Alzheimer's disease progression model using disability assessment for dementia scores from bapineuzumab trials

Abstract

Objective: Disability assessment for dementia (DAD) measurements from two phase-3 studies of bapineuzumab in APOE ε4 noncarrier and carrier Alzheimer's disease (AD) patients were integrated to develop a disease progression model.

Methods: We evaluated longitudinal changes in DAD scores, baseline factors affecting disease progression, and bapineuzumab effect on disease progression.

Results: A beta regression model best described DAD disease progression. The estimated treatment effect of bapineuzumab was not significant, consistent with lack of clinical efficacy observed in the primary analysis. The model suggested that progression of DAD tended to decrease with increase in bapineuzumab exposure. The exposure-response relationship was similar regardless of APOE ε4 status but more pronounced in patients with mild AD. Baseline disease status, age, memantine use, and years since onset (YSO) had significant effects on baseline DAD scores. AD concomitant medication use, baseline disease status, and YSO had significant effects on disease progression rate, measured by DAD score.

Conclusions: The beta regression model is a sensible modeling approach to characterize functional decline in AD patients. This analysis suggested a possible effect of bapineuzumab exposure on DAD progression. Further evaluation may be warranted in future studies.

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

Keywords: Alzheimer's disease; Bapineuzumab; Disability assessment for dementia; Disease progression model.

Figures

Fig. 1

Exploratory analysis for bapineuzumab treatment effect for studies 301 and 302: observed average (mean) DAD scores versus time. Bapineuzumab was administered as 0.5 or 1.0 mg/kg infused intravenously for 1 hour/13 weeks for six infusions in APOE ε4 noncarrier (study 301) or carrier (study 302) patients with mild-to-moderate AD; vertical error bar represents the standard deviation of the mean DAD scores. Abbreviation: DAD, disability assessment for dementia.

Fig. 2

Exposure-response relationship for bapineuzumab by study and severity of Alzheimer's disease: Observed average (mean) DAD scores versus time. Steady-state AUC is used. Patients treated with bapineuzumab were grouped by median AUC for each study. Abbreviations: DAD, disability assessment for dementia; AUC, area under the serum concentration-time curve.

Fig. 3

(A). Visual predictive check for the beta regression model based on the overall data from studies 301 and 302. The upper, middle, and lower profiles indicated by the open circles represent the 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 prediction for the 95th, 50th, and 5th percentiles, respectively, and these predictions account for missing data. The shaded areas are the 90% confidence intervals of the corresponding percentiles of the simulations based on the model. The beta regression model listed in Table 2 was used for the simulations. (B). Stratified visual predictive check for patients with mild Alzheimer's disease in study 301: exposure-response relationship. The symbols represent the mean of the observed data. The curves indicated by the lines are the mean model-based predictions that account for missing data. The shaded areas are the 90% confidence intervals of the corresponding predictions based on the model. The beta regression model listed in Table 2 was used for the simulations. Abbreviations: DAD, disability assessment for dementia; AUC, area under the serum concentration-time curve .

Fig. S1

Stratified visual predictive check for patients with mild Alzheimer's disease in studies 301 and 302: bapineuzumab versus placebo. Abbreviation: DAD, disability assessment for dementia. The symbols represent the mean of the observed data. The curves indicated by the lines are the mean model-based predictions that account for missing data. The shaded areas are the 90% confidence intervals of the corresponding predictions based on the model. The beta regression model listed in Table 2 was used for the simulations.

Fig. S2

Stratified visual predictive check for patients with moderate Alzheimer's disease in studies 301 and 302: bapineuzumab versus placebo. Abbreviation: DAD, disability assessment for dementia. The symbols represent the mean of the observed data. The curves indicated by the lines are the mean model-based predictions that account for missing data. The shaded areas are the 90% confidence intervals of the corresponding predictions based on the model. The beta regression model listed in Table 2 was used for the simulations.