Seeking optimal repeated fluid biomarker assessments to enhance precision and statistical power in clinical trials:...

Plasma biomarkers are increasingly used as surrogate outcomes in clinical trials for Alzheimer's disease and related dementias (ADRD) due to their non-invasive nature. In early-phase trials designed to evaluate mechanisms of action and biological efficacy, assessing pre-post changes in plasma biomarkers within the same individuals - using a single-arm placebo lead-in design - offers a potentially cost-effective alternative to parallel-group designs by minimizing between-subject variability. However, plasma biomarkers are also subject to within-individual variability, which can obscure true treatment effects.

One strategy to address this limitation is to collect repeated measures during each study period. This approach can improve measurement precision, enhance the signal-to-noise ratio, and increase statistical power, even with modest sample sizes.

We propose an innovative early-phase trial design, Single-arm Lead-In with Multiple measures (SLIM), which incorporates repeated biomarker assessments over a short follow-up period.

Using simulation studies, we demonstrate that the SLIM design can substantially reduce required sample sizes.

SLIM involves repeated biomarker assessments during both the lead-in and post-treatment periods. It minimizes between-subject variability and improves the precision of within-subject estimates. It is well suited for early-phase, short-duration trials. It is not suitable for cognitive tests or other outcomes prone to practice or placebo effects. SLIM design can be an alternative to the traditional parallel design by reducing required sample sizes, thereby lowering the recruitment burden.