The DIAN-TU Next Generation Alzheimer's prevention trial: Adaptive design and disease progression model

Randall J Bateman, Tammie L Benzinger, Scott Berry, David B Clifford, Cynthia Duggan, Anne M Fagan, Kathleen Fanning, Martin R Farlow, Jason Hassenstab, Eric M McDade, Susan Mills, Katrina Paumier, Melanie Quintana, Stephen P Salloway, Anna Santacruz, Lon S Schneider, Guoqiao Wang, Chengjie Xiong, DIAN-TU Pharma Consortium for the Dominantly Inherited Alzheimer Network, Randall J Bateman, Tammie L Benzinger, Scott Berry, David B Clifford, Cynthia Duggan, Anne M Fagan, Kathleen Fanning, Martin R Farlow, Jason Hassenstab, Eric M McDade, Susan Mills, Katrina Paumier, Melanie Quintana, Stephen P Salloway, Anna Santacruz, Lon S Schneider, Guoqiao Wang, Chengjie Xiong, DIAN-TU Pharma Consortium for the Dominantly Inherited Alzheimer Network

Abstract

Introduction: The Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) trial is an adaptive platform trial testing multiple drugs to slow or prevent the progression of Alzheimer's disease in autosomal dominant Alzheimer's disease (ADAD) families. With completion of enrollment of the first two drug arms, the DIAN-TU now plans to add new drugs to the platform, designated as the Next Generation (NexGen) prevention trial.

Methods: In collaboration with ADAD families, philanthropic organizations, academic leaders, the DIAN-TU Pharma Consortium, the National Institutes of Health, and regulatory colleagues, the DIAN-TU developed innovative clinical study designs for the DIAN-TU NexGen prevention trial.

Results: Our expanded trial toolbox consists of a disease progression model for ADAD, primary end point DIAN-TU cognitive performance composite, biomarker development, self-administered cognitive assessments, adaptive dose adjustments, and blinded data collection through the last participant completion.

Conclusion: These steps represent elements to improve efficacy of the adaptive platform trial and a continued effort to optimize prevention and treatment trials in ADAD.

Keywords: Adaptive clinical trial; Alzheimer's disease; Alzheimer's prevention trial; Amyloid; Autosomal dominant Alzheimer's disease; Biomarkers; Cognitive composite; DIAN-TU; Disease progression model; Dose adjustment; Tau.

Copyright © 2016 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1
Figure 1
Existing and proposed structure of the DIAN-TU trial platform including the Next Generation Prevention Trial. Pink indicates enrollment of the first two arms, pink and green the biomarker phase, and green denotes graduation to a cognitive endpoint. In this article we describe design considerations for the two NexGen arms including proposed interim analyses based on biomarkers and performance on the DIAN-TU cognitive composite.
Figure 2
Figure 2
Current and possible future DIAN-TU and DIAN Observational study sites. The trial is active at 26 sites in 7 countries.
Figure 3
Figure 3
DIAN-TU Cognitive Composite performance by estimated year to symptom onset in Mutation Carriers (red, n=223) and Non-Carriers (black, n=142) from the DIAN Observational Study Data Freeze 9. The four components of the test include Logical Memory Delayed Recall, DIAN Word List Test (comparable to International Shopping List Test used in DIAN-TU), Digit Symbol Coding and MMSE.
Figure 4
Figure 4
Longitudinal and Cross-Sectional Cognitive Performance in Mutation Carriers. Disease progression modeling demonstrating the dramatic improvement in variance for cognitive decline (right panel) after accounting for subject level EYO and subject level baseline cognitive performance.
Figure 5
Figure 5
Proportional hypothetical treatment effects yield different absolute changes depending on EYO. The red line represents the natural (i.e. placebo) rate of cognitive decline across EYO. The colored lines illustrate different levels of slowing disease progression based on drug effect across EYO.

Source: PubMed

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