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
  
  

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.