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

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.

Rosiglitazone Does Not Improve Cognition or Global Function when Used as Adjunctive Therapy to AChE Inhibitors in Mild-to-Moderate Alzheimers Disease: Two Phase 3 Studies

“…Although mean ADAS-Cog values in the placebo groups in the current studies declined over time, the magnitude of the decline was less than reported in historical studies in this population [42][43][44]. The challenges and potential limitations of current assays for measuring cognitive changes have been explored as significant limitations in several clinical investigations in mild-to-moderate disease [45,46]. Furthermore, the ADAS-Cog was developed to test efficacy of AChEIs in subjects with AD, and although widely used to assess the efficacy of therapies with other mechanisms of action, inherent limitations should be considered.…”

Rosiglitazone Monotherapy in Mild-to-Moderate Alzheimer’s Disease: Results from a Randomized, Double-Blind, Placebo-Controlled Phase III Study

“…The limitations of this study include those inherent in investigations of AD: a limitation on treatment duration for a placebo-controlled study in a significantly ill population [36] ; variability in AD progression [56] , and the use of assessment tools that may be inadequate for detecting drugs with a modest treatment effect in a mildto-moderate AD population [46,57] . The ADAS-Cog was chosen as an assessment in this study, based on published outcomes for the active control donepezil, and on its widespread use in evaluating new therapies for AD.…”

“…The ADAS-Cog may be more sensitive to disease progression and treatment effects in moderate versus mild AD [46] , and a post hoc analysis was performed to analyze whether treatment effects in this study differed by baseline MMSE scores (i.e. in subjects with moderate versus mild AD).…”

Altered lysosomal proteins in neural-derived plasma exosomes in preclinical Alzheimer disease

“…7,8 Those with probable AD and mild to moderate dementia were diagnosed by Dubois criteria 11 Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Assessment Scale-cognitive subscale were conducted as described. 12,13 Twenty-four of the 26 cross-sectional patients with AD were taking an acetyl-cholinesterase inhibitor and/or memantine, and 5 were on antidepressant medications.…”