Efficacy and Safety of Memantine Hydrochloride, a Low Affinity Antagonist to N-Methyl-D-Aspartate (NMDA) Type Receptors, in the Prevention of Cognitive Decline and Disease Progression in Down's Syndrome
试验速览
- 阶段
- 不适用
- 入组人数
- 180
- 试验地点
- 4
- 主要终点
- Down's Attention Memory and Executive Function Scale
研究概览
简要总结
This is a study to assess whether memantine is effective and safe in preventing age related cognitive deterioration and dementia in people with Down's syndrome (DS) age 40 and over. The study will last for a year and it will include 180 people with Down's syndrome with and without dementia. Participants will be assessed on memory skills, attention and problem solving abilities. Quality of life and abilities for everyday living skills will also be regularly checked.
Primary Aims
Clinical:
- To determine the clinical efficacy of memantine versus placebo in preventing cognitive decline in people with DS.
- To compare the safety and tolerability of memantine versus placebo in people with Down's syndrome (DS).
Biochemical and pathological:
- To examine the ability of memantine to alter markers of disease progression in DS patients.
Secondary Aims
Clinical:
-
To determine whether memantine has, as compared with placebo, a significant positive impact on:
-
level of independent functioning as measured by the carer-rated adaptive behavioural scale, (ABS) in adults with DS;
-
quality of life in adults with DS.
Biochemical and pathological:
- To investigate putative markers of memantine's mechanism of action in peripheral samples from living patients with DS.
详细描述
Over the age of 40, all people with Down's Syndrome have substantial changes in the brain similar to those of Alzheimer's disease and most are at very high risk of developing a clinical dementia with progressive decline of function and cognitive abilities.
There are changes to all of the key chemical messenger systems in the brain as people develop Alzheimer's disease. One of the most ubiquitous chemical messenger systems, present on the majority of nerve cells in the brain, is called the glutamatergic system. In this system the main receptors present on the nerve endings are referred to as glutamate receptors. Under certain circumstances, usually when there is damage to particular parts of the brain, these receptors can lead to "overfiring" of the nerve cells with disastrous consequences. This can result in the generation of a number of toxic chemical molecules that lead to further damage to the nerve cells (such as phopholipases, proteases, nitric oxide synthases, inflammatory molecules and free radicals), usually referred to as excitotoxicity. Memantine blocks the effects of pathologically elevated tonic levels of glutamate that may lead to dysfunction of nerve cells and in this way is thought to block the main glutamate excitotoxicity site on nerve cells.
Randomized clinical trials in people with Alzheimer's disease indicate that memantine significantly slows down the progression of functional and cognitive impairments. Memantine has now been licensed for the treatment of moderate-severe Alzheimer's disease on the basis of these trials. We would hypothesise that older people with Down's syndrome would particularly benefit from treatment with Memantine, partly because of the large amount of Alzheimer's disease changes present in the brain and partly because excessive glutamate receptor activity has been demonstrated in adults with Down's syndrome.
In a recent study we assessed 122 individuals with Down's Syndrome using newly developed neuropsychometric battery of tests, (the the Down's syndrome Attention, Memory and Executive function battery -DAME battery, Margallo-Lana 2002a,b). People with Down's Syndrome over the age of 40 without dementia experienced a decline of 11% over one year, indicating that progressive cognitive decline precedes dementia (hence offering an important opportunity for prevention) and that these measurements are sensitive to cognitive change over time, hence a trial to evaluate the prevention of dementia is feasible with current evaluation measures.
Study Design:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Inclusion criteria will be:
- •Participants with learning disabilities due to Down's syndrome (DS) confirmed by karyotype. A clinical diagnosis (provided by the participant's general practitioner or hospital specialist) will be accepted if karyotype is not known and participant does not agree to have it tested
- •Ages 40 years and over or any age if a diagnosis of dementia is established
- •In participants with dementia, the diagnosis will be consistent with the 10th version of the International Classification of Diseases (ICD-10) (World Health Organization [WHO], 1992) diagnostic criteria
- •Level of speech and comprehension of verbal commands are sufficient to understand and to answer simple requests
- •Resident in care facility or community living with a carer who is willing to accept responsibility for supervising the treatment and will provide input to efficacy parameters in accordance with protocol requirements
- •Not receiving treatment with memantine currently or in past 4 weeks and responsible clinician not considering treatment with memantine
- •Participant willing to take part in study; and carer, with capacity, willing to assent to study and agrees that participant can take part if participant is also willing.
排除标准
- •Exclusion criteria will be:
- •Participants known to have sensitivity to memantine
- •Severe, unstable or uncontrolled medical or psychiatric conditions apparent from history, physical examination or investigations
- •A current diagnosis of primary neurodegenerative disorder other than dementia such as Huntington's disease, etc.
- •Uncontrolled epilepsy
- •Presence of challenging behaviour likely to preclude the participation during testing
- •Presence of severe motor or sensory impairment (severe deafness or blindness) that renders the participant as untestable with the battery of tests used in the study
- •Current evidence of delirium
- •Severe renal impairment
- •Low probability of treatment compliance
- •Previous evidence of lack of efficacy or tolerability to memantine
- •Taking any of the following substances:
- •an investigational drug during the 4 weeks prior to randomization
- •a drug known to cause major organ system toxicity during the 4 weeks prior to randomization
- •started any new psychotropic during the 4 weeks prior to randomization; participants who had been on a stable dose of psychotropic during the 4 weeks prior to randomization are still eligible.
- •memantine during the 6 weeks prior to randomization
- •other N-methyl-D-aspartate (NMDA) antagonists: amantadine, ketamine, and dextromethorphan
- •barbiturates and primidone
- •baclofen and dantrolen
- •dextromethorphan
- •antimuscarinics
结局指标
主要结局
Down's Attention Memory and Executive Function Scale
Part I of the Adaptive Behaviour Scale
次要结局
- The Quality of Life in Alzheimer's Disease (Logsdon et al. 1998)
- Clinician's Global Impression of Change