Evaluating The Impact Of Donepezil Hydrochloride (Aricept) On Behavioral And Psychological Symptoms In Patients With Severe Alzheimer's Disease
Evaluating The Impact Of Donepezil Hydrochloride (Aricept) On Behavioral And Psychological Symptoms In Patients With Severe Alzheimer's Disease
A 12-week, multicenter, randomized, double-blind, placebo-controlled phase IV study.
 Approximately 200 subjects will be enrolled, half will receive active drug (donepezil
 hydrochloride) and half will receive matching placebo at approximately 50 research sites
 within the US, the European Union, South Africa and Australia. Eligible subjects will reside
 at home, in an assisted living facility, or nursing homes age and will be 50 years or older,
 with a diagnosis of Alzheimer's disease in the severe stage. All subjects must start with 5mg
 a day (one 5 mg tablet of donepezil HCL or matching placebo). Dose will be increased to 10 mg
 a day (two tablets of 5 mg donepezil HCL or matching placebo) after 4 weeks. Dose may be
 decreased based on side effects. The primary efficacy measure will be the Cornell Scale for
 Depression in Dementia (CSDD). Secondary measures will include Functional Assessment Staging
 (FAST), Mini-Mental State Examination (MMSE), NPI-10 (Neuropsychiatric Inventory), DEMQOL
 Proxy ( Quality of Life). Blood levels of cytokines and safety will also be assessed.
Inclusion Criteria:

 1. Age range: Patients greater than 50 years.

 2. Sex distribution: both men and women. Women must be two (2)-years post-menopausal or
 surgically sterile.

 3. MMSE scores between 1 and 12 (inclusive).

 4. Clinically significant behavioral pathology as measured by the Cornell Scale for
 Depression in Dementia(CSDD), defined as a total score on the CSDD of 5 or greater
 with at least one item rated 2 (severe) within the domains of Mood-Related Signs
 (Anxiety, Sadness, Lack of Reactivity, Irritability) or Behavioral Disturbances
 (Agitation, Retardation, Multiple Physical Complaints, Loss of Interest).

 5. Diagnostic evidence of probable or possible Alzheimer's disease (DSM-IV and
 NINCDS/ADRDA) made or confirmed by the site physician at the time of the screening
 visit. This evidence must be fully documented in the patient's file prior to the
 baseline visit.

 6. CT or MRI within the last 36 months consistent with a diagnosis of Alzheimer's disease
 without any other clinically significant comorbid pathologies found. A copy of the
 report will be required and should be appended to the case report form. If there has
 been a significant change in clinical status suggestive of stroke or other possible
 neurological disease with onset between the time of the last CT or MRI and the
 screening evaluation, the scan should be repeated if considered appropriate by the
 investigator.

 7. Prior use of cholinesterase inhibitors (Aricept®, Exelon®, Cognex®, Reminyl/Razadyne®,
 metrifonate, physostigmine) and memantine is allowed, provided that the medication was
 discontinued at least 3 months prior to screening and that it was not discontinued for
 the purpose of enrolling the patient in the study.

 8. Functional Assessment Staging (FAST) score >6a.

 9. Patients residing in the community, assisted living facilities (ALF) or skilled
 nursing homes.

 10. The patient must be expected to complete all procedures scheduled during the Screening
 and Baseline visits including all efficacy parameters. Patients must have a reliable
 caregiver or family member who agrees to accompany the patient to all clinic visits,
 provide information about the patient as required by the protocol, and ensure
 compliance with the medication schedule. For patients residing in assisted living
 facilities or skilled nursing homes, the reporting caregiver may be a professional
 staff member, provided he or she meets the criteria in number 11, and study visits may
 take place in the facility if the study site staff finds this preferable to facilitate
 the smooth conduct of the study.

 11. The caregiver must be a constant and reliable informant with a minimum of three days
 per week direct contact with the patient (for at least 4 hours per day during waking
 hours). This contact is necessary to ensure accurate reporting of the patient's
 behavior.

 12. Patients with stable Type I (Insulin-Dependent) or Type II diabetes are eligible
 provided they are monitored regularly prior to and during the study to ensure adequate
 glucose control (hemoglobin A1c <8%).

 13. Clinical laboratory values within normal limits and within the sponsor's guidelines,
 or abnormalities considered not clinically significant by the investigator and
 sponsor.

 14. Patients with controlled hypertension (sitting diastolic BP < 95 mmHg and/or sitting
 systolic BP <160 mmHg), right bundle branch block (complete or partial), and
 pacemakers may be included in the study.

 15. Patients 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.

 16. Patients with a history of seizure disorder are allowed provided that they are on
 stable treatment for at least 3 months and have not had a seizure within the past 6
 months.

 17. Patients must be able to swallow tablet medication; no crushing of tablets is allowed.

 18. Patients should be independent in ambulation or ambulatory-aided (i.e., walker, cane,
 or wheelchair); vision and hearing (eyeglasses and/or hearing aids permissible) should
 be sufficient for compliance with testing procedures.

 19. Patients must be sufficiently proficient in the language in which the assessments are
 to be conducted.

 Exclusion Criteria:

 1. Age range: Patients less than 50 years.

 2. MMSE score of <1 or >12.

 3. FAST score of < 6a.

 4. CSDD>18

 5. Patients 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).

 6. Patients with a known hypersensitivity to piperidine derivatives or cholinesterase
 inhibitors.

 7. Patients without a reliable caregiver, or patients or caregivers who are unwilling or
 unable to complete any of the outcome measures and fulfill the requirements of this
 study.

 8. Patients with clinically significant obstructive pulmonary disease or asthma,
 untreated or not controlled by treatment within 3 months prior to screening.

 9. Patient's with recent (< 2 years) hematologic/oncologic disorders (mild anemia
 allowed).

 10. Evidence of active, clinically significant and unstable gastrointestinal, renal,
 hepatic, endocrine or cardiovascular system disease.

 11. Patients with a current DSM-IV diagnosis of Major Depressive Disorder (MDD) or any
 current primary psychiatric diagnosis other than Alzheimer's disease (as per DSM-IV).
 Patients with CSDD scores >19 will be considered to have MDD and are excluded.

 12. Patients with dementia complicated by other organic disease (DSM 290.30 or 290.11) are
 excluded; depressive symptoms and delusions are common in Alzheimer's disease, but
 patients with severe symptoms so pronounced that they warrant an alternative,
 concurrent diagnosis, are excluded.

 13. Patients with vascular dementia or dementia complicated by tertiary syphilis

 14. Patients with a known or suspected history of alcoholism or drug abuse (within the
 past 10 years).

 15. Any condition which would make the patient or the caregiver, in the opinion of the
 investigator, unsuitable for the study.