Alzheimer's Disease Clinical Trials: Moving Toward Successful Prevention

Abstract

Despite major academic and industry efforts, Alzheimer's disease (AD) remains the only leading cause of death for which no disease-modifying treatment is available. Disappointing clinical trials over the last several years have led to a growing consensus on the need to intervene earlier in the disease process, before the onset of any clinical symptoms. However, drug development at this stage is challenging given the difficulty of assessing a therapeutic benefit in subjects who are, by definition, clinically healthy. The US FDA recently issued new draft guidance for trials in early AD, which revised the taxonomy of AD by recognizing four stages of the disease, including an expanded view of the predementia stage. These guidelines further advance regulatory support for clinical trials in earlier stages of AD. We discuss the basis for this change and the impact it may have on early-intervention AD trials as well as on stimulating the need for improved biomarkers and outcome measures that will be required for a disease-modifying drug to win approval.

Figure 1.. The Delayed-Start Design

Participants are randomized to the same active treatment but starting at different times, resulting in two treatment periods: a placebo-controlled period followed by an active period. During the placebo-controlled period, participants receive either placebo or active treatment. During the delayed-start period, placebo participants are switched to active treatment and thus become delayed-start participants. Participants on active treatment during the placebo-controlled period continue to receive active treatment during the delayed-start period and are labeled as early-start participants. If the treatment difference observed at the end of the placebo-controlled period was preserved at the end of the delayed-start period (i.e. delayed-start patients do not “catch up” with the early start patients), the treatment effect is considered consistent with a disease-modifying effect.

Figure 2.. Steps in Recruiting Biomarker Eligible Participants into Preclinical/Prodromal trials

Implementation of a web-based tool to capture demographic, genetic and longitudinal clinical and cognitive information on cognitively normal individuals interested in AD prevention trials. The data generates risk scores for AD pathology that allows selection of candidates for in-person biomarker and clinical assessment. Individuals with biomarker-confirmed evidence of brain amyloid accumulation are invited to join the Trial Ready Cohort (TRC) with semi-annual in-person follow-up visits within the network of pre-qualified clinical sites from which they can be invited to enroll in prevention trials.