title: 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.affiliation: *AbbVie Inc., North Chicago, IL †Berry Consultants, LLC, Austin, TX ‡MD Anderson Cancer Center, University of Texas, Houston, TX §Division of Neurology, Nova Southeastern University, Fort Lauderdale, FL ∥Palm Beach Neurology, West Palm Beach, FL, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Lenz
authors.forename: Yili L
authors.initials: YL
authors.lastname: Pritchett
authors.forename: Scott M
authors.initials: SM
authors.lastname: Berry
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Llano
authors.forename: Shu
authors.initials: S
authors.lastname: Han
authors.forename: Donald A
authors.initials: DA
authors.lastname: Berry
authors.forename: Carl H
authors.initials: CH
authors.lastname: Sadowsky
authors.forename: Walid M
authors.initials: WM
authors.lastname: Abi-Saab
authors.forename: Mario D
authors.initials: MD
authors.lastname: Saltarelli
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis / Q000188:drug therapy*; D001499:Bayes Theorem; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D003071:Cognition / Q000187:drug effects*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011725:Pyridines / Q000008:administration & dosage / Q000627:therapeutic use*; D011759:Pyrrolidines / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D002800:Cholinesterase Inhibitors; D011725:Pyridines; D011759:Pyrrolidines; C108326:pozanicline