Therapy in Amyotrophic Lateral Sclerosis (TAME)

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects 30,000
Americans each year. Of these 30,000 Americans, it has been suggested that up to 50% will
experience cognitive and behavioral changes in the form of frontotemporal dysfunction and up
to 40% will meet criteria for frontotemporal dementia (FTD). Riluzole the only FDA approved
agent for ALS extends a patient's lifespan by 2-3 months, and there are no proven therapies
for the cognitive changes associated with ALS. More effective therapy for this universally
fatal disease is desperately needed.

Results from an open label pilot trial of 20 patients treated with memantine at 10 mg BID
suggested that treatment with the combination of memantine and riluzole slowed ALS disease
progression. This trial also showed that levels of specific protein biomarkers in the CSF at
baseline correlated with the rate of disease progression. A concurrent phase II study
performed by Dr Carvalho, found no effect with similar dosing; however, the study was limited
in terms of power. Comments on previous failed drug trials in ALS have raised the concern
that many ALS trials study a potential therapeutic agent at only a single dose and thus may
miss the potential efficacy of non FDA approved doses; therefore, this proposed study will
test a higher dose of memantine, 20 mg BID, in a double blind, placebo controlled, randomized
trial of 90 patients with ALS to determine if a therapy of memantine, especially in
combination with riluzole, can slow disease progression compared to treatment with riluzole
alone or no treatment. The primary outcome measure will be the rate of disease progression as
measured by the ALS Functional Rating Scale- Revised (ALSFRS-R). In addition the
investigators will examine the cognitive deficits seen in ALS patients measured by the ALS
Cognitive Behavioral Screen (ALS-CBS) and the Neuropsychiatric Inventory Questionnaire
(NPI-Q). Finally the investigators will examine specific validated protein serum biomarkers
to determine if there is a correlation between the levels of these biomarkers and the rate of
disease progression. In particular the investigators will measure the ratio of phosphorylated
heavy neurofilament to Complement 3 to see if this ratio is predictive of disease progression
and if the levels change during therapy with memantine.

This project will offer unique insights into this untreatable disease. If this study confirms
earlier results and suggests that memantine, when used in conjunction with riluzole,
significantly slows down the progression of the disease, as well as ameliorates cognitive
deficits in patients with fronto-temporal dysfunction, it will set the groundwork for
conducting a larger phase III trial.

Inclusion Criteria:

1. Age 18-85

2. Male or Female

3. Clinically definite, probable, probable lab-supported, or possible ALS by El Escorial
criteria

4. ALSFRS-R > 25

5. Must be willing to undergo longitudinal blood draws for biomarker analysis

6. Must have a caregiver

7. Availability and willingness to complete the study

8. Capable of providing informed consent and complying with trial procedures

9. If patients are taking riluzole and/or Radicava, they must be a on a stable dose for
at least thirty days prior to the baseline.

Exclusion Criteria:

1. Patients with FVC ≤ 60%

2. History of liver disease

3. Severe renal failure

4. History of intolerance to memantine

5. Onset of weakness for greater than 3 years

6. Any other co-morbid condition which would make completion of the trial unlikely

7. If female, pregnant or breast-feeding; or, if of childbearing age, an unwillingness to
use birth control.

8. Taking any trial medications. Non-trial medications are not cause for exclusion.

9. Unwillingness to provide consent