ORIGINAL ARTICLE Adaptive, Dose-finding Phase 2 Trial Evaluating the Safety and Efficacy of ABT-089 in Mild to Moderate Alzheimer Disease Robert A. Lenz, MD, PhD,* Yili L. Pritchett, PhD,* Scott M. Berry, PhD,w Daniel A. Llano, MD, PhD,* Shu Han, PhD,* Donald A. Berry, PhD,wz Carl H. Sadowsky, MD,y8 Walid M. Abi-Saab, MD,* and Mario D. Saltarelli, MD, PhD* concept, and dose-finding study adaptively randomized patients to Abstract: ABT-089, an a4b2 neuronal nicotinic receptor partial ago- receive ABT-089 (5, 10, 15, 20, 30, or 35 mg once daily) or placebo for nist, was evaluated for efficacy and safety in mild to moderate Alz- 12 weeks. The primary efficacy endpoint was the Alzheimer’s Disease heimer disease patients receiving stable doses of acetylcholinesterase Assessment Scale, cognition subscale (ADAS-Cog) total score. A inhibitors. This phase 2 double-blind, placebo-controlled, proof-of- 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 Received for publication June 26, 2014; accepted January 30, 2015. and a longitudinal model for predicting final ADAS-cog score were From the *AbbVie Inc., North Chicago, IL; wBerry Consultants, LLC, Austin, TX; zMD Anderson Cancer Center, University of Texas, employed in the algorithm. Stopping criteria for futility or success were Houston, TX; yDivision of Neurology, Nova Southeastern defined. The futility stopping criterion was met, terminating the study University, Fort Lauderdale, FL; and 8Palm Beach Neurology, with 337 patients randomized. No dose-response relationship was West Palm Beach, FL, USA. observed and no dose demonstrated statistically significant improve- Present address: Robert A. Lenz, MD, PhD, Amgen, Thousand Oaks, ment over placebo on ADAS-Cog or any secondary endpoint. ABT- CA. 089 was well tolerated at all dose levels. When administered as Present address: Yili L. Pritchett, PhD, Astellas Pharma Global Develop- adjunctive therapy to acetylcholinesterase inhibitors, ABT-089 was not ment Inc., Northbrook, IL. efficacious in mild to moderate Alzheimer disease. The adaptive study Present address: Daniel A. Llano, MD, PhD, Beckman Institute, University of Illinois, Urbana, IL. design enabled the examination of a broad dose range, enabled rapid Present address: Shu Han, PhD, Hospira Inc., Lake Forest, IL. determination of futility, and reduced patient exposure to noneffica- Present address: Walid M. Abi-Saab, MD, Shire AG, Nyon, cious doses of the investigational compound. Switzerland. Present address: Mario D. Saltarelli, MD, PhD, Mallinckrodt Phar- Key Words: Alzheimer disease, neuronal nicotinic receptor, partial maceuticals, Hazelwood, MO. agonist, adaptive trial design Supported by AbbVie Inc. (CT.gov registry number: NCT00555204; http:// clinicaltrials.gov/ct2/show/NCT00555204? term = m06-876&rank = 2). (Alzheimer Dis Assoc Disord 2015;29:192–199) AbbVie was involved in the study design, collection, and interpretation of data, and writing, reviewing, and approving the publication. R.A.L. is a former employee of Abbott (now AbbVie) and holds AbbVie stock. Y.L.P. is a former employee of Abbott (now Abb- Vie), and holds AbbVie stock. S.M.B. is the President and coowner lzheimer disease (AD) is a progressive, neuro- of Berry Consultants, LLC. Berry Consultants, LLC, consults with degenerative disorder that accounts for 60% to 70% of AbbVie and other pharmaceutical and medical device companies A 1 regarding the design of clinical trials. D.A.L. is a former employee progressive cognitive impairment in the elderly. Because of of Abbott (now AbbVie). S.H. is a former employee of Abbott (now the modest efficacy of available treatments, much attention AbbVie) and holds AbbVie stock. D.A.B. is a member of the has been focused on developing better AD medications. University of Texas MD Anderson Cancer Center and is coowner However, these endeavors have resulted in more failures of Berry Consultants, LLC. Berry Consultants, LLC, consults with AbbVie and other pharmaceutical and medical device companies than successes, and no new therapies have been approved regarding the design of clinical trials. C.H.S. has participated on for AD since 2003. Numerous recent clinical failures in AD speaker bureaus for Novartis, Forest Laboratories, and Accera. He have led some companies to abandon pursuit of treatments is also a member of the Pharmaceutical Advisory Board for Eli Lilly for this indication.2 Novel trial designs to aid in the and the Scientific Advisory Board for the Alzheimer’s Drug Dis- covery Foundation. He received payment from Abbott (now development of AD agents are therefore needed. AbbVie) as an investigator in the trial. W.M.A.-S. is a former Among the reasons for failed AD trials is ineffective employee of Abbott (now AbbVie), and is currently employed by trial design and execution, often resulting in inadequate Shire AG. He holds equity in AbbVie, Novartis, Pfizer, and Shire evaluation of a drug’s full dose range.3,4 Adaptive trial and is an AbbVie patent holder. M.D.S. is a former employee of Abbott (now AbbVie), Shire, and Pfizer. He is currently employed designs that use accumulating data to continuously modify by Mallinckrodt Pharmaceuticals and receives various forms of specific trial aspects offer particular advantages over tra- compensation from Mallinckrodt. M.D.S. holds equity in AbbVie ditional, resource-intensive, often inefficient phase 2 trials. and Mallinckrodt, and is an inventor on AbbVie and Pfizer patents. Predefined decision rules and frequent interim efficacy Reprints: Robert A. Lenz, MD, PhD, One Amgen Center Drive, Mail Stop 38-2-B, Thousand Oaks, CA 91320 (e-mail: robertlenz00@ evaluations can efficiently assess success and failure. gmail.com). Response-adaptive randomization uses interim data to Supplemental Digital Content is available for this article. Direct URL allocate patients to more informative treatment arms, citations appear in the printed text and are provided in the HTML allowing efficient evaluation of a wide range of doses.5,6 and PDF versions of this article on the journal’s Website, www.alzheimerjournal.com. Employing these tools can achieve proof-of-concept (POC) Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. and determine an effective dose range in a single trial. 192 | www.alzheimerjournal.com Alzheimer Dis Assoc Disord Volume 29, Number 3, July–September 2015 Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. Alzheimer Dis Assoc Disord Volume 29, Number 3, July–September 2015 Adaptive, Dose-finding Phase 2 Trial of ABT-089 ABT-089 is a partial agonist of the a4b2 neuronal randomized (after 12 interim adaptive calculations). This nicotinic receptor (NNR).7 Multiple pharmacologically and adjustment was made based on the recommendation of the functionally distinct NNR subtypes mediate the broad Data Monitoring Committee and was due to the higher range of effects of nicotine.8–11 Several preclinical and than usual placebo response seen in the first 12 interim clinical studies have demonstrated that NNR agonists, efficacy evaluations. Given the observations in the first 12 including a4b2 NNR agonists, improve cognitive perform- interim assessments, the Data Monitoring Committee sug- ance.12–14 Given the loss of cholinergic afferent terminals gested that increasing the sample size of the placebo group characteristic of the progression of AD, it was predicted could result in a more precise estimate of the mean change that the administration of an agonist at a4b2 receptors in the ADAS-Cog total score for placebo-treated patients would provide benefit above that seen with acetylcholines- and therefore a more precise estimation of treatment effect. terase inhibitors (AChEIs) alone. The current study was The sponsor was not involved in or informed of this deci- designed to assess the safety and efficacy of ABT-089 in sion. A normal dynamic linear model (NDLM) was used to broad dose range in patients with mild to moderate AD as guide the estimation of the dose-response relationship an adjunctive agent to donepezil. It is a POC study as well among dose groups.16 The NDLM was used because it is as a dose-finding study. To gain efficacy, response-adaptive flexible enough to capture both monotonic and non- randomization design was utilized. monotonic dose-response relationships. The objective of the adaptive algorithm was to identify METHODS the ED90 (lowest dose of ABT-089 that resulted in 90% of the maximal effect compared with placebo) and the minimum Standard Protocol Approvals, Registrations, and effective dose (MED; lowest dose of ABT-089 that resulted in Patient Consent at least a 1.75-point ADAS-Cog improvement over placebo in The study protocol was approved by the independent mean change from baseline). The reason for choosing a 1.75- ethics committee or institutional review board at each study point improvement as the minimum clinically meaningful site, and the study was conducted in accordance with the difference was that this amount was considered to be 75% of ethical principles that have their origin in the Declaration of the monotherapy effect of donepezil on mild to moderate AD Helsinki.15 All patients (or their legally acceptable repre- patients, which is approximately 2.33 units on the ADAS-Cog sentatives) provided written informed consent. Clinical trial total score as reported by the Cochrane Collaboration registration (clinicaltrials.gov): NCT00555204. (2006).17 As an adjunctive therapy, it was estimated that the effectofABT-089wouldbeless,andwasestimatedtobe75% Study Design of the effect of donepezil alone. Stopping criteria were assessed This was a phase 2, randomized, double-blind, pla- once 150 patients were randomized, and at each subsequent cebo-controlled, multicenter (41 US sites) study using a biweekly interim analysis. Biweekly interims are operationally Bayesian response-adaptive randomization design5,6 con- easy to implement, as opposed to subject thresholds, with no ducted from November 2007 to June 2009. Subjects were on loss in efficiency.