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

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 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.

Study Overview

• Status: Not yet recruiting
• Conditions: Intellectual Disability; Down Syndrome
• Intervention / Treatment: Drug: Memantine

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 adolescents and 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, 40 mg/day and 60 mg/day; for 9 weeks at each of these dosing stages). 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.

• Study Type: Interventional
• Enrollment (Estimated): 25
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Melissa R Stasko, JD; Phone Number: 216-844-7281; Email: Melissa.Stasko@case.edu
• Study Contact Backup: Name: Alberto C Costa, MD, PhD; Phone Number: 216-844-7395; Email: Alberto.Costa@case.edu

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Case Medical Center
      • Contact: Melissa R Stasko, JD; Phone Number: 216-983-2153; Email: Melissa.Stasko@case.edu
      • Contact: Alberto C Costa, MD, PhD; Phone Number: 216-983-5613; Email: Alberto.Costa@case.edu
      • Principal Investigator: Alberto C Costa, MD, PhD
      • Sub-Investigator: Stephen L Ruedrich, MD
      • Sub-Investigator: Katherine Koenig, PhD
      • Sub-Investigator: Richard Boada, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Memantine; 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; Escalating doses of Memantine (20 mg/day; 40 mg/day; 60 mg/day); Other Names: Namenda

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 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.	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)	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.	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)	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.	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)	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.	36 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 (which is assumed to be 60 mg/day; i.e., at T4, or week 27).	27 weeks
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 (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.	27 weeks
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 (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.	27 weeks
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 (which is assumed to be 60 mg/day; i.e., at T4, or week 27).	27 weeks
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, 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).	36 weeks
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.	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.	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.	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.	197 hours

Collaborators and Investigators

• Sponsor: University Hospitals Cleveland Medical Center
• Investigators: Principal Investigator: Alberto C Costa, MD, PhD, University Hospitals Cleveland Medical Center; Study Director: Stephen L Ruedrich, MD, University Hospitals Cleveland Medical Center

Publications and helpful links

General Publications

• 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.
• Hithersay R, Startin CM, Hamburg S, Mok KY, Hardy J, Fisher EMC, Tybulewicz VLJ, Nizetic D, Strydom A. Association of Dementia With Mortality Among Adults With Down Syndrome Older Than 35 Years. JAMA Neurol. 2019 Feb 1;76(2):152-160. doi: 10.1001/jamaneurol.2018.3616.
• Sinis N, Birbaumer N, Gustin S, Schwarz A, Bredanger S, Becker ST, Unertl K, Schaller HE, Haerle M. Memantine treatment of complex regional pain syndrome: a preliminary report of six cases. Clin J Pain. 2007 Mar-Apr;23(3):237-43. doi: 10.1097/AJP.0b013e31802f67a7.
• 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.
• 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.
• Hanney M, Prasher V, Williams N, Jones EL, Aarsland D, Corbett A, Lawrence D, Yu LM, Tyrer S, Francis PT, Johnson T, Bullock R, Ballard C; MEADOWS trial researchers. Memantine for dementia in adults older than 40 years with Down's syndrome (MEADOWS): a randomised, double-blind, placebo-controlled trial. Lancet. 2012 Feb 11;379(9815):528-36. doi: 10.1016/S0140-6736(11)61676-0. Epub 2012 Jan 10.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• McShane R, Westby MJ, Roberts E, Minakaran N, Schneider L, Farrimond LE, Maayan N, Ware J, Debarros J. Memantine for dementia. Cochrane Database Syst Rev. 2019 Mar 20;3(3):CD003154. doi: 10.1002/14651858.CD003154.pub6.
• Ahmad-Sabry MH, Shareghi G. EFFECTS OF MEMANTINE ON PAIN IN PATIENTS WITH COMPLEX REGIONAL PAIN SYNDROME--A RETROSPECTIVE STUDY. Middle East J Anaesthesiol. 2015 Feb;23(1):51-4.
• Strupp M, Kremmyda O, Brandt T. Pharmacotherapy of vestibular disorders and nystagmus. Semin Neurol. 2013 Jul;33(3):286-96. doi: 10.1055/s-0033-1354594. Epub 2013 Sep 21.
• Carr J, Collins S. 50 years with Down syndrome: A longitudinal study. J Appl Res Intellect Disabil. 2018 Sep;31(5):743-750. doi: 10.1111/jar.12438. Epub 2018 Mar 2.
• Maekawa Y, Hasegawa S, Ishizuka T, Shiosakai K, Ishizuka H. Pharmacokinetics and Bioequivalence of Memantine Tablet and a New Dry Syrup Formulation in Healthy Japanese Males: Two Single-Dose Crossover Studies. Adv Ther. 2019 Oct;36(10):2930-2940. doi: 10.1007/s12325-019-01044-y. Epub 2019 Aug 9.

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): May 1, 2028
• Study Completion (Estimated): May 1, 2028

Study Registration Dates

• First Submitted: April 4, 2026
• First Submitted That Met QC Criteria: April 13, 2026
• First Posted (Actual): April 15, 2026

Study Record Updates

• Last Update Posted (Actual): May 11, 2026
• Last Update Submitted That Met QC Criteria: May 5, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Memantine; Short-term memory; Episodic Memory; CVLT
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Mental Disorders; Genetic Diseases, Inborn; Neurobehavioral Manifestations; Congenital Abnormalities; Neurodevelopmental Disorders; Abnormalities, Multiple; Chromosome Disorders; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Intellectual Disability; Down Syndrome; Organic Chemicals; Hydrocarbons; Hydrocarbons, Cyclic; Adamantane; Bridged-Ring Compounds; Amantadine; Memantine
• Other Study ID Numbers: STUDY20260078

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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.
• IPD Sharing Time Frame: 12 months after the report published.
• IPD Sharing Access Criteria: Each request will be checked for compatibility with regulatory (institutional review board) requirements as well as compatibility with participant informed consent.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No