Safety and Efficacy of Donepezil in Mild to Moderate Alzheimer's Disease: A Multi-center Single-arm Study in China
Phase: PHASE4
Conditions: Alzheimer's Disease
Sponsor: Beijing Friendship Hospital

 
 
 
 
 
 
 
 
 
 
 
 
 
Safety and Efficacy of Donepezil in Mild to 
Moderate Alzheimer's Disease: A Multi-center 
Single-arm Study in China 
Protocol & SAP Synopsis 
 
 
2016.10.09 
 
 
NCT02787746

 
 
PROTOCOL TITLE 
Safety and Efficacy of Donepezil in Mild to Moderate 
Alzheimer's Disease: A Multi-center Single-arm Study in China 
STUDY SPONSOR 
Beijing Friendship Hospital & Eisai (China) Pharmaceutical Co., 
Ltd. 
STUDY PHASE 
4 
INDICATION 
For the treatment of mild to moderate Alzheimer's disease. 
PRIMARY ENDPOINT 
Monitoring and recording the count and incidence of adverse 
events (AEs). 
SECONDARY ENDPOINTS 
• Monitor and record the number of patients withdrew from 
trial for adverse events. 
• Change from baseline to 20 weeks in MMSE scores. 
• Change from baseline to 20 weeks in ADL scores. 
• Correlation analysis between Apo-E genotyping and adverse 
events of donepezil. 
STUDY DESIGN 
This is a Phase 4 multi-center, single-arm, open labeling study. 
SAMPLE SIZE 
The main indicator of this study was the incidence of adverse 
events in the treatment of Alzheimer's disease with 10 mg 
donepezil hydrochloride tablets. According to the safety data in 
the comprehensive literature, the incidence of adverse events is 
basically between 69.4%-81%, and the expected total incidence 
of adverse events is about 76%, estimated with a 95% 
confidence interval. With reference to the research data, the 
width of the confidence interval for the incidence of adverse 
events is 8%, and the significance level is set as 0.05. The 
sample size is estimated to be 461 cases by using PASS11.0 
software. Considering the 20% drop out rate, 554 cases are 
finally planned to enter the group. 

ELIGIBILITY CRITERIA 
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. 
DRUG DOSAGE AND 
FORMULATION 
Once a day, two tablets at a time. Take it orally before bed at 
night (insomniacs can take it after breakfast). If the subject cannot 
tolerate 10 mg, he can return to the 5 mg dose, and after 4 weeks 
of use, increase the dose to 10 mg for the second time. If the 
second dose is increased to 10 mg and can not tolerate, the person 
who returns 5 mg or discontinues the drug is considered to be 
discontinued. 
ROUTE OF ADMINISTRATION 
Oral 
TREATMENT DURATION 
Use 10mg dose for 20 weeks. 

PROCEDURES 
Subjects conducted 3 visits at baseline (-5 to 0 days), 
maintained 10mg dose within 7 days after 4 weeks and 
maintained 10mg dose for 20 weeks ± 7 days, during which  the 
follow-ups of subjects can be increase at any time with safety of 
drug . 
Visit 1 baseline (- 5 to 0 days)      
1. The purpose of this visit is to examine whether the 
subjects are suitable for the study.  
2. The subjects and their guardians sign the informed consent 
form after understanding the research.    
3. General information collection: fill in demographic data, 
inquire about allergy history, inquire about past diseases, 
record combined diseases and medication, etc.      
4. Vital signs measurement.  
5. MMSE score, MIS score, ADL score, HAMD score. 
6. Laboratory inspection.         
7. Syphilis, folic acid and vitamin B12 examination, thyroid 
function T3, T4 examination. 
8. Head MRI (head MRI should include axial position and 
coronal position. Previous head MRI with diagnostic 
reference value can be exempted from this item, but it 
should have detailed image description).            
9. ECG examination.             
10. Record adverse events.             
11. Record combined medication.             
12. Inform the subjects to follow up within 7 days after 
maintaining the dose of 10mg for 4 weeks. If the subjects 
have any questions or abnormal conditions during this 
period, they can contact the researchers at any time. 

 
Visit 2  (maintain 10mg dose within 7 days after 4 weeks)      
1. Check whether the subjects take the medicine strictly 
according to the clinical trial plan. 
2. Vital signs measurement. 
3. MMSE score, ADL score. 
4. APOE genotyping test. 
5. Blood biochemical examination. 
6. ECG examination. 
7. Record adverse events. 
8. Record combined medication. 
9. Instruct the subjects to follow up after being enrolled for 
20 weeks. If the subjects have any questions or abnormal 
conditions during this period, they can contact the 
researchers at any time. 
Visit 3 (maintain 10 mg dose for 20 weeks ± 7 d)  
1. Check whether the subjects take the medicine strictly 
according to the clinical trial plan. 
2. Vital signs measurement. 
3. MMSE score, ADL score. 
4. Laboratory inspection. 
5. ECG examination. 
6. Record adverse events. 
7. Record combined medication. 

 
1. STATISTICAL METHODS 
 
1.1 Sample Size Determination 
The main indicator of this study was the incidence of adverse events in the 
treatment of Alzheimer's disease with 10 mg donepezil hydrochloride tablets. 
According to the safety data in the comprehensive literature, the incidence of 
adverse events is basically between 69.4%-81%, and the expected total 
incidence of adverse events is about 76%, estimated with a 95% confidence 
interval. With reference to the research data, the width of the confidence 
interval for the incidence of adverse events is 8%, and the significance  
level is set as 0.05. The sample size is estimated to be 461 cases by using 
PASS11.0 software. Considering the 20% drop out rate, 554 cases are finally  
enter the group. 
 
1.2 Elimination criteria 
1. After the clinical study started, it was found that the subjects did not meet the 
case inclusion criteria or the case exclusion criteria. 
2. Subjects had poor compliance and never used study medication. 
3. Those who seriously violate the research plan. 
 
1.3 Analysis Populations 
Full Analysis Set (FAS) refers to the ideal subject set as close as possible to 
the principle of intention analysis (the main analysis includes all randomized 
subjects). The data set is obtained by excluding all randomized subjects with 
the smallest and reasonable method. For the estimation of the missing values 
of the main variables, the last carry-forward obsevation (LOCF) was used to 
the point where the test data was missing, and the number of subjects who 
evaluated the efficacy at the end point of each group was consistent with that 
at the beginning of the test . 
Per-Protocol Set (PPS) is composed of all cases that meet the test protocol, 
have good compliance (the actual dose takes 80% to 120% of the applied 
dose), do not take prohibited drugs during the test, and complete the contents 
specified in CRF. 
Safety Analysis Set (SAS) is composed of all cases taking drugs at least once 
and having safety evaluation at least once. 

 
1.4 Efficacy Endpoints 
 
⚫ 
Primary Efficacy Endpoints 
Monitoring and recording the count and incidence of adverse events (AEs). 
 
⚫ 
Secondary Efficacy Endpoints 
1. Monitor and record the number of patients withdrew from trial for adverse 
events. 
2. Change from baseline to 20 weeks in MMSE scores. 
3. Change from baseline to 20 weeks in ADL scores. 
4. Correlation analysis between Apo-E genotyping and adverse events of 
donepezil. 
1.5 Safety Endpoints 
Laboratory indicators, vital signs, weight and ECG 
The laboratory inspection indicators include: 
        1. Blood routine: red blood cell count RBC, hemoglobin HGB, platelet count PLT, 
white blood cell count WBC. 
2. Urine routine: urine protein PRO, urine red blood cell count URBC, urine white 
blood cell count UWBC, urine ketone body KET. 
3. Blood biochemistry: liver function (ALT,  aspartate aminotransferase AST, 
alkaline phosphatase ALP, total bilirubin TBIL, γ-glutamyl transferase γ-GT, total 
protein TP), renal function (creatinine Cr , Urea nitrogen BUN), myocardial enzymes 
(creatine kinase CK, lactate dehydrogenase LDH), fasting blood glucose GLU, 
electrolytes (Na+, K+, Cl-, Ca2+). 
 
1.6 Statistical Methods 
Complete details of efficacy and safety analyses will be provided in a  separate 
Statistical Analysis Plan (SAP). 

 
1.7 Efficacy Analysis 
1. Primary indicators analysis 
For the incidence of adverse events, list the number of subjects with adverse events, 
and calculate the incidence and confidence interval, and at the same time list the 
number of various adverse events and their incidence and confidence interval. 
2. Secondary indicators analysis 
The analysis of the loss rate caused by adverse events is the same as the adverse 
events. 
For the changes in MMSE and ADL scores, list the mean, median, standard 
deviation, maximum, minimum, 25%, and 75% quantiles. The paired t-test should 
be carried out for the scores before and after treatment to obtain 95% confidence 
interval of the changes before and after treatment. 
 
1.8 Other Safety Data Analysis 
For the QT interval and heart rate before and after treatment, the mean, median, 
standard deviation, maximum, minimum, 25%, 75% quantiles were used for statistical 
description, and the scores before and after treatment were paired t-tested. At the same 
time, the 95% confidence interval of the change value before and after treatment is 
obtained. Based on the predetermined MCID value, the 95% confidence interval is 
compared with the lower limit of the 95% confidence interval to determine whether the 
changes in QT interval and heart rate have clinical significance. 
For vital signs, the mean, median, standard deviation, maximum, minimum, and 95% 
confidence intervals were used to describe the changes in vital signs at each follow-up 
point. 
For laboratory examination and ECG, the clinical significance judgment and frequency 
(or frequency) of all indexes before and after treatment are made in a cross table, and 
the details of abnormal examination items after treatment are listed. 
For quantitative laboratory test values, list the mean, median, standard deviation, 
maximum, minimum, 25%, 75% quantiles, and paired t-test for the scores before and 
after treatment to obtain 95% confidence interval of the changed value to evaluate its 
safety. 
 

 
⚫ 
Adverse Events 
When filling out the adverse event form, the researcher should use mild, moderate, and 
severe to describe the intensity of the adverse event. To unify the standard, the 
classification of event intensity is as follows: 
 
Moderate: To some extent affects the normal function of the subject. 
Severe: Obviously affect the normal function of the subject. 
• Mild: Does not affect the normal function of the subject. 
• Moderate: To some extent affects the normal function of the subject. 
• Severe: Obviously affect the normal function of the subject.