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Down SyndromePhase 2NCT02304302

Down Syndrome Memantine Follow-up Study

A Phase 2 study testing Memantine in people with Down Syndrome and Intellectual Disability, run by University Hospitals Cleveland Medical Center at 2 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

The purpose of this research study is to learn if the medication Memantine Hydrochloride (the study medication) can help adolescents and young adults with Down syndrome. Dr. Alberto Costa and his research team want to see if a 16-week treatment with this medication can improve the participant's ability to learn and… Read more about this study

Who is it for?
Ages 15 to 32 yearsHealthy volunteers can take part
Conditions the study is for
Down Syndrome, Intellectual Disability
What is being tested?
Memantine
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
160 participants
Where
2 sitesin 2 countries
Study dates
Oct 2014to 22 Jul 2020
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

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 15 to 32 years
  • All sexes
  • Healthy volunteers accepted
  • Child, 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
  • 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
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  • 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 (USA) or Portuguese (Brazil) 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

Who cannot join

  • 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)
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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
  • 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
  • Exclusion criteria for controls without Down syndrome: History of substance abuse, major psychiatric disorder, attention deficit disorder, or learning disability; Beck Depression Score greater than 10; Exclusion criteria specific to MR scanning; Pregnancy; Neurologic history

Trial locations and contacts

2 sites in 2 countries.

2 sites in 2 countries

United States1 site

  • University Hospitals Case Medical Center

    Cleveland, Ohio, 44106

Other trials in United States

Brazil1 site

  • Sociedade Beneficente Israelita Brasileira Albert Einstein

    São Paulo, São Paulo, 05652- 900

Other trials in Brazil

About this study

Official title: Phase II Multicenter 16-Week Randomized Double Blind Placebo-Controlled Evaluation of the Efficacy, Tolerability and Safety of Memantine Hydrochloride on Enhancing the Cognitive Abilities of Adolescents and Young Adults With Down Syndrome

The purpose of this research study is to learn if the medication Memantine Hydrochloride (the study medication) can help adolescents and young adults with Down syndrome. Dr. Alberto Costa and his research team want to see if a 16-week treatment with this medication can improve the participant's ability to learn and remember things. In this study, memantine hydrochloride will be used. Thus, the researchers want to learn whether the study drug can help improve memory in young adults with Down syndrome. To test the effect of the study medicine, half of the people in the study will receive the study medicine and half will receive a placebo (an inactive substance). Memantine is an approved medication to treat memory and thinking problems in persons with Alzheimer disease. However, little is known about the effect of this medication in persons with Down syndrome and it has not been approved for use in persons with Down syndrome.

Read the detailed description

This study seeks to investigate if the medication Memantine Hydrochloride can help young adults with Down syndrome. Two hundred persons with Down syndrome from both genders and between 15 and 32 years of age will be recruited from two sites: Cleveland, OH, USA and São Paulo, SP, Brazil. Participants will be assigned randomly to either a placebo group or a group taking the active medication with a 50% probability of being on either group. Neither the participants nor the investigators will know who will be taking the study medication and who will be taking the placebo during the study. Only the investigational pharmacist will have access to this information.

Up to 60 people with Down syndrome of the recruited study participants will take part on an optional magnetic resonance imaging (MRI) study. This investigation is aimed at helping to make the EEG study more precise and to find out whether the study medication has any significant effect on the structure of the brain.

Additionally, we will recruit a control group of 60 age- and gender-matched participants without Down syndrome. The goal is to investigate how different groups of people activate their brains when they hear or see something, and if he can use high-density EEG and MRI to see how this study medication works in persons with Down syndrome. In other words, this additional control group should help us ascertain which parts of the test results are due to a person having Down syndrome and which ones are not. Persons without Down syndrome will only come for one EEG visit and one MRI visit, and not be asked to take the study medication.

The visits for the participants with Down syndrome will be as follows:

Screening visit (approximately 2-hour long). The subject will be asked about his/her health, medical history, social background, and work background, as well as some simple questions to determine performance on tests of memory and function that are part of this study. Informed consent and assent will be obtained in this visit. At the end of this visit, an EEG machine will be used to access brain responses to different auditory and visual stimuli. Some will be asked if they would be willing to have an MRI performed, but this portion is not imperative.

A urine sample will be collected and used to obtain cells that will be kept frozen for potential future studies. If the date of the screening visit is not convenient, this sample can be collected during any of the next five visits.

Visit 1 (approximately 1 hour). Pulse, blood pressure, and an electrocardiogram (ECG) will be taken. At the end of the visit, urine and blood samples will be taken. Pregnancy will also be checked.

Visit 2 (2-3 hours). Tests of memory, learning, and reasoning skills will be conducted before the start of the study medicine or placebo. At the end of this visit, a 60-day supply of either the study medicine or the placebo will be given. This will need to be taken for 16 weeks.

Visit 3 (approximately 30 minutes). Eight weeks after the beginning of the treatment, the participant will return to assess how she/he is doing under the treatment. Pulse, blood pressure, a physical exam, and pregnancy will be checked. At this visit, another supply of study medicine will be given.

Visit 4 (2-3 hours). Sixteen weeks after starting the medicine, the participant will take a second series of tests in learning, memory, and reasoning skills to find out whether there were any changes in these skills.

Visit 5 (approximately 1 hour). In the 16th or 17th week after starting the medicine, the participant will meet one more time with the doctor from visits 1 and 3. Vital signs, a physical exam, and an ECG will be taken, as well as a blood sample to ensure nothing has changed with the participant's general health. For women, a pregnancy test will be performed.

If for some reason the subject withdraws from this study prior to Visit 5, he/she will be asked to return to the clinic for a "Treatment Discontinuation Visit." In addition, if the participant discontinues the medication prior to the end of the study, he/she will be asked to complete a "Retrieved Dropout Visit" on the date that should have represented Visit 5. Study medication will not be provided beyond the study period.

Being tested
Memantine, Placebo
Keywords
Memantine, Episodic Memory, CVLT, Hippocampus dependent memory, Short-term memory
Medical subject headings
Down Syndrome, Intellectual Disability

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • MemantineDrug

    Also called Namenda

    Encapsulated Namenda 10 mg bid (after four-week standard dose titration protocol)

  • PlaceboDrug

    Also called Inactive Capsules

    Identically looking placebo capsules bid (after a four-week regimen designed to mimic standard dose titration protocol)

Study groups in NCT02304302
Study groupRoleWhat they receive
PlaceboPlacebo comparatorIdentically-looking placebo pills to memantine will be dispensed in a 66-day supply (56 days plus 10 extra days) by the study coordinator to participants receiving the placebo at the end of visits 2 and 3.
Receives: Drug: Placebo
MemantineExperimentalMemantine will be dispensed in a 66-day supply (56 days plus 10 extra days) by the study coordinator to participants receiving the placebo at the end of visits 2 and 3.
Receives: Drug: Memantine

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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

    The primary efficacy measure is focused on episodic memory. The CVLT-II short form assesses supraspan word learning ability as an index of episodic verbal long-term memory. We hypothesize 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 have been recorded as change in score from baseline (T1) to after the treatment (T2). Scale Range: from 0 to 36; higher scores represent better outcomes.

    Measured: baseline and 16 weeks from start of treatment

Secondary outcomes (7)

  1. 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 have been recorded as change in score from baseline (T1) to after the treatment (T2). The minimum value of the PAL Memory Score Scale is 0 and the maximum value is 21; higher scores mean better outcomes.

    Measured: baseline and 16 weeks from start of treatment

  2. 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. Total number of items correct were used as the dependent variable. The values for this measure have been recorded as change in score from baseline (T1) to after the treatment (T2). The minimum value for this scale is 0 and the maximum value is 38; higher scores mean a better outcome.

    Measured: baseline and 16 weeks from start of treatment

  3. 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 was used as the dependent variable. We used the PRM total scale 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.

    Measured: baseline and 16 weeks from start of treatment

  4. Efficacy of the Drug Memantine as Assessed by Change in Score on the Spatial Working Memory (Part of the Cambridge Neuropsychological Test Automated Battery -- CANTAB)

    The test requires participants to search under a series of colored boxes to locate a "blue token" hidden underneath one of them. During a series of trials, the participant is told that the token will be in a new location each time and that they should not go back to a location he or she has looked in previously. The main dependent variable was the total number of errors ("between errors"), which indexes the number of times a participant went back to a box where a token had already been found, lower scores mean better performance. The minimum value of the Spatial Working Memory scale is 0 and the maximum value is 137 (which was computed as the equivalent to -4 standard deviations from the mean of this measure); higher scores mean worse outcomes. The values for this measure have been recorded as change in score from baseline (T1) to after the treatment (T2).

    Measured: baseline and 16 weeks from start of treatment

  5. Efficacy of the Drug Memantine as Assessed by Change in Score on the Spatial Span (Part of the Cambridge Neuropsychological Test Automated Battery -- CANTAB)

    This measure is a computerized version of the Corsi Blocks task, a long-standing neuropsychological test. The main dependent variables selected for this test was the span length, which is the longest sequence of numbers recalled accurately. The minimum value of the Spatial Span Length Score Scale is 0 and the maximum value is 9; higher scores mean better outcomes. The values for this measure have been recorded as change in score from baseline (T1) to after the treatment (T2).

    Measured: baseline and 16 weeks from start of treatment

  6. Efficacy of the Drug Memantine as Assessed by Change in Score on the The Go - No Go Task

    This is a measure of inhibitory control, often used as a marker for prefrontal-striatal function integrity. Specifically, it measures the participant's ability to inhibit pre-potent behavioral responses that have been established by provision of prior "go" or "no-go" cues in a classical conditioning paradigm. The main dependent variables selected was speed of response of execution to Go targets. The minimum value of the speed of response of execution to Go targets is 280 milliseconds (ms) and the maximum value is 1000 ms; higher scores mean worse outcomes. The values for this measure have been recorded as change in score from baseline (T1) to after the treatment (T2).

    Measured: baseline and 16 weeks from start of treatment

  7. Safety and Tolerability of the Drug Memantine as Assessed by Change in QTc Interval

    Incidence of adverse events was monitored by clinical history, physical examinations, electrocardiograms (ECGs), clinical laboratory tests, the Screen for Childhood Anxiety Related Emotional Disorders (SCARED). Here, we report the analysis of the effect of memantine treatment on QTc intervals because of its clinical importance for this analysis for potential drug toxicity. QTc intervals ≥ 450 ms are generally considered long, and drug-induced QTc interval prolongations ≥ 60 ms are generally considered clinically relevant.

    Measured: baseline and 16 weeks from start of treatment

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted1 Dec 2014 (estimated)
  2. Study startOct 2014
  3. Primary completion22 Jul 2020
  4. Study completion22 Jul 2020

Resources

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 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
160 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02304302
Sponsor's protocol ID
121971
Status last verified
Apr 2022
First submitted
24 Nov 2014
Last updated
27 Jun 2023
Data monitoring committee
Yes

Publications

  • Abbeduto L, Pavetto M, Kesin E, Weissman MD, Karadottir S, O'Brien A, Cawthon S. The linguistic and cognitive profile of Down syndrome: evidence from a comparison with fragile X syndrome. Downs Syndr Res Pract. 2001 Oct;7(1):9-15. doi: 10.3104/reports.109.

    PubMed 11706811

  • Bittles AH, Glasson EJ. Clinical, social, and ethical implications of changing life expectancy in Down syndrome. Dev Med Child Neurol. 2004 Apr;46(4):282-6. doi: 10.1017/s0012162204000441. No abstract available.

    PubMed 15077706

  • 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.

    PubMed 22806212

  • Brock J, Jarrold C. Serial order reconstruction in Down syndrome: evidence for a selective deficit in verbal short-term memory. J Child Psychol Psychiatry. 2005 Mar;46(3):304-16. doi: 10.1111/j.1469-7610.2004.00352.x.

    PubMed 15755306

  • Carr J. Six weeks to twenty-one years old: a longitudinal study of children with Down's syndrome and their families. Third Jack Tizard memorial lecture. J Child Psychol Psychiatry. 1988 Jul;29(4):407-31. doi: 10.1111/j.1469-7610.1988.tb00734.x.

    PubMed 2975288

  • Carr J. Stability and change in cognitive ability over the life span: a comparison of populations with and without Down's syndrome. J Intellect Disabil Res. 2005 Dec;49(Pt 12):915-28. doi: 10.1111/j.1365-2788.2005.00735.x.

    PubMed 16287480

  • Chen KH, Reese EA, Kim HW, Rapoport SI, Rao JS. Disturbed neurotransmitter transporter expression in Alzheimer's disease brain. J Alzheimers Dis. 2011;26(4):755-766. doi: 10.3233/JAD-2011-110002.

    PubMed 21743130

  • Chez MG, Burton Q, Dowling T, Chang M, Khanna P, Kramer C. Memantine as adjunctive therapy in children diagnosed with autistic spectrum disorders: an observation of initial clinical response and maintenance tolerability. J Child Neurol. 2007 May;22(5):574-9. doi: 10.1177/0883073807302611.

    PubMed 17690064

  • Costa AC, Scott-McKean JJ. Prospects for improving brain function in individuals with Down syndrome. CNS Drugs. 2013 Sep;27(9):679-702. doi: 10.1007/s40263-013-0089-3.

    PubMed 23821040

  • 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.

    PubMed 17700645

  • Danysz W, Parsons CG. Alzheimer's disease, beta-amyloid, glutamate, NMDA receptors and memantine--searching for the connections. Br J Pharmacol. 2012 Sep;167(2):324-52. doi: 10.1111/j.1476-5381.2012.02057.x.

    PubMed 22646481

  • Erickson CA, Mullett JE, McDougle CJ. Open-label memantine in fragile X syndrome. J Autism Dev Disord. 2009 Dec;39(12):1629-35. doi: 10.1007/s10803-009-0807-3. Epub 2009 Jul 16.

    PubMed 19609663

  • Erickson CA, Posey DJ, Stigler KA, Mullett J, Katschke AR, McDougle CJ. A retrospective study of memantine in children and adolescents with pervasive developmental disorders. Psychopharmacology (Berl). 2007 Mar;191(1):141-7. doi: 10.1007/s00213-006-0518-9. Epub 2006 Oct 3.

    PubMed 17016714

  • Fernandez G, Weyerts H, Schrader-Bolsche M, Tendolkar I, Smid HG, Tempelmann C, Hinrichs H, Scheich H, Elger CE, Mangun GR, Heinze HJ. Successful verbal encoding into episodic memory engages the posterior hippocampus: a parametrically analyzed functional magnetic resonance imaging study. J Neurosci. 1998 Mar 1;18(5):1841-7. doi: 10.1523/JNEUROSCI.18-05-01841.1998.

    PubMed 9465008

  • Findling RL, McNamara NK, Stansbrey RJ, Maxhimer R, Periclou A, Mann A, Graham SM. A pilot evaluation of the safety, tolerability, pharmacokinetics, and effectiveness of memantine in pediatric patients with attention-deficit/hyperactivity disorder combined type. J Child Adolesc Psychopharmacol. 2007 Feb;17(1):19-33. doi: 10.1089/cap.2006.0044.

    PubMed 17343551

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Memantine in people with Down Syndrome and Intellectual Disability, run by University Hospitals Cleveland Medical Center at 2 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 9 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 27 Jun 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States, Brazil. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 5 Apr 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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 (time frame: baseline and 16 weeks from start of treatment). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02304302, which also lists 61 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Jun 2023.

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