Lenz Robert A, Pritchett Yili L, Berry Scott M, Llano Daniel A, Han Shu, Berry Donald A, Sadowsky Carl H, Abi-Saab Walid M, Saltarelli Mario D
*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.
Alzheimer Dis Assoc Disord. 2015 Jul-Sep;29(3):192-9. doi: 10.1097/WAD.0000000000000093.
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.
ABT-089是一种α4β2神经元烟碱受体部分激动剂，在接受稳定剂量乙酰胆碱酯酶抑制剂治疗的轻至中度阿尔茨海默病患者中对其疗效和安全性进行了评估。这项2期双盲、安慰剂对照、概念验证和剂量探索研究将患者适应性随机分组，接受ABT-089（5、10、15、20、30或35毫克，每日一次）或安慰剂治疗12周。主要疗效终点是阿尔茨海默病评估量表认知分量表（ADAS-Cog）总分。一种贝叶斯反应适应性随机化算法根据中期ADAS-Cog总分动态分配分配概率。该算法采用了剂量反应关系的正态动态线性模型和预测最终ADAS-Cog分数的纵向模型。定义了无效或成功的停止标准。达到了无效停止标准，337例患者随机分组后研究终止。未观察到剂量反应关系，在ADAS-Cog或任何次要终点上，没有剂量显示出比安慰剂有统计学显著改善。ABT-089在所有剂量水平下耐受性良好。当作为乙酰胆碱酯酶抑制剂的辅助治疗给药时，ABT-089在轻至中度阿尔茨海默病中无效。适应性研究设计能够检查广泛的剂量范围，能够快速确定无效性，并减少患者接触无效剂量的研究化合物。
