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. 2023 Feb;19(2):708-720.
doi: 10.1002/alz.12773. Epub 2022 Sep 10.

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

Roos J Jutten  1 , Kathryn V Papp  1   2 , Suzanne Hendrix  3 , Noel Ellison  3 , Jessica B Langbaum  4 , Michael C Donohue  5 , Jason Hassenstab  6 , Paul Maruff  7   8 , Dorene M Rentz  1   2 , John Harrison  9   10   11 , Jeffrey Cummings  12 , Philip Scheltens  11 , Sietske A M Sikkes  11   13
Affiliations

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

Roos J Jutten et al. Alzheimers Dement. 2023 Feb.

Abstract

A crucial aspect of any clinical trial is using the right outcome measure to assess treatment efficacy. Compared to the rapidly evolved understanding and measurement of pathophysiology in preclinical and early symptomatic stages of Alzheimer's disease (AD), relatively less progress has been made in the evolution of clinical outcome assessments (COAs) for those stages. The current paper aims to provide a benchmark for the design and evaluation of COAs for use in early AD trials. We discuss lessons learned on capturing cognitive changes in predementia stages of AD, including challenges when validating novel COAs for those early stages and necessary evidence for their implementation in clinical trials. Moving forward, we propose a multi-step framework to advance the use of more effective COAs to assess clinically meaningful changes in early AD, which will hopefully contribute to the much-needed consensus around more appropriate outcome measures to assess clinical efficacy of putative treatments. HIGHLIGHTS: We discuss lessons learned on capturing cognitive changes in predementia stages of AD. We propose a framework for the design and evaluation of performance based cognitive tests for use in early AD trials. We provide recommendations to facilitate the implementation of more effective cognitive outcome measures in AD trials.

Keywords: Alzheimer's disease; clinical outcome assessments; clinical trial; cognition; preclinical; prodromal.

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Conflict of interest statement

CONFLICTS OF INTEREST

R.J.J., P.M., and S.A.M.S. report no relevant conflicts of interests. K.V.P. has served on scientific advisory boards for Cogstate; she has consulted for Biogen, Eli Lilly, Novoic, and Digital Cognition Technologies. S.H. is owner and employee of Pentara Corporation. N.E. is a contractor for Pentara Corporation. Pentara consults for several dozen pharmaceutical, biotech, non-profit and academic groups in the Alzheimer’s disease space. J.L. has served on a scientific advisory board for Biogen and has consulted for Alector. M.D. has served on scientific advisory boards for Biogen, Eli Lilly, and Neurotrack; and has consulted for Roche. His spouse is a full-time employee of Janssen. Jason Hassenstab has served as a paid consultant for Roche, Lundbeck, Eisai, and Parabon Nanolabs. John Harrison reports receipt of personal fees in the past 2 years from Actinogen, AlzeCure, Aptinyx, Astra Zeneca, Athira Therapeutics, Axon Neuroscience, Axovant, Bial Biotech, Biogen Idec, BlackThornRx, Boehringer Ingelheim, Brands2life, Cerecin, Cognito, Cognition Therapeutics, Compass Pathways, Corlieve, Curasen, EIP Pharma, Eisai, G4X Discovery, GfHEU, Heptares, Ki Elements, Lundbeck, Lysosome Therapeutics, MyCognition, Neurocentria, Neurocog, Neurodyn Inc, Neurotrack, the NHS, Novartis, Novo Nordisk, Nutricia, Probiodrug, Prothena, Recognify, Regeneron, reMYND, Rodin Therapeutics, Samumed, Sanofi, Signant, Syndesi Therapeutics, Takeda, Vivoryon Therapeutics and Winterlight Labs. Additionally, he holds stock options in Neurotrack Inc. and is a joint holder of patents with My Cognition Ltd. J.C. has provided consultation to AB Science, Acadia, Alkahest, AlphaCognition, ALZPathFinder, Annovis, AriBio, Artery, Avanir, Biogen, Biosplice, Cassava, Cerevel, Clinilabs, Cortexyme, Diadem, EIP Pharma, Eisai, GatehouseBio, GemVax, Genentech, Green Valley, Grifols, Janssen, Karuna, Lexeo, Lilly, Lundbeck, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, Ono, Otsuka, PharmacotrophiX, PRODEO, Prothena, ReMYND, Renew, Resverlogix, Roche, Signant Health, Suven, Unlearn AI, Vaxxinity, VigilNeuro pharmaceutical, assessment, and investment companies. P.S. has received consultancy fees (paid to the institution) from AC Immune, Brainstorm Cell, EIP, ImmunoBrain Checkpoint, Genentech, Novartis, Novo Nordisk. He is PI of studies with AC Immune, FUJI-film/Toyama, UCB, and Vivoryon. He is a part-time employee of Life Sciences Partners Amsterdam. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Recommendation for selecting clinical outcome assessments (COAs) for Alzheimer’s disease trials based on the hypothesized mode of action, target population (e.g., clinical disease stage) and measurement characteristics of available tests
See this image and copyright information in PMC

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