Neural Correlates In Mild Alzheimer's Disease
Study Details
Study Description
Brief Summary
The objective of this study was to identify neural correlates of cognitive improvement after 3 months of donepezil hydrochloride treatment using either or both of two functional magnetic resonance imaging (fMRI) measures - the functional Hippocampus Connectivity Index (HCI) and Cerebral Blood Flow (CBF) Perfusion; in the Medial Temporal Lobe (MTL) network in subjects in the early stage of Alzheimer's Disease (AD).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 4 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Donepezil hydrochloride
|
Drug: Donepezil hydrochloride
Donepezil hydrochloride 5 mg per day orally, once daily for 4 weeks, followed by 10 mg per day (two 5-mg tablets) for 8 weeks
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Percent Change From Baseline to Week 12 Based on Hippocampus Connectivity Index (HCI) [Week 12]
All neuroimaging procedures were performed on a research-dedicated GE 3.0 Tesla whole-body Excite scanner with 8-channel phase-array head coil. Resting-state functional magnetic resonance imaging (fMRI) of the medial temporal lobe (MTL) was performed. The functional HCI was derived from the MTL network using a data driven approach corresponding voxel time courses from the fMR images were processed to extract low frequency fluctuations. Functional connectivity was quantified by calculating the cross-correlation of each voxel time course in the hippocampus to all voxel time courses of the whole brain and the mean of absolute cross-correlation coefficients between a hippocampus voxel to the whole-brain voxels. HCI was then calculated as the average of all hippocampus cross-correlation coefficients. Change from baseline (CFB) was calculated using the CBF-Perfusion Processing Method. A positive change from baseline for HCI indicates improved function.
Secondary Outcome Measures
- Change From Baseline at Week 12 in Alzheimer's Disease Assessment Scale - Cognitive Scale (ADAS)-Cog Score [Baseline and Week 12]
The ADAS-cog is a 13-item performance-based test that examines selected aspects of cognition including memory, orientation, attention, reasoning, language, and praxis. Total score ranges from 0 to 70 with higher scores indicating greater cognitive impairment. A decrease from baseline indicates improved cognitive function. The ADAS-cog was administered by a trained individual unaware of adverse events reported during this trial.
- Change From Baseline at Week 12 in Mini-Mental State Examination (MMSE) Score [Baseline and Week 12]
MMSE was a 11-item scale to measure cognitive status where a higher score indicated better cognitive state. The score ranged from 0 to 30, with a higher score indicating better function. A positive change score indicated improvement from baseline. The mean change was analyzed by Wilcoxon's signed rank test.
- Change From Baseline at Week 12 in the Instrumental Activities of Daily Living (IADL) Assessment Score [Baseline and Week 12]
IADL Scale measures 7 areas of more complex activities required for optimal independent functioning, as reported by the caregiver. The scoring indicates whether the participant was completely independent (3), requires assistance (2), or is dependent (1) for the performance of each activity. A summary score ranges from 7 (high function, independent) to 21 (low function, dependent). The mean change was analyzed by Wilcoxon's signed rank test. A decrease from Baseline to Week 12 indicates improved function.
- Change From Baseline at Week 12 in the Neuropsychiatric Inventory (NPI) Score [Baseline and Week 12]
NPI was a 12-item caregiver-based assessment of behavioral disturbances commonly occurring in participants with AD. NPI includes 12 sections which are Delusions, Hallucinations, Agitation, Depression, Anxiety, Euphoria, Apathy, Disinhibition, Irritability, Aberrant motor behavior, Night-time behaviors and Appetite and eating disorders. The score of each section ranges from 0 to 12, and higher score means higher severity and frequency of the neuropsychiatric disturbances. The mean change was analyzed by Wilcoxon's signed rank test.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Men and women, aged 50 and older with mild Alzheimer's disease (MMSE scores of 20 to 30 are allowed).
-
Diagnostic evidence of Alzheimer's disease.
-
Previous use of cholinesterase inhibitors (other than Aricept) and memantine allowed.
Exclusion Criteria:
- Prior use of Aricept, pacemakers and insulin dependent diabetes are not allowed.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Medical College of Wisconsin | Milwaukee | Wisconsin | United States | 53226 |
Sponsors and Collaborators
- Eisai Inc.
- Pfizer
Investigators
- Study Director: Pfizer CT.gov Call Center, Pfizer
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- E2020-A001-416
- A2501055
Study Results
Participant Flow
| Recruitment Details | Participants took part in this study at one investigative site in the United States from 23 July 2007 to 15 August 2008. |
|---|---|
| Pre-assignment Detail | Out of the 16 participants who were screened, 14 participants were enrolled into the study. |
| Arm/Group Title | Donepezil Hydrochloride |
|---|---|
| Arm/Group Description | Participants received donepezil hydrochloride 5 mg per day orally, once daily for 4 weeks, followed by 10 mg per day (two 5-mg tablets) for 8 weeks. |
| Period Title: Overall Study | |
| STARTED | 14 |
| COMPLETED | 14 |
| NOT COMPLETED | 0 |
Baseline Characteristics
| Arm/Group Title | Donepezil |
|---|---|
| Arm/Group Description | Participants received donepezil hydrochloride 5 mg per day orally, once daily for 4 weeks, followed by 10 mg per day (two 5-mg tablets) for 8 weeks. |
| Overall Participants | 14 |
| Age (Count of Participants) | |
| <=18 years |
0
0%
|
| Between 18 and 65 years |
0
0%
|
| >=65 years |
14
100%
|
| Age (years) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [years] |
77.6
(6.6)
|
| Sex: Female, Male (Count of Participants) | |
| Female |
5
35.7%
|
| Male |
9
64.3%
|
| Race (NIH/OMB) (Count of Participants) | |
| American Indian or Alaska Native |
0
0%
|
| Asian |
0
0%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
| Black or African American |
0
0%
|
| White |
14
100%
|
| More than one race |
0
0%
|
| Unknown or Not Reported |
0
0%
|
| Region of Enrollment (participants) [Number] | |
| United States |
14
100%
|
Outcome Measures
| Title | Percent Change From Baseline to Week 12 Based on Hippocampus Connectivity Index (HCI) |
|---|---|
| Description | All neuroimaging procedures were performed on a research-dedicated GE 3.0 Tesla whole-body Excite scanner with 8-channel phase-array head coil. Resting-state functional magnetic resonance imaging (fMRI) of the medial temporal lobe (MTL) was performed. The functional HCI was derived from the MTL network using a data driven approach corresponding voxel time courses from the fMR images were processed to extract low frequency fluctuations. Functional connectivity was quantified by calculating the cross-correlation of each voxel time course in the hippocampus to all voxel time courses of the whole brain and the mean of absolute cross-correlation coefficients between a hippocampus voxel to the whole-brain voxels. HCI was then calculated as the average of all hippocampus cross-correlation coefficients. Change from baseline (CFB) was calculated using the CBF-Perfusion Processing Method. A positive change from baseline for HCI indicates improved function. |
| Time Frame | Week 12 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The ITT set included all participants who received at least one dose of study medication, had a baseline efficacy evaluation, and had at least one post-baseline efficacy evaluation. |
| Arm/Group Title | Donepezil Hydrochloride |
|---|---|
| Arm/Group Description | Participants received donepezil hydrochloride 5 mg per day orally, once daily for 4 weeks, followed by 10 mg per day (two 5-mg tablets) for 8 weeks. |
| Measure Participants | 14 |
| Mean (Standard Deviation) [percent change] |
7.47
(17.23)
|
| Title | Change From Baseline at Week 12 in Alzheimer's Disease Assessment Scale - Cognitive Scale (ADAS)-Cog Score |
|---|---|
| Description | The ADAS-cog is a 13-item performance-based test that examines selected aspects of cognition including memory, orientation, attention, reasoning, language, and praxis. Total score ranges from 0 to 70 with higher scores indicating greater cognitive impairment. A decrease from baseline indicates improved cognitive function. The ADAS-cog was administered by a trained individual unaware of adverse events reported during this trial. |
| Time Frame | Baseline and Week 12 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The ITT set included all participants who received at least one dose of study medication, had a baseline efficacy evaluation, and had at least one post-baseline efficacy evaluation. |
| Arm/Group Title | Donepezil Hydrochloride |
|---|---|
| Arm/Group Description | Participants received donepezil hydrochloride 5 mg per day orally, once daily for 4 weeks, followed by 10 mg per day (two 5-mg tablets) for 8 weeks. |
| Measure Participants | 14 |
| Baseline |
12.0
(4.85)
|
| Change at Week 12 |
-1.6
(2.81)
|
| Title | Change From Baseline at Week 12 in Mini-Mental State Examination (MMSE) Score |
|---|---|
| Description | MMSE was a 11-item scale to measure cognitive status where a higher score indicated better cognitive state. The score ranged from 0 to 30, with a higher score indicating better function. A positive change score indicated improvement from baseline. The mean change was analyzed by Wilcoxon's signed rank test. |
| Time Frame | Baseline and Week 12 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The ITT set included all participants who received at least one dose of study medication, had a baseline efficacy evaluation, and had at least one post-baseline efficacy evaluation. |
| Arm/Group Title | Donepezil Hydrochloride |
|---|---|
| Arm/Group Description | Participants received donepezil hydrochloride 5 mg per day orally, once daily for 4 weeks, followed by 10 mg per day (two 5-mg tablets) for 8 weeks. |
| Measure Participants | 14 |
| Baseline |
26.1
(1.33)
|
| Change at Week 12 |
0.1
(2.70)
|
| Title | Change From Baseline at Week 12 in the Instrumental Activities of Daily Living (IADL) Assessment Score |
|---|---|
| Description | IADL Scale measures 7 areas of more complex activities required for optimal independent functioning, as reported by the caregiver. The scoring indicates whether the participant was completely independent (3), requires assistance (2), or is dependent (1) for the performance of each activity. A summary score ranges from 7 (high function, independent) to 21 (low function, dependent). The mean change was analyzed by Wilcoxon's signed rank test. A decrease from Baseline to Week 12 indicates improved function. |
| Time Frame | Baseline and Week 12 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The ITT set included all participants who received at least one dose of study medication, had a baseline efficacy evaluation, and had at least one post-baseline efficacy evaluation. |
| Arm/Group Title | Donepezil Hydrochloride |
|---|---|
| Arm/Group Description | Participants received donepezil hydrochloride 5 mg per day orally, once daily for 4 weeks, followed by 10 mg per day (two 5-mg tablets) for 8 weeks. |
| Measure Participants | 14 |
| Baseline |
13.1
(3.71)
|
| Change at Week 12 |
-0.3
(2.70)
|
| Title | Change From Baseline at Week 12 in the Neuropsychiatric Inventory (NPI) Score |
|---|---|
| Description | NPI was a 12-item caregiver-based assessment of behavioral disturbances commonly occurring in participants with AD. NPI includes 12 sections which are Delusions, Hallucinations, Agitation, Depression, Anxiety, Euphoria, Apathy, Disinhibition, Irritability, Aberrant motor behavior, Night-time behaviors and Appetite and eating disorders. The score of each section ranges from 0 to 12, and higher score means higher severity and frequency of the neuropsychiatric disturbances. The mean change was analyzed by Wilcoxon's signed rank test. |
| Time Frame | Baseline and Week 12 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The ITT set included all participants who received at least one dose of study medication, had a baseline efficacy evaluation, and had at least one post-baseline efficacy evaluation. |
| Arm/Group Title | Donepezil Hydrochloride |
|---|---|
| Arm/Group Description | Participants received donepezil hydrochloride 5 mg per day orally, once daily for 4 weeks, followed by 10 mg per day (two 5-mg tablets) for 8 weeks. |
| Measure Participants | 14 |
| Baseline |
9.2
(10.00)
|
| Change at Week 12 |
-3.4
(11.25)
|
Adverse Events
| Time Frame | All adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 12 weeks) | |
|---|---|---|
| Adverse Event Reporting Description | Safety analysis set included all participants who received at least one dose of study medication. | |
| Arm/Group Title | Donepezil Hydrochloride | |
| Arm/Group Description | Participants received donepezil hydrochloride 5 mg per day orally, once daily for 4 weeks, followed by 10 mg per day (two 5-mg tablets) for 8 weeks. | |
All Cause Mortality |
||
| Donepezil Hydrochloride | ||
| Affected / at Risk (%) | # Events | |
| Total | 0/14 (0%) | |
Serious Adverse Events |
||
| Donepezil Hydrochloride | ||
| Affected / at Risk (%) | # Events | |
| Total | 0/14 (0%) | |
Other (Not Including Serious) Adverse Events |
||
| Donepezil Hydrochloride | ||
| Affected / at Risk (%) | # Events | |
| Total | 11/14 (78.6%) | |
| Ear and labyrinth disorders | ||
| Ear pain | 1/14 (7.1%) | |
| Eye disorders | ||
| Eye pain | 1/14 (7.1%) | |
| Vision blurred | 1/14 (7.1%) | |
| Gastrointestinal disorders | ||
| Diarrhea | 2/14 (14.3%) | |
| Feces discolored | 1/14 (7.1%) | |
| Flatulence | 1/14 (7.1%) | |
| Stomach discomfort | 1/14 (7.1%) | |
| General disorders | ||
| Asthenia | 1/14 (7.1%) | |
| Injury, poisoning and procedural complications | ||
| Contusion | 1/14 (7.1%) | |
| Metabolism and nutrition disorders | ||
| Decreased appetite | 1/14 (7.1%) | |
| Weight loss | 1/14 (7.1%) | |
| Hypercholesterolemia | 1/14 (7.1%) | |
| Musculoskeletal and connective tissue disorders | ||
| Muscle spasms | 1/14 (7.1%) | |
| Nervous system disorders | ||
| Headache | 1/14 (7.1%) | |
| Psychiatric disorders | ||
| Abnormal dreams | 1/14 (7.1%) | |
| Nervousness | 1/14 (7.1%) | |
| Nightmare | 1/14 (7.1%) | |
| Obsessive thoughts | 1/14 (7.1%) | |
| Sleep disorder | 1/14 (7.1%) | |
| Renal and urinary disorders | ||
| Micturition urgency | 1/14 (7.1%) | |
| Respiratory, thoracic and mediastinal disorders | ||
| Cough | 1/14 (7.1%) | |
| Rhinorrhea | 2/14 (14.3%) | |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Eisai Medical Services |
|---|---|
| Organization | Eisai, Inc. |
| Phone | 1-888-422-4743 |
| esi_medinfo@eisai.com |
- E2020-A001-416
- A2501055