Efficacy, Safety, & Tolerability of AZD3480 Patients With Mild to Moderate Dementia of the Alzheimer's Type (AD)

A parallel group design allows the effects of AZD3480 to be compared directly to a positive
comparator, donepezil, and the randomized nature of the design minimizes observer and
subject bias. Donepezil was chosen as the positive comparator since it is widely used in
the long-term treatment of AD, has an efficacy profile similar to other AChEIs and is better
tolerated than other drugs in this class. The choice of a positive comparator such as
donepezil rather than placebo allows the ethical use of a one-year treatment period. The
assessment of the efficacy of AZD3480 versus donepezil will satisfy the regulatory
requirements for an adequate and well-controlled study, if it is positive.

The dose of AZD3480 evaluated in this study, 30 mg free base (48mg as the p-hydroxybenzoic
acid salt), reflects an appropriate dose for AZD3480 based upon extrapolations from earlier
preclinical and clinical findings: (a) 30mg is expected to produce plasma concentrations of
AZD3480 similar to or exceeding those leading to a cognitive enhancing effect in animal
models; (b) it matches the exposure observed to enhance cognitive function in elderly
patients with AAMI, MCI, and AD in earlier studies; and (c) it has 80% receptor occupancy at
the α4β2 NNR based on a PET receptor occupancy study. (Donepezil is being used in doses as
recommended in the data sheet which states that treatment should be initiated with 5 mg and
then increased to a 10 mg daily dose).

Patients with an MMSE ranging from 12-22 have been specifically selected to enhance the
likelihood of seeing a difference in the efficacy endpoints with AZD3480 vs. donepezil;
instead of the mild group of AD patients who usually have an MMSE greater then 22.

Inclusion Criteria:

1. A clinical diagnosis of AD per NINCDS-ADRDA criteria; mild to moderate severity as
defined by Mini-Mental State Examination (MMSE) scores of 12 to 22.

2. AD diagnosed at least 12 months prior to Screening, and supported by brain imaging
studies within 6 months prior to Screening.

3. Absence of vascular dementia both per AIRENS criteria and as defined by modified
Hachinski ischemia score (HIS) of
4. Presence of a caregiver with significant proportion of time in contact with subject
and who will oversee administration of study drug during the trial

5. Able to complete test assessments and to sign informed consent with the help of a
caregiver if needed

Exclusion Criteria:

1. Diagnosis or presence of other dementing illnesses

2. Use of mood stabilizers, antidepressants, anxiolytics, antipsychotics or hypnotics

3. Treatment within 1 month prior to Screening using cognition-affecting agents (e.g.
CNS stimulants)

4. Tobacco user within 4 months prior to Screening

5. Use of smoking cessation therapy within 4 months prior to Screening

6. History within past 6 months of alcohol abuse or illicit drug abuse

7. Unable, even with caregiver assistance, to comply with study procedures in opinion of
investigator

8. Myocardial infarction within the 12 months prior to Screening

9. Hypothyroidism, vitamin B12 or folic acid deficiency

10. Known systemic infection (HBV, HCV, HIV, TB)

11. Vascular dementia per NINDS-AIRENS criteria and as defined by a modified Hachinski
ischemia score (HIS, Appendix 4) score of > 4 (i.e., vascular dementia is consistent
with a modified HIS > 4).