Alzheimer Disease
Conditions
Keywords
Alzheimer's Disease, Alzheimer Disease, Alzheimer, AD, Alzheimer's
Brief summary
The effects of the medication, memantine, on brain functions and the symptoms of Alzheimer's Disease will be tested
Detailed description
Memantine (MEM) is an FDA-approved treatment for Alzheimer's Disease (AD), but its clinical effects vary from person-to-person. We have reported that a "test dose" of MEM significantly enhances early auditory information processing (EAIP) indices of brain function in both healthy adults and psychiatric patients, suggesting that these EAIP measures can be used as "biomarker" evidence that - in a given person - MEM is active within brain circuitry relevant to cognition. This study tests the hypothesis that the EAIP response to a "test dose" of MEM can be used to predict which patients with AD will be most vs. least sensitive to the clinical benefits of this medication over a 24-week trial. Subjects with mild-to-moderate severity AD who meet criteria for study entry come to UCSD where consenting and a comprehensive screening and diagnostic assessment including a physical exam, EKG, and neuropsychological assessment are conducted. In addition, subjects are assessed on the Alzheimer's Disease Assessment Scale (ADAS-cog), which is the primary clinical outcome measure, and behavioral symptoms documented by the Neuropsychiatric Inventory (NPI-Q) and the Geriatric Depression Scale (GDS), which are secondary assessment measures. Blood is collected in order to assess APOE genotype (rs7412, rs429358) and characterize MEM-sensitive vs. -insensitive patients. After initial screening, subjects return twice, approximately 7 days apart, for biomarker assessment after challenge with placebo (PBO) or memantine 20 mg po (MEM) in a double-blind, randomized order cross-over design. Subjects are assessed on prepulse inhibition of acoustic startle (PPI), mismatch negativity (MMN) and auditory steady state response (ASSR) as well as AD-relevant cognitive measures via the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Subjects then enter the "treatment phase." MEM is initiated at 5 mg/d and titrated with 5 mg weekly increments. During this time, subjects / caregivers are contacted weekly by study staff to assess adherence. Intervention Week 1 will begin when dosing reaches the full dose of 10 mg bid. Subjects are reassessed on the primary (ADAS-cog) and secondary (NPI-Q and GDS) outcome measures after 8, 16 and 24 weeks of treatment at the full dose. Subjects are then offered the opportunity to remain at this dose of MEM, or to taper off MEM, under the care of their primary provider.
Interventions
DRUGMemantine
Phase 1 will test the acute effects of memantine (20 mg po) vs. placebo (PBO) on early auditory information processing measures in 32 carefully characterized patients with mild-to-moderate severity AD who are not currently taking AD medications. From this "challenge" test, a set of "early auditory information processing memantine sensitivity" measures will be derived for each patient. In Phase 2, all patients will begin an open-label trial of memantine, titrated to 10 mg bid, with outcome measures collected after 8, 16 and 24 weeks of treatment. Medication adjustments are not restricted, and response heterogeneity is anticipated.
Sponsors
University of California, San Diego
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
50 Years to 83 Years
Healthy volunteers
No
Inclusion criteria
Inclusion: 1. Alzheimer's Disease Research Center-confirmed diagnosis of AD 2. Mini-Mental State Examination (MMSE) score 10-22 OR a Montreal Cognitive Assessment (MOCA) score of 15-24 3. Age 50-83 y 4. Knowledgeable caregiver 5. Ambulatory 6. Medically stable; 7. Audiometric testing (detection \< or = to 45 db(A) at 1000 Hz) 8. Informed consent Exclusion: 1. Active systemic illness (e.g. heart disease, liver failure, renal insufficiency, cancer, HIV, tuberculosis, Hepatitis C) 2. Current psychiatric or neurologic illness other than AD 3. History of vascular disease, myocardial infarction, cerebrovascular accidents, transient ischemic attack, seizure, head injury with loss of consciousness; substance dependence (including alcohol and Opioid) 4. Past treatment with memantine; unable to tolerate acetylcholinesterase inhibitor 5. Investigational drug treatment \< 30 d of screening 6. Current meds: amantadine, riluzole, other pro-cognitive medication, opioids 7. Positive urine toxicology for non-prescribed psychoactive substance 8. Actively enrolled in cognitive remediation therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline Measure in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog) at 8, 16 and 24 Weeks | 0, 8, 16, 24 weeks | The Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) is a tool used to assess the severity of cognitive impairment in individuals with Alzheimer's disease. It includes 11 tasks that evaluate memory, language, and praxis. The total score can range from 0 to 70 with higher scores indicating more severe impairment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline Measure in Neuropsychiatric Inventory-Questionnaire (NPI-Q) at 8, 16 and 24 Weeks | 0, 8, 16, 24 weeks | The NPI-Q measures behavioral symptoms in and is a self-administered questionnaire completed by informants about patients for whom they care. Each of the 12 NPI-Q domains contains a survey question that reflects cardinal symptoms of that domain. Symptoms are rated as present or absent, and if they are present the informant rates the severity of the symptom on a 3-point scale from mild to severe. The sum of severity scores across all 12 items ranges from 0 to 36 with higher scores indicate higher severity of symptoms. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORNeal Swerdlow, M.D., Ph.D.
UCSD
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Memantine EAIP are assessed 210 (PPI) and 345 min (MMN, ASSR) after administration of placebo or memantine (MEM 20 mg po), in a randomized order double-blind design. In this arm subjects are administered MEM 20 mg. Pills look identical so both the subject and research staff are blind to condition.
Memantine: Phase 1 will test the acute effects of memantine (20 mg po) vs. placebo (PBO) on early auditory information processing measures in 32 carefully characterized patients with mild-to-moderate severity AD who are not currently taking AD medications. From this challenge test, a set of early auditory information processing memantine sensitivity measures will be derived for each patient. In Phase 2, all patients will begin an open-label trial of memantine, titrated to 10 mg bid, with outcome measures collected after 8, 16 and 24 weeks of treatment. Medication adjustments are not restricted, and response heterogeneity is anticipated. | 53 |
| Total | 53 |
Baseline characteristics
| Characteristic | Memantine |
|---|---|
| Age, Continuous | 71.61 years STANDARD_DEVIATION 6.89 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 48 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants |
| Race (NIH/OMB) White | 42 Participants |
| Sex: Female, Male Female | 27 Participants |
| Sex: Female, Male Male | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 53 |
| other Total, other adverse events | 13 / 53 |
| serious Total, serious adverse events | 2 / 53 |
Outcome results
Primary
Change From Baseline Measure in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog) at 8, 16 and 24 Weeks
The Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) is a tool used to assess the severity of cognitive impairment in individuals with Alzheimer's disease. It includes 11 tasks that evaluate memory, language, and praxis. The total score can range from 0 to 70 with higher scores indicating more severe impairment.
Time frame: 0, 8, 16, 24 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Memantine | Change From Baseline Measure in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog) at 8, 16 and 24 Weeks | Baseline | 19.76 scores on a scale | Standard Deviation 8.97 |
| Memantine | Change From Baseline Measure in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog) at 8, 16 and 24 Weeks | Week 8 | 19.81 scores on a scale | Standard Deviation 9.85 |
| Memantine | Change From Baseline Measure in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog) at 8, 16 and 24 Weeks | Week 16 | 19.94 scores on a scale | Standard Deviation 9.55 |
| Memantine | Change From Baseline Measure in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog) at 8, 16 and 24 Weeks | Week 24 | 20.79 scores on a scale | Standard Deviation 11.03 |
Comparison: Change in ADAS-Cog score over timep-value: 0.68ANOVA
Secondary
Change From Baseline Measure in Neuropsychiatric Inventory-Questionnaire (NPI-Q) at 8, 16 and 24 Weeks
The NPI-Q measures behavioral symptoms in and is a self-administered questionnaire completed by informants about patients for whom they care. Each of the 12 NPI-Q domains contains a survey question that reflects cardinal symptoms of that domain. Symptoms are rated as present or absent, and if they are present the informant rates the severity of the symptom on a 3-point scale from mild to severe. The sum of severity scores across all 12 items ranges from 0 to 36 with higher scores indicate higher severity of symptoms.
Time frame: 0, 8, 16, 24 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Memantine | Change From Baseline Measure in Neuropsychiatric Inventory-Questionnaire (NPI-Q) at 8, 16 and 24 Weeks | Baseline | 4.27 score on a scale | Standard Deviation 4.05 |
| Memantine | Change From Baseline Measure in Neuropsychiatric Inventory-Questionnaire (NPI-Q) at 8, 16 and 24 Weeks | Week 8 | 3.55 score on a scale | Standard Deviation 3.36 |
| Memantine | Change From Baseline Measure in Neuropsychiatric Inventory-Questionnaire (NPI-Q) at 8, 16 and 24 Weeks | Week 16 | 3.05 score on a scale | Standard Deviation 2.38 |
| Memantine | Change From Baseline Measure in Neuropsychiatric Inventory-Questionnaire (NPI-Q) at 8, 16 and 24 Weeks | Week 24 | 4.09 score on a scale | Standard Deviation 3.57 |
p-value: >0.05ANOVA
Other Pre-specified
Change From Baseline Measure in Geriatric Depression Scale (GDS) at 8, 16 and 24 Weeks
The Geriatric Depression Scale (GDS) is a self-report measure of depression in older adults using a Yes/No format. The GDS consists of 30 items with higher scores indicating greater levels or depression. A score of 0-9 is normal, 10-19 is mild depression, and 20-30 is severe depression.
Time frame: 0, 8, 16, 24 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Memantine | Change From Baseline Measure in Geriatric Depression Scale (GDS) at 8, 16 and 24 Weeks | Week 8 | 6.05 score on a scale | Standard Deviation 5.92 |
| Memantine | Change From Baseline Measure in Geriatric Depression Scale (GDS) at 8, 16 and 24 Weeks | Week 16 | 6.09 score on a scale | Standard Deviation 6.69 |
| Memantine | Change From Baseline Measure in Geriatric Depression Scale (GDS) at 8, 16 and 24 Weeks | Week 24 | 6.64 score on a scale | Standard Deviation 6.89 |
| Memantine | Change From Baseline Measure in Geriatric Depression Scale (GDS) at 8, 16 and 24 Weeks | Baseline | 6.23 score on a scale | Standard Deviation 5.66 |
p-value: >0.05ANOVA