Down Syndrome Memantine Follow-up Study

This study seeks to investigate if the medication Memantine Hydrochloride can help young
adults with Down syndrome. Two hundred persons with Down syndrome from both genders and
between 15 and 32 years of age will be recruited from two sites: Cleveland, OH, USA and São
Paulo, SP, Brazil. Participants will be assigned randomly to either a placebo group or a
group taking the active medication with a 50% probability of being on either group. Neither
the participants nor the investigators will know who will be taking the study medication and
who will be taking the placebo during the study. Only the investigational pharmacist will
have access to this information.

Up to 60 people with Down syndrome of the recruited study participants will take part on an
optional magnetic resonance imaging (MRI) study. This investigation is aimed at helping to
make the EEG study more precise and to find out whether the study medication has any
significant effect on the structure of the brain.

Additionally, we will recruit a control group of 60 age- and gender-matched participants
without Down syndrome. The goal is to investigate how different groups of people activate
their brains when they hear or see something, and if he can use high-density EEG and MRI to
see how this study medication works in persons with Down syndrome. In other words, this
additional control group should help us ascertain which parts of the test results are due to
a person having Down syndrome and which ones are not. Persons without Down syndrome will only
come for one EEG visit and one MRI visit, and not be asked to take the study medication.

The visits for the participants with Down syndrome will be as follows:

Screening visit (approximately 2-hour long). The subject will be asked about his/her health,
medical history, social background, and work background, as well as some simple questions to
determine performance on tests of memory and function that are part of this study. Informed
consent and assent will be obtained in this visit. At the end of this visit, an EEG machine
will be used to access brain responses to different auditory and visual stimuli. Some will be
asked if they would be willing to have an MRI performed, but this portion is not imperative.

A urine sample will be collected and used to obtain cells that will be kept frozen for
potential future studies. If the date of the screening visit is not convenient, this sample
can be collected during any of the next five visits.

Visit 1 (approximately 1 hour). Pulse, blood pressure, and an electrocardiogram (ECG) will be
taken. At the end of the visit, urine and blood samples will be taken. Pregnancy will also be
checked.

Visit 2 (2-3 hours). Tests of memory, learning, and reasoning skills will be conducted before
the start of the study medicine or placebo. At the end of this visit, a 60-day supply of
either the study medicine or the placebo will be given. This will need to be taken for 16
weeks.

Visit 3 (approximately 30 minutes). Eight weeks after the beginning of the treatment, the
participant will return to assess how she/he is doing under the treatment. Pulse, blood
pressure, a physical exam, and pregnancy will be checked. At this visit, another supply of
study medicine will be given.

Visit 4 (2-3 hours). Sixteen weeks after starting the medicine, the participant will take a
second series of tests in learning, memory, and reasoning skills to find out whether there
were any changes in these skills.

Visit 5 (approximately 1 hour). In the 16th or 17th week after starting the medicine, the
participant will meet one more time with the doctor from visits 1 and 3. Vital signs, a
physical exam, and an ECG will be taken, as well as a blood sample to ensure nothing has
changed with the participant's general health. For women, a pregnancy test will be performed.

If for some reason the subject withdraws from this study prior to Visit 5, he/she will be
asked to return to the clinic for a "Treatment Discontinuation Visit." In addition, if the
participant discontinues the medication prior to the end of the study, he/she will be asked
to complete a "Retrieved Dropout Visit" on the date that should have represented Visit 5.
Study medication will not be provided beyond the study period.

Inclusion Criteria:

- Cytogenetically documented Trisomy 21 or Complete Unbalanced Translocation of
Chromosome 21. Mosaic Trisomy 21 and partial translocations will be excluded from the
study

- No pregnancy by serum testing at screening. Females of child-bearing potential,
sexually active must be practicing a reliable method of birth control. Urine pregnancy
tests will be done at the 2 follow-up medical visits

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

- Vital signs within normal limits for age. Stable, medically treated hypotension will
be allowed

- ECG must demonstrate predominately normal sinus rhythm. Minor abnormalities documented
as clinically insignificant will be allowed

- Participants and their authorized representatives will provide written informed
consent

- Participants who have received any experimental drug for Down syndrome must undergo a
washout

- All participants must: Be in general good health as judged by the investigators; Be
able to swallow oral medication; Have a reliable caregiver or family member who agrees
to accompany participant to all visits, provide information about the participant as
required by the protocol, and ensure compliance with the medication schedule; Be
sufficiently proficient in English (USA) or Portuguese (Brazil) to reliably complete
the study assessments

- Age and gender matching participants without Down syndrome, must be: Males or females
without Down syndrome aged-matching (within 3 years) participants with Down syndrome
whom they are expected to serve as controls

Exclusion Criteria:

- Participant weighing less than 40 kg

- Current psychiatric or neurologic diagnosis other than Down syndrome (e.g., major
depressive disorder, schizophrenia, bipolar disorder, autism, Alzheimer disease)

- Current treatment with psychotropic drugs

- Drug or alcohol abuse or dependence

- 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.

- Current or expected (within the next 6 months) hospitalization or residence in a
skilled nursing facility (may reside in group homes or other residential settings with
no skilled nursing)

- Active or clinically significant conditions affecting absorption, distribution, or
metabolism of study drug (e.g. inflammatory bowel disease or celiac disease)

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

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

- Presence or recent history of seizure disorder (< 3 years).

- Clinically significant and/or clinically unstable systemic disease. (Those with
controlled 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; and those with
controlled diabetes mellitus must have an HbA1c of < 8.0% and a 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.

- Donation of blood or blood products less that 30 days prior to screening, while
participating in the study, or four weeks after completion of the study

- Inability 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

- Exclusion criteria for controls without Down syndrome: History of substance abuse,
major psychiatric disorder, attention deficit disorder, or learning disability; Beck
Depression Score greater than 10; Exclusion criteria specific to MR scanning;
Pregnancy; Neurologic history