Disclosure of amyloid status is not a barrier to recruitment in preclinical Alzheimer's disease clinical trials

Abstract

Preclinical Alzheimer's disease (AD) clinical trials may require participants to learn if they meet biomarker enrollment criteria. To examine whether this requirement will impact trial recruitment, we presented 132 older community volunteers who self-reported normal cognition with 1 of 2 hypothetical informed consent forms (ICFs) describing an AD prevention clinical trial. Both ICFs described amyloid Positron Emission Tomography scans. One ICF stated that scan results would not be shared with the participants (blinded enrollment); the other stated that only persons with elevated amyloid would be eligible (transparent enrollment). Participants rated their likelihood of enrollment and completed an interview with a research assistant. We found no difference between the groups in willingness to participate. Study risks and the requirement of a study partner were reported as the most important factors in the decision whether to enroll. The requirement of biomarker disclosure may not slow recruitment to preclinical AD trials.

Introduction

Biomarkers of Alzheimer's disease (AD) are present years before a person has overt cognitive impairment (Bateman et al., 2011, Lim et al., 2014, Morris et al., 2009, Pietrzak et al., 2015, Price et al., 2009), supporting the hypothesis that interventions initiated at these early “preclinical” stages, when neurodegeneration is minimal, may have the greatest likelihood of altering the natural history of AD (Sperling et al., 2011b). To facilitate testing this hypothesis, a working group sponsored by the National Institute on Aging and the Alzheimer's Association proposed research diagnostic criteria for a preclinical stage of AD (Sperling et al., 2011a). In this stage, cognition remains normal or only subtly impaired, but biomarker evidence of AD is present.

Preclinical AD trials must implement 1 of 2 designs: blinded or transparent enrollment (Kim et al., 2015). Blinded designs do not disclose biomarker results to participants. They enroll a proportion of participants who do not demonstrate AD biomarkers so that enrollment is not a de facto disclosure of biomarker status. These participants are nonrandomly assigned to placebo, undergo all study procedures, and are followed for the duration of the study. With transparent enrollment, only those who demonstrate biomarker criteria are enrolled and randomized. Biomarker results are disclosed when an investigator informs a person whether he or she is eligible. Both designs have unique risks. For example, blinded enrollment trials may inadvertently disclose biomarker status to participants who do not wish to learn it (Hooper et al., 2013, Kim et al., 2015), whereas transparent enrollment trials bring unique challenges related to confidentiality and the social and psychological impact of learning biomarker results (Arias and Karlawish, 2014).

Which of these designs should researchers use? The answer to this question engages several considerations, including the use of limited resources, the need for timely progress, study feasibility, and the ethical implications of trial designs. The purpose of this study was to empirically inform 1 specific consideration: the impact on participant recruitment. It is unknown how these 2 designs will impact recruitment timelines. Also unknown are the factors that might explain why one design is more appealing than the other. Participants' views cannot entirely settle the competing ethical, clinical, and resource considerations, but they do provide an important perspective on how, on a person-by-person basis, they settle these issues. Absent empirical data, trialists, institutional review boards, and funders can only speculate over how blinded versus transparent designs impact enrollment, or simply implement these designs and learn from the efforts.

Transparent enrollment preclinical AD trials require people to learn risk information for a disease for which no treatment exists or may ever exist. But compared to blinded enrollment trials, these trials require fewer participants and closely approximate how clinicians will diagnose and treat sporadic preclinical AD (Burns and Klunk, 2012). If transparent enrollment trials suffer from slow recruitment, then, despite smaller overall sample sizes, these trials may be less efficient than those using blinded designs. Here, we test the hypothesis that a preclinical AD trial with transparent enrollment will have poorer recruitment than one with blinded enrollment. A secondary aim was to identify clinical and trial factors associated with willingness to enroll. We chose to study persons with interest in AD research because they approximate the kinds of persons who would be recruited for a preclinical AD trial.