Escalating Doses of Memantine in Down Syndrome (MEDS-123)

Safety and Tolerability (as measured by incidence of adverse events)

Incidence of adverse events (AEs) will be monitored by clinical history, physical examinations, electrocardiograms (ECGs), and clinical laboratory tests during and after exposure to the up to three doses of memantine (20, 40, and potentially 60 mg/day; PO). Investigators will record any AE reported by the participants and caregivers and any clinically significant abnormalities. Memantine is expected to be well tolerated at higher than the typical dose used in the treatment of Alzheimer's disease (20 mg/day) by at least 80% of the study participants (more precisely, \< 6 participants will drop out of the study due to AEs related to the study medication). Participation discontinuation can be initiated by either the PI/co-investigators or participant/caregiver. Safety data will be collected at the 40 mg/day dose in the first 10 study participants, and a third dose (60 mg/day) will be added (in consultation with the FDA) for the next 15 participants only if 40 mg/day proves to be safe.

Efficacy of the Drug Memantine as Assessed by Change in Score on the California Verbal Learning Test-II (CVLT-II) Short Form Total Free Recall

This secondary outcome measure is focused on episodic memory. The CVLT-III short form assesses supraspan word learning ability as an index of episodic verbal long-term memory. The hypothesis to be tested is that treatment with memantine will produce significant improvements in this test. The main dependent variable selected, based on prior literature was the total number of target items correct summed across learning trials 1-4. The values for this measure will be recorded as change in score from baseline (i.e., before drug intervention or T1) to after the treatment at each of the two-to-three doses and at washout \[T2, T3, T4, and potentially T5 (if the 60 mg/day receives the go-ahead from the FDA\]. Scale Range: from 0 to 36; higher scores represent better outcomes. Different word lists will be used at each testing session to reduce practice effects.

Efficacy of the Drug Memantine as Assessed by Change in Score on the Recall of Digits Forward (From the Differential Ability Scales; DAS-II)

This is a measure of rote short-term verbal memory. The hypothesis to be tested is that treatment with memantine will produce significant improvements in this test. Total number of items correct will be used as the dependent variable. The values for this measure will be recorded as change in score from baseline (i.e., before drug intervention or T1) to after the treatment at each of the two-to-three doses and at washout \[T2, T3, T4, and potentially T5 (if the 60 mg/day receives the go-ahead from the FDA\]. The minimum value for this scale is 0 and the maximum value is 38; higher scores mean a better outcome.

Exploratory Assessment of Change in Score on the Paired Associates Learning (PAL) From the Cambridge Neuropsychological Test Automated Battery (CANTAB)

This is a measure of non-verbal memory that requires the participant to learn associations between an abstract visual pattern and its location. Two dependent variables have been selected: Total number of items correct on the first trial of each stage, and total number of stages completed. The values for this measure will be recorded as change in score from baseline (i.e., before drug intervention or T1) to after the treatment at each of the two-to-three doses and at washout \[T2, T3, T4, and potentially T5 (if the 60 mg/day receives the go-ahead from the FDA\]. The minimum value of the PAL Memory Score Scale is 0 and the maximum value is 21; higher scores mean better outcomes.

Exploratory Assessment of Change in Score on the Pattern Recognition Memory (PRM; Part of the Cambridge Neuropsychological Test Automated Battery -- CANTAB)

This is a measure of non-verbal memory. Total number correct across the two series of items presented will be used as the dependent variable. The values for this measure have been recorded as change in score from baseline (i.e., before drug intervention or T1) to after the treatment at each of the two-to-three doses and at washout \[T2, T3, T4, and potentially T5 (if the 60 mg/day receives the go-ahead from the FDA\]. The PRM total scale will be used in this study, which represents the sum of the PRM correct scores (ranging from 0 to 24) and the PRM delayed scores (ranging from 0 to 24). Therefore, the range of the PRM total scale is from 0 to 48; higher values mean better outcomes.

Intellectual Functioning of the Participants as Assessed by Change in Score on the Matrices Subtest of the Differential Ability Scales-II (DAS-II)

This test provides a measure of non-verbal reasoning ability that requires subjects to visually inspect a matrix of 4 or 9 pictures that has a missing piece. Participants have to infer a rule or pattern in the stimuli and select the appropriate response from a range of 4-6 possibilities. Because age norms are not available for individuals older than 17y11m, the ability score will be used as the dependent variable. This is an intermediate score based on Rasch modeling that corrects for different items set being administered to participants. The minimum value of the DAS-II Rasch Score Scale is 0 and the maximum value is 153; higher scores mean better outcomes. Values for this measure will be recorded as changes in score from baseline (T1) to after treatment with the highest tolerable dose of memantine.

Linguistic Functioning of the Participants as Assessed by Change in Score on the Test for Reception of Grammar 2nd Edition (TROG-II)

This is a measure of receptive syntax skills. Participants are asked to point to a picture (out of 4) that corresponds to a phrase or sentence spoken by the examiner. The total number of items correct (rather than blocks passed) will be used as the dependent variable, following the administration manual's ceiling rule. Values for this measure will be recorded as changes in score from baseline (T1) to after treatment with the highest tolerable dose of memantine. The minimum value of the scores is 0 and the maximum value is 40; with higher scores considered to be a better outcome.