This perspective evaluates what constitutes robust evidence of disease modification in Alzheimer's disease (AD) trials, with a focus on appraising extension data from lecanemab (Clarity AD OLE) and donanemab (TRAILBLAZER-ALZ 2 LTE) using a proposed clinician's appraisal checklist and hierarchy of trial designs.
Neither the Clarity AD OLE (lecanemab) nor the TRAILBLAZER-ALZ 2 LTE (donanemab) meets criteria for demonstrating disease modification: both lack a pre-specified disease-modification hypothesis, formal hypothesis testing, an effect-preservation margin, and transparent tabular LS mean data. In TRAILBLAZER-ALZ 2, both early- and delayed-start groups worsened by ~4 points on CDR-SB regardless of timing, suggesting delayed-start participants did catch up to early-start ones.
This is a perspective/commentary, not an original trial — no new primary data are generated. The appraisal checklist and design hierarchy are expert-proposed frameworks, not empirically validated tools. The authors have a stated critical stance toward the extension studies, which may influence framing.
Clinicians should not accept open-label extension or external-control comparison data as proof of disease modification for lecanemab or donanemab — neither study was designed or analyzed to support that claim. When evaluating any AD disease-modification claim, apply the checklist: look for a prospective delayed-start RCT design, a pre-specified effect-preservation margin, reported LS mean differences with 95% CIs, and pre-specified missing-data sensitivity analyses.
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