Richard E Kennedy1, Gary R Cutter2, Lon S Schneider3. 1. University of Alabama, Birmingham, Birmingham, AL, USA. Electronic address: rekenned@mail.ad.uab.edu. 2. University of Alabama, Birmingham, Birmingham, AL, USA. 3. University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
Abstract
BACKGROUND: The apolipoprotein E (APOE) ε4 genotype has been recommended as a potential inclusion or exclusion criterion in targeted clinical trials for Alzheimer's disease (AD) and mild cognitive impairment (MCI) resulting from AD, and has been implemented in trials of immunotherapeutic agents. METHODS: We tested this recommendation with clinical trial simulations using participants from a meta-database of 19 studies to create trial samples with APOE ε4 proportions ranging from 0% (all noncarriers) to 100% (all carriers). For each percentage of APOE ε4 carriers, we resampled the database randomly for 1000 trials for each trial scenario, planning for 18- or 24-month trials with samples from 50 to 400 patients per treatment or placebo group, up to 40% dropouts, and outcomes on the Alzheimer's Disease Assessment Scale, cognitive subscale (ADAS-cog) with effect sizes from 0.15 to 0.75, and calculated statistical power. RESULTS: Enrichment of clinical trial participants based on APOE ε4 carrier status resulted in minimal increases in power compared with enrolling participants with the APOE ε3 genotype only or enrolling patients without regard to APOE genotype. Increased screening requirements to enhance the sample would offset gains in power. CONCLUSIONS: Although samples enriched for APOE ε4 carriers in AD or MCI clinical trials showed slightly more cognitive impairment and greater decline using the number APOE ε4 alleles as an inclusion criterion most likely would not result in more efficient trials, and trials would take longer because fewer patients would be available. The APOE ε4/εX (where X = 2, 3 or 4) genotype could be useful, however, as an explanatory variable or covariate if warranted by a drug's action.
BACKGROUND: The apolipoprotein E (APOE) ε4 genotype has been recommended as a potential inclusion or exclusion criterion in targeted clinical trials for Alzheimer's disease (AD) and mild cognitive impairment (MCI) resulting from AD, and has been implemented in trials of immunotherapeutic agents. METHODS: We tested this recommendation with clinical trial simulations using participants from a meta-database of 19 studies to create trial samples with APOE ε4 proportions ranging from 0% (all noncarriers) to 100% (all carriers). For each percentage of APOE ε4 carriers, we resampled the database randomly for 1000 trials for each trial scenario, planning for 18- or 24-month trials with samples from 50 to 400 patients per treatment or placebo group, up to 40% dropouts, and outcomes on the Alzheimer's Disease Assessment Scale, cognitive subscale (ADAS-cog) with effect sizes from 0.15 to 0.75, and calculated statistical power. RESULTS: Enrichment of clinical trial participants based on APOE ε4 carrier status resulted in minimal increases in power compared with enrolling participants with the APOE ε3 genotype only or enrolling patients without regard to APOE genotype. Increased screening requirements to enhance the sample would offset gains in power. CONCLUSIONS: Although samples enriched for APOE ε4 carriers in AD or MCI clinical trials showed slightly more cognitive impairment and greater decline using the number APOE ε4 alleles as an inclusion criterion most likely would not result in more efficient trials, and trials would take longer because fewer patients would be available. The APOE ε4/εX (where X = 2, 3 or 4) genotype could be useful, however, as an explanatory variable or covariate if warranted by a drug's action.
Authors: Shannon L Risacher; Li Shen; John D West; Sungeun Kim; Brenna C McDonald; Laurel A Beckett; Danielle J Harvey; Clifford R Jack; Michael W Weiner; Andrew J Saykin Journal: Neurobiol Aging Date: 2010-08 Impact factor: 4.673
Authors: Dan Mungas; Laurel Beckett; Danielle Harvey; Sarah Tomaszewski Farias; Bruce Reed; Owen Carmichael; John Olichney; Joshua Miller; Charles DeCarli Journal: Psychol Aging Date: 2010-09
Authors: Adam S Fleisher; Kewei Chen; Xiaofen Liu; Napatkamon Ayutyanont; Auttawut Roontiva; Pradeep Thiyyagura; Hillary Protas; Abhinay D Joshi; Marwan Sabbagh; Carl H Sadowsky; Reisa A Sperling; Christopher M Clark; Mark A Mintun; Michael J Pontecorvo; R Edward Coleman; P M Doraiswamy; Keith A Johnson; Alan P Carpenter; Daniel M Skovronsky; Eric M Reiman Journal: Neurobiol Aging Date: 2012-05-24 Impact factor: 4.673
Authors: T Tokuda; M Calero; E Matsubara; R Vidal; A Kumar; B Permanne; B Zlokovic; J D Smith; M J Ladu; A Rostagno; B Frangione; J Ghiso Journal: Biochem J Date: 2000-06-01 Impact factor: 3.857
Authors: J Aerssens; P Raeymaekers; S Lilienfeld; H Geerts; F Konings; W Parys Journal: Dement Geriatr Cogn Disord Date: 2001 Mar-Apr Impact factor: 2.959
Authors: Mackenzie E Fowler; Kristen L Triebel; Gary R Cutter; Lon S Schneider; Richard E Kennedy Journal: J Alzheimers Dis Date: 2020 Impact factor: 4.472
Authors: Christina M Lill; Aina Rengmark; Lasse Pihlstrøm; Isabella Fogh; Aleksey Shatunov; Patrick M Sleiman; Li-San Wang; Tian Liu; Christina F Lassen; Esther Meissner; Panos Alexopoulos; Andrea Calvo; Adriano Chio; Nil Dizdar; Frank Faltraco; Lars Forsgren; Julia Kirchheiner; Alexander Kurz; Jan P Larsen; Maria Liebsch; Jan Linder; Karen E Morrison; Hans Nissbrandt; Markus Otto; Jens Pahnke; Amanda Partch; Gabriella Restagno; Dan Rujescu; Cathrin Schnack; Christopher E Shaw; Pamela J Shaw; Hayrettin Tumani; Ole-Bjørn Tysnes; Otto Valladares; Vincenzo Silani; Leonard H van den Berg; Wouter van Rheenen; Jan H Veldink; Ulman Lindenberger; Elisabeth Steinhagen-Thiessen; Stefan Teipel; Robert Perneczky; Hakon Hakonarson; Harald Hampel; Christine A F von Arnim; Jørgen H Olsen; Vivianna M Van Deerlin; Ammar Al-Chalabi; Mathias Toft; Beate Ritz; Lars Bertram Journal: Alzheimers Dement Date: 2015-04-30 Impact factor: 21.566