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

NCT07531940 | Not Yet Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: STUDY20260078
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

Brief 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. 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 adolescents and 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.

Conditions

Down Syndrome; Intellectual Disability

Keywords

Memantine; Episodic Memory; CVLT; Short-term memory

Outcome Measures

Primary Outcomes (1)

• 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 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.

  36 weeks

Secondary Outcomes (4)

• 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

  36 weeks

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

  36 weeks

• Efficacy of the Drug Memantine as Assessed by Change in Score on the Paired Associates Learning (PAL) From the Cambridge Neuropsychological Test Automated Battery (CANTAB)

  36 weeks

• Efficacy of the Drug Memantine as Assessed by Change in Score on the Pattern Recognition Memory (PRM; Part of the Cambridge Neuropsychological Test Automated Battery -- CANTAB)

  36 weeks

Other Outcomes (9)

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

  27 weeks

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

  27 weeks

• Linguistic Functioning of the Participants as Assessed by Change in Score on the Peabody Picture Vocabulary Test-IV (PPVT-IV)

  27 weeks

Study Arms (1)

Memantine

EXPERIMENTAL

Three escalating oral doses of Memantine will be administered: 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); 3) Memantine 10 mg, three tablets bid orally for nine weeks (including four-week dose titration). 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

Interventions

Memantine DRUG

Escalating doses of Memantine (20 mg/day; 40 mg/day; 60 mg/day)

Also known as: Namenda

Memantine

Eligibility Criteria

• Age: 15 Years - 32 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University Hospitals Cleveland Medical Center: lead

Study Sites (1)

University Hospitals Case Medical Center

Cleveland, Ohio, 44106, United States

Location

Related Publications (24)

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  PMID: 24152324 BACKGROUND

• Costa 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.

  PMID: 17700645 BACKGROUND

• Scott-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.

  PMID: 22101180 BACKGROUND

• Scott-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.

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• Rueda 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.

  PMID: 20421694 BACKGROUND

• Lockrow 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.

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• Mann 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.

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• Zigman 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.

  PMID: 17910085 BACKGROUND

• Sinai 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.

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• Rubenstein 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.

  PMID: 39312235 BACKGROUND

• Parsons 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.

  PMID: 17904591 BACKGROUND

• Boada 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.

  PMID: 22806212 BACKGROUND

• Victorino 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.

  PMID: 28557265 BACKGROUND

• Costa 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.

  PMID: 34942135 BACKGROUND

• Costa 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.

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• Jack CR Jr, Andrews SJ, Beach TG, Buracchio T, Dunn B, Graf A, Hansson O, Ho C, Jagust W, McDade E, Molinuevo JL, Okonkwo OC, Pani L, Rafii MS, Scheltens P, Siemers E, Snyder HM, Sperling R, Teunissen CE, Carrillo MC. Revised criteria for the diagnosis and staging of Alzheimer's disease. Nat Med. 2024 Aug;30(8):2121-2124. doi: 10.1038/s41591-024-02988-7.

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  PMID: 31399883 BACKGROUND

MeSH Terms

Conditions

Down Syndrome; Intellectual Disability

Interventions

Memantine

Condition Hierarchy (Ancestors)

Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Chromosome Disorders; Genetic Diseases, Inborn; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Neurodevelopmental Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Amantadine; Adamantane; Bridged-Ring Compounds; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Study Officials

• Alberto C Costa, MD, PhD

  University Hospitals Cleveland Medical Center

  PRINCIPAL INVESTIGATOR

• Stephen L Ruedrich, MD

  University Hospitals Cleveland Medical Center

  STUDY DIRECTOR

Central Study Contacts

Melissa R Stasko, JD

CONTACT

216-844-7281; Melissa.Stasko@case.edu

Alberto C Costa, MD, PhD

CONTACT

216-844-7395; Alberto.Costa@case.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Physician

Study Record Dates

• First Submitted: April 4, 2026
• First Posted: April 15, 2026
• Study Start: June 1, 2026
• Primary Completion (Estimated): May 1, 2028
• Study Completion (Estimated): May 1, 2028
• Last Updated: May 11, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• 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.

Locations

US (1)