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
1. Age range: Patients greater than 50 years.
2. Sex distribution: both men and women. Women must be two (2)-years post-menopausal or
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
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
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
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
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
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
17. Patients must be able to swallow tablet medication; no crushing of tablets is
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.
1. Age range: Patients less than 50 years.
2. MMSE score of <1 or >12.
3. FAST score of < 6a.
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
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
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
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.