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Effects of AZD3480 on cognition in patients with mild-to-moderate Alzheimer's disease: a phase IIb dose-finding study.
J Alzheimers Dis. 2011; 24(2):363-74.JA

Abstract

AZD3480 is a selective agonist of the central α4β2 and α2β2 neuronal nicotinic cholinergic receptors (NNRs). Its effects on cognition were investigated in 567 patients with mild-to-moderate Alzheimer's disease (AD) (Mini Mental State Examination [MMSE] 12-26). Mean baseline MMSE was 21 (SD ± 3.7), with 61% of patients having mild disease (MMSE 21-26). Mean age was 74 (range 58-85) 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 25-26) 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 α4β2 receptors with NNRs in AD patients.

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Publisher Full Text

Authors+Show Affiliations

Frölich L
Division of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. lutz.froelich@zi-mannheim.de
Ashwood T
No affiliation info available
Nilsson J
No affiliation info available
Eckerwall G
No affiliation info available
Sirocco Investigators
No affiliation info available

MeSH

AgedAged, 80 and overAlzheimer DiseaseCholinesterase InhibitorsCognition DisordersDonepezilDose-Response Relationship, DrugDouble-Blind MethodFemaleHumansIndansMaleMental Status ScheduleNeuroprotective AgentsNeuropsychological TestsPiperidinesPyridinesTime FactorsTreatment Outcome

Pub Type(s)

Clinical Trial, Phase II
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21258153

Citation

Frölich, Lutz, et al. "Effects of AZD3480 On Cognition in Patients With Mild-to-moderate Alzheimer's Disease: a Phase IIb Dose-finding Study." Journal of Alzheimer's Disease : JAD, vol. 24, no. 2, 2011, pp. 363-74.
Frölich L, Ashwood T, Nilsson J, et al. Effects of AZD3480 on cognition in patients with mild-to-moderate Alzheimer's disease: a phase IIb dose-finding study. J Alzheimers Dis. 2011;24(2):363-74.
Frölich, L., Ashwood, T., Nilsson, J., & Eckerwall, G. (2011). Effects of AZD3480 on cognition in patients with mild-to-moderate Alzheimer's disease: a phase IIb dose-finding study. Journal of Alzheimer's Disease : JAD, 24(2), 363-74. https://doi.org/10.3233/JAD-2011-101554
Frölich L, et al. Effects of AZD3480 On Cognition in Patients With Mild-to-moderate Alzheimer's Disease: a Phase IIb Dose-finding Study. J Alzheimers Dis. 2011;24(2):363-74. PubMed PMID: 21258153.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effects of AZD3480 on cognition in patients with mild-to-moderate Alzheimer's disease: a phase IIb dose-finding study. AU - Frölich,Lutz, AU - Ashwood,Tim, AU - Nilsson,Jonas, AU - Eckerwall,Göran, AU - ,, PY - 2011/1/25/entrez PY - 2011/1/25/pubmed PY - 2011/8/5/medline SP - 363 EP - 74 JF - Journal of Alzheimer's disease : JAD JO - J Alzheimers Dis VL - 24 IS - 2 N2 - AZD3480 is a selective agonist of the central α4β2 and α2β2 neuronal nicotinic cholinergic receptors (NNRs). Its effects on cognition were investigated in 567 patients with mild-to-moderate Alzheimer's disease (AD) (Mini Mental State Examination [MMSE] 12-26). Mean baseline MMSE was 21 (SD ± 3.7), with 61% of patients having mild disease (MMSE 21-26). Mean age was 74 (range 58-85) 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 25-26) 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 α4β2 receptors with NNRs in AD patients. SN - 1875-8908 UR - https://www.unboundmedicine.com/medline/citation/21258153/Effects_of_AZD3480_on_cognition_in_patients_with_mild_to_moderate_Alzheimer's_disease:_a_phase_IIb_dose_finding_study_ L2 - https://content.iospress.com/openurl?genre=article&id=doi:10.3233/JAD-2011-101554 DB - PRIME DP - Unbound Medicine ER -