"Time Saved" Calculations to Improve Decision-Making in Progressive Disease Studies.

ABSTRACT

BACKGROUND: Disease modifying therapies (DMTs) may be most beneficial in early disease, when progression is slow and changes small, with clinical relevance difficult to interpret. OBJECTIVES: Time component tests (TCTs) translate differences between treatments from mean change, vertical distance between longitudinal trajectories, into intuitively understood time saved, horizontal distance between trajectories, which can be readily combined across endpoints in a global TCT (gTCT). DESIGN: The value of composites, time savings estimates, and combination scores to optimize measurement and interpretation of DMTs are demonstrated, along with construction details and simulation studies. SETTING: TCT methods were applied to a randomized phase II clinical trial. PARTICIPANTS: Patients with early Alzheimer's disease (N=332). INTERVENTION Three treatment groups with AFFITOPE® AD02 and two control groups with aluminum oxyhydroxide, AD04. MEASUREMENTS The co-primary efficacy outcomes were an adapted ADAS-Cog (aADAS) and adapted ADCS-ADL (aADL), which were optimized composite scales specific to cognitive and functional domains. A composite based on these two scores was the study's prespecified primary outcome. The CDR-sb and standard non-adapted ADCS-ADL and ADAS-Cog scales were prespecified secondary outcomes. RESULTS: The AD04 2 mg group showed some statistically significant effects compared with other study arms. It is unclear whether the observed 3.8-point difference on the composite is clinically meaningful. TCT results show a time savings of 11 months in an 18-month study with AD04 2 mg. CONCLUSION: The relevance of 11 months saved is more universally understood than a mean difference of 3.8 points in the composite outcome. These results suggest that a combination of a composite approach and a time savings interpretation offers a powerful approach for detecting and interpreting disease modifying effects.