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Randomized Controlled Trial
. 2024 Dec;36(12):1232-1244.
doi: 10.1017/S1041610224000711. Epub 2024 Sep 19.

Measuring clinically relevant change in apathy symptoms in ADMET and ADMET 2

Shankar Tumati  1 , Nathan Herrmann  1 , Jaime Perin  2 , Paul B Rosenberg  3 , Alan J Lerner  4 , Jacobo Mintzer  5 , Prasad R Padala  6 , Olga Brawman-Mintzer  5 , Christopher H van Dyck  7 , Anton P Porsteinsson  8 , Suzanne Craft  9 , Allan Levey  10 , David Shade  2 , Krista L Lanctôt  1   11   12
Affiliations
Randomized Controlled Trial

Measuring clinically relevant change in apathy symptoms in ADMET and ADMET 2

Shankar Tumati et al. Int Psychogeriatr. 2024 Dec.

Abstract

Objectives: Among participants with Alzheimer's disease (AD) we estimated the minimal clinically important difference (MCID) in apathy symptom severity on three scales.

Design: Retrospective anchor- and distribution-based analyses of change in apathy symptom scores.

Setting: Apathy in Dementia Methylphenidate Trial (ADMET) and ADMET 2 randomized controlled trials conducted at three and ten clinics specialized in dementia care in United States and Canada, respectively.

Participants: Two hundred and sixty participants (60 ADMET, 200 ADMET 2) with clinically significant apathy in Alzheimer's disease.

Measurements: The Clinical Global Impression of Change in Apathy scale was used as the anchor measure and the MCID on the Neuropsychiatric Inventory - Apathy (NPI-A), Dementia Apathy Interview and Rating (DAIR), and Apathy Evaluation Scale-Informant (AES-I) were estimated with linear mixed models across all study visits. The estimated thresholds were evaluated with performance metrics.

Results: Among the MCID was a decrease of four points (95% CI: -4.0 to -4.8) on the NPI-A, 0.56 points (95% CI: -0.47 to -0.65) on the DAIR, and three points on the AES-I (95% CI: -0.9 to -5.4). Distribution-based analyses were largely consistent with the anchor-based analyses. The MCID across the three measures showed ∼60% accuracy. Sensitivity analyses found that MMSE scores and apathy severity at baseline influenced the estimated MCID.

Conclusions: MCIDs for apathy on three scales will help evaluate treatment efficacy at the individual level. However, the modest correspondence between MCID and clinical impression of change suggests the need to consider other scales.

Keywords: Alzheimer’s disease; Apathy; behavioral and psychological symptoms of dementia (BPSD); clinical assessment; rating scales.

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Conflict of interest statement

Dr. Mintzer reported being an advisor for Praxis Bioresearch and Cerevel Therapeutics outside the submitted work. Dr. Lanctôt reported grants from the National Institutes of Health during the conduct of the ADMET 2 study and personal fees for serving on the advisory boards of BioXcel Therapeutics, Cerevel Therapeutics, Eisai, Exciva, Kondor Pharma, Lundbeck Otsuka, Novo Nordisk, and Sumitomo outside the submitted work. Dr. Scherer reported grants from Johns Hopkins University during the conduct of the ADMET 2 study. Dr. Rosenberg has received research grants from the National Institutes of Aging, Alzheimer’s Clinical Trials Consortium, Richman Family Precision Medicine Center of Excellence on Alzheimer’s Disease, Eisai, Functional Neuromodulation, and Lilly; honoraria from GLG, Leerink, Cerevel, Cerevance, Bioxcel, Sunovion, Acadia, Medalink, Novo Nordisk, Noble Insights, TwoLabs, Otsuka, Lundbeck, Acadia, MedaCorp, ExpertConnect, HMP Global, Synaptogenix, and Neurology Week, all outside the submitted work. Dr. Herrmann reported grants from the National Institute on Aging during the conduct of the ADMET 2 study. Dr. van Dyck reported grants from the National Institute on Aging during the conduct of the ADMET 2 study; personal fees for consulting for Roche, Eisai, Cerevel, and Ono Pharmaceutical outside the submitted work; and grants from Roche, Eisai, Eli Lilly and Company, Biogen, Biohaven Pharmaceuticals, Novartis, Janssen, Genentech, UCB, Cerevel, and Merck outside the submitted work. Dr. Padala reported grants from Office of Research Development, Department of Veterans Affairs and National Institutes of Health during the conduct of the ADMET 2 study. Dr. Brawman-Mintzer reported grants from the National Institute on Aging during the conduct of the ADMET 2 study. Dr. Porsteinsson reported grants from the National Institutes of Health during the conduct of the ADMET 2 study; personal fees for serving on the data and safety monitoring boards of Acadia Pharmaceuticals, Cadent Therapeutics, Functional Neuromodulation, Novartis, and Syneos outside the submitted work; grants from Avanir Pharmaceuticals, Biogen, Eisai, Eli Lilly and Company, Genentech/Roche, Biohaven, Athira, Alector, Vaccinex, and Novartis outside the submitted work; and personal fees from Avanir, Biogen, Eisai, Alzheon, MapLight Therapeutics, Premier Healthcare Solutions, Sunovion, IQVIA, and Ono Pharmaceuticals outside the submitted work.

Figures

Figure 1:
Figure 1:. Clinically meaningful within-person change scores on the NPI-A, AES-I and DAIR
The figure shows the least squares estimated mean change score on the target measures at any visit (v) from baseline for each level of change on the CGIC-A. The estimates were derived by including scores from all visits in a linear mixed model with CGIC-A as the predictor and subjects as the random factor. Abbreviations - ADMET: Apathy in Dementia Methylphenidate Trial; DAIR: Dementia Apathy Interview and Rating scale; AES-I: Apathy Evaluation Scale - Informant; NPI-A: Neuropsychiatric Inventory - Apathy; SD: Standard Deviation
Figure 2:
Figure 2:. Empirical CDF of change on apathy scales as per clinically meaningful change levels
The figure shows cumulative proportion and 95% confidence interval bands of participants in each level of the CGIC-A across the range of change scores (x-axis). The range of change scores where the levels of CGIC-A show a greater separation indicates thresholds that are sensitive to detecting clinically meaningful change in symptoms. Abbreviations - AES-I: Apathy Evaluation Scale - Informant; CDF: Cumulative Distribution Function; DAIR: Dementia Apathy Interview and Rating Scale; NPI-A: Neuropsychiatric Inventory – Apathy
Figure 3:
Figure 3:. Performance metrics of proposed thresholds for target measures
The figure shows sensitivity (true positives identified among actual positives), specificity (true negatives identified among actual negatives), accuracy (true positives and true negatives among all observations), precision (positive predictive value; true positives among all positives predicted by threshold), and F1 score (equally weighs precision and sensitivity).
See this image and copyright information in PMC

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