“Time Saved” Calculations to Improve Decision-Making in Proof-of-Concept Studies as Illustrated with a Post-hoc Analysis of IMM-AD04 Phase 2 Data in Patients with Early Alzheimer's Disease

Disease modifying therapies (DMTs) are hypothesized to be most beneficial in early disease when progression is slow and mean changes will be small. Therefore, even highly effective therapies will yield small absolute differences whose clinical relevance may be hard to interpret. Time component tests (TCTs) translate differences between treatments in mean change – the vertical distance between longitudinal trajectories, into an intuitively understood metric of time saved – the horizontal distance between trajectories. This corresponds to maintenance of independence with active treatment. DMTs are likely to impact multiple disease domains simultaneously and on the timescale these outcomes can be readily combined in a global time component test (gTCT). Use of gTCTs reflects a critical shift from emphasizing single outcomes and minimally clinically important effects to valuing true disease slowing, and incremental, but permanent benefits on an entire progressive disease. gTCTs are particularly helpful early in clinical development because combining across scales measuring multiple domains reduces noise and improves power. Clinical outcomes, such as ADAS-Cog, ADCS-ADL, and CDR-sb, reflect different aspects of disease progression and convergence of time savings results across these outcomes is evidence of an upstream effect on the cascade of events leading to neurodegeneration. By tailoring the statistical analysis to treatments with disease modifying effects, treatment effect estimates will be more precise thereby increasing statistical power when multiple endpoints are affected. Results will have less power with symptomatic treatments that primarily impact only one endpoint. The TCT was applied to a phase II clinical trial with a composite scale as the primary outcome. 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 measure is clinically meaningful; however, the TCT results show a time savings of 11 months in an 18 month study with AD04 2 mg. 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 gTCT (time savings) interpretation offers a powerful approach for detecting disease modifying effects.