Predictors of Placebo Group Decline in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) in 24 Week Clinical Trials of Alzheimer's Disease

Article type: Research Article

Authors: Irizarry, Michael C.^{a; *} | Webb, David J.^{a; e} | Bains, Chanchal^{a; e} | Barrett, Steven J.^{b; e} | Lai, Robert Y.^{c; e} | Laroche, Janette P.^{d; e} | Hosford, David^{d; e; 1} | Maher-Edwards, Gareth^{d; e} | Weil, John G.^{a; e}

Affiliations: [a] WW Epidemiology, GlaxoSmithKline, Harlow, UK | [b] Discovery Analytics, GlaxoSmithKline, Harlow, UK | [c] Neurology Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, UK | [d] Neurosciences Medicine Development, GlaxoSmithKline, Harlow, UK | [e] Research Triangle Park, NC, US

Correspondence: [*] Corresponding author: Michael C. Irizarry, GlaxoSmithKline, 5 Moore Drive, 17.2123, Research Triangle Park, NC 27709, USA. Tel.: +1 919 483 7701; Fax: +1 919 315 4947; E-mail: michael.c.irizarry@gsk.com.

Note: [1] Current affiliation: Targacept, 200 East First Street, Suite 300, Winston-Salem, NC.

Abstract: One limitation of several recent 24 week Alzheimer's disease (AD) clinical trials was the lack of cognitive decline detected by the AD Assessment Scale-cognitive subscale (ADAS-cog) in the placebo groups, possibly obscuring true medication effects. Data from 733 individuals in the placebo arms of six AD clinical trials performed 1996–1997 were pooled to examine the relationship of clinical, demographic, and genetic characteristics with the 24 week change in ADAS-cog. Baseline cognitive and functional status and the screening-to-baseline change in ADAS-cog were the strongest independent predictors of the 24 week change in ADAS-cog. The ADAS-cog did not detect progression in patients with mild dementia (screening Mini-Mental State Exam, MMSE, ⩾20). The change in ADAS-cog from screening to baseline was inversely correlated with the 24 week change score; it was more difficult to detect cognitive decline at 24 weeks if individuals markedly worsened from screening to baseline. The effects of baseline MMSE and screening-to-baseline change in ADAS-cog generalized to the placebo group (N=106) of another AD study performed in 2004–2005. Overcoming lack of placebo decline in AD clinical trials will require scales more sensitive to cognitive decline in mild AD and strategies to reduce within-person variability in outcome measures.

Keywords: ADAS-cog, Alzheimer's disease, clinical trials, MMSE, rosiglitazone

DOI: 10.3233/JAD-2008-14304

Journal: Journal of Alzheimer's Disease, vol. 14, no. 3, pp. 301-311, 2008