Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Jun;19(6):2730-2736.
doi: 10.1002/alz.12959. Epub 2023 Feb 7.

Expectations and clinical meaningfulness of randomized controlled trials

Ronald C Petersen  1 , Paul S Aisen  2 , J Scott Andrews  3 , Alireza Atri  4 , Brandy R Matthews  5 , Dorene M Rentz  6 , Eric R Siemers  7 , Christopher J Weber  8 , Maria C Carrillo  8
Affiliations

Expectations and clinical meaningfulness of randomized controlled trials

Ronald C Petersen et al. Alzheimers Dement. 2023 Jun.

Abstract

Alzheimer's disease (AD) clinical trials are designed and powered to detect the impact of a therapeutic intervention, and there has been considerable discussion on what constitutes a clinically meaningful change in those receiving treatment versus placebo. The pathology of AD is complex, beginning many years before clinical symptoms are detectable, with multiple potential opportunities for therapeutic engagement. Introducing treatment strategies early in the disease and assessing meaningful change over the course of an 18-month clinical trial are critical to understanding the value to an effective intervention. With new clinical trial data expected soon on emerging therapeutics from several AD studies, the Alzheimer's Association convened a work group of experts to discuss key considerations for interpreting data from cognitive and functional measures and what is considered a clinically meaningful benefit or meaningful slowing of this fatal disease. Our expectations of outcomes from therapeutic interventions in AD may need to be modified.

Keywords: Alzheimer disease; MCI; amyloid; clinical meaningfulness; clinical trial; cognition; cognitive impairment; dementia; mild cognitive impairment; tau.

PubMed Disclaimer

Conflict of interest statement

Ronald C. Petersen is a full-time employee of the Mayo Foundation for Education and Research, has received grants or contracts from the National Institute on Aging Alzheimer’s Disease Research Centers (NIA ADRC), MCSA, Alzheimer’s Disease Neuroimaging Inititative (ADNI), Alzheimer’s Clinical Trials Consortium (ACTC), and National Institute of Neurological Disorders and Stroke (NINDS). MarkVCID (Vascular contributions to cognitive impairment & dementia), royalties or licenses from Oxford University Press and UpToDate, consulting fees from Roche, Nestle, Merck, Biogen, Eisai, and Genentech, and participated on a Data Safety Monitoring Board (DSMB) or Advisory Board (AB) for Genentech. Paul S. Aisen has received grants or contracts from the National Institutes of Health (NIH), Alzheimer’s Association, Foundation for NIH (FNIH), Lilly, Janssen, and Eisai and consulting fees from Merck, Biogen, AbbVie, Roche, and Immunobrain Checkpoint. J. Scott Andrews is a full-time employee and minor shareholder of Takeda Pharmaceuticals. Alireza Atri has received consulting fees from Roche/Genentech, Novo Nordisk, Eisai, Acadia, AZ Therapies, Biogen, Japanese Organization for Medical Device Development, Inc. (JOMDD), Mundbeck, Qynapse, and Suven, grants from Alzheon, Athira, Biohaven (with Alzheimer’s Disease Cooperative Study), Eisai (with Alzheimer’s Therapeutic Research Institute/ Alzheimer’s Clinical Trials Consortium), Lilly (with ATRI/ACTC), Vivoryon (with ADCS), ACTC, ADCS, AZ Alzheimer’s Research Consortium, ATRI, Global Alzheimer’s Platform (GAP), University of Southern California (USC), Indiana University, Johns Hopkins, Washington University St. Louis, Gates Ventures, Arizona Department of Health Services (AZ DHS), NIA/NIH, and the FNIH, royalties from Oxford University Press, educational presentation fees from AbbVie, Acadia, Biogen, Eisai, and Lundbeck, and travel compensation from the Alzheimer’s Association, Alzheimer’s Disease International (ADI), American Academy of Neurology (AAN). Brandy R. Matthews is a full-time employee and minor shareholder at Eli Lilly & Co. Dorene M. Rentz has received consulting fees from the Dana Foundation, payment or honoraria from USC, Institute on Methods and Protocols for Advancement of Clinical Trials in ADRD (IMPACT-AD) course 2021, Grand Rounds, and External Scientific Advisory Boards, and support for travel to ACTC meetings and University of California-Davis Advisory Board meetings. Eric R. Siemers has received consulting fees from Biogen, Cogstate, Cortexyme, Partner Therapeutics, Pinteon Therapeutics, Vaccinex, Acumen Pharmaceuticals, Gates Ventures, and Hoffman LaRoche, has participated on an advisory board for Hoffman LaRoche, has held leadership roles at the Alzheimer’s Association and Bright Focus Foundation, and holds stock or stock options in Acumen Pharmaceuticals. Christopher J. Weber and Maria C. Carrillo are full-time employees of the Alzheimer’s Association. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
A progression model for repeated measures (PMRM), adapted from Raket, illustrates the time savings between a CDR-SB change score at a specific time point and the slowing or delay of disease progression
FIGURE 2
FIGURE 2
Adapted from Assunção et al. Widening drug-placebo difference shows that there is a cumulative benefit with long-term treatment, and this is critical to meaningful benefit
See this image and copyright information in PMC

References

    1. Food and Drug Administration. Peripheral and central nervous system drugs advisory committee meeting, July 7, 1989. Rockville, MD: Department of Health and Human Services, Public Heath Service; 1989. p. 227.
    1. Hansson O Biomarkers for neurodegenerative diseases. Nat Med. 2021;27(6):954–963. - PubMed
    1. Teunissen CE, Verberk IMW, Thijssen EH, et al. Blood-based biomarkers for Alzheimer’s disease: towards clinical implementation. Lancet Neurol. 2022;21(1):66–77. - PubMed
    1. Jack CR jr, Bennett DA, Blennow K, et al. NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14(4):535–562. doi:10.1016/j.jalz.2018.02.018. - DOI - PMC - PubMed
    1. Janelidze S, Mattsson N, Palmqvist S, et al. Plasma p-Tau181 in Alzheimer’s disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer’s dementia. Nat Med. 2020;26:379–386. - PubMed

Publication types

MeSH terms