A Phase 1 interventional study of Memantine in Down Syndrome, Intellectual Disability and Alzheimer Dementia (AD), sponsored by University Hospitals Cleveland Medical Center. Not yet recruiting at 1 site in United States. Open to participants aged 18 Years to 32 Years. Per ClinicalTrials.gov, last updated 2026-10-05.
Sponsored by University Hospitals Cleveland Medical Center · Phase 1, Interventional, and Treatment
Down syndrome (DS) is typically caused by an extra chromosome 21 in the cell nucleus (trisomy 21, or T21). T21 is both the most common cause of genetically defined intellectual disability and the earliest documented cause of Alzheimer's disease (AD)-type pathology. Currently, all presymptomatic individuals with DS are classified as having 'Stage 0' DS-associated AD (DSAD). DSAD pathology evolves inexorably, with virtually all individuals with DS developing AD pathology by age 40, and approximately 50% meeting clinical dementia diagnosis criteria at 55 years of age. This study will test the hypothesis that the FDA-approved AD drug memantine, at higher-than-standard doses, may be effective as a cognitive enhancer in young adults with DS. The primary goal of this phase 1b clinical trial will be the assessment of the safety and tolerability of three memantine doses in persons with DS. In addition, we will assess the effect of this drug on cognitive test scores and plasma biomarkers of AD in the study participants. Finally, we will also investigate steady-state plasma levels of memantine and the time course of memantine plasma levels after a single dose in the study participants (pharmacokinetics, or PK). The data generated through this phase 1b study will provide the essential safety, PK, and preliminary efficacy signals required to advance a phase 2 trial evaluating high-dose memantine as a first-in-class therapeutic strategy in DS.
Based on preclinical evidence from mouse models of DS collected by our research team and others, we hypothesized over a decade ago that NMDA receptor dysfunction may play significant pathogenic roles in both the neurodevelopmental and the neurodegenerative components of DS. Four years ago, our research team published in the results of a two-site, randomized phase 2 trial of the AD drug memantine to investigate the safety, efficacy, and tolerability of this drug on cognitive and adaptive outcome measures in young adults with DS. In this study, we found no evidence of cognitive-enhancing effects of standard doses of memantine treatment in the primary analysis. Memantine was well tolerated, with infrequent mild-to-moderate adverse events observed. Notably, however, measured plasma memantine levels in more than 90% of study participants were lower than those considered therapeutic in patients with AD (0.5 -1 μmol/l), and much lower than the doses used in preclinical behavioral studies in mouse models of DS (1.7 μmol/l). In this same clinical study, an exploratory analysis of data from 23 participants with memantine plasma levels >0.4 μmol/l (representing the top quartile of quantified memantine plasma levels) revealed significant improvement in scores on two neuropsychological measures in the memantine arm compared to the placebo arm. One of these measures (the California Verbal Learning Test short form second version, or CVLT-II sf) assessed episodic memory, whereas the other (the Recall of Digits Forward from the Differential Ability Scales Second Edition, or DAS-II) measured short-term memory. These findings led us to hypothesize that higher-than-standard doses of memantine should produce significant cognitive improvements in most individuals with DS, with minimal adverse events.
The exploratory analysis performed in that study pointed to possibility that higher-than-standard therapeutic memantine doses might not only produce statistically significant efficacy in a larger proportion of individuals with DS but also yield effect sizes significantly higher than those observed in that study. Although there are several examples in the literature where memantine was used at doses as high as 60 mg/day in the treatment of various neurological disorders, the key question is whether the majority of individuals with DS would tolerate such doses.
Here we describe an open-label phase 1b clinical trial, in which 25 participants with DS will receive escalating doses of memantine (20 mg/day and 40 mg/day for 9 weeks at each of these dosing stages; a third dose of 60 mg/day may be approved by the Food and Drug Administration (FDA), pending safety data to be collected at the 40 mg/day dose level in the first 10 study participants). Safety and tolerability will be the primary outcome measures for this phase of the project. However, this initial study will also provide a unique chance for us to fine tune the neuropsychological test battery to better understand the psychometric properties of each test, including test-retest reliability across multiple, closely spaced retest sessions. Assessments of plasma levels of memantine at each dose level will allow us to confirm the expected linear relationship between oral dose and steady state levels of this drug. Additionally, the assessment of plasma levels of various AD plasma biomarkers should provide preliminary objective information on whether memantine can affect such biomarkers at Stage 0 DSAD. The inclusion of a washout visit will allow us to evaluate the reversibility of any observed drug effect. 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 (through PK properties, such as time to peak, peak concentration, and half-life), which are expected to approximate first order kinetics.
438 studies on the registry are indexed under Down Syndrome; 99 are open to participants now.
This study's planned enrollment of 25 is below the median of 37 across 286 interventional studies indexed under Down Syndrome.
Browse Down Syndrome studies →University Hospitals Cleveland Medical Center is the lead sponsor of 295 studies on the registry; 45 are open to participants now.
Of its 36 completed or terminated interventional studies of FDA-regulated products, 30 (83%) have results posted.
Counted across the registry records on this site, refreshed daily.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
A recording of the heart’s electrical activity, taken with stickers on the chest, arms and legs. It takes a few minutes and does not hurt.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
A planned gap after a treatment, so that its effects can lessen before the study treatment or a study assessment. Ask the study team and the doctor who prescribed it before changing any medicine.
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
A blood test of average blood sugar over the past two to three months, given as a percentage or in mmol/mol. 6.5% (48 mmol/mol) or more is the usual threshold for diabetes, normally confirmed by a second test.
GFR (glomerular filtration rate) is how much blood the kidneys filter each minute. It is usually estimated from a blood test — eGFR, by formulas such as CKD-EPI or MDRD — and some studies ask for it to be measured directly instead. Usually given in mL/min/1.73 m².
Check the method, the units and the minimum the study states. A value of 90 or above is in the normal-or-high range, but kidney damage can show in other tests too.
A score of how well the liver works in people with liver disease such as cirrhosis: class A is mild, B moderate and C severe.
On an ECG, the QT interval is the time the heart’s lower chambers take to activate electrically and recover in each beat. QTc is that time adjusted for heart rate (QTcF by Fridericia’s formula, QTcB by Bazett’s). Some medicines lengthen it, and a long QTc can raise the risk of a dangerous heart rhythm.
The study may name a correction formula and a limit in milliseconds, often around 450–480.
Childbearing potential
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraception
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ECG (electrocardiogram)
A recording of the heart’s electrical activity, taken with stickers on the chest, arms and legs. It takes a few minutes and does not hurt.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Washout period
A planned gap after a treatment, so that its effects can lessen before the study treatment or a study assessment. Ask the study team and the doctor who prescribed it before changing any medicine.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Clinically significant
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraindication
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
HbA1c
A blood test of average blood sugar over the past two to three months, given as a percentage or in mmol/mol. 6.5% (48 mmol/mol) or more is the usual threshold for diabetes, normally confirmed by a second test.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
GFR and eGFR (kidney filtering)
GFR (glomerular filtration rate) is how much blood the kidneys filter each minute. It is usually estimated from a blood test — eGFR, by formulas such as CKD-EPI or MDRD — and some studies ask for it to be measured directly instead. Usually given in mL/min/1.73 m².
Check the method, the units and the minimum the study states. A value of 90 or above is in the normal-or-high range, but kidney damage can show in other tests too.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Child-Pugh class
A score of how well the liver works in people with liver disease such as cirrhosis: class A is mild, B moderate and C severe.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
QT and QTc
On an ECG, the QT interval is the time the heart’s lower chambers take to activate electrically and recover in each beat. QTc is that time adjusted for heart rate (QTcF by Fridericia’s formula, QTcB by Bazett’s). Some medicines lengthen it, and a long QTc can raise the risk of a dangerous heart rhythm.
The study may name a correction formula and a limit in milliseconds, often around 450–480.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Two escalating oral doses of Memantine will be administered (with a third dose of 60 mg/day that may be approved by the FDA, pending safety data to be collected at the 40 mg/day dose level in the first 10 study participants): 1) Memantine 10 mg, one tablet bid orally for nine weeks (including four-week standard dose titration protocol); 2) Memantine 10 mg, two tablets bid orally for nine weeks (including four-week dose titration); and potentially Memantine 10 mg, three tablets bid orally for nine weeks (pending FDA approval). This will be followed by a nine-week washout period and a single 20 mg oral dose of memantine to generate pharmacokinetic (PK) data.
Drug: Memantine
Escalating doses of Memantine: 20 mg/day; 40 mg/day; and potentially 60 mg/day (pending FDA approval after safety data review at the 40 mg/day dose level in the first 10 study participants).
Also known as: Namenda
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.
Time frame: 27 weeks for the first 10 participants and 36 weeks for the next 15 participants if the 60 mg/day-dose 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.
Time frame: 27 weeks for the first 10 participants and 36 weeks for the next 15 participants if the 60 mg/day-dose proves to be safe.
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.
Time frame: 27 weeks for the first 10 participants and 36 weeks for the next 15 participants if the 60 mg/day-dose proves to be safe.
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.
Time frame: 27 weeks for the first 10 participants and 36 weeks for the next 15 participants if the 60 mg/day-dose proves to be safe.
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.
Time frame: 27 weeks for the first 10 participants and 36 weeks for the next 15 participants if the 60 mg/day-dose proves to be safe.
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.
Time frame: 18 weeks for the first 10 participants and 27 weeks for the next 15 participants if the 60 mg/day-dose proves to be safe.
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.
Time frame: 18 weeks for the first 10 participants and 27 weeks for the next 15 participants if the 60 mg/day-dose proves to be safe.
Linguistic Functioning of the Participants as Assessed by Change in Score on the Peabody Picture Vocabulary Test-IV (PPVT-IV)
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. The minimum value for this scale is 0 and the maximum value is 192, higher scores mean a better outcome.
Time frame: 18 weeks for the first 10 participants and 27 weeks for the next 15 participants if the 60 mg/day-dose proves to be safe.
Adaptive/Behavioral Functioning of the Participants as Assessed by Change in Score on the Vineland Adaptive Behavior Scales, Third Edition (Vineland 3)
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.
Time frame: 18 weeks for the first 10 participants and 27 weeks for the next 15 participants if the 60 mg/day-dose proves to be safe.
Measurement of plasma biomarkers of Alzheimer's disease
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, GFAP, 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 two-to-three doses and at washout \[T2, T3, T4, and potentially T5 (if the 60 mg/day receives the go-ahead from the FDA\].
Time frame: 27 weeks for the first 10 participants and 36 weeks for the next 15 participants if the 60 mg/day-dose proves to be safe.
Pharmacokinetics (PK): Maximum Plasma Concentration [Cmax]
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.
Time frame: 197 hours
Pharmacokinetics (PK): Time to Reach Cmax (Tmax)
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.
Time frame: 197 hours
Pharmacokinetics (PK): Half-Life (T½)
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.
Time frame: 197 hours
Pharmacokinetics (PK): Area Under the Concentration-Time Curve (AUC)
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.
Time frame: 197 hours
Plan to share: Yes — Trial data can be made available on reasonable request to the corresponding author and must be accompanied by detailed study proposals, a description of study objectives, and a statistical analysis plan. Access to available deidentified individual participant data (IPD) and the trial protocol may be granted 12 months after publication. Any request must be approved by the corresponding author and the principal investigators of each center. Each request will be checked for compatibility with regulatory (institutional review board) requirements as well as compatibility with participant informed consent.
Supporting information: Study protocol, Statistical analysis plan, Informed consent form, Clinical study report
Time frame: 12 months after the report published.
Access criteria: Each request will be checked for compatibility with regulatory (institutional review board) requirements as well as compatibility with participant informed consent.
From the registry record's own update history. This site started tracking changes on Sep 25, 2026; for anything earlier, see the record history on ClinicalTrials.gov ↗
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Studies of the drug tested here: Memantine
University Hospitals Cleveland Medical Center →