The development of new cardiovascular therapies carries significant risk into Phase 3, with substantial investment required on the basis of surrogate endpoint data which may support engagement with a novel mechanism of action that is not yet validated in terms of a link with clinical outcome. A case-study will be presented describing how this risk was managed via a novel two-stage design as implemented in the LATITUDE TIMI 60 trial [1], which was conducted to assess a p38 MAP kinase inhibitor in the treatment of acute coronary syndrome. The trial comprised a leading cohort (Part A) to support an initial assessment of safety and efficacy, with sponsor review of Part A results prior to starting a much larger confirmatory cohort (Part B). The two parts of the study were designed as a single, operationally-seamless protocol. The statistical and graphical techniques employed to support the trial design will be presented, with reference to simulation of virtual trials for determining a risk-balanced size for Part A in the absence of a traditional power-based significance test, and the use of trellis graphics describing the operating characteristics of futility interims embedded in Part B. The underlying theory supporting the assessment of the multi-interim Part B design will be briefly discussed with illustration of how the integrals required for operating-characteristic assessment can be straightforwardly calculated in R. General questions regarding interim-analysis governance will also be raised for further discussion.

[1].O ’Donoghue ML, Glaser R, Aylward PE, Cavender MA, Crisp A, Fox KAA, Laws L, Lopez-Sendon JL, Steg PG, Theroux P, Sabatine MS and Morrow DA. Rationale and design of the LosmApimod To Inhibit p38 MAP kinase as a TherapeUtic target and modify outcomes after an acute coronary syndrome trial. American Heart Journal 2015; 169 (5): 622 – 630.