Alzheimer's disease assessment scale-cognitive 11-item progression model in mild-to-moderate Alzheimer's disease trials of bapineuzumab

Abstract

Introduction: The objective of this study was to estimate longitudinal changes in disease progression (measured by Alzheimer's disease assessment scale-cognitive 11-item [ADAS-cog/11] scale) after bapineuzumab treatment and to identify covariates (demographics or baseline characteristics) contributing to the variability in disease progression rate and baseline disease status.

Methods: A population-based disease progression model was developed using pooled placebo and bapineuzumab data from two phase-3 studies in APOE ε4 noncarrier and carrier Alzheimer's disease (AD) patients.

Results: A beta regression model with the Richard's function as the structural component best described ADAS-cog/11 disease progression for mild-to-moderate AD population. This analysis confirmed no effect of bapineuzumab exposure on ADAS-cog/11 progression rate, consistent with the lack of clinical efficacy observed in the statistical analysis of ADAS-cog/11 data in both studies. Assessment of covariates affecting baseline severity revealed that men had a 6% lower baseline ADAS-cog/11 score than women; patients who took two AD concomitant medications had a 19% higher (worse) baseline score; APOE ε4 noncarriers had a 5% lower baseline score; and patients who had AD for a longer duration had a higher baseline score. Furthermore, shorter AD duration, younger age, APOE ε4 carrier status, and use of two AD concomitant medications were associated with faster disease progression rates. Patients who had an ADAS-cog/11 score progression rate that was not statistically significantly different from 0 typically took no AD concomitant medications.

Discussion: The beta regression model is a sensible modeling approach to characterize cognitive decline in AD patients. The influence of bapineuzumab exposure on disease progression measured by ADAS-cog/11 was not significant.

Trial registration: ClinicalTrials.gov identifier: NCT00575055 and NCT00574132.

Keywords: ADAS-cog/11; Alzheimer's disease; Bapineuzumab; Disease progression model.

Figures

Fig. 1

Overview of model building process. Abbreviations: GAM, generalized additive modeling; VPC, visual predictive check.

Fig. 2

Results of the exploratory placebo covariate analysis. Two Alzheimer's disease concomitant medications: acetylcholinesterase inhibitors and memantine; one Alzheimer's disease concomitant medication: acetylcholinesterase inhibitors alone or memantine alone. Responses are scaled to a 0–1 range for data analysis but for plotting the graphical results are back transformed to present the model performance on the original scale. Abbreviations: ADAS-cog/11, Alzheimer's disease assessment scale-cognitive 11-item; AD, Alzheimer's disease; APOE ε4, apolipoprotein E, ε4 allele; CI, confidence interval; MMSE, mini-mental state examination.

Fig. 3

Stratified visual predictive checks: bapineuzumab versus placebo. The upper, middle, and lower profiles indicated by the open circles represent 95th, 50th, and 5th percentiles of the observed data, respectively. The upper, middle, and lower curves indicated by the lines are the median model–based predictions for 95th, 50th, and 5th percentiles, respectively, and these predictions account for missing data. The shaded areas are 90% confidence intervals of the corresponding percentiles of the simulations based on the model. To allow stratification by baseline disease status (mild AD vs. moderate AD), baseline ADAS-cog/11 scores were resampled from the observed scores at time 0 in the respective populations from the PK/PD database. The number of observations at 0, 13, 26, 39, 52, 65, and 78 wk were 2451, 2331, 2215, 2093, 1989, 1870, and 1808 and thus 74% of patients (1808/2451) completed the study. Seventy-four years (age) and 2.8 y (duration of AD) used as cutoffs in the figures represents the median. Abbreviations: ADAS-cog/11, Alzheimer's disease assessment scale-cognitive 11-item; AD, Alzheimer's disease; CI, confidence interval; PK/PD, pharmacokinetic/pharmacodynamic.