Trial of Memantine for Cognitive Impairment in Multiple Sclerosis

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.

Inclusion Criteria:

1. 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.

2. Age between 18 and 65 years.

3. 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:

1. A history of major depression, psychosis, or a score > 19 on the Beck's Depression
Inventory.

2. Corrected binocular visual acuity worse than 20/50; any impairment of binocular color
vision.

3. Patients that do not speak English as a primary language (fluency may impact
performance).

4. A clinically significant MS exacerbation within 30 days of the screening

5. Pregnancy

6. Renal insufficiency.

7. History of seizures.

8. Patients using acetazolamide (Diamox, Ak-sol, Storzolamide), dichlorphenamide
(Daranide), methazolamide (Neptazane) or topiramate (Topamax), dextromethorphan
(Robitussin DM and other cold remedies), or amantadine (Symmetrel).

9. Use of medical marijuana in the prior six months.

10. History of alcohol abuse or illicit drug use in the prior six months.