Open-Label Extension Study of 23 mg Donepezil SR in Participants With Moderate to Severe Alzheimer's Disease

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and efficacy of long-term administration of 23 milligram (mg) donepezil sustained release (SR) in participants with moderate to severe Alzheimer's disease. Participants who complete study E2020-G000-326 (NCT00478205) with no ongoing serious adverse events (SAEs) and no serious adverse drug reactions will be eligible to enter the open-label extension study.

Official Title
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Open-Label Extension Study of 23 mg Donepezil SR in Patients With Moderate to Severe Alzheimer's Disease

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: Donepezil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for Participants: Written informed consent from the participant (if possible) or from the participant's legal guardian or other representative at the time of the Baseline visit, prior to beginning any assessments or activities. Completion of study E2020-G000-326 (NCT00478205) without ongoing SAEs or history of serious adverse drug reactions during study E2020-G000-326 (NCT00478205). Participant must enroll in the present study within 3 days of completion of study E2020-G000-326 (NCT00478205). Health: physically healthy and ambulatory or ambulatory-aided (that is, walker or cane); corrected vision and hearing sufficient for compliance with testing procedures. Co-morbid medical conditions must be well-controlled as determined by the investigator. Participants undergoing treatment with selective serotonin reuptake inhibitors (SSRIs) may be included, provided that doses are within the approved dose range as specified in the Physician's Desk Reference or local equivalent Concomitant Medications: Participants undergoing treatment with the following medications may be enrolled in the study provided the following conditions are met: chronic daily benzodiazepine use if doses are stable within an approved dose range; bronchodilator medications for treatment of chronic obstructive pulmonary disease (COPD) as long as drug is administered via metered dose inhaler within approved dose range; memantine if taken at doses of 20 mg/day or less, provided that the dose is stable. The participants must have a relative/caregiver who supervises the regular taking of the drug at the correct dose and is alert for possible side effects, unless the participant's legal guardian takes on this task. Inclusion Criteria for Caregivers. Written informed consent will be obtained from the designated caregiver for participation in study assessments. The caregiver must be sufficiently familiar with the participant (as determined by the investigator) to provide accurate data. Specifically, the caregiver must have sufficient contact with the participant to provide accurate reports of the participant's functioning, must be able to observe for possible adverse events, and must be able to accompany the participant to all visits. It is preferable that the caregiver be the same as in study E2020-G000-326 (NCT00478205). If no replacement caregiver is available who meets the caregiver inclusion/exclusion criteria, the participant must be discontinued from the study. Exclusion Criteria for Participants: No caregiver available to meet the inclusion criteria for caregivers. Participants with any active or clinically-significant conditions affecting absorption, distribution, or metabolism of the study medication (example, inflammatory bowel disease, gastric or duodenal ulcers, hepatic disease, or severe lactose intolerance). Known plan for elective surgery during the study period that would require general anesthesia and administration of neuromuscular blocking agents, such as succinylcholine, to induce paralysis/muscle relaxation. Minor surgery, such as colonoscopy or cataract surgery, will be permitted as long as it does not require the use of these paralytic agents. Participants who are unwilling or unable to fulfill the requirements of the study. Use of any prohibited prior or concomitant medications. Any condition that would make the participant, in the opinion of the investigator, unsuitable for the study. Participant taking concomitant antidepressant medication known to have significant anticholinergic effects, such as tricyclic antidepressants prescribed at doses recommended for the treatment of major depression. Participants who cannot swallow or who have difficulty swallowing whole tablets. Participants taking any alternative medication such as vitamins and/or herbal products or alternative medical techniques such as acupuncture or acupressure specifically for the treatment of Alzheimer's disease. Exclusion Criteria for Caregivers. Caregivers who are unwilling or unable to give informed consent or otherwise to fulfill the requirements of the study. Any condition that would make the caregiver, in the opinion of the investigator, unsuitable for the study.

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 91 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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Donepezil SR 23 mg (Donepezil SR 23 mg in Study NCT00478205)<br>Donepezil SR 23 mg once daily orally for 12 months to participants who received donepezil 23 mg SR in the preceding double-blind study E2020-G000-326 (NCT00478205). | Drug: Donepezil<br>* Donepezil SR 23 mg once daily orally.<br>* Other names: Aricept;|
| Experimental: Donepezil SR 23 mg (Donepezil IR 10 mg in Study NCT00478205)<br>Donepezil SR 23 mg once daily orally for 12 months to participants who received donepezil 10 mg immediate release (IR) in the preceding double-blind study E2020-G000-326 (NCT00478205). | Drug: Donepezil<br>* Donepezil SR 23 mg once daily orally.<br>* Other names: Aricept;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) | An AE was defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of an investigational product, whether or not considered related to the investigational product, a change in treatment, or discontinuation of study drug, recurrence of an intermittent medical condition not present pretreatment, an abnormal laboratory test result was considered an AE if the identified laboratory abnormality led to any type of intervention, withdrawal of study drug, or withholding of study drug, whether prescribed in the protocol or not. All AEs in Study 328 (NCT00566501) excluding treatment-emergent signs or symptoms continuing from Study 326 (NCT00478205) were reported. | From the enrollment of the study up to 30 days after last dose of the study drug (up to 2 years 3 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With at Least 1 Treatment-Emergent Abnormal Laboratory Values (TEAVs): Hematology | A TEAV for a laboratory parameter was defined as a value that was clinically significantly outside (above or below) the normal range post-dose, but within the normal range prior to drug administration, or a value that represented a clinically significant exacerbation of an abnormality present prior to drug administration. Abnormal values for hematology parameters were: White Blood cells count: less than or equal to [<=] 2,800/per millimeter (mm) or greater than or equal to [>=] 16,000/mm; Neutrophils: <=15 percent (%); Hemoglobin: Male (<=11.5 gram per deciliter [g/dL]), Female (<=9.5 g/dL); Hematocrit: Male (<=37%), Female (<=32%); Eosinophils: >=10%; Platelet Count: <=75,000/mm or >=700,000/mm. Percentage of participants with at least 1 abnormal TEAV for hematology was reported. | From the first dose of study drug up to 2 years 3 months | 
| Percentage of Participants With at Least 1 TEAVs for Selected Parameters: Clinical Chemistry | A TEAV for a laboratory parameter was defined as a value that was clinically significantly outside (above or below) the normal range postdose, but within the normal range prior to drug administration,or a value that represented a clinically significant exacerbation of an abnormality present prior to drug administration.Abnormal values for clinical chemistry parameters were:Sodium:Less than(<)130 milliequivalents per litre (mEq/L) or greater than(>)150 mEq/L;Potassium:<3 mEq/L or >5.5 mEq/L; Calcium: <8.4 milligram per deciliter (mg/dL) or >1.5 mg/dL;Albumin: 50% lower limit of normal (LLN); Alkaline Phosphatase:>=3*upper limit of normal (ULN);Aspartate aminotransferase (AST):>=3*ULN;Alanine aminotransferase(ALT):>=3*ULN;Total Bilirubin:>=2.0 mg/dL;Chloride:<90 mEq/L or >115 mEq/L;Creatinine:>=2.0 mg/dL;Creatine phosphokinase:>=3*ULN;Blood Urea Nitrogen (BUN):>=30 mg/dL. Percentage of participants with at least 1 abnormal TEAV (selected parameters) for clinical chemistry was reported. | From the first dose of study drug up to 2 years 3 months | 
| Change From Baseline in Severe Impairment Battery (SIB) Total Score | The SIB evaluated the severity of cognitive dysfunction in participants with more advanced dementia. Test questions measured attention, language, orientation, memory, praxis, visuospatial ability, construction, social skills, orienting head to name. Non-verbal responses were allowed, thus decreasing the need for language output. Forty questions were included with a total possible score range of 0-100. Lower scores indicated greater cognitive impairment. | At Baseline, Month 3, Month 6, Month 9 and Month 12 | 
| Change From Baseline in Mini-Mental State Examination (MMSE) Total Score | MMSE is a 30-point scale that measured orientation to time and place, registration, immediate and delayed recall, attention, language, and drawing. Scores ranged from 0 (most impaired) to 30 (no impairment). Lower score indicated more impairment. | At Baseline, Month 3, Month 6, Month 9 and Month 12 | 
| Change From Baseline in Modified Alzheimer's Disease Cooperative Study Activities of Daily Living Severe Scale (ADCS-ADL) Total Score | ADCS-ADL is a comprehensive battery of ADL questions used to measure a participant's functional capabilities. The modified ADCS-ADL-severe scale is a 19-item scale that has been validated for the assessment of participants with moderate to severe dementia. It measured the most appropriate basic and instrumental abilities (such as walking, grooming, bathing, and eating) in this participant population. Response to each item was obtained by interview with the caregiver. Ratings reflected caregiver observations about the participant's actual functioning and provided an assessment of change in the functional state of the participant over time. The total score ranged from 0 to 54. Lower scores indicated greater functional impairment. | At Baseline, Month 3, Month 6, Month 9 and Month 12 | 
| Change From Baseline in Quality of Life-Alzheimer's Disease (Qol-AD) Total Score | QoL-AD is a 13-item quality of life instrument developed to specifically assess QoL in participants who have dementia. Each item was scored on a 4-point scale (poor, fair, good, excellent) and a single score was calculated, ranging from 13 (low functioning) to 52 (normal function). Higher score indicated better QoL. The QoL-AD total scores for the participants and caregiver were the sum of the 13 items on each test. | At Baseline, Month 6 and Month 12 | 
| Change From Baseline in European Quality of Life-5 Dimension (EQ-5D) Total Score | EQ-5D is a health profile questionnaire assessing quality of life along 5 domains. Caregivers rated 5 domains of health (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) by choosing from 3 answering options (1=no problems; 2=some problems; 3=extreme problems). The EQ-5D Health Utilities Index (HUI) is derived from the five dimensions of the EQ-5D, using country-specific preference weights (tariffs) to summarize how good or bad each health state is on a scale from 1 to 0. HSI total score ranged from 1 (full health) and 0 (worst health/death). | At Baseline, Month 6 and Month 12 | 
| Change From Baseline in Screen for Caregiver Objective Burden (SCB) Total Score | The SCB is a 25-item instrument that questions caregivers about the occurrence and degree of distress as aspects of the burden of care during the preceding two weeks. It was designed specifically for use with caregivers of Alzheimer's disease participants. Each item was assessed on a 5-point scale ranging from 0 (no occurrence) to 4 (occurrence with severe distress). The objective burden was the sum of the total numbers of (1 2 3 4) in all items. Total score ranged from 0 (low distress) to 100 (high distress). | At Baseline, Month 6 and Month 12 | 
| Change From Baseline in Screen for Caregiver Subjective Burden (SCB) Total Score | The SCB is a 25-item instrument that questioned caregivers about the occurrence and degree of distress as aspects of the burden of care during the preceding two weeks. It was designed specifically for use with caregivers of Alzheimer's disease participants. Each item was assessed on a 5-point scale ranging from 0 (no occurrence) to 4 (occurrence with severe distress). The subjective burden was the sum of the (total number with score*score). Total score ranged from 0 (no occurrence) to 100 (occurrence with severe distress). | At Baseline, Month 6 and Month 12 | 
| Number of Participants With Treatment Outcome Scale (TOS) Score | TOS is a pilot instrument designed to evaluate the caregiver's assessment of the participant's status. The caregiver was asked how much he/she thinks the participant has been helped by participating in the study. This instrument comprised a 7-point Likert scale in which a rating of 1=Very much improved; 2=Moderately improved; 3=Minimally improved; 4=About the same; 5=Minimally worse; 6=Moderately worse; 7=Very much worse. The total scale ranged from 1 (marked improvement) to 7 (marked worsening). | At Months 6 and 12 | 
| Goal Attainment Scaling (GAtS) Score Total Score | GAtS is a technique that is standardized with respect to the general approach, but individualized with respect to the outcome goals of each participant. GAtS was designed to provide insight into the changes that are considered as important by the caregiver and (if feasible) by the participants. At study initiation, the participants (if capable) and, separately, the caregiver were asked to specify up to 4 goals for the participants during study participation. For each goal, a description of the current state (or one supplied with the help of the clinician if necessary) was provided to anchor the baseline assessment at 0, and other possible outcomes were described. The outcome for each goal was quantified by a 4-point scale that provided for improvement (+1, +2), no change (0) or worsening (-1, -2). Total score ranged from -30 (worsened) to 130 (most improved). Baseline score was set to be 50 (when scores of all goals are '0' [no change]). | At Months 6 and 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Moderate-to-severe, Alzheimer's, Disease