Adaptive, dose-finding phase 2 trial evaluating the safety and efficacy of ABT-089 in mild to moderate Alzheimer disease.

Abstract

ABT-089, an α4β2 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.

• Authors: 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
• Journal: Alzheimer disease and associated disorders (Alzheimer Dis Assoc Disord) 2015 Jul-Sep Vol. 29 Issue 3 Pg. 192-9 ISSN: 1546-4156 [Electronic] United States
• PMID: 25973909 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Cholinesterase Inhibitors
• Pyridines
• Pyrrolidines
• pozanicline

Topics

• Aged
• Aged, 80 and over
• Alzheimer Disease (diagnosis, drug therapy)
• Bayes Theorem
• Cholinesterase Inhibitors (administration & dosage, therapeutic use)
• Cognition (drug effects)
• Double-Blind Method
• Female
• Humans
• Male
• Middle Aged
• Pyridines (administration & dosage, therapeutic use)
• Pyrrolidines (administration & dosage, therapeutic use)
• Treatment Outcome