@article{fe6472b076f845379c870cc2b09c6617,
title = "Impact of potential modifications to Alzheimer{\textquoteright}s disease clinical trials in response to disruption by COVID-19: a simulation study",
abstract = "Background: The COVID-19 pandemic disrupted Alzheimer disease randomized clinical trials (RCTs), forcing investigators to make changes in the conduct of such trials while endeavoring to maintain their validity. Changing ongoing RCTs carries risks for biases and threats to validity. To understand the impact of exigent modifications due to COVID-19, we examined several scenarios in symptomatic and disease modification trials that could be made. Methods: We identified both symptomatic and disease modification Alzheimer disease RCTs as exemplars of those that would be affected by the pandemic and considered the types of changes that sponsors could make to each. We modeled three scenarios for each of the types of trials using existing datasets, adjusting enrollment, follow-ups, and dropouts to examine the potential effects COVID-19-related changes. Simulations were performed that accounted for completion and dropout patterns using linear mixed effects models, modeling time as continuous and categorical. The statistical power of the scenarios was determined. Results: Truncating both symptomatic and disease modification trials led to underpowered trials. By contrast, adapting the trials by extending the treatment period, temporarily stopping treatment, delaying outcomes assessments, and performing remote assessment allowed for increased statistical power nearly to the level originally planned. Discussion: These analyses support the idea that disrupted trials under common scenarios are better continued and extended even in the face of dropouts, treatment disruptions, missing outcomes, and other exigencies and that adaptations can be made that maintain the trials{\textquoteright} validity. We suggest some adaptive methods to do this noting that some changes become under-powered to detect the original effect sizes and expected outcomes. These analyses provide insight to better plan trials that are resilient to unexpected changes to the medical, social, and political milieu.",
keywords = "Alzheimer, COVID-19, Clinical trials, Disease modification, Mild cognitive impairment, Simulations, Symptomatic treatment",
author = "Schneider, {Lon S.} and Yuqi Qiu and Thomas, {Ronald G.} and Carol Evans and Jacobs, {Diane M.} and Shelia Jin and Kaye, {Jeffrey A.} and LaCroix, {Andrea Z.} and Karen Messer and Salmon, {David P.} and Mary Sano and Kimberly Schafer and Feldman, {Howard H.}",
note = "Funding Information: LSS reports grants and personal fees from Eli Lilly, personal fees from Boehringer Ingelheim, grants and personal fees from Merck, personal fees from Neurim, Ltd., personal fees from Cognition, personal fees from Eisai, personal fees from Takeda, personal fees from vTv, grants and personal fees from Roche/Genentech, grants from Biogen, grants from Novartis, grants from Biohaven, grants from Washington Univ/NIA DIAN-TU, personal fees from Samus, personal fees from Novo Nordisk, personal fees from IBC, Ltd., and personal fees from Cortexyme outside the submitted work. Funding Information: The authors wish to acknowledge the ADCS Data and Sample Sharing Committee. LSS reports grants and personal fees from Eli Lilly, personal fees from Boehringer Ingelheim, grants and personal fees from Merck, personal fees from Neurim, Ltd., personal fees from Cognition, personal fees from Eisai, personal fees from Takeda, personal fees from vTv, grants and personal fees from Roche/Genentech, grants from Biogen, grants from Novartis, grants from Biohaven, grants from Washington Univ/NIA DIAN-TU, personal fees from Samus, personal fees from Novo Nordisk, personal fees from IBC, Ltd., and personal fees from Cortexyme outside the submitted work. YQ, KM, CE, DMJ, SJ, AZL, and KS have no disclosures to report. RGT reports personal fees from Biogen. JAK in the last 24 months has been directly compensated for serving on a Data Safety Monitoring Committee for Eli Lilly, the Scientific Advisory Board of Sage Bionetworks, the Roche/Genentech Scientific Advisory Committee for Digital Health Solutions in Alzheimer{\textquoteright}s Disease, and as an external Advisory Committee member for the Rush and Stanford Alzheimer's Disease Research Centers. He has received research support awarded to his institution (Oregon Health & Science University) from the NIH, NSF, the Department of Veterans Affairs, USC Alzheimer{\textquoteright}s Therapeutic Research Institute, Merck, AbbVie, Eisai, Green Valley Pharmaceuticals, and Alector. He receives reimbursement through Medicare or commercial insurance plans for providing clinical assessment and care for patients. He serves on the editorial advisory board and as Associate Editor of the journal, Alzheimer{\textquoteright}s & Dementia and as Associate Editor for the Journal of Translational Engineering in Health and Medicine. DPS reports personal consulting fees from Biogen, Aptinyx, and Takeda. MS has received grants or contracts from NIA and Biohaven consulting fees from Avenir, Biogen Idec, BioXcel, Eisai, Genentech, F. Hoffman LaRoche, Minerva Neuroscience, Novartis, NovoNordisk, Pfizer, Takeda, vTv Therapeutics, Karuna. MS has received support for attending meetings and/or travel for Alzheimer{\textquoteright}s Association activities as a member of the Medical and Scientific Advisory Group (MSAG). MS has participated in a Data Safety Monitoring Board or Advisory Board for Syneos and reports roles as President of the International Psychogeriatric Association and Board Member of the National Association of Veteran Research and Education Foundations. HHF reports UCSD service agreements for consulting services with Axon Neuroscience, Banner Health, Roche/Genentech, Samumed, Samus Therapeutics, Tau Consortium, Novo Nordisk, and Janssen with no personal funds received and payments to UCSD. Clinical trial grant funding to the ADCS at UCSD from Annovis (Posiphen), Biohaven (BH 4157), Vivoryon (PQ 912), AC Immune (ACI-24-1301), and LuMind (ADC-059-LIFE-DSR). Funding Information: This work was supported the UCSD ADCS U19 AG010483, P30 AG062429; USC P30 AG066530, R01 AG057684, R01 AG051346; OHSU P30 AG066518; MSSM P50 AG005138, and P30 AG066514. Funding Information: JAK in the last 24 months has been directly compensated for serving on a Data Safety Monitoring Committee for Eli Lilly, the Scientific Advisory Board of Sage Bionetworks, the Roche/Genentech Scientific Advisory Committee for Digital Health Solutions in Alzheimer{\textquoteright}s Disease, and as an external Advisory Committee member for the Rush and Stanford Alzheimer's Disease Research Centers. He has received research support awarded to his institution (Oregon Health & Science University) from the NIH, NSF, the Department of Veterans Affairs, USC Alzheimer{\textquoteright}s Therapeutic Research Institute, Merck, AbbVie, Eisai, Green Valley Pharmaceuticals, and Alector. He receives reimbursement through Medicare or commercial insurance plans for providing clinical assessment and care for patients. He serves on the editorial advisory board and as Associate Editor of the journal, Alzheimer{\textquoteright}s & Dementia and as Associate Editor for the Journal of Translational Engineering in Health and Medicine. Publisher Copyright: {\textcopyright} 2021, The Author(s).",
year = "2021",
month = dec,
doi = "10.1186/s13195-021-00938-w",
language = "English (US)",
volume = "13",
journal = "Alzheimer's Research and Therapy",
issn = "1758-9193",
publisher = "BioMed Central",
number = "1",
}