Dementia Associated With Cerebrovascular Disease
Conditions
Brief summary
The primary objectives are to confirm that donepezil hydrochloride has superior efficacy compared with placebo in improving cognitive function, as measured by Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-cog), and to demonstrate that donepezil hydrochloride has superior efficacy compared with placebo in improving global function, as measured by Clinician's Interview-Based Impression of Change-plus Caregiver Input (CIBIC-plus), in patients with dementia associated with cerebrovascular disease (VaD).
Detailed description
This is a multi-center, randomized, double-blind, placebo-controlled, parallel-group study with an open-label extension. The study consists of 3 phases; screening phase (1 to 4 weeks), double-blind phase (24 weeks), and Open-label extension phase (24 weeks). Participants, who have completed the double-blind phase and want to continue the study participation, can be enrolled in the 24-week open-label extension phase.
Interventions
DRUGDonepezil hydrochloride
DRUGDonepezil matching placebo
Sponsors
Eisai Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Patients who meet all of the following criteria will be eligible for inclusion in the study: 1. Male or female, age greater than or equal to (\>=) 40 years at the time of informed consent. 2. Possible or probable dementia associated with cerebrovascular disease as defined by National Institute of Neurological Disorders and Stroke (NINDS) and the Association Internationale pour la Recherche et l'Enseignement en Neurosciences (AIREN) criteria (NINDS-AIREN Criteria) with dementia of greater than 3 months duration. 3. Radiological evidence of cerebrovascular disease. 4. Mini-Mental Status Examination (MMSE) score is ≥ 10 and ≤ 24. 5. Clinical Dementia Rating (CDR) ≥ 1. 6. Outpatients who are physically healthy, and ambulatory or ambulatory-aided (i.e., walker, cane or wheelchair). 7. Written informed consent (IC) is obtained from the patient (if possible) and from the patient's legal guardian prior to being exposed to any study-related procedures. The caregiver must separately provide IC for his/her own participation in the study. 8. Patients having caregivers who submit written consent to cooperate with this study, have regular contact with the patient (i.e., an average of ≥ 4 hours/day and ≥ 3 days/week), provide patients' information necessary for this study, ensure the regular administration of assigned donepezil, as well as all concomitant therapies, at the correct dose, and escort the patients on required visits to study institution. 9. Comorbid medical conditions are clinically stable prior to Baseline, unless otherwise specified.
Exclusion criteria
Patients who meet any of the following criteria will be excluded: 1. Anti-dementia drug therapy (cholinesterase inhibitors or memantine) within 12 weeks prior to Screening. 2. Clinical and/or radiological evidence for other serious degenerative neurological disorders or neuropsychiatric disorders. 3. Known human immunodeficiency virus disease, neurosyphilis, or a history of significant head trauma followed by persistent neurological deficits or known structural brain abnormalities. 4. Hypothyroidism at Screening. 5. Vitamin B12 or folate deficiency at Screening. 6. Evidence of a new transient ischemic attack (TIA) or stroke that occurs within 12 weeks prior to Screening, even if the symptoms are minor and do not require hospitalization, are excluded. 7. Supine diastolic blood pressure ≥ 95 mmHg. 8. Complication of sick sinus syndrome, abnormal auricular and atrioventricular (AV) junction conductions (AV block, ≥ II ventricular block, etc.), or with a prolonged QT/QTc interval (\> 450 ms) as demonstrated by a repeated electrocardiogram (ECG). 9. A history of life-threatening arrhythmias. 10. A history of malignant neoplasms treated within 5 years prior to study entry, current evidence of malignant neoplasm, recurrent, or metastatic disease. 11. A known or suspected history of drug or alcohol dependency or abuse. 12. Abnormal clinical laboratory values which are judged clinically significant by the investigator. 13. Patients who cannot swallow or who have difficulty swallowing whole tablets, as tablets should not be broken or crushed. 14. Known plan for elective surgery that would require general anesthesia and administration of neuromuscular blocking agents. 15. Pregnant women, lactating women, or women of child-bearing potential who don't agree to practice effective contraception throughout the entire study period and for 30 days after donepezil discontinuation, or who don't have a negative serum â-Human chorionic gonadotropin (HCG) test result or a negative urine pregnancy test result.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Double Blind (DB) Phase: Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) Score (LOCF) at Week 24 | Baseline and Week 24 | The ADAS-Cog was a validated psychometric instrument that evaluates memory (word recall, word recognition), attention, reasoning (following commands), language (naming, comprehension), orientation, ideational praxis (placing letter in envelope) and constructional praxis (copying geometric designs). The ADAS-cog scores range from 0 to 70, with negative change from baseline indicating clinical improvement. LOCF=last observation carried forward. |
| Double Blind (DB) Phase: Clinicians Interview-based Impression of Change-plus Caregiver Input (CIBIC-plus) Score (LOCF) | Week 24 | The CIBIC-plus rates change in global functioning relative to baseline on a scale. The score ranges from 1 (Marked improvement) to 7 (Marked worsening). A score of 4 represents no change from baseline. LOCF=last observation carried forward. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Double Blind (DB) Phase: Change From Baseline in Mini-mental State Examination (MMSE) Score (LOCF) at Week 24 | Baseline and Week 24 | MMSE is a well-known, gold standard test for measuring the cognitive state of dementia participants. It includes items evaluating orientation to time and place, recall of objects, attention, language, and conversational abilities. The total score ranges from 0 (most impaired) to 30 (no impairment). The lower score means severe cognitive deficit. A positive change score indicated improvement from baseline. LOCF=last observation carried forward. |
| Double Blind (DB) Phase: Change From Baseline in Executive Function Test (Korean Trail Making Test Elderly [K-TMT-e]) Score (LOCF) at Week 24 | Baseline and Week 24 | The trail making test (TMT) was an evaluation tool used to assess the cognitive function, especially for executive function. The K-TMT-e has two parts that are referred to as part A (component: serial numbers) and part B (component: serial numbers and days). The K-TMT-e was a timed test and the goal was to complete the tests accurately and as quickly as possible. Higher scores reveal greater impairment. K-TMT-e Score was measured as time taken by participants to complete goal. LOCF=last observation carried forward. |
Countries
South Korea
Participant flow
Recruitment details
Participants took part in the study at 32 investigative sites in Korea from 05 August 2013 to 21 December 2018.
Pre-assignment details
A total of 425 participants were screened, of which 123 were screen failures and 302 were enrolled and randomized to receive study treatment. For Double Blind (DB) Phase both efficacy and safety data is presented while for Open Label Extension (OLE) Phase, only safety data is presented.
Participants by arm
| Arm | Count |
|---|---|
| Double Blind (DB) Phase: Placebo Participants received placebo matched to donepezil 5 mg tablet, orally, once daily in the evening for up to Week 4 in titration period, followed by placebo matched to donepezil 10 mg or 5 mg tablet, orally, once daily for up to Week 24 in maintenance period. Total duration of titration and maintenance period in DB Phase was up to 24 weeks. | 146 |
| Double Blind (DB) Phase: Donepezil Participants received donepezil 5 mg, tablet, orally, once daily in the evening for up to Week 4 in titration period, followed by donepezil 10 mg, tablet, orally, once daily for up to Week 24 in maintenance period. Dose reduction to 5 mg/day was permitted only when 10 mg/day was intolerable due to an occurrence of adverse events of which the causal relationship with the donepezil was not ruled out. Total duration of titration and maintenance period in DB Phase was up to 24 weeks. | 137 |
| Total | 283 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double-blind (DB) Phase (24 Weeks) | Adverse Event | 8 | 9 |
| Double-blind (DB) Phase (24 Weeks) | Protocol Violation | 1 | 5 |
| Double-blind (DB) Phase (24 Weeks) | Withdrawal by Subject | 15 | 12 |
| Open Label Extension Phase (24 Weeks) | Adverse Event | 1 | 3 |
| Open Label Extension Phase (24 Weeks) | Other | 0 | 1 |
| Open Label Extension Phase (24 Weeks) | Protocol Violation | 1 | 1 |
| Open Label Extension Phase (24 Weeks) | Withdrawal by Subject | 1 | 4 |
Baseline characteristics
| Characteristic | Double Blind (DB) Phase: Placebo | Double Blind (DB) Phase: Donepezil | Total |
|---|---|---|---|
| Age, Continuous | 72.96 years STANDARD_DEVIATION 7.94 | 72.31 years STANDARD_DEVIATION 7.06 | 72.64 years STANDARD_DEVIATION 7.52 |
| Race/Ethnicity, Customized Korean | 146 Participants | 137 Participants | 283 Participants |
| Sex: Female, Male Female | 55 Participants | 48 Participants | 103 Participants |
| Sex: Female, Male Male | 91 Participants | 89 Participants | 180 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 153 | 1 / 147 | 2 / 161 |
| other Total, other adverse events | 73 / 153 | 86 / 147 | 63 / 161 |
| serious Total, serious adverse events | 24 / 153 | 18 / 147 | 12 / 161 |
Outcome results
Primary
Double Blind (DB) Phase: Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) Score (LOCF) at Week 24
The ADAS-Cog was a validated psychometric instrument that evaluates memory (word recall, word recognition), attention, reasoning (following commands), language (naming, comprehension), orientation, ideational praxis (placing letter in envelope) and constructional praxis (copying geometric designs). The ADAS-cog scores range from 0 to 70, with negative change from baseline indicating clinical improvement. LOCF=last observation carried forward.
Time frame: Baseline and Week 24
Population: The FAS, LOCF, included all randomized participants who received at least one dose of study drug and had at least one postdose primary efficacy measurement. Overall number of participants analyzed included participants who were evaluable at a particular time point for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Double Blind (DB) Phase: Placebo | Double Blind (DB) Phase: Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) Score (LOCF) at Week 24 | -2.06 score on a scale | Standard Error 0.42 |
| Double Blind (DB) Phase: Donepezil | Double Blind (DB) Phase: Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) Score (LOCF) at Week 24 | -2.64 score on a scale | Standard Error 0.44 |
p-value: 0.345595% CI: [-1.79, 0.63]ANCOVA
Primary
Double Blind (DB) Phase: Clinicians Interview-based Impression of Change-plus Caregiver Input (CIBIC-plus) Score (LOCF)
The CIBIC-plus rates change in global functioning relative to baseline on a scale. The score ranges from 1 (Marked improvement) to 7 (Marked worsening). A score of 4 represents no change from baseline. LOCF=last observation carried forward.
Time frame: Week 24
Population: The FAS, LOCF, included all randomized participants who received at least one dose of study drug and had at least one postdose primary efficacy measurement. Overall number of participants analyzed included participants who were evaluable at a particular time point for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Double Blind (DB) Phase: Placebo | Double Blind (DB) Phase: Clinicians Interview-based Impression of Change-plus Caregiver Input (CIBIC-plus) Score (LOCF) | 3.85 score on a scale | Standard Error 0.07 |
| Double Blind (DB) Phase: Donepezil | Double Blind (DB) Phase: Clinicians Interview-based Impression of Change-plus Caregiver Input (CIBIC-plus) Score (LOCF) | 3.73 score on a scale | Standard Error 0.07 |
p-value: 0.25795% CI: [-0.32, 0.09]ANCOVA
Secondary
Double Blind (DB) Phase: Change From Baseline in Executive Function Test (Korean Trail Making Test Elderly [K-TMT-e]) Score (LOCF) at Week 24
The trail making test (TMT) was an evaluation tool used to assess the cognitive function, especially for executive function. The K-TMT-e has two parts that are referred to as part A (component: serial numbers) and part B (component: serial numbers and days). The K-TMT-e was a timed test and the goal was to complete the tests accurately and as quickly as possible. Higher scores reveal greater impairment. K-TMT-e Score was measured as time taken by participants to complete goal. LOCF=last observation carried forward.
Time frame: Baseline and Week 24
Population: The FAS, LOCF, included all randomized participants who received at least one dose of study drug and had at least one postdose primary efficacy measurement. Number analyzed signifies participants who were evaluable at a particular part of study for this outcome measure.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Double Blind (DB) Phase: Placebo | Double Blind (DB) Phase: Change From Baseline in Executive Function Test (Korean Trail Making Test Elderly [K-TMT-e]) Score (LOCF) at Week 24 | Part A | -5.10 seconds | Standard Error 4.38 |
| Double Blind (DB) Phase: Placebo | Double Blind (DB) Phase: Change From Baseline in Executive Function Test (Korean Trail Making Test Elderly [K-TMT-e]) Score (LOCF) at Week 24 | Part B | 1.16 seconds | Standard Error 5.41 |
| Double Blind (DB) Phase: Donepezil | Double Blind (DB) Phase: Change From Baseline in Executive Function Test (Korean Trail Making Test Elderly [K-TMT-e]) Score (LOCF) at Week 24 | Part A | -12.82 seconds | Standard Error 4.52 |
| Double Blind (DB) Phase: Donepezil | Double Blind (DB) Phase: Change From Baseline in Executive Function Test (Korean Trail Making Test Elderly [K-TMT-e]) Score (LOCF) at Week 24 | Part B | -13.73 seconds | Standard Error 5.52 |
Comparison: Part Ap-value: 0.221395% CI: [-20.13, 4.68]ANCOVA
Comparison: Part Bp-value: 0.055195% CI: [-30.1, 0.33]ANCOVA
Secondary
Double Blind (DB) Phase: Change From Baseline in Mini-mental State Examination (MMSE) Score (LOCF) at Week 24
MMSE is a well-known, gold standard test for measuring the cognitive state of dementia participants. It includes items evaluating orientation to time and place, recall of objects, attention, language, and conversational abilities. The total score ranges from 0 (most impaired) to 30 (no impairment). The lower score means severe cognitive deficit. A positive change score indicated improvement from baseline. LOCF=last observation carried forward.
Time frame: Baseline and Week 24
Population: The FAS, LOCF, included all randomized participants who received at least one dose of study drug and had at least one postdose primary efficacy measurement. Overall number of participants analyzed included participants who were evaluable at a particular time point for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Double Blind (DB) Phase: Placebo | Double Blind (DB) Phase: Change From Baseline in Mini-mental State Examination (MMSE) Score (LOCF) at Week 24 | 0.59 score on a scale | Standard Error 0.22 |
| Double Blind (DB) Phase: Donepezil | Double Blind (DB) Phase: Change From Baseline in Mini-mental State Examination (MMSE) Score (LOCF) at Week 24 | 1.23 score on a scale | Standard Error 0.22 |
p-value: 0.039695% CI: [0.03, 1.26]ANCOVA