OBJECTIVES: Alzheimer’s Disease (AD) is a progressive neurodegenerative disease associated with significant costs. Many AD therapeutic trials fail to demonstrate clinical significance. This work presents a method for reframing clinical significance in terms of a meaningful delay in time to the level of cognitive functioning associated with substantial new costs (e.g., increased home care needs [HCN] or care facility admission [CFA]).

METHODS: We propose employing a time-to-event (TTE) model to evaluate AD treatment benefit in the context of cognitive functioning. First, an event is defined as the threshold of cognitive functioning associated with new financial costs. Second, statistical significance is determined: a TTE model evaluates the significance of the association between treatment and TTE delay. Lastly, clinical significance is determined: the calculated TTE delay is presented to an appropriate audience to evaluate clinical meaningfulness of the estimated effect. For example, an estimated 4-month delay in time to CFA is presented to AD caregivers. Caregivers then rate the extent to which this delay would be meaningful to them. If an acceptably high percentage agree it’s meaningful, then a clinical significance criterion has been generated and validated. To illustrate the approach, results are presented from an empirical AD trial.

RESULTS: An ADAS-Cog score of ≥31.92 was associated with a substantial HCN increase and defined as an event. Assumptions were met and a Cox model was fit; AD treatment significantly reduced the hazard of increased HCN by 27.4% and delayed median TTE 3 months compared to placebo.

CONCLUSIONS: This analysis can be seen as proof-of-concept for an approach characterizing treatment effect in terms of delays to pre-defined cognitive thresholds. This approach provides objective valuation information by linking AD therapy value to avoided costs that would otherwise occur in the absence of treatment. Next steps include presenting the estimated TTE delay to AD caregivers to determine clinical meaningfulness.