Toward the optimized assessment of clinical outcomes in studies of novel treatments for Alzheimer’s disease

ABSTRACT

Introduction

Alzheimer’s disease (AD) is characterized by a progressive decline in cognition and daily function, leading to a greater need for caregiver support. Clinical disease is segmented into a preclinical stage, mild cognitive impairment, and mild, moderate, and severe stages of Alzheimer’s dementia. Although AD trials enroll participants at various stages of illness, treatment efficacy is often assessed using endpoints based on measures of outcomes that are held fixed across disease stages. We hypothesize that matching the primary outcomes measured in the endpoint hierarchy to the stage of disease targeted by the trial will increase the likelihood of detecting true treatment benefits.

Areas covered

We discuss current approaches to assessing clinical outcomes in AD trials, followed by a consideration of how effect detection can be improved by linking the stage of AD to the endpoints that most likely reflect stage-specific disease progression.

Expert opinion

Failing to account for stage-specific relevance and sensitivity of clinical outcomes may be one factor that contributes to trial failures in AD. Given the history of failure, experts have begun to scrutinize the relevance and sensitivity of outcomes as a potentially modifiable barrier to successful trials. To this end, we present a framework for refining trial endpoint selection and evaluation.

KEYWORDS:

• Alzheimer’s disease (AD)
• clinical outcomes
• dementia
• disease staging
• trial endpoints

Article highlights

• Alzheimer’s disease (AD) typically progresses through well-defined stages. Whereby clinical disease is segmented into a preclinical stage, mild cognitive impairment, and mild, moderate, and severe stages of Alzheimer’s dementia. Each stage of the disease is characterized by stage-specific symptoms.

• In contemporary clinical trials of AD, treatment efficacy is often evaluated using primary and secondary endpoints based on measures of outcomes that are held fixed across different disease stages. Repeated selection of outcomes and endpoints that are suboptimal for the stage of illness under investigation can result in measurement issues and, ultimately, trial failure.

• There have been tremendous advances in using neuroimaging and biomarkers, in both cerebrospinal fluid and blood, as outcomes. However, these advances have not been matched by advances in our measures of objective or subjective clinical outcomes (e.g. cognitive status, quality of life, and function).

• One of the greatest challenges we currently face in AD research is ensuring that the instruments and subsequent trial endpoints are appropriate for the stage of disease being studied. In this paper, we present strategies we have advocated to overcome such issues.

Acknowledgments

The authors thank E. Anne Davis for the thoughtful scientific insights and expertise provided in the initial discussions of the work presented in this manuscript.

Declaration of interest

R Lipton serves on the editorial boards of Neurology and Cephalalgia and is a senior advisor for Headache. He has received research support from the National Institutes of Health. He also receives support from the Migraine Research Foundation and the National Headache Foundation. He has reviewed for the National Institute on Aging and National Institute of Neurological Disorders and Stroke; serves as consultant, advisory board member, or has received honoraria or research support from AbbVie, Amgen, Biohaven, Dr. Reddy’s Laboratories, electroCore, Eli Lilly, eNeura Therapeutics, GlaxoSmithKline, Merck, Novartis, Teva, Vector, and Vedanta Research. He receives royalties from Wolff’s Headache, eighth edition (Oxford University Press, 2009), and Informa. He holds stock options at Biohaven and Ctrl M. W Stewart serve as a consultant for Grifols and Amgen. L Podger, D Serrano, and F Barnes, are employees of OPEN Health Group. W Rodriguez, M Runken, and D Gomez-Ulloa, are employees of Grifols. The development of this manuscript was sponsored by Grifols SSNA. All authors met the ICMJE authorship criteria. Neither honoraria nor any other form of payment was made for authorship. Financial arrangements of the authors with companies whose products may be related to the present manuscript are listed in the Disclosure Statement, as declared by the authors. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The development of this manuscript was sponsored by Grifols SSNA.