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.

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.

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

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.

12 months after the report published.

Each request will be checked for compatibility with regulatory (institutional review board) requirements as well as compatibility with participant informed consent.