Table 1.

Data supporting disease-modification by a putative DMT

Trial design

• Staggered start

• Randomized withdrawal

• Drug-placebo difference at trial completion on accepted clinical outcomes and validated biomarkers

• Delay to clinical milestones with supporting biomarkers

Supportive analyses of the trial data

• Change in slope of decline over multiple observation points

• Increasing drug-placebo difference over time

• Biomarker changes correlated with clinical changes

• Dose response relationship of clinical outcomes with the intervention

• Delay to milestone (e.g., % of subjects with prodromal AD reaching CDR 1 at specified times)

• In a modified delayed start design, observe if patients switched from placebo to active therapy when entering the open label extension phase of the study “catch up” with those on active treatment throughout the study

Biomarker measures

• Single biomarker outcomes reflecting an effect on underlying pathophysiology contributing to clinical progression

• Multiple biomarker outcomes measuring one aspect of the disease (e.g, CSF Aβ and amyloid imaging)

• Multiple biomarker outcomes assessing downstream or independent effects of an intervention (e.g, CSF tau/p-tau or MRI following anti-amyloid treatment)

• Dose-response relationship of biomarker changes with the intervention

Non-clinical observations

• Effect on mechanisms central to the proposed pathophysiology of AD