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

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 three doses of memantine (20, 40, and 60 mg/day; PO). Investigators will record any AE reported by the participants and caregivers and any clinically significant abnormalities in physical examination, ECGs, and laboratory tests. 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 70% of the study participants (more precisely, < 8 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. If a high number of AEs happen at the 60 mg/day dose of the study medication, the use of this particular dose may be suspended, with only the 40 mg/day dose used thereafter.

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 three doses and at washout (T2, T3, T4, T5, respectively). 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.

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 three doses and at washout (T2, T3, T4, T5). The minimum value for this scale is 0 and the maximum value is 38; higher scores mean a better outcome.

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 three doses and at washout (T2, T3, T4, T5). The minimum value of the PAL Memory Score Scale is 0 and the maximum value is 21; higher scores mean better outcomes.

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 three doses and at washout (T2, T3, T4, T5). 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.

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 (which is assumed to be 60 mg/day; i.e., at T4, or week 27).

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 (which is assumed to be 60 mg/day; i.e., at T4, or week 27). The minimum value of the scores is 0 and the maximum value is 40; with higher scores considered to be a better outcome.

This is a measure of receptive semantics, whereby the participant is asked to point to a picture (out of 4) that corresponds to a word spoken by the examiner. As this test has a 0.85 correlation with composite measures of Verbal IQ (i.e. from the Wechsler Intelligence Scale series), it can be used in conjunction with the Matrices subtest to estimate overall intellectual functioning. The total number of items correct will be used as the dependent variable, following the administration manual's rules for floors and ceilings. Values for this measure will be recorded as changes in score from baseline (T1) to after treatment with the highest tolerable dose of memantine (which is assumed to be 60 mg/day; i.e., at T4, or week 27). The minimum value for this scale is 0 and the maximum value is 192, higher scores mean a better outcome.

This is a measure of adaptive functioning that integrates information from 4 different domains (Communication, Daily Living Skills, Socialization, Motor Skills). It is in a questionnaire format, which a caregiver can complete while the participant is being tested. The Interview and Parent/Caregiver Form will be used. This form is normed for 3-21 years old. Standard scores for all indices will be derived from age norms and raw score will used as dependent variables. The Broad Independence Score will be recorded as change in score from baseline (T1) to after treatment with the highest tolerable dose of memantine (which is assumed to be 60 mg/day; i.e., at T4, or week 27).

The hypothesis to be tested is that either 40 mg/day or 60 mg/day memantine will produce significant improvements in neuropsychological test scores and, potentially, in plasma biomarkers of Alzheimer's disease (such as Aβ40, Aβ42, p-tau181, pTau217, p-tau231, sTREM2, and NfL). Assessments of plasma levels will be made as change in biomarker levels from baseline (i.e., before drug intervention or T1) to after the treatment at each of the three doses and at washout (T2, T3, T4, T5, respectively).

After the washout phase, a single oral dose (20 mg) will be used to evaluate the absorption, distribution, and excretion of memantine in young individuals with DS, which are expected to approximate first order kinetics. Discomfort caused by blood sampling for PK studies will be minimized by using minimally invasive procedures (finger pricks on a different finger at each prick) to obtain very small blood samples (100-200 microliters). Blood samples will be collected in cryotubes containing the anti-coagulant sodium heparin at pre-dosing, and at 1, 2, 4, 8, 24, 53, 101, and 197 hours after drug administration to perform PK analyses. Gas chromatography/mass spectrometry (GC/MS) will be used to perform measurements of plasma memantine concentrations. The resulting concentration values will be used to construct a concentration-time curve from which Cmax will be derived and expressed in ng/ml.

This parameter represents the time taken to reach the peak drug concentration (Cmax) after administration and indicates the rate of drug absorption. Concentration values from the concentration-time curve (see Outcome 11) will be used to calculate Tmax, which will be expressed in hours.

This parameter represents the time required for the drug concentration in the plasma to decrease by half. T½ will be calculated from the concentration-time curve (see Outcome 11) as the time it will take for the drug concentration to drop from Cmax to one half of Cmax, which will be expressed in hours.

This parameter represents the total drug exposure over time. AUC will be calculated by integrating the concentration-time curve (see Outcome 11) from time 0 to infinity (using a single-exponential decay model) and will be expressed in ng/ml.