Participant registries are repositories of individuals who have expressed willingness to learn about studies for which they may be eligible. Registries are increasingly being utilized to improve recruitment to preclinical Alzheimer's disease (AD) clinical trials, which require large screening efforts to identify adequate numbers of participants who meet enrollment criteria. Recruiting to preclinical AD trials from registries is made more efficient through registry collection of data that permits exclusion of those who will not be eligible and identifies individuals most likely to qualify for trials. Such data could include self-reported disease family history or other risk factors, but could also include cognitive, genetic, or biomarker testing outcomes. Few data are available to guide investigators overseeing registries and important ethical questions are likely to arise related to their conduct, especially in registries collecting AD risk information. This article outlines three areas of consideration for registry investigators: informed consent, disclosure, and sponsorship.

The goal of clinical research is to improve clinical practice. In progressive neurodegenerative conditions without any disease-slowing therapies, this will result in eventual approval of a first disease-modifying treatment. Clinical trials will still be needed to discover treatments that are more effective, safer, or more convenient. This will generate controversies over how to design these trials; specifically, controversies about the use of a placebo control. We consider ethical guidance for these studies with attention to 3 designs: placebo-controlled trials in the absence of the new drug, placebo-controlled trials with the approved drug as background therapy, and trials with the new drug as an active control. To understand the practical implications of these designs, we examine experiences in drug development in multiple sclerosis. We conclude by contemplating the future of clinical trials in Alzheimer disease.

Among the key challenges in Alzheimer's disease drug development is the timely completion of clinical trials. Unfortunately, clinical trials often suffer from slow or insufficient enrollment. Successful clinical trial recruitment describes a balance between expeditiously achieving full enrollment and ensuring an appropriate study sample. Investigators face a number of challenges to the successful negotiation of this balance. The failure to address these challenges means that drug development may take more time and money and that trial results may not adequately represent drug efficacy or may not be applicable beyond the study. We review the challenges to recruitment and retention in Alzheimer's disease clinical trials and present a framework to address them.

This chapter will provide an overview of the fundamentals of clinical trials in Alzheimer’s disease (AD). A basic understanding of disease biology and clinical presentation is necessary to interpret matters regarding AD trials and we begin with an overview of the disease. We review the goals of AD trials, the basic tools used in their conduct, current and future trial designs, limitations and challenges to trial conduct, and controversies that exist in the field of AD clinical research. The field of AD trials is a rapidly evolving one. We attempt to address recent changes in trial conduct and to consider future changes that will be needed. Introduction to Alzheimer’s disease: Alzheimer’s disease is a progressive neurodegenerative disorder characterized over 100 years ago but still lacking adequate therapies. To date, the US FDA has approved five drugs for the treatment of AD. Most studies suggest that these agents provide only symptomatic improvement in AD and pursuit of treatments capable of altering the natural history of AD is rigorous. Therefore, clinical trials of new therapies in AD in the coming years will continue to be a mainstay of AD research.

Background

In an effort to intervene earlier in Alzheimer's disease (AD), clinical trials are testing promising candidate therapies in preclinical disease. Preclinical AD trial participants are cognitively normal, functionally independent, and autonomous decision-makers. Yet, like AD dementia trials, preclinical trials require dual enrollment of a participant and a knowledgeable informant, or study partner.

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The requirement of dyadic enrollment is a barrier to recruitment and may present unique ethical challenges. Despite these limitations, the requirement should continue. Study partners may be essential to ensure participant safety and wellbeing, including overcoming distress related to biomarker disclosure and minimizing risk for catastrophic reactions and suicide. The requirement may maximize participant retention and ensure data integrity, including that study partners are the source of data that will ultimately instruct whether a new treatment has a clinical benefit and meaningful impact on the population health burden associated with AD. Finally, study partners are needed to ensure the scientific and clinical value of trials.

Conclusions

Preclinical AD will represent a new model of care, in which persons with no symptoms are informed of probable cognitive decline and eventual dementia. The rationale for early diagnosis in symptomatic AD is equally applicable in preclinical AD-to minimize risk, maximize quality of life, and ensure optimal planning and communication. Family members and other sources of support will likely be essential to the goals of this new model of care for preclinical AD patients and trials must instruct this clinical practice.

Background/aims

Alzheimer's disease (AD) clinical trials enroll two participants: a patient and a study partner. The primary caregiver most often fills the role of study partner and most trial study partners are spousal caregivers.

Methods

AD trial inclusion criteria were applied to baseline data from 5,674 probable AD dementia research participants in the National Alzheimer's Coordinating Center Uniform Data Set. Eligibility was compared among patients with spousal, adult child, and other types of study partners.

Results

Patients with spousal study partners were more frequently eligible than patients with adult child study partners. Compared to patients with spousal study partners, patients with adult child study partners were more frequently ineligible because of age, residence in skilled nursing facility, low scores on the Mini-Mental State Examination, highscores on the Hachinski Ischemia Scale, and failure to fulfill a minimum number of weekly visits with the study partner.

Conclusions

In this sample, patients with adult child study partners were less likely to qualify for AD clinical trials than were patients with spousal study partners. This may contribute to the lower representation of patients with adult child caregivers in these studies.

To assist investigators in making design choices, we modeled Alzheimer's disease prevention clinical trials. We used longitudinal Clinical Dementia Rating Scale Sum of Boxes data, retention rates, and the proportions of trial-eligible cognitively normal participants age 65 and older in the National Alzheimer's Coordinating Center Uniform Data Set to model trial sample sizes, the numbers needed to enroll to account for drop out, and the numbers needed to screen to successfully complete enrollment. We examined how enrichment strategies affected each component of the model. Relative to trials enrolling 65-year-old individuals, trials enriching for older (minimum 70 or 75) age required reduced sample sizes, numbers needed to enroll, and numbers needed to screen. Enriching for subjective memory complaints reduced sample sizes and numbers needed to enroll more than age enrichment, but increased the number needed to screen. We conclude that Alzheimer's disease prevention trials can enroll elderly participants with minimal effect on trial retention and that enriching for older individuals with memory complaints might afford efficient trial designs.