Potential impact of unblinding on observed treatment effects in Alzheimer's disease trials.

Abstract

Adverse effects of monoclonal antibodies against amyloid beta are common, and may affect validity of randomized controlled trials (RCTs) through unblinding of participants. We used observations from published phase 3 RCTs in Alzheimer's disease to calculate the magnitude of unblinding effects on cognition that would be required to explain observed cognitive benefits in RCTs. In trials of lecanemab, aducanumab, and donanemab, incidence of amyloid-related imaging abnormalities with active treatment ranged from 22% to 44%, the vast majority of which presumably led to unblinding. Effects of unblinding on the Clinical Dementia Rating Sum of Boxes required to fully explain observed drug effects ranged from 1.1 point (95% confidence interval: 0.2-2.0) with aducanumab, to 3.3 points (2.1-4.4) with donanemab and 3.7 points (2.0-5.6) with lecanemab. Infusion-related reactions were common, with potential unblinding effects particularly for lecanemab. Similar patterns were observed for the Alzheimer's Disease Assessment Scale Cognitive subscale. Psychological treatment effects due to unblinding may explain a substantial share of observed treatment effects in RCTs.