The Effectiveness And Safety Of Donepezil Hydrochloride (E2020) In Subjects With Mild To Severe Alzheimer's Disease Residing In An Assisted Living Facility

Study Overview
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Brief Summary
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This is a study to determine the effectiveness and safety of donepezil hydrochloride (E2020) used to treat residents of assisted living facilities diagnosed with mild, moderate, or severe stage Alzheimer's disease.

Official Title
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A 12-Week, Multicenter, Open Label Study To Evaluate The Effectiveness And Safety Of Donepezil Hydrochloride (E2020) In Subjects With Mild To Severe Alzheimer's Disease Residing In An Assisted Living Facility

Conditions
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Mild to Severe Alzheimer's Disease

Intervention / Treatment
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* Drug: Donepezil HCl


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age range: Subjects > 50 years of age. Sex distribution: both men and women. Women must be two (2) years post-menopausal or surgically sterile. Women of child bearing potential (< 1 year post menopausal) must be practicing effective contraception and have a negative ß-hCG at screening (Women who are breast feeding are excluded). MMSE scores between 5 and 24 (inclusive). Subjects must have diagnostic evidence of possible or probable AD either prior to or at the screening visit based on Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) and National Institute of Neurological and Communicative Disorders and Stroke criteria. CT or MRI within the last 12 months consistent with a diagnosis of AD without any other clinically significant comorbid pathologies found. A copy of the report will be required and will be collected. If there has been a significant change in clinical status suggestive of stroke or other neurological disease in addition to AD with onset between the time of the last CT or MRI and the screening evaluation, the scan should be repeated during screening. The caregiver/ informant can be a family member or a professional and must have had contact with the subject at least 6 Weeks prior to study entry and spent at minimum 3 days a Week (10 hours per Week) with the subject. For study visit, the subject can be seen at the Assisted Living Facility (ALF) or in the clinic setting of the Investigator. At each visit, the caregiver/informant will provide the information for completion of the safety and efficacy assessments based on knowledge of and time spent with the subject. Subjects must reside in an ALF. The subject is expected to complete all procedures scheduled during the screening, baseline, interim, and final visits including all efficacy assessments. Putative non-prescription/prescription cognitive enhancers (e.g. ginkgo, high-dose vitamin E, lecithin, estrogen, non-steroidal anti-inflammatory drugs [NSAIDs]) will not be excluded but will be discouraged. If a putative cognitive enhancer is present, the dosage must have been stable for at least 3 months prior to the screening visit and should not change during the course of the study. Subjects with controlled hypertension (sitting diastolic BP < 95 mmHg), right bundle branch block (complete or partial), and pacemakers may be included in the study. Subjects with thyroid disease also may be included in the study provided they are euthyroid and stable on treatment for at least 3 months prior to screening. Subjects with a history of seizure disorder are allowed provided that they are on stable treatment for at least 3 months prior to screening and have not had a seizure within the past 6 months. Subjects must be able to swallow tablet medication -- no crushing of tablet is allowed. Health: independent or ambulatory aided (i.e., walker or cane, to wheelchair); vision and hearing (eyeglasses and/or hearing aid permissible) sufficient for compliance with testing procedures. Subjects must be sufficiently proficient in the language in which the assessments are to be conducted. Subjects must have clinical laboratory values within normal limits, and within the Eisai (sponsor) guidelines, or abnormalities considered not clinically significant by the investigator and sponsor. Exclusion Criteria: Age range: Subjects < 50 years of age. MMSE score of ≤4 or ≥25. Subjects with active or clinically significant conditions affecting absorption, distribution or metabolism of the study medication (e.g., inflammatory bowel disease, gastric or duodenal ulcers or severe lactose intolerance). Subjects with a known hypersensitivity to piperidine derivatives or cholinesterase inhibitors. Subjects living in a skilled nursing home or subjects living in an ALF who may be moved to a skilled nursing home during the course of the study. Subjects who transfer from an ALF to a skilled nursing home during this study will be discontinued. Subjects who have taken the following medications within the last 3 months prior to screening will be not eligible: Aricept, Exelon, Cognex, Razadyne, Metrifonate, Namenda or propentofylline. Subjects without a reliable caregiver/informant or subjects whose caregiver is unwilling or unable to complete the outcome measures and fulfill the requirements of this study. Subjects with clinically significant obstructive pulmonary disease or asthma, untreated for > 3 months. Subjects with recent (< 2 years) hematologic/ oncologic disorders, not including mild anemia or basal or squamous cell carcinoma of the skin. Subjects with current evidence of malignant neoplasm or recurrent or metastatic disease will be excluded. Evidence of clinically significant, active gastrointestinal, renal, hepatic, endocrine or cardiovascular system disease. Subject with a current DSM-lV diagnosis of Major Depressive Disorder (MDD) or any current primary psychiatric diagnosis other than Alzheimer's disease (as per DSM-lV). Subjects with dementia complicated by other organic disease (DSM 290.30 or 290.11) are excluded; depression or delusions are common in Alzheimer's disease, and subjects with severe symptoms so pronounced that they warrant an alternative, concurrent diagnosis, are excluded. Subjects with a known or suspected history of alcoholism or drug abuse (within the past 10 years). Subjects with treated hypothyroidism that have not been on a stable dose of medication for 3 months prior to screening and who do not have normal serum Free T3, Free T4 and TSH at screening. Subjects with treated vitamin B-12 deficiency who have not been on a stable dose of medication for at least 3 months prior to the study screening visit and who do not have normal serum B-12 levels at screening. Any subject taking a prohibited medication will be excluded. Any condition which would make the subject or the caregiver, in the opinion of the investigator, unsuitable for the study.

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: Donepezil HCl<br>* One 5 mg tablet per day (for the first 6 weeks) with a full glass of water. For the last 6 weeks, one 10mg tablet per day with a full glass of water.<br>* Other names: Aricept;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mini Mental State Examination (MMSE) Total Scores by Visit | The MMSE was a brief test that assessed the cognitive status of the participant. The 30-point test included items that evaluate orientation to time and place, immediate and delayed recall, attention, language, and construction. The total number of correct responses was obtained. The scores ranged from 0 to 30, with higher scores representing better performance. Summaries and analyses in the Intent-to-Treat (ITT) population were carried out using observed cases at each visit. A Study Endpoint evaluation was performed using the last observation carried forward (LOCF) from the open label treatment phase for each participant. The outcome of the study was based on analyses of the primary efficacy variable at Study Endpoint, which was defined as end of study assessment, using the ITT population with LOCF. | Baseline (Visit 2), Week 6 (Visit 3), Week 12 (Visit 4) or Early Termination (ET) Visit, Week 12 LOCF (Study Endpoint) | 
| Change From Baseline in MMSE Total Score by Visit | The MMSE was a brief test that assessed the cognitive status of the participant. The 30-point test included items that evaluated orientation to time and place, immediate and delayed recall, attention, language, and construction. The total number of correct responses was obtained. The scores ranged from 0 to 30, with higher scores representing better performance. Summaries and analyses in the ITT population were carried out using observed cases at each visit. A Study Endpoint evaluation was performed using the LOCF from the open label treatment phase for each participant. The outcome of the study was based on analyses of the primary efficacy variable at Study Endpoint, which was defined as end of study assessment, using the ITT population with LOCF. Change from Baseline in MMSE Total Score at Week 6 (Visit 3), Week 12 (Visit 4) or ET Visit, Week 12 LOCF (Study Endpoint) has been reported. | Baseline, Week 6 (Visit 3), Week 12 (Visit 4) or ET Visit, Week 12 LOCF (Study Endpoint) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Caregiver Activity Survey (CAS) Total Time by Visit | The CAS was a validated tool that measured the time caregivers spent aiding Alzheimer's participants with their day-to-day activities. The CAS recorded time spent on six activities of daily living, communicating with the person, using transportation, dressing, eating, looking after one's appearance, and supervising the person. Caregivers were asked to report the amount of time spent on each activity during a 'typical' caregiving day. Total time for the CAS was calculated as the sum of the sub-item times. | Baseline (Visit 2), Week 6 (Visit 3), Week 12 (Visit 4) or ET Visit, Week 12 LOCF (Study Endpoint) | 
| Change From Baseline in CAS Total Time by Visit | The CAS was a validated tool that measured the time caregivers spent aiding Alzheimer's participants with their day-to-day activities. The CAS recorded time spent on six activities of daily living, communicating with the person, using transportation, dressing, eating, looking after one's appearance, and supervising the person. Caregivers were asked to report the amount of time spent on each activity during a 'typical' caregiving day. Total time for the CAS was calculated as the sum of the sub-item times. Change from Baseline in CAS Total Time at Week 6 (Visit 3), Week 12 (Visit 4) or ET Visit, Week 12 LOCF (Study Endpoint) has been reported. | Baseline, Week 6 (Visit 3), Week 12 (Visit 4) or ET Visit, Week 12 LOCF (Study Endpoint) | 
| Neuropsychiatric Inventory (NPI-8) Total Score by Visit | The NPI-8 was an 8-item scale that assessed eight behavioral domains: delusions, hallucinations, agitation, depression, anxiety, apathy, irritability, and aberrant motor behavior. The frequency (0 to 4) and severity (0 to 3) of each domain were assessed; the sub-score for each domain was calculated as the product of the frequency and severity rating. The total score for the NPI was calculated as the sum of the domain sub-score, range from 0 to 96, with higher scores indicating greater behavior disturbances. | Baseline (Visit 2), Week 12 (Visit 4) or ET Visit, Week 12 LOCF (Study Endpoint) | 
| Change From Baseline in NPI-8 Total Score by Visit | The NPI-8 was an 8-item scale that assessed eight behavioral domains: delusions, hallucinations, agitation, depression, anxiety, apathy, irritability, and aberrant motor behavior. The frequency (0 to 4) and severity (0 to 3) of each domain were assessed; the sub-score for each domain was calculated as the product of the frequency and severity rating. The total score for the NPI was calculated as the sum of the domain sub-score, range from 0 to 96, with higher scores indicating greater behavior disturbances. Change from Baseline in NPI-8 Total Score at Week 12 (Visit 4) or ET Visit, Week 12 LOCF (Study Endpoint) has been reported. | Baseline, Week 12 (Visit 4) or ET Visit, Week 12 LOCF (Study Endpoint) | 
| Alzheimer Disease-related Quality of Life (ADRQL) Total Score by Visit | The ADRQL was an observer-rated quality of life instrument that measured the following domains: social interaction, awareness of self, feelings and mood, enjoyment of activities, and response to surroundings. The ADRQL was a 47-item questionnaire with five domains: relating to and being around other people (ADRQL-A; 12 items), a person's special identity and important relationships (ADRQL-B; 8 items), different types of behavior (ADRQL-C; 15 items), usual activities (ADRQL-D; 5 items), and behavior in a person's living environment (ADRQL-E; 7 items). Domain sub-scores were summed to yield a total raw score, which was divided by the total possible score and multiplied by 100 to produce the final score. Each subscale score could be calculated in the similar approach. Total score ranges from 0-100 where higher scores reflected a better quality of life. | Baseline (Visit 2), Week 12 (Visit 4) or ET Visit, Week 12 LOCF (Study Endpoint) | 
| Change From Baseline in ADRQL Total Score by Visit | The ADRQL was an observer-rated quality of life instrument that measured the following domains: social interaction, awareness of self, feelings and mood, enjoyment of activities, and response to surroundings. The ADRQL was a 47-item questionnaire with five domains: relating to and being around other people (ADRQL-A; 12 items), a person's special identity and important relationships (ADRQL-B; 8 items), different types of behavior (ADRQL-C; 15 items), usual activities (ADRQL-D; 5 items), and behavior in a person's living environment (ADRQL-E; 7 items). Domain sub-scores were summed to yield a total raw score, which was divided by the total possible score and multiplied by 100 to produce the final score. Each subscale score could be calculated in the similar approach. Higher scores reflected a better quality of life. Change from Baseline in ADRQL Total Score at Week 12 (Visit 4) or ET Visit, Week 12 LOCF (Study Endpoint) has been reported. | Baseline, Week 12 (Visit 4) or ET Visit, Week 12 LOCF (Study Endpoint) | 
| Disability Assessment in Dementia (DAD) Total Score by Visit | The DAD was a 10 domain 40-item scale that measured a participant's ability to initiate, plan, organize, and perform both basic and instrumental activities of daily living. These domains were: hygiene (7 items), dressing (5 items), continence (2 items), eating (3 items), meal preparation (3 items), telephoning (4 items), going on an outing (5 items), finance (4 items), medication (2 items), and leisure (5 items). The three responses to the DAD items were No, Yes, and N/A. A No answer scored 0 and a Yes answer scored 1. The scoring range was 0-40, with a higher score indicating less disability (better quality of life). If N/A was selected then it was treated as missing. When there were items with missing values, the domain sub-scores and the total score were imputed. Domain sub-scores were summed to yield a total raw score. This was divided by the total possible score and multiplied by 100 to produce the final score. Each subscale score can be calculated in the similar approach. | Baseline (Visit 2), Week 6 (Visit 3), Week 12 (Visit 4) or ET Visit, Week 12 LOCF (Study Endpoint) | 
| Change From Baseline in DAD Total Score by Visit | The DAD was a 10 domain 40-item scale that measured a participant's ability to initiate, plan, organize, and perform both basic and instrumental activities of daily living. These domains were: hygiene (7 items), dressing (5 items), continence (2 items), eating (3 items), meal preparation (3 items), telephoning (4 items), going on an outing (5 items), finance (4 items), medication (2 items), and leisure (5 items). The three responses to the DAD items were No, Yes, and N/A. A No answer scored 0 and a Yes answer scored 1. The scoring range was 0-40, with a higher score indicating less disability (better quality of life). If N/A was selected then it was treated as missing. When there were items with missing values, the domain sub-scores and the total score were imputed. Domain sub-scores were summed to yield a total raw score. This was divided by the total possible score and multiplied by 100 to produce the final score. Each subscale score can be calculated in the similar approach. | Baselinw, Week 6 (Visit 3) and Week 12 (Visit 4) or ET Visit, Week 12 LOCF (Study Endpoint) |