Clinical trial NCT02787746
Conditions: Alzheimer's Disease
Keywords: AD Donepezil Safety
Sponsor: Beijing Friendship Hospital
Start date: 2016-04-01; Completion date: 2019-03-01
Enrollment: 241 participants; Allocation: NA; Intervention model: SINGLE_GROUP

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.

Arms: arm 1: This is a multi-center single-arm study, which assess the safety and efficacy of donepezil in mild to moderate Alzheimer's disease in China.
Interventions: intervention 1: Donepezil
Intervention descriptions: intervention 1: 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.

Protocol documents:
ICF_002.pdf: 
Safety and Efficacy of Donepezil in Mild to Moderate Alzheimer's Disease: A Multi-center 
Single-arm Study in China 
NCT02787746 
July 15, 2015 
 
Informed Consent Form 
 


A single-arm multicenter clinical study on the safety and efficacy of donepezil 
hydrochloride tablets in the treatment of Alzheimer's disease 
Informed Consent Form 
We are here to introduce you to participate in a single-arm multicenter (post-marketing) 
clinical study of the safety and efficacy of donepezil hydrochloride tablets in the treatment 
of Alzheimer's disease. This clinical study is a clinical observation of a medicine that has 
been on the market for many years, and before deciding whether to participate, it 
is necessary for you to understand the purpose of the study, the study medication, the 
possible benefits and risks to you, what you are expected to do in the study, and your rights 
as a subject. 
 
1. Project Introduction 
The name of this study is: A single-arm multicenter clinical study on the safety and 
efficacy of donepezil hydrochloride tablets in the treatment of Alzheimer's disease. The 
study you are participating in is a clinically validated study of a medicine that has been on 
the market for many years. 
Donepezil hydrochloride tablets (trade name: Aricept) is manufactured by Eisai (China) 
Pharmaceutical Co., Ltd. and was approved by the State Food and Drug Administration in 
2007 (Approval No. H20050978) for the treatment of mild-to-moderate Alzheimer's disease, 
which is also widely used all over the world. 
The purpose of this study is to evaluate the safety and efficacy of donepezil 
hydrochloride tablets in the treatment of Alzheimer's disease, and to systematically 
accumulate the safety data of donepezil hydrochloride tablets in clinical practice in China, 
to better serve the general population of patients. 
The study used a single-arm design without a control group; therefore, all patients 
received Aricept, and the medication regimen was consistent with routine clinical care. The 
specific medication method is as follows: once a day, 2 tablets at a time. Take it orally at 
night before going to bed (after breakfast for patients with insomnia). If subjects cannot 
tolerate 10mg, they may return to the 5mg dose, with a second dosage of 10mg after 4 
weeks of use; if the second dosage of 10mg is not tolerated, returning to 5mg or 
discontinuing the drug will be considered as discontinuation of the study. The overall 
treatment period is 20 weeks. 
You will be required to have a total of 3 visits, one at baseline, 4 weeks after 
maintaining the 10mg dose, and 20 weeks after maintaining the 10mg dose, and safety 
need be observed at any time during the medication. The following things you need to do 
with your doctor during each visit: 
Visit 1 (baseline): sign informed consent after learning about the study; General 
information collection: filling in demographic data, allergy history, medical history inquiry, 
recording of concomitant diseases, combined medications, etc.; vital signs measurement; 
relevant scale scoring; laboratory tests; Syphilis, folic acid, vitamin B12, thyroid function 
T3, T4 tests; Brain MRI (should include axial and coronal position, which can be exempted 
with previous brain MRI with diagnostic reference value, but should have a detailed image 
description); Electrocardiographic examination（ECG） 
Visit 2 (within 7 days after the 10-mg dose was maintained for 4 weeks): vital signs 


were measured; Relevant scale scores; APOE genotyping was performed. Blood 
biochemical tests; ECG 
Visit 3 (within 7 days after the 10-mg dose was maintained for 20 weeks): vital signs 
were measured; Relevant scale scores; Laboratory tests; ECG 
 
Inclusion and exclusion criteria are as follows: 
Inclusion criteria 
The age ranged from 50 to 85 years old, both male and female, 
Patients with a diagnosis of Alzheimer's disease consistent with the 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 for probable AD), with mild to moderate 
AD as assessed with a Mini-Mental State Examination (MMSE) score (a score range of 0 
to 30, with higher scores indicating better cognitive function) of between 10 and 24 
(inclusive), Modified Hachinski Ischemia Scale (MHIS)≤4, Activity of daily life scale (ADL) 
≥23, and Hamilton Depression Scale (HAMD) <7 at screening. The diagnosis of AD should 
also be supported by magnetic resonance imaging (MRI) scans (medial temporal lobe 
atrophy, Fazekas scale of white matter lesions ≤2 within 6 months prior to the screening).  
Have been taking donepezil 5 mg/day for at least 4 weeks before the screening, 
Have an exclusive caregiver, 
Be ambulatory or ambulatory aided by a walker or cane, 
Have good eyesight and hearing, 
Could cooperate with the examination and treatment. 
Subjects volunteered and had a guardian sign an informed consent form. 
 
Exclusion criteria 
Patients with vascular dementia, other types of dementia or with other psychiatric or 
neurological disorders (e.g., delirium, depression, Parkinson’s disease, etc.).  
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]) 
Epilepsy or head trauma resulting in unconsciousness that occurred in the two years 
prior to the screening.  
Patients with hematologic diseases (such as anemia, granulocytes, leukemia, etc.), 
tumor, neoplasms within 2 years prior to the screening.  
Patients with a history of alcohol dependence and drug abuse.  
Patients with known hypersensitivity to medicines or foods.  
Patients taking anticholinergic agents or antihistaminic agents.  
Current use of anticholinergic drugs (e.g., atropine, ipratropium bromide, pirenzepine, 
isopropyl atropine, anisodamine, scopolamine, hexamethylene diamine, succinylcholine) 
or antihistamine drugs (e.g., chlorphenamine, loratadine, proglumide, famotidine). 
Patients who had been hospitalized continuously for more than 3 months before the 
screening. 


2. Research units and qualifications of personnel 
This clinical study was led by Xuanwu Hospital of Capital Medical University and 
Beijing Friendship Hospital affiliated to Capital Medical University. More than 20 research 
centers nationwide participated in this clinical study. The principal investigator of this study 
is Professor Jia Jianping. Researchers have rich clinical experience and through the GCP 
training, has the high academic level. 
 
3.  Possible benefits of participating in this study 
Your benefits from this study include that your condition may be improved or slower 
degeneration, you will receive good medical services during the study, and your 
participation will also contribute to the systematic accumulation of safety data of the drug 
in clinical use in China which will make more patients with Alzheimer's disease (AD) will 
have access to better treatment. 
 
4. Possible discomfort and risks to you from the study 
All possible drug adverse reaction. The most common adverse reactions of Aricept® 
include diarrhea, muscle spasms, fatigue, nausea, vomiting, and insomnia. The following 
is a list of adverse reactions in addition to individual cases according to the organ, system, 
and frequency of occurrence. [The frequency of adverse reactions was defined as 
extremely common (≥1 in 10), common (≥1 in 100, < 1 in 10), uncommon (≥1 in 1,000, 
< 1 in 100), and rare (≥1 in 10,000, < 1 in 1,000). ]Extremely common: diarrhea, nausea, 
headache; Common: common cold, anorexia, vomiting, rash, itching, hallucinations, 
irritability, aggressive behavior, fainting, vertigo, insomnia, gastrointestinal dysfunction, 
muscle cramps, urinary incontinence, fatigue, pain, accidental injury; Uncommon: epilepsy, 
bradycardia, gastrointestinal bleeding, gastric and duodenal ulcer, slight increase in serum 
creatine kinase concentration; Rare: extrapyramidal symptoms, sinoatrial block, 
atrioventricular block, abnormal liver function, including hepatitis. In general, the adverse 
reactions of the study were mostly tolerable, and the study sites and sponsors would 
provide corresponding support and treatment. In general, the risks were manageable. 
 
5. Contingency plans to be taken in the event of an emergency during the study 
If you experience any discomfort during the clinical study, new changes in your 
condition, or any unexpected situation, regardless of whether it is related to the drug, you 
should promptly notify your doctor in charge, he/she will make a judgment and medical 
treatment. Your doctor in charge and the hospital will do their best to prevent any possible 
risks associated with this study. 
If an adverse event occurs during a clinical study, your study physician will provide 
you with support and treatment. You will be compensated appropriately depending on the 
circumstances of your injury and relevant laws and regulations.  
 
6. Other matters requiring your cooperation 
Please follow the instructions of the responsible doctor of the study. If you need 
other treatment (including medication), please contact your responsible study doctor in 
advance. 


About drug combination: 
CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, and erythromycin) and CYP2D6 
inhibitors (e.g., quinidine, fluoxetine), which inhibit the metabolism of donepezil, were 
prohibited during the study. 
During the study period to ban the use of enzyme inducers (e.g., rifampicin, sodium 
phenytoin, carbamazepine) and alcohol. 
Anticholinergic drugs such as neuromuscular blocking agents (succinylcholine, 
neostigmine), cholinergic agonists (pilocarpine), or beta-blockers (atenolol, propranolol 
hydrochloride) were prohibited during the study. 
All concomitant medications used during the study period should be consulted before 
administration. 
Please according to the appointment to see a doctor. you may be reimbursed $100 for 
transportation costs with invoice after each visit.  
 
7. Your rights and obligations 
1) Rights 
The study doctor will introduce you to the study drug and the study arrangement, and 
participation is completely voluntary. 
The study doctor will report to you all events relevant to you so that you can decide at 
any time whether to continue participating. 
If you have any questions, you can call or speak directly to the study physician. 
You may refuse to participate in the study or withdraw from the study at any time during 
the study, without affecting your relationship with your doctor, your medical care, or any 
other loss of benefits.  
 
2) Obligations 
Adhere to the principle of voluntary participation and sign the informed 
consent form before the start of the study. Please follow the unified arrangement of 
the research doctor and cooperate with the research doctor to complete the research task. 
Please do not use other drugs without authorization during the study. If you must use them, 
please consult your research doctor in advance. 
You need to go to the hospital in time during the study follow-up. 
 
8. Reasons for terminating your participation in the study 
1) 
The study physician determined that you would not benefit from the study. 
2) 
You did not take the medication as directed by your study physician. 
3) 
There is a potential risk of harm to your health during the study. 
If the above occurs, the study physician has the right to terminate your participation 
in the study without your consent. 
 
9. Confidentiality 
Your records will be safeguarded and treated in confidence. Only authorized 
personnel can access your records. At the same time, we allow the ethics committee to 
review your records, but it won't appear in your name and identification. 


10. Protocol approval and conduct 
The trial protocol was approved by the ethics committee of the primary investigator’s  
institution. If there is any violation of the study protocol during the trial, you can directly 
complain to the Ethics Committee of Xuanwu Hospital at 010-83198935. 
 
 
Signed Informed Consent 
Study Name: A single-arm multicenter clinical study on the safety and efficacy of 
donepezil hydrochloride tablets in the treatment of Alzheimer's disease 
Sponsor: Eisai (China) Pharmaceutical Co., Ltd 
SFDA approval number: H20050978 
Centre for the study of Numbers: ________________ 
Subject Consent Statement: 
I have read the above description of the study and had the opportunity to discuss it 
with physicians and ask questions. All my questions were satisfactorily answered. I am 
aware of the risks and benefits that may arise from participation in this study. I know in 
the study is voluntary, I confirm that has sufficient time to consider, and understand: 
I can always ask the doctor for more information. 
I can withdraw from this study at any time without discrimination or retaliation, and 
my medical treatment and rights and interests will not be affected. 
I also knew that if I withdrew from the study, especially for medical reasons, it would 
be in my best interests and the best interests of the study if I informed my doctor of any 
changes in my condition and completed the physical and physical examinations. 
Because of illness change if I need to take any other medication, I will consult the 
doctor in advance and tell the doctor afterwards. I have obtained a signed and dated 
copy of the informed consent form. 
I volunteered to participate in this study. 
 
Signature of subjects: ______________            Date: _____________ 
Contact number: ___________________ 
Signature of guardian of subject: ______________   Date: _____________ 
Relationship with the subject: _________ Contact number: __________________ 
 
The study physician declares: 
I confirm that the details of the study have been explained to the subject (and/or the 
subject's legal representative) so that he or she is fully aware of the above, including his 
or her rights and possible benefits and risks; Participants were given time to consider and 
make a decision to participate in the study and a copy of their signed informed consent 
form was provided. 
 
The doctor signature: _________         Date: _____________ 
Contact number: ___________________ 
 

Prot_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
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. 

SAP_001.pdf: 
1 
 
Safety and Efficacy of Donepezil in Mild to Moderate Alzheimer's Disease: A Multi-center 
Single-arm Study in China 
NCT02787746 
September 18, 2016 
 
Statistical Analysis Plan (SAP) 
 
 


2 
 
Safety analysis is conducted on the safety set (SS, patients who receive at least one dose of 
donepezil 10mg/day and have at least one safety evaluation). Efficacy analysis is conducted on 
the per protocol analysis set (PPS, patients who complete the study with no major protocol 
violations) with last observation carried forward (LOCF) as well as the full analysis set (FAS, all 
enrolled patients are included) LOCF. In addition, in order to test the robustness and accuracy of 
our results, efficacy analysis is further conducted on the PPS and FAS wherein missing data is 
not filled in and not included and thus only actual data of every patient who take the efficacy test 
are included (FAS [actual number] and PPS [actual number], respectively). 
   For the safety analysis, overall incidence of AEs and SAEs, incidence of AEs and SAEs by 
organ systems, severity, and AEs' relationship to donepezil are calculated and/or assessed by 
calculating the number of patients having AEs and SAEs, the prevalence of AEs and SAEs and 
their 95% confidence intervals (95% CI). Laboratory abnormalities such as changes in alanine 
aminotransferase (ALT) and aspartate aminotransferase (AST), and changes in EKG and ECG 
such as HR, QT, QTc are summarized and described using means, standard deviation (SD), 
median, maximal, minimal, 25th and 75th percentile values, and further analyzed with paired t-
test. Correlations of AEs and various risk factors are first assessed with univariate logistic 
regression analysis, and variables included patients' medical history (history of neurological, 
cardiovascular, mental, liver and gastrointestinal diseases), age ( grouped into ≤75 and >75 
years), gender, body weight (≤55kg and >55kg), APOE genotype (2/2, 3/3, 4/4, 2/3, 
2/4, and 3/4), the presence or absence of APOE 4/4, concomitant medications 
(cardiovascular and cerebrovascular, gastrointestinal, liver, neurological, mental and 
hypoglycemic medications), and duration of donepezil 5mg/day treatment prior to the study 
(days). Forward stepwise multivariate logistic regression analysis is subsequently performed to 


3 
 
further assess correlations between various risk factors and incidence of AEs using variables 
chosen from those used in the univariate analysis (SLSTAY=0.3, a significance value of 0.3 is 
required for a variable to stay in the multivariate model). 
   MMSE and ADCS-ADL are assessed at each visit. Their changes at each visit from baseline 
are calculated. Factors affecting MMSE and ADCS-ADL changes are assessed with a mixed 
model-repeated measures using an autoregressive covariance structure. Variables are the same as 
those used in the univariate analysis of correlations between AEs and various risk factors 
   All analyses are performed with SAS 9.4 (SAS Institute Inc.; Cary, NC, USA), data is analyzed 
with a two-tailed hypothesis, and a p value < 0.05 is considered to indicate statistical significance.