Alzheimer's Dementia
Conditions
Keywords
Alzheimer's dementia, Cilostazol
Brief summary
The purpose of this study is to examine the effects of cilostazol augmentation in mild to moderate Alzheimer disease patients with subcortical white matter hyperintensities (WMHI) treated by donepezil. Dementia is the most disabling disease in the old age. The prevalence of dementia is 5-10% of the elders. AchEIs (donepezil, galantamine, rivastigmine) are used to treat mild to moderate dementia, but these drugs only relate to symptomatic improvement and the response rates are less than 30%. Cilostazol is a cyclic adenosine monophosphate phosphodiesterase 3 inhibitor (PDE3I) and used as antiplatelet agent in subcortical vascular disease (WMHI). And it upregulates phosphorylation of cyclic adenosine monophosphate-pathway response element binding protein (CREB) which plays a crucial role in memory enhancement and synaptic plasticity related to neurodegeneration prevention. The investigators will try cilostazol augmentation in dementia patients with WMHI receiving donepezil to see the addictive effects of cilostazol using cognitive tasks and PET imaging.
Interventions
DRUGCilostazol
Cilostazol 100mg bid per day will be administered orally and the period is total 24 weeks. The first week is a period for increasing the quantity, and during this period, cilostazol 50mg bid per day will be administered orally.
DRUGPlacebo
Placebo with similar shape and color to cilostazol 100mg bid per day will be administered orally and the period is total 24 weeks. The first week is a period for increasing the quantity, and during this period, placebo 50mg bid per day will be administered orally.
Sponsors
Korea OIAA
Seoul National University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Men/women over sixty years old * Patients with slight and moderate dementia (MMSE score is over 10 under 26.) * Patients with probable Alzheimer's disease according to the standard of NINCDS-ADRDA * Patients accompanied with WMHI on Brain MRI (Fazeka's scale 1\ 3)
Exclusion criteria
* Those who do not agree to the test in a written form * Patients who accompany other diseases except cerebral atrophy or change of subcortical white matter due to Alzheimer's disease on brain MRI * Patients who should not use Cilostazol (① patients with bleeding tendency ② patients with congestive heart failure ③ patients who have a medical history of hypersensitivity to this medicine or constituent of this medicine ④ those who use anticoagulant and clot buster) * Patients who suffer from nerve diseases or mental diseases which have influence on cognitive function except Alzheimer's disease (for example, schizophrenia, severe depression, mental retardation and etc.) * Patients who are suspected to have a personal history of drug addiction or alcoholism within recent 10 years * Patients who have severe problems in eye sight or hearing so that it is impossible to conduct the test smoothly * Patients who the researchers think are inappropriate for taking part in the test
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Regionally Averaged Cerebral Glucose Uptake Changes Measured by FDG PET Uptake With Voxel-based Method | Baseline, 24-week | Regional cerebral glucose uptake level was measured as the ratio value of FDG uptake of the each unit level to the global mean uptake value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mini-Mental State Examination (MMSE) in the Korean Version of the CERAD Assessment Packet) | Baseline, 12-month, 24-month | Basic cognitive functions are checked. (0-30) The score is better when higher. |
| Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) | Baseline, 12-week, 24-week | The ADAS-Cog score is measured by the number of questions answered incorrectly, therefore the higher is the worse. Score Scale: 0-75 (min-MAX) Each subcategory scores are summed. 1. Word-recall test (0-10) 2. Commands (0-5) 3. Constructional praxis (0-5) 4. Naming Objects/ Fingers (0-5) 5. Ideational Praxis (0-5) 6. Orientation (0-8) 7. Word Recognition (0-12) 8. Remembering Test Instructions (0-5) 9. Spoken Language Ability (0-5) 10. Word Finding Difficulty (0-5) 11. Comprehension (0-5) |
| Activities of Daily Living (ADCS-ADL) | Baseline, 12-month, 24-month | The caregiver answered to the questions given to measure the cognitive function level of the patients in daily living. Lower scores indicate greater severity. 23 questions Score Scale: 0-78 (min-MAX) |
| Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) | Baseline, 12-month, 24-month | Measured by professionally trained clinicians. Higher score indicates more severe AD symptoms. Score Scale: 0-18 (min-MAX) |
| Fazekas Scale | Baseline | Level of severity of white matter lesions in AD patients who can be legitimately administered with cilostazol. Measured by professionally trained clinicians. The higher score indicates more severe white matter lesion. Max-min: 0-3 |
Countries
South Korea
Participant flow
Recruitment details
46 Subjects were enrolled in the single center of Seoul National University Boramae Hospital. The diagnosis of probable AD was made according to the criteria of NINCDS-ADRDA (MMSE score 10 \ 26). Enrollment has started in July 2010 to end in March 2012.
Participants by arm
| Arm | Count |
|---|---|
| Cilostazol Cilostazol group means dementia patients group receiving donepezil with cilostazol augmentation. | 18 |
| Placebo Placebo group means dementia patients group receiving donepezil with placebo. | 18 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | brain abnormalities found in T1 MR | 1 | 2 |
| Overall Study | low medication compliance | 4 | 3 |
Baseline characteristics
| Characteristic | Placebo | Cilostazol | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 18 Participants | 18 Participants | 36 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 78.05 years STANDARD_DEVIATION 6.09 | 79.00 years STANDARD_DEVIATION 6.26 | 78.53 years STANDARD_DEVIATION 6.11 |
| Region of Enrollment Korea, Republic of | 18 participants | 18 participants | 36 participants |
| Sex: Female, Male Female | 15 Participants | 13 Participants | 28 Participants |
| Sex: Female, Male Male | 3 Participants | 5 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 18 | 3 / 18 |
| serious Total, serious adverse events | 0 / 18 | 0 / 18 |
Outcome results
Primary
Regionally Averaged Cerebral Glucose Uptake Changes Measured by FDG PET Uptake With Voxel-based Method
Regional cerebral glucose uptake level was measured as the ratio value of FDG uptake of the each unit level to the global mean uptake value.
Time frame: Baseline, 24-week
Population: Number of patients with increased whole brain glucose uptake level. In the real analysis, however, a voxel-based image analysis results were used; therefore, data which can be entered here is not much meaningful.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cilostazol, Baseline | Regionally Averaged Cerebral Glucose Uptake Changes Measured by FDG PET Uptake With Voxel-based Method | Left Parietal Lobe | 81.70 Bq/Bq (no unit) | Standard Deviation 9.51 |
| Cilostazol, Baseline | Regionally Averaged Cerebral Glucose Uptake Changes Measured by FDG PET Uptake With Voxel-based Method | Right Parietal Lobe | 80.03 Bq/Bq (no unit) | Standard Deviation 10.26 |
| Cilostazol, Baseline | Regionally Averaged Cerebral Glucose Uptake Changes Measured by FDG PET Uptake With Voxel-based Method | Left Inferior Frontal Gyrus | 85.74 Bq/Bq (no unit) | Standard Deviation 7.03 |
| Cilostazol, Baseline | Regionally Averaged Cerebral Glucose Uptake Changes Measured by FDG PET Uptake With Voxel-based Method | Right Inferior Frontal Gyrus | 72.11 Bq/Bq (no unit) | Standard Deviation 6.48 |
| Cilostazol, 24-week | Regionally Averaged Cerebral Glucose Uptake Changes Measured by FDG PET Uptake With Voxel-based Method | Right Parietal Lobe | 79.00 Bq/Bq (no unit) | Standard Deviation 9.55 |
| Cilostazol, 24-week | Regionally Averaged Cerebral Glucose Uptake Changes Measured by FDG PET Uptake With Voxel-based Method | Left Inferior Frontal Gyrus | 86.82 Bq/Bq (no unit) | Standard Deviation 6.06 |
| Cilostazol, 24-week | Regionally Averaged Cerebral Glucose Uptake Changes Measured by FDG PET Uptake With Voxel-based Method | Right Inferior Frontal Gyrus | 71.39 Bq/Bq (no unit) | Standard Deviation 4.82 |
| Cilostazol, 24-week | Regionally Averaged Cerebral Glucose Uptake Changes Measured by FDG PET Uptake With Voxel-based Method | Left Parietal Lobe | 80.40 Bq/Bq (no unit) | Standard Deviation 8.27 |
| Placebo, Baseline | Regionally Averaged Cerebral Glucose Uptake Changes Measured by FDG PET Uptake With Voxel-based Method | Left Inferior Frontal Gyrus | 85.97 Bq/Bq (no unit) | Standard Deviation 5.72 |
| Placebo, Baseline | Regionally Averaged Cerebral Glucose Uptake Changes Measured by FDG PET Uptake With Voxel-based Method | Right Parietal Lobe | 85.29 Bq/Bq (no unit) | Standard Deviation 8.62 |
| Placebo, Baseline | Regionally Averaged Cerebral Glucose Uptake Changes Measured by FDG PET Uptake With Voxel-based Method | Right Inferior Frontal Gyrus | 74.02 Bq/Bq (no unit) | Standard Deviation 6.38 |
| Placebo, Baseline | Regionally Averaged Cerebral Glucose Uptake Changes Measured by FDG PET Uptake With Voxel-based Method | Left Parietal Lobe | 84.60 Bq/Bq (no unit) | Standard Deviation 7.47 |
| Placebo, 24-week | Regionally Averaged Cerebral Glucose Uptake Changes Measured by FDG PET Uptake With Voxel-based Method | Right Inferior Frontal Gyrus | 71.44 Bq/Bq (no unit) | Standard Deviation 5.53 |
| Placebo, 24-week | Regionally Averaged Cerebral Glucose Uptake Changes Measured by FDG PET Uptake With Voxel-based Method | Right Parietal Lobe | 81.91 Bq/Bq (no unit) | Standard Deviation 8.37 |
| Placebo, 24-week | Regionally Averaged Cerebral Glucose Uptake Changes Measured by FDG PET Uptake With Voxel-based Method | Left Parietal Lobe | 81.33 Bq/Bq (no unit) | Standard Deviation 6.82 |
| Placebo, 24-week | Regionally Averaged Cerebral Glucose Uptake Changes Measured by FDG PET Uptake With Voxel-based Method | Left Inferior Frontal Gyrus | 83.12 Bq/Bq (no unit) | Standard Deviation 5.81 |
Comparison: Repeated-measures analysis of variance (ANOVA) was used to test group\*time interaction effect in glucose uptake of Left Parietal Lobe in two groups on two data points (baseline, 24-week).p-value: 0.14Repeated ANOVA
Comparison: Repeated-measures analysis of variance (ANOVA) was used to test group\*time interaction effect in glucose uptake of Right Parietal Lobe in two groups on two data points (baseline, 24-week).p-value: 0.08Repeated ANOVA
Comparison: Repeated-measures analysis of variance (ANOVA) was used to test group\*time interaction effect in glucose uptake of Left Inferior Frontal Gyrus in two groups on two data points (baseline, 24-week).p-value: <0.01Repeated ANOVA
Comparison: Repeated-measures analysis of variance (ANOVA) was used to test group\*time interaction effect in glucose uptake of Right Inferior Frontal Gyrus in two groups on two data points (baseline, 24-week).p-value: 0.08Repeated ANOVA
Secondary
Activities of Daily Living (ADCS-ADL)
The caregiver answered to the questions given to measure the cognitive function level of the patients in daily living. Lower scores indicate greater severity. 23 questions Score Scale: 0-78 (min-MAX)
Time frame: Baseline, 12-month, 24-month
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cilostazol, Baseline | Activities of Daily Living (ADCS-ADL) | Baseline | 50.17 units on a scale | Standard Deviation 11.61 |
| Cilostazol, Baseline | Activities of Daily Living (ADCS-ADL) | 12-week | 48.00 units on a scale | Standard Deviation 13.14 |
| Cilostazol, Baseline | Activities of Daily Living (ADCS-ADL) | 24-week | 46.33 units on a scale | Standard Deviation 15.88 |
| Cilostazol, 24-week | Activities of Daily Living (ADCS-ADL) | Baseline | 53.56 units on a scale | Standard Deviation 14.86 |
| Cilostazol, 24-week | Activities of Daily Living (ADCS-ADL) | 12-week | 49.33 units on a scale | Standard Deviation 17.38 |
| Cilostazol, 24-week | Activities of Daily Living (ADCS-ADL) | 24-week | 51.17 units on a scale | Standard Deviation 16.53 |
Comparison: Repeated ANOVA, tested for group\*time interaction effect of ADCS-ADL scores on three data points (Baseline, 12-week, 24-week)p-value: 0.82Repeated ANOVA
Secondary
Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog)
The ADAS-Cog score is measured by the number of questions answered incorrectly, therefore the higher is the worse. Score Scale: 0-75 (min-MAX) Each subcategory scores are summed. 1. Word-recall test (0-10) 2. Commands (0-5) 3. Constructional praxis (0-5) 4. Naming Objects/ Fingers (0-5) 5. Ideational Praxis (0-5) 6. Orientation (0-8) 7. Word Recognition (0-12) 8. Remembering Test Instructions (0-5) 9. Spoken Language Ability (0-5) 10. Word Finding Difficulty (0-5) 11. Comprehension (0-5)
Time frame: Baseline, 12-week, 24-week
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cilostazol, Baseline | Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) | Baseline | 29.28 units on a scale | Standard Deviation 8.79 |
| Cilostazol, Baseline | Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) | 12-week | 26.33 units on a scale | Standard Deviation 6.75 |
| Cilostazol, Baseline | Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) | 24-week | 25.78 units on a scale | Standard Deviation 8.19 |
| Cilostazol, 24-week | Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) | Baseline | 27.78 units on a scale | Standard Deviation 7.89 |
| Cilostazol, 24-week | Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) | 12-week | 24.83 units on a scale | Standard Deviation 7.67 |
| Cilostazol, 24-week | Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) | 24-week | 24.78 units on a scale | Standard Deviation 7.41 |
Comparison: Repeated ANOVA, tested for group\*time interaction effect of ADAS-Cog scores on three data points (Baseline, 12-week, 24-week)p-value: 0.93Repeated ANOVA
Secondary
Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB)
Measured by professionally trained clinicians. Higher score indicates more severe AD symptoms. Score Scale: 0-18 (min-MAX)
Time frame: Baseline, 12-month, 24-month
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cilostazol, Baseline | Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) | Baseline | 5.11 units on a scale | Standard Deviation 2.3 |
| Cilostazol, Baseline | Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) | 12-week | 5.42 units on a scale | Standard Deviation 2.05 |
| Cilostazol, Baseline | Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) | 24-week | 5.44 units on a scale | Standard Deviation 2.49 |
| Cilostazol, 24-week | Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) | Baseline | 4.72 units on a scale | Standard Deviation 1.56 |
| Cilostazol, 24-week | Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) | 12-week | 5.28 units on a scale | Standard Deviation 2.18 |
| Cilostazol, 24-week | Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) | 24-week | 5.33 units on a scale | Standard Deviation 2.88 |
Comparison: Repeated ANOVA, tested for group\*time interaction effect of Summed CDR scores on three data points (Baseline, 12-week, 24-week)p-value: 0.79Chi-squared
Secondary
Fazekas Scale
Level of severity of white matter lesions in AD patients who can be legitimately administered with cilostazol. Measured by professionally trained clinicians. The higher score indicates more severe white matter lesion. Max-min: 0-3
Time frame: Baseline
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cilostazol, Baseline | Fazekas Scale | Number of Patients Scored 2 | 3 participants |
| Cilostazol, Baseline | Fazekas Scale | Number of Patients Scored 1 | 13 participants |
| Cilostazol, Baseline | Fazekas Scale | Number of Patients Scored 3 | 2 participants |
| Cilostazol, 24-week | Fazekas Scale | Number of Patients Scored 1 | 11 participants |
| Cilostazol, 24-week | Fazekas Scale | Number of Patients Scored 2 | 5 participants |
| Cilostazol, 24-week | Fazekas Scale | Number of Patients Scored 3 | 2 participants |
Comparison: Distribution of Fazekas scale in two groups according to Chi-square test results.p-value: 0.87Chi-squared
Secondary
Mini-Mental State Examination (MMSE) in the Korean Version of the CERAD Assessment Packet)
Basic cognitive functions are checked. (0-30) The score is better when higher.
Time frame: Baseline, 12-month, 24-month
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cilostazol, Baseline | Mini-Mental State Examination (MMSE) in the Korean Version of the CERAD Assessment Packet) | Baseline | 15.11 units on a scale | Standard Deviation 3.61 |
| Cilostazol, Baseline | Mini-Mental State Examination (MMSE) in the Korean Version of the CERAD Assessment Packet) | 12-week | 16.67 units on a scale | Standard Deviation 4.04 |
| Cilostazol, Baseline | Mini-Mental State Examination (MMSE) in the Korean Version of the CERAD Assessment Packet) | 24-week | 15.39 units on a scale | Standard Deviation 3.94 |
| Cilostazol, 24-week | Mini-Mental State Examination (MMSE) in the Korean Version of the CERAD Assessment Packet) | Baseline | 15.44 units on a scale | Standard Deviation 3.96 |
| Cilostazol, 24-week | Mini-Mental State Examination (MMSE) in the Korean Version of the CERAD Assessment Packet) | 12-week | 15.83 units on a scale | Standard Deviation 4.84 |
| Cilostazol, 24-week | Mini-Mental State Examination (MMSE) in the Korean Version of the CERAD Assessment Packet) | 24-week | 16.22 units on a scale | Standard Deviation 4.91 |
Comparison: Repeated ANOVA, tested for group\*time interaction effect of MMSE scores on three data points (Baseline, 12-week, 24-week)p-value: 0.15Repeated ANOVA