Efficacy and Safety of Memantine Hydrochloride in Enhancing the Cognitive Abilities of Young Adults With Down Syndrome

A Sixteen-Week, Randomized, Double Blind, Placebo-Controlled Evaluation of the Efficacy, Tolerability and Safety of Memantine Hydrochloride on Enhancing the Cognitive Abilities of Young Adults With Down Syndrome

The purpose of this 16-week research study is to determine whether a drug called memantine hydrochloride (memantine) has the potential to help improve memory and other cognitive abilities of young adults with Down syndrome (DS). Memantine (Namenda®) is a drug approved by the Food and Drug Administration (FDA) for patients with moderate to severe Alzheimer-type dementia. About 40 persons of both genders with Down syndrome aged 18-32 years will take part in this study. This is a randomized and double blind study. This means that subjects will have a 50/50 chance of being assigned to receive either the memantine pills or placebo (inactive pills). Neither the study participants nor the research personnel will know who is receiving active medication or placebo. Based on memantine's mode of action, current knowledge on brain pathology in persons with Down syndrome, and some preclinical data on mouse models of Down syndrome, we hypothesize that memantine may improve test scores of young adults with Down Syndrome on memory tests targeted at the function of the brain structure called the hippocampus. This research project has three specific aims: 1) investigate whether memantine has the potential to improve test scores on hippocampus-dependent measures in young adults with Down syndrome; 2) investigate whether memantine has the potential to improve test scores by these subjects on other cognitive measures; 3) investigate whether memantine is well tolerated by these subjects.

Down syndrome, which is the result of the trisomy of Chromosome 21, is the most common genetically defined cause of intellectual disabilities. The estimated number of people with Down syndrome in the United States is approximately 300,000, and this figure is expected to continue increasing due to projected increases in the life expectancy of people with Down syndrome. Although this population trend reflects improvements in the general health care of individuals with Down syndrome, there has not been a parallel progress in the understanding of the pathogenesis and potential treatment of the psychological and neurological components of this genetic condition. These include various degrees of intellectual disability, increased incidence of seizure disorder in relation to the general population, motor dysfunction (including hypotonia), abnormal oculomotor and vestibular functions, substantial visual deficits, a neuropathology indistinguishable from Alzheimer disease, and increased incidence of major depression and dementia in adults.

Over the last fifteen years, progress in the quantitative description of specific traits associated with Down syndrome, the availability of postnatal-viable aneuploid mouse models of Down syndrome, and our progressively more sophisticated knowledge of the human and mouse genomes have provided investigators in this field with a realistic opportunity to start bridging the gap between basic and clinical research.

Whereas individuals with Down syndrome maintain relatively high levels of social intelligence and procedural learning, they often suffer from grossly impaired declarative or explicit memory. Not surprisingly, brain structures associated with declarative memory, namely the hippocampal and parahippocampal regions of the medial temporal lobe, are the most severely affected in persons with Down syndrome. The nature of these deficits suggests that therapies targeting hippocampal function would be particularly efficacious in ameliorating the cognitive deficits seen in persons with Down syndrome and, consequently, would enhance their quality of life.

Glutamatergic neurons form the major excitatory system in the brain and play a pivotal role in many physiological functions. Apart from the physiological role of glutamate, excessive activation of its receptors can also evoke neuronal dysfunction and even damage/death. Cell death ascribed to an excessive activation of glutamate receptors has been termed 'excitotoxicity' and seems to occur in acute insults such as stroke and trauma, but it may be also associated with chronic neurodegenerative diseases such as Alzheimer disease. N-methyl-D-aspartate (NMDA) receptor (NMDAR) mediated glutamate excitotoxicity is thought to play a major role in Aβ-induced neuronal death. This idea is part of the foundation of the glutamatergic hypothesis (as opposed to the cholinergic hypothesis) for Alzheimer disease.

Memantine is an NMDAR antagonist that has been reported to be effective therapeutically in Alzheimer disease. It has been available in Germany as well as in most of the European Union for more than two decades. Recently, it has been approved for moderate to severe dementia in the US. The chemical name for memantine hydrochloride is 1-amino-3,5-dimethyladamantane hydrochloride. Memantine is an uncompetitive, moderate affinity, antagonist of NMDARs. It has been proposed that therapeutic doses of this drug inhibit the pathological effect of NMDAR activation while leaving unaffected NMDAR-mediated physiological processes involved in learning and memory. Recent preclinical data from the laboratory of this trial's P.I. on the mouse model for DS (Ts65Dn) have suggested a dysregulation of NMDAR activity in these animals and demonstrated improvement on learning and memory measures by the use of acute doses of memantine.

In all clinical trials so far, memantine was found safe and well tolerated. The tolerability of an NMDAR antagonist depends upon its affinity towards the receptors, unbinding kinetics, and voltage dependency. Memantine is thought to improve the fidelity of synaptic transmission. Such action is predicted to provide both neuroprotection and symptomatic restoration of synaptic plasticity by one and the same mechanism.

Recent open-label studies suggest that memantine may be clinically useful and well tolerated in young individuals with other conditions that produce cognitive disabilities, such as autism and attention deficit hyperactivity disorder (ADHD).

Because of the ubiquity of Alzheimer disease-type pathology in persons with Down syndrome, the preclinical findings consistent with dysregulation of NMDAR activity in mouse models of Down syndrome, the safety profile of memantine (which is superior to the AChE inhibitors that are already being tested in persons with Down syndrome), and the possibility that memantine may indeed delay the onset of Alzheimer disease-type pathology in young adults with Down syndrome, all the professionals involved with this project decided that a small-scale randomized controlled clinical trial was warranted at present.

We would like to emphasize that the goal of this study is to evaluate the efficacy, tolerability and safety of memantine hydrochloride in enhancing the cognitive abilities of young adults with Down syndrome aged 18-32 years. Therefore, the present investigation is a non-overlapping and complementary clinical trial to the randomized, placebo-controlled clinical trial on the efficacy and tolerability of memantine in preventing age-related cognitive deterioration and dementia in people with Down syndrome age 40 and over (http://www.clinicaltrials.gov/ct2/show/record/NCT00240760?term=down+syndrome\&rank=15) currently being carried out by our colleagues in London.

Inclusion Criteria:

• Males or females with Down syndrome aged 18 to 32 years. The documented cytogenetic diagnosis should be either "Trisomy 21", or "Complete Unbalanced Translocation of the Chromosome 21".
• Female subjects must be documented not to be pregnant by serum testing at screening.
• Laboratory findings within normal limits or judged clinically insignificant at baseline.
• Vital signs must be within normal limits for their age. (Medically treated hypotension will be allowed.)
• Screening ECG must demonstrate predominately normal sinus rhythm. Minor abnormalities documented as clinically insignificant by the investigator will be allowed. (Subjects with clinically significant but stable ECG abnormalities may enter the trial only with the permission of the principal investigators.)
• Subjects and their authorized representative will provide written informed consent and assessment.
• Subjects who have been receiving any experimental drug for Down syndrome must undergo a washout (~ 30 days or five half-lives of the drug, whichever is longer).
• Sufficiently proficient in English to be capable of reliably completing study assessments.
• Able to swallow oral medication (crushing of tablets will not be permitted).
• Must have a reliable caregiver or family member who agrees to accompany the subject to all visits, provide information about the subject as required by this protocol, and ensure compliance with the medication schedule. The subject must have contact at least once a day with the caregiver.
• Generally good health and judged by the investigators to be able to fully participate in the trial.

Exclusion Criteria:

• Subjects weighing less than 40 kg.
• Any current psychiatric or neurologic diagnosis other than Down syndrome.
• Subjects who currently meet or have within the past five years met DSM-IV (Diagnostic and Statistical Manual) criteria for drug or alcohol abuse or dependence.
• Subjects who, in the judgment of the investigators, currently represent a 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.
• Subjects who are hospitalized or residing in a skilled nursing facility or subjects who are anticipated to enter a nursing home within the next 6 months. (Subjects may reside in group homes of other residential settings where they do not require or receive skilled nursing.)
• Any active or clinically significant conditions affecting absorption, distribution or metabolism of the study drugs.
• Subjects with significant allergies to or other significant intolerance of memantine therapy, its ingredients, or with contraindications to memantine therapy as stated in the prescribing information.
• Subjects who are expected to require general anesthetics during the course of the study.
• History or presence of seizure disorder (less than 3 years) or encephalitis.
• History of malignant neoplasms treated within 3 years prior to study entry or where there is current evidence of recurrent or metastatic disease.
• Subjects with treated hypothyroidism must be on a stable dose of medication for at least 3 months prior to screening and have normal serum T-4 and thyroid-stimulating hormone at screening. Subjects with diabetes mellitus controlled by diet, oral medication or insulin must have an HbA1c of < 8.0% and 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.
• Subjects who have donated blood or blood products during the 30 days prior to screening who plan to donate blood while participating in the study or within four weeks after completion of the study.
• Subjects who may not be able 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.