Down SyndromePhase 1NCT07531940
Escalating Doses of Memantine in Down Syndrome (MEDS-123)
A Phase 1 study testing Memantine in people with Down Syndrome and Intellectual Disability, run by University Hospitals Cleveland Medical Center at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 32 years
- Conditions the study is for
- Down Syndrome, Intellectual Disability, Alzheimer Dementia (AD)
- What is being tested?
- Memantine
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 25 participants
- Where
- 1 siteUnited States
- Study dates
- 14 Oct 2026to May 2028
- Phase
- Phase 1
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 32 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- Cytogenetically documented Trisomy 21 or Complete Unbalanced Translocation of Chromosome 21. Mosaic Trisomy 21 and partial translocations will be excluded from the study.
- Vital signs within normal limits for age.
- 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.
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- Participants and their authorized representatives will provide written informed consent.
- Participants who have received any experimental drug for DS must undergo a washout for a minimum of 5 half-lives of any experimental medications.
- 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 to reliably complete the study assessments
Who cannot join
- Participant weighing less than 40 kg
- Current psychiatric or neurologic diagnosis other than Down syndrome (This includes, but is not limited to, major depressive disorder, schizophrenia, schizoaffective disorder, any other psychotic disorder, bipolar disorder, seizure disorder (no seizures for more than 3 years), autism, Down syndrome regression disorder, Alzheimer disease, Parkinson's disease, cerebrovascular disease, other dementias, brain tumor, or other known structural brain abnormalities.)
- Current treatment with psychotropic drugs.
- Drug or alcohol abuse or dependence within past 5 years.
- 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).
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- 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.
- Use of NMDA receptor antagonists, such as amantadine (Symmetrel), ketamine, or dextromethorphan during the 30 days prior to screening.
- 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.
- Unexplained alkaline urine conditions.
- Participants with severe renal impairment (i.e., estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73m2) will be excluded from the proposed clinical trial. The eGFR will be calculated using the eGFR Calculator from the National Kidney Foundation (https://www.kidney.org/professionals/gfr_calculator) using serum creatinine, age, sex, adjusted for body surface area (for medication-related decision making, using Dubois Method).
- Participants with severe hepatic impairment (Child-Pugh Category C) will also be excluded from the proposed clinical trial. Child-Pugh Category will be calculated using the MSD Professional Version online calculator (https://www.msdmanuals.com/professional/multimedia/clinical-calculator/child-pugh-classification-for-severity-of-liver-disease).
- History of persistent cognitive deficits immediately following head trauma. (Note: remote history of head trauma without cognitive sequelae is not an exclusion.)
- Cardiac QTc interval ≥ 480 ms.
- History or presence of encephalitis.
- 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 (>40 dB hearing loss) or visual impairment (best corrected visual acuity of less than 20/60) or other clinically relevant issues, such as behavioral issues that may prevent full participation in the study.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site
University Hospitals Case Medical Center
Cleveland, Ohio, 44106
Melissa R Stasko, JD, 216-983-2153, Melissa.Stasko@case.edu
Alberto C Costa, MD, PhD, 216-983-5613, Alberto.Costa@case.edu
About this study
Official title: Phase 1B Trial on Escalating Doses of Memantine in Down Syndrome
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.
Read the detailed description
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.
- Being tested
- Memantine
- Keywords
- Memantine, Episodic Memory, CVLT, Short-term memory
- Medical subject headings
- Down Syndrome, Intellectual Disability, Alzheimer Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MemantineDrug
Also called Namenda
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).
| Study group | Role | What they receive |
|---|---|---|
| Memantine | Experimental | 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. Receives: Drug: Memantine |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Secondary outcomes (2)
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.
Measured: 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.
Measured: 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.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Apr 2026
- Study start14 Oct 2026 (estimated)
- Primary completionMay 2028 (estimated)
- Study completionMay 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (24)Papers the sponsor has linked to this study.
- Other trials for Down SyndromeStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 25 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University Hospitals Cleveland Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute on Aging (NIA)
- Responsible party
- Principal investigator, Stephen Ruedrich, University Hospitals Cleveland Medical Center
- Investigators
- Alberto C Costa, MD, PhD, Principal investigator, University Hospitals Cleveland Medical CenterStephen L Ruedrich, MD, Study director, University Hospitals Cleveland Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07531940
- Sponsor's protocol ID
- STUDY20260078
- Status last verified
- Sep 2026
- First submitted
- 4 Apr 2026
- Last updated
- 5 Oct 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- 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.
Publications
Costa AC. The glutamatergic hypothesis for Down syndrome: the potential use of N-methyl-D-aspartate receptor antagonists to enhance cognition and decelerate neurodegeneration. CNS Neurol Disord Drug Targets. 2014 Feb;13(1):16-25. doi: 10.2174/18715273113126660183.
PubMed 24152324Costa AC, Scott-McKean JJ, Stasko MR. Acute injections of the NMDA receptor antagonist memantine rescue performance deficits of the Ts65Dn mouse model of Down syndrome on a fear conditioning test. Neuropsychopharmacology. 2008 Jun;33(7):1624-32. doi: 10.1038/sj.npp.1301535. Epub 2007 Aug 15.
PubMed 17700645Scott-McKean JJ, Costa AC. Exaggerated NMDA mediated LTD in a mouse model of Down syndrome and pharmacological rescuing by memantine. Learn Mem. 2011 Nov 18;18(12):774-8. doi: 10.1101/lm.024182.111. Print 2011 Dec.
PubMed 22101180Scott-McKean JJ, Roque AL, Surewicz K, Johnson MW, Surewicz WK, Costa ACS. Pharmacological Modulation of Three Modalities of CA1 Hippocampal Long-Term Potentiation in the Ts65Dn Mouse Model of Down Syndrome. Neural Plast. 2018 Apr 10;2018:9235796. doi: 10.1155/2018/9235796. eCollection 2018.
PubMed 29849573Rueda N, Llorens-Martin M, Florez J, Valdizan E, Banerjee P, Trejo JL, Martinez-Cue C. Memantine normalizes several phenotypic features in the Ts65Dn mouse model of Down syndrome. J Alzheimers Dis. 2010;21(1):277-90. doi: 10.3233/JAD-2010-100240.
PubMed 20421694Lockrow J, Boger H, Bimonte-Nelson H, Granholm AC. Effects of long-term memantine on memory and neuropathology in Ts65Dn mice, a model for Down syndrome. Behav Brain Res. 2011 Aug 10;221(2):610-22. doi: 10.1016/j.bbr.2010.03.036. Epub 2010 Apr 2.
PubMed 20363261Mann DM, Yates PO, Marcyniuk B. Alzheimer's presenile dementia, senile dementia of Alzheimer type and Down's syndrome in middle age form an age related continuum of pathological changes. Neuropathol Appl Neurobiol. 1984 May-Jun;10(3):185-207. doi: 10.1111/j.1365-2990.1984.tb00351.x.
PubMed 6234474Zigman WB, Lott IT. Alzheimer's disease in Down syndrome: neurobiology and risk. Ment Retard Dev Disabil Res Rev. 2007;13(3):237-46. doi: 10.1002/mrdd.20163.
PubMed 17910085Sinai A, Mokrysz C, Bernal J, Bohnen I, Bonell S, Courtenay K, Dodd K, Gazizova D, Hassiotis A, Hillier R, McBrien J, McCarthy J, Mukherji K, Naeem A, Perez-Achiaga N, Rantell K, Sharma V, Thomas D, Walker Z, Whitham S, Strydom A. Predictors of Age of Diagnosis and Survival of Alzheimer's Disease in Down Syndrome. J Alzheimers Dis. 2018;61(2):717-728. doi: 10.3233/JAD-170624.
PubMed 29226868Rubenstein E, Tewolde S, Michals A, Weuve J, Fortea J, Fox MP, Pescador Jimenez M, Scott A, Tripodis Y, Skotko BG. Alzheimer Dementia Among Individuals With Down Syndrome. JAMA Netw Open. 2024 Sep 3;7(9):e2435018. doi: 10.1001/jamanetworkopen.2024.35018.
PubMed 39312235Parsons CG, Stoffler A, Danysz W. Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system--too little activation is bad, too much is even worse. Neuropharmacology. 2007 Nov;53(6):699-723. doi: 10.1016/j.neuropharm.2007.07.013. Epub 2007 Aug 10.
PubMed 17904591Boada R, Hutaff-Lee C, Schrader A, Weitzenkamp D, Benke TA, Goldson EJ, Costa AC. Antagonism of NMDA receptors as a potential treatment for Down syndrome: a pilot randomized controlled trial. Transl Psychiatry. 2012 Jul 17;2(7):e141. doi: 10.1038/tp.2012.66.
PubMed 22806212Victorino DB, Bederman IR, Costa ACS. Pharmacokinetic Properties of Memantine after a Single Intraperitoneal Administration and Multiple Oral Doses in Euploid Mice and in the Ts65Dn Mouse Model of Down's Syndrome. Basic Clin Pharmacol Toxicol. 2017 Nov;121(5):382-389. doi: 10.1111/bcpt.12816. Epub 2017 Jul 10.
PubMed 28557265Costa ACS, Brandao AC, Boada R, Barrionuevo VL, Taylor HG, Roth E, Stasko MR, Johnson MW, Assir FF, Roberto MP, Salmona P, Abreu-Silveira G, Bederman I, Prendergast E, Huls A, Abrishamcar S, Mustacchi Z, Scheidemantel T, Roizen NJ, Ruedrich S. Safety, efficacy, and tolerability of memantine for cognitive and adaptive outcome measures in adolescents and young adults with Down syndrome: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2022 Jan;21(1):31-41. doi: 10.1016/S1474-4422(21)00369-0.
PubMed 34942135Costa ACS, Brandao AC, Leiva V, Taylor HG, Johnson MW, Salmona P, Abreu-Silveira G, Scheidemantel T, Roizen NJ, Ruedrich S, Boada R. Baseline Neuropsychological Characteristics of Adolescents and Young Adults with Down Syndrome Who Participated in Two Clinical Trials of the Drug Memantine. Brain Sci. 2025 Oct 29;15(11):1164. doi: 10.3390/brainsci15111164.
PubMed 41300171