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CompletedNCT02660983Updated Jan 10, 2020Results posted

A Study of Donepezil Hydrochloride in Patients With Dementia Associated With Cerebrovascular Disease

A Phase 4 interventional study of Donepezil hydrochloride and Donepezil matching placebo in Dementia Associated With Cerebrovascular Disease, sponsored by Eisai Co., Ltd.. Completed at 31 sites in Korea, Republic of. Open to participants aged 40 Years and older. Per ClinicalTrials.gov, last updated 2020-01-10.

Sponsored by Eisai Co., Ltd. · Phase 4, Interventional, and Treatment

From the registry’s dates

  • Registered 2 years 5 months after the study started (first participant enrolled Aug 2013, registered Jan 2016).
Phase
Phase 4
Study type
Interventional
Enrollment
302
Allocation
Randomized
Ages
40 Years and older
Sex
All
01

Study 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).

Read the 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.

02

Conditions studied

  • Dementia Associated With Cerebrovascular Disease
03

In context

Dementia

2,172 studies on the registry are indexed under Dementia; 540 are open to participants now.

This study's enrollment of 302 is above the median of 83 across 1,629 interventional studies indexed under Dementia.

Browse Dementia studies →

Lead sponsor

Eisai Co., Ltd. is the lead sponsor of 149 studies on the registry; 5 are open to participants now.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
40 Years and older
Sexes eligible
All
Accepts 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

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.
05

Study design

Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Double (Participant, Investigator)
Enrollment
302 participants (actual)

Study arms

  • Placebo comparator
    Double Blind Phase: Placebo

    Participants will receive donepezil matching placebo, once daily in the evening during the double blind period.

    Drug: Donepezil matching placebo

  • Experimental
    Double Blind Phase: Donepezil

    Participants will receive donepezil 5 milligram (mg), once daily in the evening during the titration phase and then the dose will be increased to 10 mg at Week 4 during the double blind period. During the maintenance period, dose reduction to 5 mg/day will be permitted only when 10 mg/day is intolerable due to adverse events.

    Drug: Donepezil hydrochloride

  • Experimental
    Open-Label Extension Phase: Donepezil

    All participants who will complete the double-blind phase and want to continue the study participation, can be enrolled in the 24-week open-label extension phase. In this phase, treatment will be initiated at 5 mg/day, and the dose will be maintained until Week 6 (Day 28-42). After assessing clinical response during the period by examination, the dose can be increased to 10 mg/day. Dose reduction (from 10 mg/day to 5 mg/day) will be permitted when the investigator judges it difficult to continue the 10 mg/day administration. It will be possible to increase the dose to 10 mg/day again.

    Drug: Donepezil hydrochloride

Interventions

  • DrugDonepezil hydrochloride

    Also known as: E2020, Aricept

  • DrugDonepezil matching placebo
  • DrugDonepezil hydrochloride

    Also known as: E2020, Aricept

06

What researchers measure

Primary outcomes

  1. 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

  2. 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

Secondary outcomes

  1. 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

  2. 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

07

Results

Posted Oct 4, 2019

Participant flow

Participants took part in the study at 32 investigative sites in Korea from 05 August 2013 to 21 December 2018.

Double-blind (DB) Phase (24 Weeks)
Participant flow — Double-blind (DB) Phase (24 Weeks)
MilestonePlacebo in DB Phase Then Donepezil in OLE PhaseDonepezil in DB Phase Then Donepezil in OLE Phase
Started154148
Treated/safety set153147
Completed130122
Not completed2426
Withdrew: Protocol violation15
Withdrew: Withdrawal by subject1512
Withdrew: Adverse event89
Open Label Extension Phase (24 Weeks)
Participant flow — Open Label Extension Phase (24 Weeks)
MilestonePlacebo in DB Phase Then Donepezil in OLE PhaseDonepezil in DB Phase Then Donepezil in OLE Phase
Started8675
Safety set8675
Completed8366
Not completed39
Withdrew: Protocol violation11
Withdrew: Withdrawal by subject14
Withdrew: Adverse event13
Withdrew: Other01

Outcome measures

PrimaryDouble 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
Reported as:
Least squares mean · score on a scale
Double Blind (DB) Phase: Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) Score (LOCF) at Week 24
score on a scaleDouble Blind (DB) Phase: PlaceboDouble 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 24-2.06 ± 0.42-2.64 ± 0.44
Statistical analysis
  • Double Blind (DB) Phase: Placebo vs Double Blind (DB) Phase: Donepezil · ANCOVA · p = 0.3455 · Difference in least square (ls) means: -0.58 · 95% CI -1.79 to 0.63
PrimaryDouble 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
Reported as:
Least squares mean · score on a scale
Double Blind (DB) Phase: Clinicians Interview-based Impression of Change-plus Caregiver Input (CIBIC-plus) Score (LOCF)
score on a scaleDouble Blind (DB) Phase: PlaceboDouble Blind (DB) Phase: Donepezil
Double Blind (DB) Phase: Clinicians Interview-based Impression of Change-plus Caregiver Input (CIBIC-plus) Score (LOCF)3.85 ± 0.073.73 ± 0.07
Statistical analysis
  • Double Blind (DB) Phase: Placebo vs Double Blind (DB) Phase: Donepezil · ANCOVA · p = 0.2570 · Difference in ls means: -0.12 · 95% CI -0.32 to 0.09LS mean of Donepezil group - LS mean of Placebo (when the difference of LS mean scores were less than 0, considered as demonstrated hypothesis), analyzed with ANCOVA model with baseline (CIBIS) as covariate and treatment as main effect.
SecondaryDouble 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
Reported as:
Least squares mean · score on a scale
Double Blind (DB) Phase: Change From Baseline in Mini-mental State Examination (MMSE) Score (LOCF) at Week 24
score on a scaleDouble Blind (DB) Phase: PlaceboDouble Blind (DB) Phase: Donepezil
Double Blind (DB) Phase: Change From Baseline in Mini-mental State Examination (MMSE) Score (LOCF) at Week 240.59 ± 0.221.23 ± 0.22
Statistical analysis
  • Double Blind (DB) Phase: Placebo vs Double Blind (DB) Phase: Donepezil · ANCOVA · p = 0.0396 · Difference in ls means: 0.65 · 95% CI 0.03 to 1.26
SecondaryDouble 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
Reported as:
Least squares mean · seconds
Double Blind (DB) Phase: Change From Baseline in Executive Function Test (Korean Trail Making Test Elderly [K-TMT-e]) Score (LOCF) at Week 24
secondsDouble Blind (DB) Phase: PlaceboDouble Blind (DB) Phase: Donepezil
Part A-5.10 ± 4.38-12.82 ± 4.52
Part B1.16 ± 5.41-13.73 ± 5.52
Statistical analysis
  • Double Blind (DB) Phase: Placebo vs Double Blind (DB) Phase: Donepezil · ANCOVA · p = 0.2213 · Difference in ls means: -7.73 · 95% CI -20.13 to 4.68
  • Double Blind (DB) Phase: Placebo vs Double Blind (DB) Phase: Donepezil · ANCOVA · p = 0.0551 · Difference in ls means: -14.88 · 95% CI -30.10 to 0.33

Adverse events

Collected over From the first dose of study drug to 30 days after the last dose of study drug (up to 52 weeks [DB Phase: From the first dose of study drug till Week 24; OLE Phase: Post Week 24 till Week 52]). Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Double Blind (DB) Phase: Placebo1/153 (0.7%)24/153 (15.7%)73/153 (47.7%)
Double Blind (DB) Phase: Donepezil1/147 (0.7%)18/147 (12.2%)86/147 (58.5%)
Open Label Extension (OLE) Phase: Donepezil2/161 (1.2%)12/161 (7.5%)63/161 (39.1%)
Most frequent serious events
Showing 10 of 56
Most frequent serious events
EventDouble Blind (DB) Phase: PlaceboDouble Blind (DB) Phase: DonepezilOpen Label Extension (OLE) Phase: Donepezil
Angina pectorisCardiac disorders0/1531/1470/161
Gastritis erosiveGastrointestinal disorders0/1531/1470/161
HaematocheziaGastrointestinal disorders0/1531/1470/161
AstheniaGeneral disorders0/1531/1470/161
Cholecystitis acuteHepatobiliary disorders0/1531/1470/161
SepsisInfections and infestations1/1531/1470/161
GastroenteritisInfections and infestations0/1531/1470/161
Subcutaneous abscessInfections and infestations0/1531/1470/161
Upper limb fractureInjury, poisoning and procedural complications1/1531/1471/161
LacerationInjury, poisoning and procedural complications0/1531/1470/161
Most frequent other events
Showing 10 of 178
Most frequent other events
EventDouble Blind (DB) Phase: PlaceboDouble Blind (DB) Phase: DonepezilOpen Label Extension (OLE) Phase: Donepezil
Decreased appetiteMetabolism and nutrition disorders5/15311/1470/161
NauseaGastrointestinal disorders3/15310/1475/161
HeadacheNervous system disorders7/1539/1475/161
NasopharyngitisInfections and infestations9/1536/1474/161
InsomniaPsychiatric disorders1/1537/1471/161
VomitingGastrointestinal disorders1/1536/1471/161
DizzinessNervous system disorders6/1535/1473/161
DiarrhoeaGastrointestinal disorders4/1535/1471/161
CoughRespiratory, thoracic and mediastinal disorders5/1531/1472/161
Abdominal painGastrointestinal disorders2/1534/1472/161

Baseline characteristics

The Full Analysis Set (FAS) was the group of randomized participants who received at least one dose of study drug and had at least one postdose primary efficacy measurement.

Age, Continuous
Age, Continuous(years)Double Blind (DB) Phase: PlaceboDouble Blind (DB) Phase: DonepezilTotal
Mean72.96 ± 7.9472.31 ± 7.0672.64 ± 7.52
Sex: Female, Male
Sex: Female, Male(Participants)Double Blind (DB) Phase: PlaceboDouble Blind (DB) Phase: DonepezilTotal
Female5548103
Male9189180
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)Double Blind (DB) Phase: PlaceboDouble Blind (DB) Phase: DonepezilTotal
Korean146137283
08

Study locations

31 sites
  • Daegu-si, Buk-gu, Korea, Republic of
  • Seongnam-si, Bundang-gu, Korea, Republic of
  • Gwangju-si, Dong-gu, Korea, Republic of
  • Seoul-si, Dongjak-gu, Korea, Republic of
  • Seoul-si, Gangdong-gu, Korea, Republic of
  • Seoul-si, Gangnam-gu, Korea, Republic of
  • Chuncheon-si, Gangwon-do, Korea, Republic of
  • Seoul-si, Gwangjin-gu, Korea, Republic of
  • Anyang-si, Gyeonggi-do, Korea, Republic of
  • Bucheon-si, Gyeonggi-do, Korea, Republic of
  • Goyang-si, Gyeonggi-do, Korea, Republic of
  • Seongnam-si, Gyeonggi-do, Korea, Republic of
  • Suwon-si, Gyeonggi-do, Korea, Republic of
  • Wonmi-Gu, Gyeonggi-do, Korea, Republic of
  • Changwon-si, Gyeongsangnam-do, Korea, Republic of
  • Yangsan-si, Gyeongsangnam-do, Korea, Republic of
  • Seoul-si, Jongro-gu, Korea, Republic of
  • Daegu-si, Jung-gu, Korea, Republic of
  • Incheon-si, Jung-gu, Korea, Republic of
  • Seoul-si, Jungnang-Gu, Korea, Republic of
  • Daegu-si, Nam-gu, Korea, Republic of
  • Incheon-si, Namdong-gu, Korea, Republic of
  • Busan-si, Seo-gu, Korea, Republic of
  • Seoul-si, Seocho-gu, Korea, Republic of
  • Seoul-si, Seodaemun-Gu, Korea, Republic of
  • Seoul-si, Seongbuk-gu, Korea, Republic of
  • Seoul-si, Seongdong-gu, Korea, Republic of
  • Jongno-Gu, Seoul, Korea, Republic of
  • Seoul-si, Songpa-Gu, Korea, Republic of
  • Seoul-si, Yangcheon-gu, Korea, Republic of
  • Seoul-si, Yeongdeungpo-gu, Korea, Republic of
09

References and documents

Study documents

  • Study protocol · Jul 6, 2017
  • Statistical analysis plan · Aug 17, 2015

Documents are hosted by the registry — open the source record to download them.

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Jan 10, 2020, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT02660983
Lead sponsor
Eisai Co., Ltd.
Responsible party
Sponsor
First posted
Jan 21, 2016
Start date
Aug 5, 2013
Primary completion
Jul 13, 2018
Completion
Dec 21, 2018
Results posted
Oct 4, 2019
Last update
Jan 10, 2020

Oversight

Data monitoring committee
No
View the source record on ClinicalTrials.gov ↗

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