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Volume 21, Issue 5
  • ISSN: 1567-2050
  • E-ISSN: 1875-5828

Abstract

Background

Disease progression in Alzheimer’s Dementia (AD) is typically characterized by accelerated cognitive and functional decline, where heterogeneous trajectories can impact the observed treatment response.

Methods

We hypothesized that unobserved heterogeneity could obscure treatment benefits in AD. The effect of unobserved heterogeneity was empirically quantified within the Alzheimer’s Management By Albumin Replacement (AMBAR) phase 2b trial data. The ADAS-Cog 12 cognition endpoint was reanalyzed in a 2-class latent growth mixture model initially fit to the treatment arm. The model with the best fit was then applied across both treatment arms to a larger (n=1000) simulated dataset that was representative of AMBAR trial cognitive data.

Results

Two classes of patients were observed: a stable cognitive trajectory class and a highly variable class. Removal of the latter (n=48, 22%) from the analysis and refitting efficacy models comparing the stable class to full placebo yielded significant treatment efficacy on cognition (=0.007, Cohen’s D=-0.4). Comparison of the stable class of each arm within the simulated dataset revealed a significant difference in treatment efficacy favoring the simulated stable treatment arm.

Conclusion

This post hoc exploratory analysis suggests that prespecified strategies for addressing unobserved heterogeneity may yield improved effect detection in AD trials. The generalizability of the analytic strategy is limited by latent stratification in only the treatment arm, a requirement given the small placebo arm in AMBAR. This limitation was partially addressed by the simulation modeling.

Clinical Trial Registration Number

NCT01561053.

© 2024 Bentham Science Publishers
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Post-Hoc Assessment of Cognitive Efficacy in Alzheimer’s Disease Using a Latent Growth Mixture Model in AMBAR, a Phase 2B Randomized Controlled Trial
Curr Alzheimer Res 21, 353 (2024); https://doi.org/10.2174/0115672050316936240905064215
/content/journals/car/10.2174/0115672050316936240905064215
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  • Article Type:     Research Article
Keyword(s): Alzheimer’s disease; AMBAR; cognition; exploratory analyses; Latent growth mixture model; plasma exchange; unobserved heterogeneity

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