Technical Review of Clinical Outcomes Assessments Across the Continuum of Alzheimer's Disease

Overview

Journal Neurol Ther

Publisher Springer

Specialty Neurology

Date 2023 Feb 15

PMID 36790638

Authors

Dana B DiBenedetti

Heather Menne

Russ Paulsen

Holly B Krasa

George Vradenburg

Meryl Comer

Leigh F Callahan

John Winfield

Michele Potashman

Kim Heithoff

Ann Hartry

Dorothee Oberdhan

Hilary Wilson

Deborah L Hoffman

Dan Wieberg

Ian N Kremer

Geraldine A Taylor

James M Taylor

Debra Lappin

Allison D Martin

Brett Hauber

Carla Romano

Affiliations

Soon will be listed here.

Abstract

Introduction: Insight into the relationship between concepts that matter to the people affected by Alzheimer's disease (AD) and the clinical outcome assessments (COAs) commonly used in AD clinical studies is limited. Phases 1 and 2 of the What Matters Most (WMM) study series identified and quantitatively confirmed 42 treatment-related outcomes that are important to people affected by AD.

Methods: We compared WMM concepts rated as "very important" or higher to items included in COAs used commonly in AD studies.

Results: Twenty COAs designed to assess signs, symptoms, and impacts across the spectrum of AD were selected for review. Among these 20 COAs, only 5 reflected 12 or more WMM concepts [Integrated Alzheimer's Disease Rating Scale (iADRS), Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL), Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory-Mild Cognitive Impairment (ADCS-ADL-MCI), Alzheimer's Disease Composite Scores (ADCOMS), and Clinical Dementia Rating; Clinical Dementia Rating-Sum of Boxes (CDR/CDR-SB)]. Multiple symptoms and impacts of AD identified as important and meaningful in the WMM studies map only indirectly at best to 7 of the 20 most widely used COAs.

Conclusion: While many frequently used COAs in AD capture some concepts identified as important to AD populations and their care partners, overlap between any single measure and the concepts that matter to people affected by AD is limited. The highest singly matched COA reflects fewer than half (45%) of WMM concepts. Use of multiple COAs expands coverage of meaningful concepts. Future research should explore the content validity of AD COAs planned for AD trials based on further confirmation of the ecological validity of the WMM items. This research should inform development and use of core outcome sets that capture WMM items and selection or development of new companion tools to fully demonstrate clinically meaningful outcomes spanning WMM.

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References

DiBenedetti D, Slota C, Wronski S, Vradenburg G, Comer M, Callahan L . Assessing what matters most to patients with or at risk for Alzheimer's and care partners: a qualitative study evaluating symptoms, impacts, and outcomes. Alzheimers Res Ther. 2020; 12(1):90. PMC: 7393916. DOI: 10.1186/s13195-020-00659-6. View

Jutten R, Papp K, Hendrix S, Ellison N, Langbaum J, Donohue M . Why a clinical trial is as good as its outcome measure: A framework for the selection and use of cognitive outcome measures for clinical trials of Alzheimer's disease. Alzheimers Dement. 2022; 19(2):708-720. PMC: 9931632. DOI: 10.1002/alz.12773. View

Bowen R, Perry G, Xiong C, Smith M, Atwood C . A clinical study of lupron depot in the treatment of women with Alzheimer's disease: preservation of cognitive function in patients taking an acetylcholinesterase inhibitor and treated with high dose lupron over 48 weeks. J Alzheimers Dis. 2014; 44(2):549-60. DOI: 10.3233/JAD-141626. View

Claxton A, Baker L, Hanson A, Trittschuh E, Cholerton B, Morgan A . Long-acting intranasal insulin detemir improves cognition for adults with mild cognitive impairment or early-stage Alzheimer's disease dementia. J Alzheimers Dis. 2014; 44(3):897-906. DOI: 10.3233/JAD-141791. View

Craft S, Claxton A, Baker L, Hanson A, Cholerton B, Trittschuh E . Effects of Regular and Long-Acting Insulin on Cognition and Alzheimer's Disease Biomarkers: A Pilot Clinical Trial. J Alzheimers Dis. 2017; 57(4):1325-1334. PMC: 5409050. DOI: 10.3233/JAD-161256. View

Cummings J, Cohen S, van Dyck C, Brody M, Curtis C, Cho W . ABBY: A phase 2 randomized trial of crenezumab in mild to moderate Alzheimer disease. Neurology. 2018; 90(21):e1889-e1897. PMC: 5962917. DOI: 10.1212/WNL.0000000000005550. View

Cummings J, Lyketsos C, Peskind E, Porsteinsson A, Mintzer J, Scharre D . Effect of Dextromethorphan-Quinidine on Agitation in Patients With Alzheimer Disease Dementia: A Randomized Clinical Trial. JAMA. 2015; 314(12):1242-54. DOI: 10.1001/jama.2015.10214. View

Fullerton T, Binneman B, David W, Delnomdedieu M, Kupiec J, Lockwood P . A Phase 2 clinical trial of PF-05212377 (SAM-760) in subjects with mild to moderate Alzheimer's disease with existing neuropsychiatric symptoms on a stable daily dose of donepezil. Alzheimers Res Ther. 2018; 10(1):38. PMC: 5887246. DOI: 10.1186/s13195-018-0368-9. View

Gauthier S, Rountree S, Finn B, LaPlante B, Weber E, Oltersdorf T . Effects of the Acetylcholine Release Agent ST101 with Donepezil in Alzheimer's Disease: A Randomized Phase 2 Study. J Alzheimers Dis. 2015; 48(2):473-81. DOI: 10.3233/JAD-150414. View

10.

Henderson V, Ala T, Sainani K, Bernstein A, Stephenson B, Rosen A . Raloxifene for women with Alzheimer disease: A randomized controlled pilot trial. Neurology. 2015; 85(22):1937-44. PMC: 4664126. DOI: 10.1212/WNL.0000000000002171. View

11.

Herrmann N, ORegan J, Ruthirakuhan M, Kiss A, Eryavec G, Williams E . A Randomized Placebo-Controlled Discontinuation Study of Cholinesterase Inhibitors in Institutionalized Patients With Moderate to Severe Alzheimer Disease. J Am Med Dir Assoc. 2015; 17(2):142-7. DOI: 10.1016/j.jamda.2015.08.019. View

12.

Kile S, Au W, Parise C, Rose K, Donnel T, Hankins A . IVIG treatment of mild cognitive impairment due to Alzheimer's disease: a randomised double-blinded exploratory study of the effect on brain atrophy, cognition and conversion to dementia. J Neurol Neurosurg Psychiatry. 2015; 88(2):106-112. DOI: 10.1136/jnnp-2015-311486. View

13.

Salloway S, Sperling R, Fox N, Sabbagh M, Honig L, Porsteinsson A . Long-Term Follow Up of Patients with Mild-to-Moderate Alzheimer's Disease Treated with Bapineuzumab in a Phase III, Open-Label, Extension Study. J Alzheimers Dis. 2018; 64(3):689-707. DOI: 10.3233/JAD-171157. View

14.

Vandenberghe R, Rinne J, Boada M, Katayama S, Scheltens P, Vellas B . Bapineuzumab for mild to moderate Alzheimer's disease in two global, randomized, phase 3 trials. Alzheimers Res Ther. 2016; 8(1):18. PMC: 4866415. DOI: 10.1186/s13195-016-0189-7. View

15.

Wharton W, Goldstein F, Zhao L, Steenland K, Levey A, Hajjar I . Modulation of Renin-Angiotensin System May Slow Conversion from Mild Cognitive Impairment to Alzheimer's Disease. J Am Geriatr Soc. 2015; 63(9):1749-56. PMC: 4743657. DOI: 10.1111/jgs.13627. View

16.

Yamamoto E, Mourany L, Colleran R, Whitman C, Tousi B . Utility of Montreal Cognitive Assessment in Differentiating Dementia With Lewy Bodies From Alzheimer's Dementia. Am J Alzheimers Dis Other Demen. 2017; 32(8):468-471. PMC: 10852593. DOI: 10.1177/1533317517725811. View

17.

Assuncao S, Sperling R, Ritchie C, Kerwin D, Aisen P, Lansdall C . Meaningful benefits: a framework to assess disease-modifying therapies in preclinical and early Alzheimer's disease. Alzheimers Res Ther. 2022; 14(1):54. PMC: 9017027. DOI: 10.1186/s13195-022-00984-y. View

18.

Rentz D, Wessels A, Annapragada A, Berger A, Edgar C, Gold M . Building clinically relevant outcomes across the Alzheimer's disease spectrum. Alzheimers Dement (N Y). 2021; 7(1):e12181. PMC: 8234696. DOI: 10.1002/trc2.12181. View

19.

Edgar C, Vradenburg G, Hassenstab J . The 2018 Revised FDA Guidance for Early Alzheimer's Disease: Establishing the Meaningfulness of Treatment Effects. J Prev Alzheimers Dis. 2019; 6(4):223-227. DOI: 10.14283/jpad.2019.30. View