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| Name | Class |
|---|---|
| Palo Alto Veterans Institute for Research | OTHER |
| Forest Laboratories | INDUSTRY |
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The aim of the proposed study is to determine if the NMDA receptor antagonist memantine has a neuroprotective effect on magnetic resonance spectroscopic imaging (MRS) measures of brain NAA and magnetic resonance imaging (MRI) volumetric measures of hippocampal volume. In secondary analyses, we will determine if measures of clinical stabilization produced by memantine in the treatment of Alzheimer's disease (AD) parallels stabilization of MRS measures of brain NAA and MRI volumetric measures of hippocampal volume.
Alzheimer's disease (AD) is the most common form of dementia. Currently, there are more than 4 million individuals with dementia in the United States with at least 400,000 deaths annually. AD is a progressive, neurodegenerative disorder, characterized neuropathologically by widespread neuronal loss, presence of neurofibrillary tangles, and deposits of beta amyloid in cerebral blood vessels and neuritic plaques. Since the medial-temporal lobes, hippocampus, and association cortex are significantly impacted it is not surprising that the primary symptom of AD is a decline in cognitive functioning that leads to marked impairment in daily functioning. In particular, memory impairments, visuospatial decline, language difficulties, and loss of executive function are central cognitive symptoms of this illness. Behavioral disturbances such as agitation and hallucinations often accompany disease progression. The illness lasts approximately 7 to 10 years, with patients requiring total care in the latter stages. Thus, AD places a tremendous emotional and economic burden on both patients and their caregivers. Beyond a cure, therapeutic approaches which would alleviate the symptoms or delay progression could be of substantial psychological and economic benefit. Recent placebo controlled clinical trials have shown memantine to be efficacious in the treatment of patients with moderate to severe AD.
The aim of the proposed study is to determine if the NMDA receptor antagonist memantine has a neuroprotective effect on magnetic resonance spectroscopic imaging (MRS) measures of brain NAA and magnetic resonance imaging (MRI) volumetric measures of hippocampal volume. In secondary analyses, we will determine if measures of clinical stabilization produced by memantine in the treatment of Alzheimer's disease (AD) parallels stabilization of MRS measures of brain NAA and MRI volumetric measures of hippocampal volume.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Memantine | Experimental | 10mg Memantine |
|
| Control | Placebo Comparator | 10 mg Placebo pill |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Memantine | Drug | 10mg Memantine |
|
|
| Measure | Description | Time Frame |
|---|---|---|
| NAA/Cr Ratio | To determine if memantine has a neuroprotective effect on magnetic resonance spectroscopic imaging (MRS) measures of hippocampal n-acetyl aspartate (NAA) and magnetic resonance imaging volumetric measures (MRI) of hippocampal volume. | Baseline; Year 1 |
| Measure | Description | Time Frame |
|---|---|---|
| Mean Change on the ADAS-Cog Score After 1 Year | Progression of cognitive functioning as measured by performance on the Alzheimer's Disease (AD) Assessment Scale-cognitive subscale (ADAS-Cog). ADAS-cog is the most popular cognitive testing instrument used in clinical trials of nootropics, and measures disturbances of of memory, language, praxis, attention and other cognitive abilities which are often referred to as the core symptoms of AD. Responses are summed for an overall score which can range from 0-70. The greater the dysfunction, the higher the score. A typical score for a person without dementia is 5. |
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Inclusion Criteria:1. Dementia criteria by DSM-IV.
2. 50-95 years of age inclusive.
3. MMSE at screen and baseline 7-28 inclusive.
4. Conversant in English.
5. Caregiver/study partner willing to participate, supervise the patient and be available for administration of study medication.
6. Able to ingest oral medication. Exclusion Criteria:1. History of clinically significant stroke without substantial recovery.
2. Neurological or medical conditions causing significant disability independent of dementia.
3. Parkinson's disease.
4. History in past two years of focal brain lesion, head injury with loss of consciousness or DSM-IV criteria for any major psychiatric disorder including psychosis, major depression, bipolar disorder, alcohol or substance abuse.
5. Dementia due to Korsakoff's syndrome or infectious diseases such as Creutzfeldt-Jakob disease, herpes, encephalitis, or human immunodeficiency virus.
6. Sensory impairment that would prevent subject from participating in or cooperating with the protocol.
7. Significant clinical disorder or laboratory finding that renders the subject unsuitable for receiving an investigational drug including: clinically significant or unstable hematologic, hepatic, cardiovascular, pulmonary, gastrointestinal, endocrine, metabolic, renal, or other systemic disease or laboratory abnormality.
8. Clinical contraindication to the use of memantine (e.g., hypersensitivity).
9. History of seizure within past 5 years prior to screening.
10. Platelet count < 100,000/mm3.
11. History of claustrophobia
12. Presence of metallic implants such as pacemakers, surgical aneurysm clips, or known metal fragments embedded in the body
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| Name | Affiliation | Role |
|---|---|---|
| J. Wesson Ashford Jr., MD, PhD | Stanford University | Study Director |
| Jerome A Yesavage | Stanford University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| VA Palo Alto Health Care System | Palo Alto | California | 94304 | United States |
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17 subjects were randomized. All subjects had completed all participation by October, 2008. All were recruited at VA Palo Alto Health Care System.
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| ID | Title | Description |
|---|---|---|
| FG000 | Memantine | 10mg Memantine Memantine |
| FG001 | Control | Participants were given Placebo |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Per protocol, only participants who completed the study were evaluable for baseline characteristics.
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| ID | Title | Description |
|---|---|---|
| BG000 | Memantine | 10mg Memantine Memantine |
| BG001 | Control | 10mg Placebo pill |
| BG002 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | NAA/Cr Ratio | To determine if memantine has a neuroprotective effect on magnetic resonance spectroscopic imaging (MRS) measures of hippocampal n-acetyl aspartate (NAA) and magnetic resonance imaging volumetric measures (MRI) of hippocampal volume. | Participants who could tolerate study medication and who completed the study were included in the analysis. | Posted | Mean | Standard Deviation | Ratio | Baseline; Year 1 |
|
1 month
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Memantine | 10mg Memantine |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Cardiac Arrythmia | Cardiac disorders | Non-systematic Assessment | Not related to study medication; incident occurred before medication was started; family notified researcher of problem and subject withdrawn. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Tattoo eyeliner | Eye disorders | Non-systematic Assessment | Study requirement is MRI. Unable to complete study procedures due to tattoo eyeliner so subject was withdrawn by the PI. Not study related. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Wes Ashford, PhD, MD | VA Palo Alto Health Care System | 650-493-5000 | wes.ashford@va.gov |
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| ID | Term |
|---|---|
| D000544 | Alzheimer Disease |
| ID | Term |
|---|---|
| D003704 | Dementia |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| D008559 | Memantine |
| ID | Term |
|---|---|
| D000547 | Amantadine |
| D000218 | Adamantane |
| D001952 | Bridged-Ring Compounds |
| D006844 | Hydrocarbons, Cyclic |
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| Placebo pill |
| Drug |
10mg placebo pill |
|
|
| Baseline; Year 1 |
| Total |
Total of all reporting groups |
| years |
|
| Sex/Gender, Customized | Number | participants |
|
| Region of Enrollment | Number | participants |
|
| Units | Counts |
|---|---|
| Participants |
|
|
| Secondary | Mean Change on the ADAS-Cog Score After 1 Year | Progression of cognitive functioning as measured by performance on the Alzheimer's Disease (AD) Assessment Scale-cognitive subscale (ADAS-Cog). ADAS-cog is the most popular cognitive testing instrument used in clinical trials of nootropics, and measures disturbances of of memory, language, praxis, attention and other cognitive abilities which are often referred to as the core symptoms of AD. Responses are summed for an overall score which can range from 0-70. The greater the dysfunction, the higher the score. A typical score for a person without dementia is 5. | Participants who could tolerate study medication and who completed the study were included in the analysis. | Posted | Mean | Standard Deviation | units on a scale | Baseline; Year 1 |
|
|
|
| 1 |
| 9 |
| 4 |
| 9 |
| EG001 | Control | Participants were given matching placebo | 2 | 8 | 0 | 8 |
|
| Crohn's disease flare-ups | Gastrointestinal disorders | Non-systematic Assessment | Not related to study medication (subject was on placebo). Notified by patient. Hospitalized, treated and released, continued with study. |
|
| complications due to type II diabetes | Endocrine disorders | Non-systematic Assessment | Not related to study medication (on placebo). Hospitalized, withdrawn from study. Later died. |
|
|
| Lethargy | Psychiatric disorders | Non-systematic Assessment | Subject discontinued medication and was terminated from the trial by the PI. |
|
| Irritability | Psychiatric disorders | Non-systematic Assessment | Subject discontinued medication and was terminated from the trial by the PI. |
|
| Study medication non compliance | Psychiatric disorders | Non-systematic Assessment | Subject discontinued medication and was terminated from the trial by the PI. |
|
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| D024801 |
| Tauopathies |
| D019636 | Neurodegenerative Diseases |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| D006838 |
| Hydrocarbons |
| D009930 | Organic Chemicals |