Estimating attrition in mild-to-moderate Alzheimer’s disease and mild cognitive impairment clinical trials

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Abstract

Background

Participant retention is a key factor that affects clinical trial integrity. Trial protocols estimate attrition as a function of sample size calculations. Alzheimer’s disease (AD) is an area of active treatment development. We aimed to quantify the association between trial duration and completion rates and provide guidance for estimating attrition in AD trial protocols.

Methods

Using the Alzforum and ClinicalTrials.gov databases, we analyzed retention data from 125 mild-to-moderate AD and 12 mild cognitive impairment (MCI) clinical trials. We compared the rates of completion between trial arms (active vs. control) and ran regression models to test the hypothesis that trials with longer study duration have lower trial completion using all available data and restricting to placebo data. Our primary outcome was the odds of trial completion for a 6-month increase in trial duration. From the regression model, we estimated the proportion of participants completing 6-, 12-, and 18-month trials.

Results

We found that 21 (17%) mild-to-moderate AD trials and 1 (8%) MCI trial demonstrated greater dropout in treatment compared to placebo arms. For every 6-month increase in trial duration, there was a 27% decrease in the odds of trial completion (OR = 0.73; 95% CI 0.66, 0.81; p < 0.001) among participants in mild-to-moderate AD trials and a 55% decrease (OR = 0.45; 95% CI 0.36, 0.57; p < 0.001) among participants in MCI trials. The proportion of participants in the placebo group completing 6-, 12-, and 18-month trials were estimated to be 85.2%, 80.0%, and 73.3% for mild-to-moderate AD trials and 91.9%, 84.2%, and 71.3% for MCI trials, respectively.

Conclusions

Longer duration trials may be underpowered to demonstrate estimated treatment effects and may suffer from a greater risk of bias than do shorter trials.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13195-023-01352-0.

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Most cited references 17

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What makes clinical research ethical?

E Emanuel, D Wendler, C. Grady (2000)

Many believe that informed consent makes clinical research ethical. However, informed consent is neither necessary nor sufficient for ethical clinical research. Drawing on the basic philosophies underlying major codes, declarations, and other documents relevant to research with human subjects, we propose 7 requirements that systematically elucidate a coherent framework for evaluating the ethics of clinical research studies: (1) value-enhancements of health or knowledge must be derived from the research; (2) scientific validity-the research must be methodologically rigorous; (3) fair subject selection-scientific objectives, not vulnerability or privilege, and the potential for and distribution of risks and benefits, should determine communities selected as study sites and the inclusion criteria for individual subjects; (4) favorable risk-benefit ratio-within the context of standard clinical practice and the research protocol, risks must be minimized, potential benefits enhanced, and the potential benefits to individuals and knowledge gained for society must outweigh the risks; (5) independent review-unaffiliated individuals must review the research and approve, amend, or terminate it; (6) informed consent-individuals should be informed about the research and provide their voluntary consent; and (7) respect for enrolled subjects-subjects should have their privacy protected, the opportunity to withdraw, and their well-being monitored. Fulfilling all 7 requirements is necessary and sufficient to make clinical research ethical. These requirements are universal, although they must be adapted to the health, economic, cultural, and technological conditions in which clinical research is conducted. JAMA. 2000;283:2701-2711.

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The prevention and treatment of missing data in clinical trials.

Debra Murphy, Ralph D’Agostino, Nadia Emerson … (2012)

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Guidelines for reporting methodological challenges and evaluating potential bias in dementia research

Jennifer Weuve, Cecile Proust-Lima, Melinda Power … (2015)

Clinical and population research on dementia and related neurologic conditions, including Alzheimer’s disease, faces several unique methodological challenges. Progress to identify preventive and therapeutic strategies rests on valid and rigorous analytic approaches, but the research literature reflects little consensus on “best practices.” We present findings from a large scientific working group on research methods for clinical and population studies of dementia, which identified five categories of methodological challenges as follows: (1) attrition/sample selection, including selective survival; (2) measurement, including uncertainty in diagnostic criteria, measurement error in neuropsychological assessments, and practice or retest effects; (3) specification of longitudinal models when participants are followed for months, years, or even decades; (4) time-varying measurements; and (5) high-dimensional data. We explain why each challenge is important in dementia research and how it could compromise the translation of research findings into effective prevention or care strategies. We advance a checklist of potential sources of bias that should be routinely addressed when reporting dementia research.

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Author and article information

Contributors

Marina Ritchie: mritchie@uci.edu

Journal

Journal ID (nlm-ta): Alzheimers Res Ther

Journal ID (iso-abbrev): Alzheimers Res Ther

Title: Alzheimer's Research & Therapy

Publisher: BioMed Central (London )

ISSN (Electronic): 1758-9193

Publication date (Electronic): 21 November 2023

Publication date PMC-release: 21 November 2023

Publication date Collection: 2023

Volume: 15

Electronic Location Identifier: 203

Affiliations

[1 ]GRID grid.266093.8, ISNI 0000 0001 0668 7243, UC Irvine Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, ; Irvine, CA 92697 USA

[2 ]GRID grid.266093.8, ISNI 0000 0001 0668 7243, Department of Neurobiology and Behavior, , University of California, Irvine, ; Irvine, CA 92697 USA

[3 ]GRID grid.266093.8, ISNI 0000 0001 0668 7243, Department of Statistics, , University of California, Irvine, ; Irvine, CA 92697 USA

[4 ]GRID grid.266093.8, ISNI 0000 0001 0668 7243, Department of Psychiatry and Human Behavior, , University of California, Irvine, ; Irvine, CA 92697 USA

Article

Publisher ID: 1352

DOI: 10.1186/s13195-023-01352-0

PMC ID: 10662394

PubMed ID: 37990339

SO-VID: ce64bb83-7608-4a38-ba85-f94e6c10fd00

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 13 June 2023

Date accepted : 12 November 2023

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000049, National Institute on Aging;

Award ID: RF1 AG059407

Award Recipient : Daniel L. Gillen Joshua D. Grill

Custom metadata

ScienceOpen disciplines: Neurology

Keywords: retention,alzheimer’s disease,clinical trials, trial duration

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ScienceOpen disciplines: Neurology

Keywords: retention, alzheimer’s disease, clinical trials, trial duration

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Estimating attrition in mild-to-moderate Alzheimer’s disease and mild cognitive impairment clinical trials

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Abstract

Background

Methods

Results

Conclusions

Supplementary Information

Related collections

Karger: Neurology and Neuroscience

Most cited references 17

What makes clinical research ethical?

The prevention and treatment of missing data in clinical trials.

Guidelines for reporting methodological challenges and evaluating potential bias in dementia research

Author and article information

Contributors

Journal

Affiliations

Article

History

Funding

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Cited by 2

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