Efficacy and Safety Study of Memantine Hydrochloride in Enhancing the Cognitive Abilities of Young Adults With Down Syndrome

Down syndrome, which is the result of the trisomy of Chromosome 21, is the most common
genetically defined cause of intellectual disabilities. The estimated number of people with
Down syndrome in the United States is approximately 300,000, and this figure is expected to
continue increasing due to projected increases in the life expectancy of people with Down
syndrome. Although this population trend reflects improvements in the general health care
of individuals with Down syndrome, there has not been a parallel progress in the
understanding of the pathogenesis and potential treatment of the psychological and
neurological components of this genetic condition. These include various degrees of
intellectual disability, increased incidence of seizure disorder in relation to the general
population, motor dysfunction (including hypotonia), abnormal oculomotor and vestibular
functions, substantial visual deficits, a neuropathology indistinguishable from Alzheimer
disease, and increased incidence of major depression and dementia in adults.

Over the last fifteen years, progress in the quantitative description of specific traits
associated with Down syndrome, the availability of postnatal-viable aneuploid mouse models
of Down syndrome, and our progressively more sophisticated knowledge of the human and mouse
genomes have provided investigators in this field with a realistic opportunity to start
bridging the gap between basic and clinical research.

Whereas individuals with Down syndrome maintain relatively high levels of social
intelligence and procedural learning, they often suffer from grossly impaired declarative or
explicit memory. Not surprisingly, brain structures associated with declarative memory,
namely the hippocampal and parahippocampal regions of the medial temporal lobe, are the most
severely affected in persons with Down syndrome. The nature of these deficits suggests that
therapies targeting hippocampal function would be particularly efficacious in ameliorating
the cognitive deficits seen in persons with Down syndrome and, consequently, would enhance
their quality of life.

Glutamatergic neurons form the major excitatory system in the brain and play a pivotal role
in many physiological functions. Apart from the physiological role of glutamate, excessive
activation of its receptors can also evoke neuronal dysfunction and even damage/death. Cell
death ascribed to an excessive activation of glutamate receptors has been termed
'excitotoxicity' and seems to occur in acute insults such as stroke and trauma, but it may
be also associated with chronic neurodegenerative diseases such as Alzheimer disease.
N-methyl-D-aspartate (NMDA) receptor (NMDAR) mediated glutamate excitotoxicity is thought to
play a major role in Aβ-induced neuronal death. This idea is part of the foundation of the
glutamatergic hypothesis (as opposed to the cholinergic hypothesis) for Alzheimer disease.

Memantine is an NMDAR antagonist that has been reported to be effective therapeutically in
Alzheimer disease. It has been available in Germany as well as in most of the European Union
for more than two decades. Recently, it has been approved for moderate to severe dementia
in the US. The chemical name for memantine hydrochloride is 1-amino-3,5-dimethyladamantane
hydrochloride. Memantine is an uncompetitive, moderate affinity, antagonist of NMDARs. It
has been proposed that therapeutic doses of this drug inhibit the pathological effect of
NMDAR activation while leaving unaffected NMDAR-mediated physiological processes involved in
learning and memory. Recent preclinical data from the laboratory of this trial's P.I. on the
mouse model for DS Ts65Dn have suggested a dysregulation of NMDAR activity in these animals
and demonstrated improvement on learning and memory measures by the use of acute doses of
memantine.

In all clinical trials so far, memantine was found safe and well tolerated. The tolerability
of an NMDAR antagonist depends upon its affinity towards the receptors, unbinding kinetics,
and voltage dependency. Memantine is thought to improve the fidelity of synaptic
transmission. Such action is predicted to provide both neuroprotection and symptomatic
restoration of synaptic plasticity by one and the same mechanism.

Recent open-label studies suggest that memantine may be clinically useful and well tolerated
in young individuals with other conditions that produce cognitive disabilities, such as
autism and attention deficit hyperactivity disorder (ADHD).

Because of the ubiquity of Alzheimer disease-type pathology in persons with Down syndrome,
the preclinical findings consistent with dysregulation of NMDAR activity in mouse models of
Down syndrome, the safety profile of memantine (which is superior to the AChE inhibitors
that are already being tested in persons with Down syndrome), and the possibility that
memantine may indeed delay the onset of Alzheimer disease-type pathology in young adults
with Down syndrome, all the professionals involved with this project decided that a
small-scale randomized controlled clinical trial was warranted at present.

We would like to emphasize that the goal of this study is to evaluate the efficacy,
tolerability and safety of memantine hydrochloride in enhancing the cognitive abilities of
young adults with Down syndrome aged 18-32 years. Therefore, the present investigation is a
non-overlapping and complementary clinical trial to the randomized, placebo-controlled
clinical trial on the efficacy and tolerability of memantine in preventing age-related
cognitive deterioration and dementia in people with Down syndrome age 40 and over
(http://www.clinicaltrials.gov/ct2/show/record/NCT00240760?term=down+syndrome&rank=15)
currently being carried out by our colleagues in London.

Inclusion Criteria:

- Males or females with Down syndrome aged 18 to 32 years. The documented cytogenetic
diagnosis should be either "Trisomy 21", or "Complete Unbalanced Translocation of the
Chromosome 21".

- Female subjects must be documented not to be pregnant by serum testing at screening.

- Laboratory findings within normal limits or judged clinically insignificant at
baseline.

- Vital signs must be within normal limits for their age. (Medically treated
hypotension will be allowed.)

- Screening ECG must demonstrate predominately normal sinus rhythm. Minor abnormalities
documented as clinically insignificant by the investigator will be allowed. (Subjects
with clinically significant but stable ECG abnormalities may enter the trial only
with the permission of the principal investigators.)

- Subjects and their authorized representative will provide written informed consent
and assessment.

- Subjects who have been receiving any experimental drug for Down syndrome must undergo
a washout (~ 30 days or five half-lives of the drug, whichever is longer).

- Sufficiently proficient in English to be capable of reliably completing study
assessments.

- Able to swallow oral medication (crushing of tablets will not be permitted).

- Must have a reliable caregiver or family member who agrees to accompany the subject
to all visits, provide information about the subject as required by this protocol,
and ensure compliance with the medication schedule. The subject must have contact at
least once a day with the caregiver.

- Generally good health and judged by the investigators to be able to fully participate
in the trial.

Exclusion Criteria:

- Subjects weighing less than 40 kg.

- Any current psychiatric or neurologic diagnosis other than Down syndrome.

- Subjects who currently meet or have within the past five years met DSM-IV criteria
for drug or alcohol abuse or dependence.

- Subjects who, in the judgment of the investigators, currently represent a significant
suicide risk or who would require treatment with electro-convulsive therapy or with
psychotropic drugs during the study or who have received treatment with a depot
neuroleptic drug within 6 months of entering the study.

- Subjects who are hospitalized or residing in a skilled nursing facility or subjects
who are anticipated to enter a nursing home within the next 6 months. (Subjects may
reside in group homes of other residential settings where they do not require or
receive skilled nursing.)

- Any active or clinically significant conditions affecting absorption, distribution or
metabolism of the study drugs.

- Subjects with significant allergies to or other significant intolerance of memantine
therapy, its ingredients, or with contraindications to memantine therapy as stated in
the prescribing information.

- Subjects who are expected to require general anesthetics during the course of the
study.

- History or presence of seizure disorder (less than 3 years) or encephalitis.

- History of malignant neoplasms treated within 3 years prior to study entry or where
there is current evidence of recurrent or metastatic disease.

- Subjects with treated hypothyroidism must be on a stable dose of medication for at
least 3 months prior to screening and have normal serum T-4 and TSH at screening.
Subjects with diabetes mellitus controlled by diet, oral medication or insulin must
have an HbA1c of < 8.0% and random serum glucose value of < 170 mg/dl.

- Severe infections or a major surgical operation within 3 months prior to screening.

- History of persistent cognitive deficits immediately following head trauma.

- Subjects who have donated blood or blood products during the 30 days prior to
screening who plan to donate blood while participating in the study or within four
weeks after completion of the study.

- Subjects who may not be able to comply with the protocol or perform the outcomes
measures due to significant hearing or visual impairment or other issues judged
relevant by the investigators.