Phase 2 and 3 clinical trials in Alzheimer disease (AD) and mild cognitive impairment (MCI) have been generally unsuccessful over the past decades. Efficacy mainly has been demonstrated in trials of 6 months or less, only with cholinesterase inhibitors for mild AD, and not in MCI or longer-term trials. Recent therapies based on the neuropathology of AD have not demonstrated efficacy in 18 month trials. Although this may reflect lack of knowledge of the biological targets and consequently the testing of ineffective drugs, it also reflects inadequacies of trials methods such that a modestly effective drug - if tested - may likely not be recognized as effective. In particular, the trials appear to choose patient samples based on assumptions about desired characteristics and outcomes that may not be valid because they are based on selected experiences from previous individual trials, further raising questions about design and validity. This project's broad, long-term objectives are to develop rational bases for designing pilot and phase 2 trials based on systematic evaluation of previous trials and testing design features prospectively. A broader goal is to encourage, complement, and accelerate the process of testing new and innovative treatments by providing models and simulations for clinical trials methods and designs. The research design and methods for achieving the objectives involves integrating patient data from 14 clinical trials and studies from the NIA's ADCS and ADNI over the last decade - including over 5200 followed from 1 to 4 years - into a common database. This allows for prospective analyses using hypothesis-based statistical techniques including simulations to better understand design parameters, outcomes, and to design better and more clinically relevant trials that would have the ability to detect change. The ADCS studies have inherent similarities that allow for combining, including common data base structures, outcomes, sites, training, and procedures. An expert steering committee formulates guiding principles and hypothesis-based research plans. Specific protocols address issues such as selection criteria, predictors of decline, and simulations to assess new trials designs. For example, we will examine the effects on outcomes of selecting patients for trials based on concomitant medication or severity using regression estimates and regression to the mean adjusted estimates, and follow this with trials simulations to empirically test validity and to plan future trials. Results of this research will have broad and lasting impact on trials designs in this therapeutic area, and especially on early phase trials in that designs can be tested and refined prior to implementing trials. The project is highly innovative in that it provides new approaches in this research area to examine the underlying patient data from numerous studies, and takes advantage of the rich database to empirically probe the assumptions under which current trials have been instigated. This will lead to improvement in trials methods and increase the likelihood for identifying effective treatments earlier in development.

Public Health Relevance

The results of this research will have a broad and lasting impact on trial designs for Alzheimer disease, mild cognitive impairment, and neurodegenerative disorders, and trials in which cognitive improvement is a targeted outcome. It will address important issues in the assumptions underlying the design decisions. This will lead to better understanding and improvement in the methods for future clinical trials and improve the likelihood for identifying effective treatments, as well as identifying ineffective treatments earlier in development.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG037561-01A1
Application #
8109764
Study Section
Special Emphasis Panel (ZRG1-BBBP-N (52))
Program Officer
Ryan, Laurie M
Project Start
2011-04-01
Project End
2014-03-31
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
1
Fiscal Year
2011
Total Cost
$561,235
Indirect Cost
Name
University of Southern California
Department
Psychiatry
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Kennedy, Richard E; Cutter, Gary R; Wang, Guoqiao et al. (2017) Challenging Assumptions About African American Participation in Alzheimer Disease Trials. Am J Geriatr Psychiatry 25:1150-1159
Kennedy, Richard E; Cutter, Gary R; Wang, Guoqiao et al. (2016) Post Hoc Analyses of ApoE Genotype-Defined Subgroups in Clinical Trials. J Alzheimers Dis 50:1205-15
Lo, Alexander X; Rundle, Andrew G; Buys, David et al. (2016) Neighborhood Disadvantage and Life-Space Mobility Are Associated with Incident Falls in Community-Dwelling Older Adults. J Am Geriatr Soc 64:2218-2225
McCaskill, Gina M; Sawyer, Patricia; Burgio, Kathryn L et al. (2015) The Impact of Veteran Status on Life-Space Mobility among Older Black and White Men in the Deep South. Ethn Dis 25:255-62
Schneider, Lon S; Kennedy, Richard E; Wang, Guoqiao et al. (2015) Differences in Alzheimer disease clinical trial outcomes based on age of the participants. Neurology 84:1121-7
Kennedy, Richard E; Cutter, Gary R; Wang, Guoqiao et al. (2015) Using baseline cognitive severity for enriching Alzheimer's disease clinical trials: How does Mini-Mental State Examination predict rate of change? Alzheimers Dement (N Y) 1:46-52
Lo, Alexander X; Flood, Kellie L; Kennedy, Richard E et al. (2015) The Association Between Life-Space and Health Care Utilization in Older Adults with Heart Failure. J Gerontol A Biol Sci Med Sci 70:1442-7
Petrov, Megan E; Sawyer, Patricia; Kennedy, Richard et al. (2014) Benzodiazepine (BZD) use in community-dwelling older adults: Longitudinal associations with mobility, functioning, and pain. Arch Gerontol Geriatr 59:331-7
Schneider, Lon S (2014) Rethinking the Food and Drug Administration's 2013 guidance on developing drugs for early-stage Alzheimer's disease. Alzheimers Dement 10:247-50
Solomon, A; Mangialasche, F; Richard, E et al. (2014) Advances in the prevention of Alzheimer's disease and dementia. J Intern Med 275:229-50

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