TRAILBLAZER‐ALZ 3 – A Deeper Dive into Time‐to‐Event Trials

Abstract

AbstractBackgroundThe pathophysiologic process of Alzheimer’s Disease (AD) is underway before cognitive decline becomes evident (i.e.; preclinical AD). Beginning treatment during this phase is believed to lead to beneficial outcomes in terms of disease progression. TRAILBLAZER‐ALZ 3 (TB3; NCT05026866) is an ongoing Phase 3 decentralized clinical trial assessing the effect of donanemab, a monoclonal antibody that removes amyloid plaques via microglial‐mediated clearance, versus placebo on clinical progression in preclinical AD. Clinical outcomes are assessed virtually by using central raters, psychometric examinations, and self‐administered tests. The primary endpoint of interest is the time to clinical progression as measured by the Clinical Dementia Rating scale global score (CDR‐GS).MethodTwo of the most frequently used methods to analyze time‐to‐event data are Kaplan‐Meier curves and Cox proportional hazards models. In TB3, the primary endpoint will be assessed via a Cox proportional hazard regression model. The key assumptions that will be made with this modeling approach are proportionality and censoring. Proportionality refers to the relative hazard being constant over time and how to treat censored observations, which refers to patients who do not reach the event during the observation period. While this approach has been used in fields such as oncology, we have adapted it for the assessment of time to clinical progression of AD cognitive decline. From this approach the hazard ratio, an estimate on the instantaneous risk, can be calculated. This measure can give insight, at a given time point, of the risk of progression of AD that a participant has.We will also look at additional considerations of collecting data in a decentralized remote manner, such as missing data due to technology issues, and highlight the approaches that will be used to analyze additional cognitive and biomarker data.ResultThis investigation will show that we have adapted analytic techniques to determine the time to clinical progression of AD as measured by an increase in CDR‐GS from baseline at 2 consecutive visits.ConclusionWe present an analytical method of assessing potential treatments to slow disease progression during the preclinical AD phase without requiring centralized assessment sites.