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

• ADAS-Cog [ Time Frame: 54 weeks ] [ Designated as safety issue: No ]
  The ADAS-Cog tests patients' abilities in memory, language, orientation, and praxis, where higher scores (sum of errors) indicate declining cognition. ADAS-Cog will be collected at Week -3, Day 1, Weeks 4, 12, 24, 36, 52, and 54 or early withdrawal.
• CIBIC-(+) [ Time Frame: 54 Weeks ] [ Designated as safety issue: No ]
  The Clinician Interview-Based Impression of Change carer interview (CIBIC-Plus) comprises Likert scales for disease severity and changes, and written accounts summarizing semistructured interviews evaluating behavior, cognition, and function. The CIBIC-(+) is a co-primary endpoint with the ADAS-Cog in the United States. It will be collected at Week -3, Day 1, Weeks 4, 12, 24, 36, 52, and 54 or early withdrawal and will be a co-primary outcome for the US.
• ADCS-ADL [ Time Frame: 54 Weeks ] [ Designated as safety issue: No ]
  Alzheimer's Disease Cooperative Study - Activities of Daily Living is a caregiver rated questionnaire of 23 items, with possible scores over a range of 0-78, where 78 implies full functioning with no impairment. It will be the co-primary outcome measure in Europe. The ADCS-ADL is the co-primary endpoint with the ADAS-Cog in Europe. ADCS-ADL will be collected at Week -3, Day 1, Weeks 4, 12, 24, 36, 52, and 54 or early withdrawal.

• NPI [ Time Frame: 52 Weeks ] [ Designated as safety issue: No ]
  Neuropsychiatric Inventory (NPI) at Day 1, Week 12, Week 24, and Week 52 or EW.
• ADCS-ADL (in United States) [ Time Frame: 52 Weeks ] [ Designated as safety issue: No ]
  Alzheimer's Disease Cooperative Study - Activities of Daily Living is a caregiver rated questionnaire of 23 items, with possible scores over a range of 0-78, where 78 implies full functioning with no impairment. ADCS-ADL will be collected at Week -3, Day 1, Weeks 4, 12, 24, 36, 52, and 54 or early withdrawal.
• CIBIC-(+) [ Time Frame: 52 Weeks ] [ Designated as safety issue: No ]
  The Clinician Interview-Based Impression of Change carer interview (CIBIC-Plus) comprises Likert scales for disease severity and changes, and written accounts summarizing semistructured interviews evaluating behavior, cognition, and function. It will be collected at Week -3, Day 1, Weeks 4, 12, 24, 36, 52, and 54 or early withdrawal.
• MMSE [ Time Frame: 52 Weeks ] [ Designated as safety issue: No ]
  The MMSE (Folstein et al., 1975) consists of 11 tests of orientation, memory (recent and immediate), concentration, language, and praxis. Scores range from 0 to 30, with lower scores indicating greater cognitive impairment. The scale is completed by the investigator, based on the performance of the subject. The MMSE will be administered at Week -3 (Screen), Day 1 (Baseline), and Weeks 4, 12, 24, 36, and 52.
• Proportion of responders defined by improvement on ADAS-Cog [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
  Proportion of responders on ADAS-Cog at Weeks 24 and 52 (defined as the proportion of subjects with >/= 1 point improvement from Baseline)
• Percent showing no deterioration in CIBIC-(+) or ADCS-ADL) [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
  Percent of subjects showing no deterioration in CIBIC-(+) or ADCS-ADL from baseline to Weeks 24 and 52

AD is the most common form of dementia, affecting more than half of demented patients. It is the fourth leading cause of death among people 65 years of age or older (Sadik, 2003). In the US, the disease affects 6-10% of people between the ages of 65 and 85 years, and from 25 to 45% of those over the age of 85 (Evans et al., 1991; US General Accounting Office, 1998). It has been estimated that AD affects approximately 4.5 million people in the US (Hebert et al., 2003). The global prevalence of the disease will increase significantly as the population ages, unless preventative treatments can be identified and marketed.

AZD3480 is a selective partial agonist of the α4β2 subtype of NNRs with marked CNS selectivity. In a comparative non clinical study of visual memory (novel object recognition test) the AChEI donepezil showed substantially less effect compared to AZD3480 in enhancing cognition. Moreover, results from non clinical and clinical studies in healthy volunteers and patients with AAMI, MCI, and AD have demonstrated that AZD3480 has the potential to have a disease modifying effects in AD and could be very beneficial in improving cognition in these patients.

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.

• Drug: Donepezil
  Subjects taking Donepezil will take a 5mg capsule from Day 1 to Week 4, and a 10mg capsule from Week 4 to Week 52. Subjects who did not tolerate donepezil at 5mg or 10mg will be withdrawn from the study. Subjects taking donepezil will take a blinded capsule containing commercial donepezil and excipients and a placebo for AZD3480 p.o. qd.
  Other Name: Aricept
• Drug: AZD3480
  Subjects taking 30mg AZD3480 will take a 30mg capsule of AZD3480 and a placebo for donepezil (to maintain blind) p.o. qd.
  Other Name: TC-1734

• Experimental: AZD3480
  AZD3480 is manufactured as hard gelatin capsules for oral administration. The capsule formulation is a blend of AZD3480 and excipients. The excipients are pregelatinized starch, magnesium stearate, and microcrystalline cellulose. Matching placebo will also be provided to maintain the blind.
  Intervention: Drug: AZD3480
• Active Comparator: Donepezil

  Donepezil drug product will be provided as one (1) tablet of an over-encapsulated commercially available 5 mg dose strength as a single capsule, or two (2) tablets of over-encapsulated commercially available 5mg dose strengths as a single capsule. The excipients are magnesium stearate and mannitol.

  The hard gelatin capsules are grey opaque, using titanium dioxide as the opacifier and iron oxide black as the colorant. All components comply with the relevant Ph. Eur. And USP monographs. The matching placebo capsule for donepezil contains the excipients magnesium stearate, and microcrystalline cellulose.

  Intervention: Drug: Donepezil

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.
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).