Trial of Memantine for Cognitive Impairment in Multiple Sclerosis

Sponsor

Oregon Health and Science University (Other)

Overall Status

Completed

CT.gov ID

NCT00300716

Collaborator

Forest Laboratories (Industry), University of Southern California (Other), University of Texas Southwestern Medical Center (Other), MS-Hub Seattle (Other)

Enrollment

Locations

Duration (Months)

20.5

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study is designed to determine whether memantine is an effective treatment for memory and cognitive problems associated with multiple sclerosis when compared to placebo.

Condition or Disease	Intervention/Treatment	Phase
Multiple Sclerosis Cognition Disorders	Drug: Memantine	Phase 2/Phase 3

Detailed Description

Objective:

The objective of this pilot project is to conduct a clinical trial to assess the efficacy of memantine as a treatment for cognitive dysfunction in multiple sclerosis (MS). We hypothesize that MS patients with cognitive impairment treated with memantine will demonstrate an improvement in performance on a neuropsychological test battery as compared to placebo treated patients.

Background and Significance:

Cognitive dysfunction is a major cause of disability in multiple sclerosis (MS). The estimated prevalence of cognitive dysfunction in the MS population is 45% to 65%. MS patients with cognitive dysfunction have fewer social interactions, more sexual dysfunction, greater difficulty with household tasks and higher unemployment than those with normal cognition. At present, there is no effective pharmacological symptomatic treatment for the cognitive dysfunction of MS. One agent that may have some benefit in treating this condition is the N-methyl-D-aspartate (NMDA) receptor antagonist memantine.

Memantine is a NMDA antagonist that has been shown to be effective in treating Alzheimer's disease. Glutamate toxicity has been implicated in the pathogenesis of a variety of neurologic diseases, including MS. Glutamate receptor activation may be involved both in mediation of neural injury and in neuronal dysfunction. By blocking NMDA receptors, memantine may both improve neuronal function, explaining symptomatic improvement in some Alzheimer's patients, and slow progressive neuronal death, potentially resulting in a slowing of cognitive decline in Alzheimer's patients. The pathogenesis of cognitive dysfunction in MS relates at least in part to the extent of cerebral demyelination, axonal loss and atrophy. Some cognitive dysfunction is reversible. Reduction in inflammation can result in improvement in cognitive performance. What role NMDA receptors and glutamate toxicity may play in cognitive dysfunction is uncertain but, given the lack of any treatment for cognitive dysfunction in MS, performing a pilot trial of memantine in MS is clearly warranted.

Overall Design:

This is a placebo-controlled, double-blinded, randomized, parallel-group pilot study of 16 weeks duration in MS patients with cognitive impairment. There will be 73 patients per treatment arm among all sites. The intervention arm will receive 20 mg of memantine a day. Randomization into each treatment arm will be stratified on age and CVLT score. A double-blind, placebo controlled trial is critical to perform even for a pilot trial. Both learning and placebo effect are likely to improve the cognitive performance of some subjects. An open labeled trial would likely show some improvement in the patients but the results would not be interpretable.

Memantine:

Both memantine and the placebo will be provided by Forest Laboratories Inc.

Scheduled Visits:

Visit 1:

The subject will receive a consent form. After signing, visual acuity will be tested. The Multiple Sclerosis Screening Neuropsychological Questionnaire (MSNQ) and the Modified Neuropsychiatric Inventory (MNPI) will be given to the primary caregiver if present, or to the patient instructing him to have the primary caregiver fill it out and return it in the next visit. They will receive the first half of the neuropsychological test battery, which includes the Paced Auditory Serial Addition Test (PASAT) and California Verbal Learning Test II (CVLT-II). They will also receive the Beck Depression Inventory (BDI). Women of childbearing potential will be asked to give a urine sample for a pregnancy test (beta HCG). At this point, patients will be informed whether they have met the full criteria for enrollment. If they qualify then they will receive the second half of the neuropsychological tests (Controlled Oral Word Association Test, Stroop Color And Word Association Test, Symbol Digit Modalities Test and Delis-Kaplan Executive Function System). This visit will last approximately 1½ hour if the patient does not qualify for the study and 2 hours if they qualify.

Visit 2:

The subjects will receive the Fatigue Severity Scale (FSS), Modified Fatigue Impact Scale (MFIS), the Medical Outcomes Study 36 Item Short Form Health Survey (SF-36) and the Perceived Deficits Questionnaire (PDQ) from the Multiple Sclerosis Quality of Life Inventory (MSQLI). A physical exam and a neurological exam will be performed. Memantine and placebo pills will be dispensed; the neurological exam will include the Expanded Disability Status Scale, a 25 feet timed walk and the nine-hole peg test. The starting dose of memantine will be 5 mg once daily. The dose will be increased in 5 mg increments to 10 mg/day (5 mg twice a day), 15 mg/day (5 mg and 10 mg as separate doses), and 20 mg/day (10 mg twice a day) over 4 weeks and then continued at 20 mg for the rest of the study. In case of intolerable side effects when titrating the dose up the dose can be decreased to the previously tolerated dose. This visit will last 1 1/2 hours.

Telephone follow-up:

Four telephone follow-up visits will be carried-out for all enrolled subjects between Visits 2 and 3. These will occur at two weeks after Visit 2 and again at four, seven, and eleven weeks after Visit 2. These calls will review study procedures, check for compliance and reports of side effects. The person calling should be different from the person that administers the neuropsychological tests. The total time for the telephone visit is 15 minutes.

Side effect evaluation visit:

If any unexpected side effects occur, subjects will be evaluated with a physical exam and a neurological exam. This visit will last approximately 1 hour. Relapses will be documented as adverse events and the evaluation will include the EDSS, timed walk and 9 hole peg test.

Visit 3:

Subjects will return to clinic for the final assessment 4 weeks after the last telephone follow-up visit. At this visit, subjects will complete the full neuropsychological test battery. The SF-36 and PDQ, BDI, FSS, and MFIS will be administered. The MSNQ and the MNPI will be given to the caregiver. A repeat neurological and physical exam will be performed. This visit will last 2 ½ hours.

Study Design

Study Type:

Interventional

Actual Enrollment :

82 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double

Primary Purpose:

Treatment

Official Title:

Double Blind Placebo Controlled Pilot Trial of Memantine for Cognitive Impairment in Multiple Sclerosis

Study Start Date :

Apr 1, 2004

Actual Primary Completion Date :

Jan 1, 2009

Actual Study Completion Date :

Jan 1, 2009

Outcome Measures

Primary Outcome Measures

Change in the Paced Auditory Serial Addition Test and the California Verbal Learning Test II (multivariate end-point) after 15 weeks of treatment. []

Secondary Outcome Measures

Controlled Oral Word Association Test []
Stroop Color and Word Test []
Symbol Digit Modalities Test []
Delis-Kaplan Executive Function System []
Perceived Deficit Questionnaire []
Multiple Sclerosis Screening Neuropsychological Questionnaire []
Modified Neuropsychiatric Inventory []
Fatigue Severity Scale []
Modified Fatigue Impact Scale []
MS Quality of Life Inventory []
Beck Depression Inventory []

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

A diagnosis of multiple sclerosis as defined by the McDonald criteria. Patients with relapsing-remitting, secondary progressive, and primary progressive forms of MS are eligible.
Age between 18 and 65 years.
Demonstrated cognitive dysfunction at screening defined as a score worse than 1.0 standard deviations below the mean on the PASAT or the CVLT-II.

Exclusion Criteria:

A history of major depression, psychosis, or a score > 19 on the Beck's Depression Inventory.
Corrected binocular visual acuity worse than 20/50; any impairment of binocular color vision.
Patients that do not speak English as a primary language (fluency may impact performance).
A clinically significant MS exacerbation within 30 days of the screening
Pregnancy
Renal insufficiency.
History of seizures.
Patients using acetazolamide (Diamox, Ak-sol, Storzolamide), dichlorphenamide (Daranide), methazolamide (Neptazane) or topiramate (Topamax), dextromethorphan (Robitussin DM and other cold remedies), or amantadine (Symmetrel).
Use of medical marijuana in the prior six months.
History of alcohol abuse or illicit drug use in the prior six months.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	USC	Los Angeles	California	United States	90033
2	OHSU	Portland	Oregon	United States	97201
3	UT Southwestern	Dallas	Texas	United States	75390-9036
4	MS Hub	Seattle	Washington	United States	98101

Sponsors and Collaborators

Oregon Health and Science University
Forest Laboratories
University of Southern California
University of Texas Southwestern Medical Center
MS-Hub Seattle

Investigators

Principal Investigator: Dennis Bourdette, MD, Oregon Health and Science University
Principal Investigator: Lovera Jesus, MD, Oregon Health and Science University
Principal Investigator: Daniel Bandari, MD, University of Southern California
Principal Investigator: Ted Brown, MD, MS Hub
Principal Investigator: Elliot Frohman, MD, UT Southwestern