Adaptive, Dose-finding Phase 2 Trial Evaluating the Safety and Efficacy of ABT-089 in Mild to Moderate Alzheimer Disease

Robert A. Lenz, Yili L. Pritchett, Scott M. Berry, Daniel A. Llano, Shu Han, Donald A. Berry, Carl H. Sadowsky, Walid M. Abi-Saab, Mario D. Saltarelli

Research output: Contribution to journalArticle

Abstract

ABT-089, an α 4 β 2 neuronal nicotinic receptor partial agonist, was evaluated for efficacy and safety in mild to moderate Alzheimer disease patients receiving stable doses of acetylcholinesterase inhibitors. This phase 2 double-blind, placebo-controlled, proof-of-concept, and dose-finding study adaptively randomized patients to receive ABT-089 (5, 10, 15, 20, 30, or 35 mg once daily) or placebo for 12 weeks. The primary efficacy endpoint was the Alzheimer's Disease Assessment Scale, cognition subscale (ADAS-Cog) total score. A Bayesian response-adaptive randomization algorithm dynamically assigned allocation probabilities based on interim ADAS-Cog total scores. A normal dynamic linear model for dose-response relationships and a longitudinal model for predicting final ADAS-cog score were employed in the algorithm. Stopping criteria for futility or success were defined. The futility stopping criterion was met, terminating the study with 337 patients randomized. No dose-response relationship was observed and no dose demonstrated statistically significant improvement over placebo on ADAS-Cog or any secondary endpoint. ABT-089 was well tolerated at all dose levels. When administered as adjunctive therapy to acetylcholinesterase inhibitors, ABT-089 was not efficacious in mild to moderate Alzheimer disease. The adaptive study design enabled the examination of a broad dose range, enabled rapid determination of futility, and reduced patient exposure to nonefficacious doses of the investigational compound.

Original languageEnglish (US)
Pages (from-to)192-199
Number of pages8
JournalAlzheimer Disease and Associated Disorders
Volume29
Issue number3
DOIs
StatePublished - Sep 7 2015

Keywords

  • Alzheimer disease
  • adaptive trial design
  • neuronal nicotinic receptor
  • partial agonist

ASJC Scopus subject areas

  • Clinical Psychology
  • Gerontology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

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    Lenz, R. A., Pritchett, Y. L., Berry, S. M., Llano, D. A., Han, S., Berry, D. A., Sadowsky, C. H., Abi-Saab, W. M., & Saltarelli, M. D. (2015). Adaptive, Dose-finding Phase 2 Trial Evaluating the Safety and Efficacy of ABT-089 in Mild to Moderate Alzheimer Disease. Alzheimer Disease and Associated Disorders, 29(3), 192-199. https://doi.org/10.1097/WAD.0000000000000093