed recognition. It is administered by reading the words aloud, then asking the client to verbally repeat the list of words (immediately; then after a delay), and identify the words from a word list that is presented verbally. The HVLT-R is easy to administer and score, and is well-tolerated by even significantly-impaired individuals. Tasks include three learning trials, which, when combined produce a total recall score; a delayed recall (25-30 minute delay) trial, and a yes/no delayed recognition trial. Raw scores are derived for Total Recall, Delayed Recall, Retention (percent retained) and a Recognition Discrimination Index. These results are for the HVLT-R total recall raw learning score. The HVLT-R total recall raw learning score ranges from 0 to 36 with 36 being the highest and best possible score.	Baseline, 6 weeks, and 12 weeks after beginning memantine or placebo
Improvements From Baseline Scores After 6 and 12 Weeks of Memantine Compared to Placebo on the Hopkins Verbal Learning Test Revised (HVLT-R) Delayed Recall Scores.	HVLT-R Learning Scores provide a brief assessment of immediate recall, delayed recall and delayed recognition. It is administered by reading the words aloud, then asking the client to verbally repeat the list of words (immediately; then after a delay), and identify the words from a word list that is presented verbally. The HVLT-R is easy to administer and score, and is well-tolerated by even significantly-impaired individuals. Tasks include three learning trials, which, when combined produce a total recall raw score; a delayed recall (25-30 minute delay) trial, and a yes/no delayed recognition trial. Raw scores are derived for Total Recall, Delayed Recall, Retention (percent retained) and a Recognition Discrimination Index. These scores are for the delayed recall learning raw score. The HVLT-R delayed recall raw score ranges from 0 to 12 with 12 being the highest and best possible score.	Baseline, 6 weeks, and 12 weeks after beginning memantine or placebo
Improvements From Baseline Scores After 6 and 12 Weeks of Memantine Compared to Placebo on the Brief VisuoSpatial Memory Test Revised (BVMT-R) Total Recall Score.

Secondary Outcomes

Measure	Description	Time Frame
Improvements From Baseline Scores After 6 and 12 Weeks of Memantine Compared to Placebo on the Trail Making Test Part A.	Trail Making Test Part A consists of 25 circles on a piece of paper with the numbers 1-25 written randomly in the circles. The test taker's task is to start with number one and draw a line from that circle to the circle with the number two in it to the circle with the three in it, etc. The person continues to connect the circles in numerical order until they reach number 25. Lower scores are better scores and the range of scores can be from 0 to no limit for Trail Making Test part A. This is a timed test and the number of seconds to complete the task is recorded.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

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.
Meet or exceed American Congress of Rehabilitation Medicine (ACRM) criteria for mild TBI.
Mini-Mental State Exam (MMSE) score of 20 to 27 at the screening visit or a California Verbal Learning Test (CVLT) score for trials 1-5 one standard deviation lower than the age matched normative score. The CVLT score from the medical record may be used for entry criteria if it was obtained one year or more post-TBI and within two years of study entry.
Galveston Orientation and Amnesia Test (GOAT) score of at least 75.
Be of sufficient cognitive ability to complete neuropsychological tests.
Male or female, 18-50 years of age.
Females of childbearing potential must use acceptable means of birth control and have a negative screening beta-human chorionic gonadotrophin (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.
Patients taking donepezil (Aricept) or rivastigmine (Exelon) must be at a steady state dose for a minimum of six months.
Patients taking any other medication(s) affecting cognition must be at a steady state dose for a minimum of two months.
Able to provide written informed consent.
Able to read, write, and speak in English.
Willing and able to comply with the physician's instructions for all aspects of the study.

Exclusion Criteria:

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.
Patients with a history of seizure are excluded.
Patients with a history of severe renal insufficiency are excluded.
Patients must not have taken any experimental drug within the last 30 days prior to entering the protocol.
Patients must not have taken any drug known to have major organ system toxicity within the last 30 days prior to entering the protocol.
Women who are pregnant, nursing, or intend to become pregnant during the study are excluded.
Patients with a penetrating TBI are excluded.
Patients whose screening laboratory values are 1.5 times greater than upper limits of normal range(ULN) are excluded.
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.
Concomitant use of amantadine (Symmetrel) is prohibited and a washout period of 4 weeks is required before study entry.

Name	Affiliation	Role
S. Jon Rupright, D.O.	Associate Professer, Clinical Physical Medicine & Rehabilitation, School of Medicine, University of Missouri-Columbia	Principal Investigator
George R. Johnstone, Ph.D.	Professor, Department of Health Psychology, University of Missouri-Columbia	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
University of Missouri-Columbia		Columbia	Missouri	65212	United States

ID	Title	Description
FG000	Overall Study	All 11 baseline subjects completed the three periods of the study: memantine treatment, placebo treatment, and no treatment (washout period) in this crossover design. Five subjects were randomized to begin the study by taking memantine and crossover to placebo; seven subjects began with placebo and crossed over to memantine.

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Overall Study	All 11 baseline subjects completed the three periods of the study: memantine treatment, placebo treatment, and no treatment (washout period) in this crossover design.

Units	Counts
Participants	BG000

Baseline Measures

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Categorical			Count of Participants

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Improvements From Baseline Scores After 6 and 12 Weeks of Memantine Compared to Placebo on the Hopkins Verbal Learning Test Revised (HVLT-R) Total Recall Learning Scores.

HVLT-R Learning Scores provide a brief assessment of immediate recall, delayed recall and delayed recognition. It is administered by reading the words aloud, then asking the client to verbally repeat the list of words (immediately; then after a delay), and identify the words from a word list that is presented verbally.

The HVLT-R is easy to administer and score, and is well-tolerated by even significantly-impaired individuals. Tasks include three learning trials, which, when combined produce a total recall score; a delayed recall (25-30 minute delay) trial, and a yes/no delayed recognition trial. Raw scores are derived for Total Recall, Delayed Recall, Retention (percent retained) and a Recognition Discrimination Index.

These results are for the HVLT-R total recall raw learning score. The HVLT-R total recall raw learning score ranges from 0 to 36 with 36 being the highest and best possible score.

All subjects completing the study.

Posted

Mean

Standard Deviation

units on a scale

Baseline, 6 weeks, and 12 weeks after beginning memantine or placebo

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Placebo	All 11 subjects completed 12 weeks of placebo treatment. Subjects were given 5 mg per day for 7 days, then 5 mg twice per day for 7 days, then 10 mg AM, 5 mg PM for 7 days, then 10 mg twice daily, as tablet form.

ID	Term
D001930	Brain Injuries
D001927	Brain Diseases
D002493	Central Nervous System Diseases
D009422	Nervous System Diseases

ID	Term
D000547	Amantadine
D000218	Adamantane
D001952	Bridged-Ring Compounds
D006844	Hydrocarbons, Cyclic

OG000	Memantine	All subject scores for memantine regardless of sequence in the crossover design.
OG001	Placebo	All subject scores for placebo regardless of sequence in the crossover design.