Alzheimer's Disease
Conditions
Keywords
AD, Donepezil, Safety
Brief summary
This study will evaluate the safety and Efficacy of donepezil in treatment of AD patients in China.
Detailed description
This study is a multi-center, single-arm, open labeling clinical trial, which the objective is to evaluate the safety and Efficacy of donepezil in Alzheimer's disease( AD) patients in China, and investigate the relationship between Apo-E gene type with adverse events of donepezil.
Interventions
DRUGDonepezil
Eligible patients were treated with Aricept® 10 mg/day for 20 weeks of study period. Aricept® should be taken at night, just prior to sleeping. If patient cannot endure 10mg/d，the dose could be reduce to 5mg/d for 4 weeks and then increase back to 10mg/d. Patients who could not endure the 10mg/d titration the 2nd time and were put back to 5mg/d or discontinuance of Aricept® should be considered as withdrawal from the study. There were a visit (visit 1) at week 0, the end of week 4 (visit 2) and the end of week 20 (visit 3), respectively.
Sponsors
Eisai China Inc.
Xuanwu Hospital, Beijing
Beijing Friendship Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
multi-center, single-arm, open labeling clinical trial
Eligibility
Sex/Gender
ALL
Age
50 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
1. Patients between 50 and 85 years of age. 2. Patients newly diagnosed as probable AD based on Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) criteria and National Institute of Neurologic and Communicative Disorders and Stroke-AD and Related Disorders Association (NINCDS-ADRDA) criteria; Mild to moderate AD with Mini-Mental State Examination (MMSE) 10-24, modified Hachinski ischaemic scale (MHIS)≤4, Activity of daily life scale (ADL)≥23, and Hamilton Depression Scale (HAMD) \<7. 3. MRI image supports the diagnosis of AD (medial temporal lobe atrophy, Fazekas scale of white matter lesions≤2 within 6 months prior to the screening). 4. 5mg daily of Donepezil for at least four weeks before the screening. 5. Patient with exclusive caregiver. 6. Patient should be ambulatory or ambulatory aided by a walker or cane. 7. With good eyesight and hearing, can cooperate with the examination and treatment.
Exclusion criteria
1. Patients with vascular dementia, other types of dementia or with other psychiatric or neurological disorders (e.g. delirium, depression, Parkinson's disease, etc.). 2. Patients with type I diabetes, obstructive lung disease or asthma, vitamin B12 or folic acid deficiency, thyroid dysfunction, severe liver or kidney dysfunction, severe cardiac insufficiency (congestive heart failure, myocardial infarction, sick sinus syndrome, II-III degree atrioventricular block or heart rate\<50 beats/minute \[bpm\]). 3. Epilepsy or head trauma resulting in unconsciousness that occurred in the two years prior to the screening. 4. Patients with hematologic diseases (such as anemia, granulocytes, leukemia, etc.), tumor, neoplasms within 2 years prior to the screening. 5. Patients with a history of alcohol dependence and drug abuse. 6. Patients with known hypersensitivity to medicines or foods; 7. Patients taking anticholinergic agents or antihistaminic agents; 8. Patients who had been hospitalized continuously for more than 3 months before the screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Adverse Events (AEs) | 20 weeks | Physical examinations such as vital signs and weight, clinical laboratory tests, and electrocardiograms (ECGs) during the 20 weeks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Who Withdrew From the Trial Due to Adverse Events. | 20 weeks | Number of patients who withdrew due to adverse events |
| Changes in Mini-Mental State Examination Scores From Baseline | Baseline, 4, 20 weeks | Comparison of Mental state examination (MMSE) scores (range 0-30) at 4 weeks and 20 weeks with baseline in mild to moderate AD patients. A higher score indicates better cognitive function.Higher score indicates better cognition function. |
| Changes in Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Scores From Baseline | Baseline, 4, 20 weeks | Comparison of Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) scores (range 0-78) at 4 weeks and 20 weeks with baseline scores in patients with mild to moderate Alzheimer's Disease. A higher score indicates better activities of daily living (ADL). |
| Correlation Between Apolipoprotein E.(APOE) Genotype and Incidence of Adverse Events of Donepezil | 20 weeks | Comparison of incidence of adverse events among patients with different APOE genotypes |
| APOE Genotype | 4 weeks | A patient's APOE genotype (ɛ2/ɛ2, ɛ3/ɛ3, ɛ4/ɛ4, ɛ2/ɛ3, ɛ2/ɛ4 and ɛ3/e4) was tested by tested by Sanger sequencing from blood collected from the the patient at Visit 2. APOE genotype is not mandatory |
Countries
China
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Donepezil Daily single dose of donepezil 10mg | 241 |
| Total | 241 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 42 |
| Overall Study | Failure to up-titrate to 10mg/day: 12 patients; Other reasons: 30 patients | 41 |
| Overall Study | Withdrawal by Subject | 65 |
Baseline characteristics
| Characteristic | Donepezil | — |
|---|---|---|
| ADCS-ADL(Alzheimer's disease cooperative study - activities of daily living) | 53.29 Score unit STANDARD_DEVIATION 11.55 | — |
| Age, Customized 65-74 Years old | 84 Participants | — |
| Age, Customized <65 Years old | 44 Participants | — |
| Age, Customized 75-84 Years old | 110 Participants | — |
| Age, Customized ≥85 Years old | 3 Participants | — |
| Aspartate aminotransferase (AST) | 23.16 U/L STANDARD_DEVIATION 14.09 | — |
| Concomitant drugs Antipsychiatric drugs | 18 Participants | — |
| Concomitant drugs Cardiovascular drugs | 22 Participants | — |
| Concomitant drugs Central nervous system drugs | 106 Participants | — |
| Concomitant drugs Did not use | 86 Participants | — |
| Concomitant drugs Gastrointestinal diseases drugs | 5 Participants | — |
| Concomitant drugs Hepatology drugs | 1 Participants | — |
| Concomitant drugs Other drugs | 3 Participants | — |
| Corrected QT interval (QTc) | 419.16 msec STANDARD_DEVIATION 29.9 | — |
| HAMD | 3.09 Score unit STANDARD_DEVIATION 2.56 | — |
| Heart rate | 72.35 beat/min STANDARD_DEVIATION 9.49 | — |
| MMSE | 18.69 score STANDARD_DEVIATION 4.35 | — |
| Past Medical history Cardiovascular diseases | 39 Participants | — |
| Past Medical history Gastrointestinal diseases | 17 Participants | — |
| Past Medical history Liver disease | 13 Participants | — |
| Past Medical history Mental disease | 10 Participants | — |
| Past Medical history Neurologic disease | 58 Participants | — |
| Past Medical history No disease | 58 Participants | — |
| Past Medical history Other disease | 46 Participants | — |
| Previous duration of donepezil 5mg/d therapy | 70.97 day STANDARD_DEVIATION 123.95 | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Sex: Female, Male Female | 134 Participants | — |
| Sex: Female, Male Male | 107 Participants | — |
| Weight ≤55 kg | 97 Participants | — |
| Weight 56-65 kg | 74 Participants | — |
| Weight 66-75 kg | 47 Participants | — |
| Weight >75 kg | 23 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 241 |
| other Total, other adverse events | 93 / 241 |
| serious Total, serious adverse events | 3 / 241 |
Outcome results
Primary
Number of Patients With Adverse Events (AEs)
Physical examinations such as vital signs and weight, clinical laboratory tests, and electrocardiograms (ECGs) during the 20 weeks.
Time frame: 20 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Donepezil | Number of Patients With Adverse Events (AEs) | 93 Participants |
Secondary
APOE Genotype
A patient's APOE genotype (ɛ2/ɛ2, ɛ3/ɛ3, ɛ4/ɛ4, ɛ2/ɛ3, ɛ2/ɛ4 and ɛ3/e4) was tested by tested by Sanger sequencing from blood collected from the the patient at Visit 2. APOE genotype is not mandatory
Time frame: 4 weeks
Population: 115 patients in the study had their APOE genotype tested by Sanger sequencing from blood collected from the the patient at Visit 2.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Donepezil | APOE Genotype | APOE ɛ2/ɛ2 | 1 Participants |
| Donepezil | APOE Genotype | APOE ɛ3/ɛ3 | 58 Participants |
| Donepezil | APOE Genotype | APOE ɛ4/ɛ4 | 7 Participants |
| Donepezil | APOE Genotype | APOE ɛ2/ɛ3 | 11 Participants |
| Donepezil | APOE Genotype | APOE ɛ2/ɛ4 | 1 Participants |
| Donepezil | APOE Genotype | APOE ɛ3/e4 | 37 Participants |
Secondary
Changes in Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Scores From Baseline
Comparison of Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) scores (range 0-78) at 4 weeks and 20 weeks with baseline scores in patients with mild to moderate Alzheimer's Disease. A higher score indicates better activities of daily living (ADL).
Time frame: Baseline, 4, 20 weeks
Population: 241 patients were included in the FAS and 93 patients who completed the study constituted the PPS. Therefore, FAS \[LOCF\] and PPS \[LOCF\] included 241 and 93 patients, respectively.~FAS \[actual data\] at baseline, Week 4 and Week 20 all included 42 patients, while PPS \[actual data\] at baseline, Week 4 and Week 20 all included 26 patients
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Donepezil | Changes in Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Scores From Baseline | FAS LOCF | 53.29 score on a scale | Standard Deviation 11.55 |
| Donepezil | Changes in Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Scores From Baseline | FAS (actual data) | 34.76 score on a scale | Standard Deviation 14.04 |
| Donepezil | Changes in Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Scores From Baseline | PPS LOCF | 54.31 score on a scale | Standard Deviation 10.63 |
| Donepezil | Changes in Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Scores From Baseline | PPS (actual data) | 33.31 score on a scale | Standard Deviation 13.58 |
| Week 4 | Changes in Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Scores From Baseline | FAS LOCF | 53.71 score on a scale | Standard Deviation 12.97 |
| Week 4 | Changes in Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Scores From Baseline | PPS (actual data) | 32.71 score on a scale | Standard Deviation 13.5 |
| Week 4 | Changes in Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Scores From Baseline | FAS (actual data) | 33.31 score on a scale | Standard Deviation 13.75 |
| Week 4 | Changes in Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Scores From Baseline | PPS LOCF | 54.35 score on a scale | Standard Deviation 12.5 |
| Change From Baseline at Week 4 | Changes in Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Scores From Baseline | PPS (actual data) | -0.65 score on a scale | Standard Deviation 6.69 |
| Change From Baseline at Week 4 | Changes in Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Scores From Baseline | FAS (actual data) | -0.66 score on a scale | Standard Deviation 6.04 |
| Change From Baseline at Week 4 | Changes in Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Scores From Baseline | PPS LOCF | 0.04 score on a scale | Standard Deviation 6.2 |
| Change From Baseline at Week 4 | Changes in Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Scores From Baseline | FAS LOCF | 0.43 score on a scale | Standard Deviation 7.34 |
| Week 20 | Changes in Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Scores From Baseline | FAS LOCF | 53.62 score on a scale | Standard Deviation 12.82 |
| Week 20 | Changes in Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Scores From Baseline | FAS (actual data) | 30.86 score on a scale | Standard Deviation 11.01 |
| Week 20 | Changes in Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Scores From Baseline | PPS (actual data) | 30.9 score on a scale | Standard Deviation 11.07 |
| Week 20 | Changes in Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Scores From Baseline | PPS LOCF | 54.19 score on a scale | Standard Deviation 12.25 |
| Change From Baseline at Week 20 | Changes in Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Scores From Baseline | PPS (actual data) | -1.13 score on a scale | Standard Deviation 11.11 |
| Change From Baseline at Week 20 | Changes in Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Scores From Baseline | PPS LOCF | -0.12 score on a scale | Standard Deviation 6.44 |
| Change From Baseline at Week 20 | Changes in Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Scores From Baseline | FAS (actual data) | -1.15 score on a scale | Standard Deviation 11.04 |
| Change From Baseline at Week 20 | Changes in Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Scores From Baseline | FAS LOCF | 0.33 score on a scale | Standard Deviation 7.47 |
Secondary
Changes in Mini-Mental State Examination Scores From Baseline
Comparison of Mental state examination (MMSE) scores (range 0-30) at 4 weeks and 20 weeks with baseline in mild to moderate AD patients. A higher score indicates better cognitive function.Higher score indicates better cognition function.
Time frame: Baseline, 4, 20 weeks
Population: 241 patients were included in the full analysis set (FAS) and 93 patients who completed the study constituted the per-protocol set (PPS). Therefore, FAS last-observation-carried-forward \[LOCF\] and PPS \[LOCF\] included 241 and 93 patients, respectively.~FAS \[actual data\] at baseline, Week 4 and Week 20 included 238, 145 and 94 patients, respectively.~PPS \[actual data\] at baseline, Week 4 and Week 20 included 148, 113 and 93 patients, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Donepezil | Changes in Mini-Mental State Examination Scores From Baseline | FAS LOCF | 18.69 score on a scale | Standard Deviation 4.35 |
| Donepezil | Changes in Mini-Mental State Examination Scores From Baseline | FAS (actual data) | 18.69 score on a scale | Standard Deviation 4.35 |
| Donepezil | Changes in Mini-Mental State Examination Scores From Baseline | PPS LOCF | 18.45 score on a scale | Standard Deviation 4.39 |
| Donepezil | Changes in Mini-Mental State Examination Scores From Baseline | PPS (actual data) | 18.45 score on a scale | Standard Deviation 4.39 |
| Week 4 | Changes in Mini-Mental State Examination Scores From Baseline | FAS LOCF | 19.12 score on a scale | Standard Deviation 5.06 |
| Week 4 | Changes in Mini-Mental State Examination Scores From Baseline | PPS (actual data) | 19.33 score on a scale | Standard Deviation 5.53 |
| Week 4 | Changes in Mini-Mental State Examination Scores From Baseline | FAS (actual data) | 18.87 score on a scale | Standard Deviation 5.76 |
| Week 4 | Changes in Mini-Mental State Examination Scores From Baseline | PPS LOCF | 19.22 score on a scale | Standard Deviation 5.18 |
| Change From Baseline at Week 4 | Changes in Mini-Mental State Examination Scores From Baseline | PPS (actual data) | 1.01 score on a scale | Standard Deviation 2.86 |
| Change From Baseline at Week 4 | Changes in Mini-Mental State Examination Scores From Baseline | FAS (actual data) | 0.72 score on a scale | Standard Deviation 3.19 |
| Change From Baseline at Week 4 | Changes in Mini-Mental State Examination Scores From Baseline | PPS LOCF | 0.77 score on a scale | Standard Deviation 2.53 |
| Change From Baseline at Week 4 | Changes in Mini-Mental State Examination Scores From Baseline | FAS LOCF | 0.44 score on a scale | Standard Deviation 2.51 |
| Week 20 | Changes in Mini-Mental State Examination Scores From Baseline | FAS LOCF | 19.07 score on a scale | Standard Deviation 5.3 |
| Week 20 | Changes in Mini-Mental State Examination Scores From Baseline | FAS (actual data) | 19.62 score on a scale | Standard Deviation 5.8 |
| Week 20 | Changes in Mini-Mental State Examination Scores From Baseline | PPS (actual data) | 19.57 score on a scale | Standard Deviation 5.81 |
| Week 20 | Changes in Mini-Mental State Examination Scores From Baseline | PPS LOCF | 19.11 score on a scale | Standard Deviation 5.54 |
| Change From Baseline at Week 20 | Changes in Mini-Mental State Examination Scores From Baseline | PPS (actual data) | 0.94 score on a scale | Standard Deviation 3.18 |
| Change From Baseline at Week 20 | Changes in Mini-Mental State Examination Scores From Baseline | PPS LOCF | 0.66 score on a scale | Standard Deviation 2.74 |
| Change From Baseline at Week 20 | Changes in Mini-Mental State Examination Scores From Baseline | FAS (actual data) | 0.97 score on a scale | Standard Deviation 3.18 |
| Change From Baseline at Week 20 | Changes in Mini-Mental State Examination Scores From Baseline | FAS LOCF | 0.39 score on a scale | Standard Deviation 2.64 |
Secondary
Correlation Between Apolipoprotein E.(APOE) Genotype and Incidence of Adverse Events of Donepezil
Comparison of incidence of adverse events among patients with different APOE genotypes
Time frame: 20 weeks
Population: 115 patients in the safety set had their APOE gene sequenced and have data on their APOE genotype. Among these patients, 1 carries APOE ɛ2/ɛ2, 58 carry APOE ɛ3/ɛ3, 7 carry APOE ɛ4/ɛ4, 11 carry APOE ɛ2/ɛ3, 1 carries APOE ɛ2/ɛ4, and 37 carry APOE ɛ3/e4.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Donepezil | Correlation Between Apolipoprotein E.(APOE) Genotype and Incidence of Adverse Events of Donepezil | Numbe of patients who experienced adverse events | 0 Participants |
| Donepezil | Correlation Between Apolipoprotein E.(APOE) Genotype and Incidence of Adverse Events of Donepezil | Number of patients who did not experience adverse events | 1 Participants |
| Week 4 | Correlation Between Apolipoprotein E.(APOE) Genotype and Incidence of Adverse Events of Donepezil | Numbe of patients who experienced adverse events | 34 Participants |
| Week 4 | Correlation Between Apolipoprotein E.(APOE) Genotype and Incidence of Adverse Events of Donepezil | Number of patients who did not experience adverse events | 24 Participants |
| Change From Baseline at Week 4 | Correlation Between Apolipoprotein E.(APOE) Genotype and Incidence of Adverse Events of Donepezil | Numbe of patients who experienced adverse events | 5 Participants |
| Change From Baseline at Week 4 | Correlation Between Apolipoprotein E.(APOE) Genotype and Incidence of Adverse Events of Donepezil | Number of patients who did not experience adverse events | 2 Participants |
| Week 20 | Correlation Between Apolipoprotein E.(APOE) Genotype and Incidence of Adverse Events of Donepezil | Numbe of patients who experienced adverse events | 6 Participants |
| Week 20 | Correlation Between Apolipoprotein E.(APOE) Genotype and Incidence of Adverse Events of Donepezil | Number of patients who did not experience adverse events | 5 Participants |
| Change From Baseline at Week 20 | Correlation Between Apolipoprotein E.(APOE) Genotype and Incidence of Adverse Events of Donepezil | Numbe of patients who experienced adverse events | 0 Participants |
| Change From Baseline at Week 20 | Correlation Between Apolipoprotein E.(APOE) Genotype and Incidence of Adverse Events of Donepezil | Number of patients who did not experience adverse events | 1 Participants |
| APOE ɛ3/e4 Carriers | Correlation Between Apolipoprotein E.(APOE) Genotype and Incidence of Adverse Events of Donepezil | Numbe of patients who experienced adverse events | 13 Participants |
| APOE ɛ3/e4 Carriers | Correlation Between Apolipoprotein E.(APOE) Genotype and Incidence of Adverse Events of Donepezil | Number of patients who did not experience adverse events | 24 Participants |
Comparison: Age (\>75y vs ≤75y）p-value: 0.974495% CI: [0.466, 2.095]Regression, Logistic
Comparison: APOE ɛ4 (carrier vs non-carrier)p-value: 0.328895% CI: [0.29, 40.354]Regression, Logistic
Comparison: Concomitant medication：Gastrointestinal drugsp-value: 0.573295% CI: [0.158, 28.171]Regression, Logistic
Comparison: Concomitant medication：Hypoglycemic drugsp-value: 0.969495% CI: [0.281, 3.387]Regression, Logistic
Comparison: Concomitant medication：Cardiovascular and Cerebrovascular drugsp-value: 0.039695% CI: [1.039, 4.748]Regression, Logistic
Comparison: Concomitant medication：Hepatology drugsp-value: 0.588995% CI: [0.151, 28.074]Regression, Logistic
Comparison: Duration of previous donepezil 5mg/d therapy (day)p-value: 0.118195% CI: [0.999, 1.008]Regression, Logistic
Secondary
Number of Patients Who Withdrew From the Trial Due to Adverse Events.
Number of patients who withdrew due to adverse events
Time frame: 20 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Donepezil | Number of Patients Who Withdrew From the Trial Due to Adverse Events. | 42 Participants |