Effects of AZD3480 on cognition in patients with mild-to-moderate Alzheimers disease : a phase IIb dose-finding study
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences . Biomedical Sciences
Journal of Alzheimer's disease
, p. 363-374
University of Antwerp
AZD3480 is a selective agonist of the central 42 and 22 neuronal icotinic cholinergic receptors (NNRs). Its effects on cognition were investigated in 567 patients with mild-to-moderate Alzheimers disease (AD) (Mini Mental State Examination [MMSE] 1226). Mean baseline MMSE was 21 (SD ± 3.7), with 61% of patients having mild disease (MMSE 2126). Mean age was 74 (range 5885) years. Patients were randomized to one of 5 treatment groups: AZD3480 5 mg, 20 mg or 35/100 mg, donepezil 10 mg (active comparator) or placebo, and treated once daily for 12 weeks. The primary outcome measure was change from baseline at Week 12 on the AD Assessment Scale-Cognitive Subscale (ADAS-Cog). Neither AZD3480 nor donepezil showed a statistically significant improvement versus placebo on ADAS-Cog. Improvements in a number of secondary outcome measures (MMSE, AD Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) and Disability Assessment for Dementia [DAD]) were observed for AZD3480 and for donepezil. A post-hoc analysis on ADAS-Cog, excluding patients with very mild AD (MMSE 2526) indicated improvement versus placebo for AZD3480 20 mg (−1.4, 95% CI: −3.0; 0.2) and donepezil (−1.0, 95% CI: −2.3; 0.3). AZD3480 was well tolerated. The study did not meet proof of concept criteria, since neither AZD3480 nor donepezil were statistically significantly superior to placebo on ADAS-Cog and was considered to be inconclusive. Further studies are required to determine the therapeutic potential of stimulating 42 receptors with NNRs in AD patients.