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Down Syndrome Memantine Follow-up Study

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ClinicalTrials.gov Identifier: NCT02304302
Recruitment Status : Recruiting
First Posted : December 1, 2014
Last Update Posted : October 10, 2018
Sponsor:
Collaborator:
Alana USA Foundation
Information provided by (Responsible Party):
Dr. Alberto Costa, University Hospitals Cleveland Medical Center

Tracking Information
First Submitted Date  ICMJE November 24, 2014
First Posted Date  ICMJE December 1, 2014
Last Update Posted Date October 10, 2018
Study Start Date  ICMJE October 2014
Estimated Primary Completion Date November 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 25, 2014)
Efficacy of the drug Memantine as assessed by the California Verbal Learning Test-II (CVLT-II) short form [ Time Frame: 3 years ]
The primary efficacy measure is focused on episodic memory. It assesses supraspan word learning ability as an index of episodic verbal long-term memory. The choice of the appropriate measure for individuals with Down syndrome was based on results of our pilot clinical trial of the drug memantine in young adults with Down syndrome (Boada et al., 2012). We hypothesize that treatment with memantine will produce significant improvements in the CVLT-II short form. Two dependent variables were selected, based on prior literature, as indexing hippocampal function: Total number of target items correct summed across learning trials 1-4, and total free recall discriminability for the learning trials, which takes into account hits as well as false positives.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02304302 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: November 25, 2014)
  • Efficacy of the drug Memantine as assessed by Paired Associates Learning (PAL) from the Cambridge Neuropsychological Test Automated Battery (CANTAB) [ Time Frame: 3 years ]
    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.
  • Efficacy of the drug Memantine as assessed by Recall of Digits (Differential Ability Scales; DAS-II). [ Time Frame: 3 years ]
    This is a measure of rote short-term verbal memory. Total number of items correct will be used as the dependent variable.
  • Efficacy of the drug Memantine as assessed by Pattern Recognition Memory (PRM; part of the CANTAB) [ Time Frame: 3 years ]
    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.
  • Efficacy of the drug Memantine as assessed by Spatial Working Memory (part of the CANTAB) [ Time Frame: 3 years ]
    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. Two dependent variables were selected: 1) 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; and 2) a "strategy" score, which indexes the number of times the participant started a search with a different box, the latter being an inefficient strategy (i.e., high strategy scores denote poorer performance).
  • Efficacy of the drug Memantine as assessed by Spatial Span (part of the CANTAB) [ Time Frame: 3 years ]
    This measure is a computerized version of the Corsi Blocks task, a long-standing neuropsychological test. Two dependent variables were selected for this test: 1) span length, which is the longest sequence of numbers recalled accurately (possible score ranges from 2 to 9); and 2) total usage errors, which represents the number of times a subject selects a box no in the sequence being recalled.
  • Efficacy of the drug Memantine as assessed by The Go - No Go task [ Time Frame: 3 years ]
    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. Two dependent variables were selected: 1) the proportion of no-go targets in which a subject fails to inhibit a response under the go-cue (pre-potent) condition; and 2) speed of response execution to Go targets.
  • Safety and tolerability of the drug Memantine as assessed by the incidence of adverse events [ Time Frame: 3 years ]
    Incidence of adverse events will be monitored by clinical history, physical examinations, electrocardiograms (ECGs), clinical laboratory tests, and the Screen for Childhood Anxiety Related Emotional Disorders (SCARED).
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: November 25, 2014)
  • Intellectual functioning of the participants as assessed by Matrices subtest of the Differential Ability Scales-II (DAS-II) [ Time Frame: 3 years ]
    This test will provide 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. Since 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.
  • Linguistic functioning of the participants as assessed by the Test for Reception of Grammar 2nd edition (TROG-II) [ Time Frame: 3 years ]
    This is a measure of receptive syntax skills (Bishop, 1983). 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.
  • Linguistic functioning of the participants as assessed by the Peabody Picture Vocabulary Test-IV (PPVT-IV) [ Time Frame: 3 years ]
    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 was used as the dependent variable, following the administration manual's rules for basals and ceilings.
  • Adaptive/Behavioral Functioning of the participants as assessed by the Scales of Independent Behavior-Revised (SIB-R) [ Time Frame: 3 years ]
    This is a measure of adaptive functioning that integrates information from 13 different domains (e.g., gross motor, social interaction, eating, toileting, dressing, personal self-care, etc.). It is in a questionnaire format, which a caregiver can complete while the participant is being tested. Standard scores for all indices will be derived from age norms that extend from birth to age 80, as these will be used as dependent variables.
  • Exploratory study of electroencephalographic (EEG) Recordings of Evoked Potentials as potential biomarkers for the severity of the cognitive disability associated to Down syndrome and for the efficacy of the memantine treatment [ Time Frame: 3 years ]
    Auditory and visual evoked potential experiments will search for significant differences in peak amplitude and latency of MMNs in persons with Down syndrome in relation to typically developing persons without Down syndrome, and in participants with Down syndrome before and after memantine treatment
  • Exploratory study of magnetic resonance imaging (MRI) as potential biomarkers for the severity of the cognitive disability associated to Down syndrome and for the efficacy of the memantine treatment [ Time Frame: 3 years ]
    MRI studies will be to provide precise source localization for the high-density EEG recordings of evoked potentials in a subset of 30-60 participants of this trial. In addition, these experiments will also produce high resolution sagittal slice images of the hippocampus and simple connectivity data sets
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Down Syndrome Memantine Follow-up Study
Official Title  ICMJE 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
Brief 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 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.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Down Syndrome
  • Intellectual Disability
Intervention  ICMJE
  • Drug: Memantine
    Encapsulated Namenda 10 mg bid (after four week dose escalation protocol)
    Other Name: Namenda
  • Drug: Placebo
    Identically looking placebo capsules bid (after a four-week regimen designed to mimic dose escalation protocol)
    Other Name: Inactive Capsules
Study Arms  ICMJE
  • Placebo Comparator: Placebo
    Identically-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.
    Intervention: Drug: Placebo
  • Experimental: Memantine
    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.
    Intervention: Drug: Memantine
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 25, 2014)
200
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2019
Estimated Primary Completion Date November 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 (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

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
  • 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 15 Years to 32 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: Melissa R Stasko, JD 216-844-7281 Melissa.Stasko@case.edu
Contact: Alberto C Costa, MD, PhD 216-844-7395 Alberto.Costa@case.edu
Listed Location Countries  ICMJE Brazil,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02304302
Other Study ID Numbers  ICMJE 121971
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Dr. Alberto Costa, University Hospitals Cleveland Medical Center
Study Sponsor  ICMJE University Hospitals Cleveland Medical Center
Collaborators  ICMJE Alana USA Foundation
Investigators  ICMJE
Principal Investigator: Alberto C Costa, MD, PhD University Hospitals Cleveland Medical Center
Study Director: Stephen L Ruedrich, MD University Hospitals Cleveland Medical Center
PRS Account University Hospitals Cleveland Medical Center
Verification Date October 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP