Sepsis
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Introduction
Sepsis is an exceptionally challenging area to do research, with virtually no effective treatments. Berry designed trials in this area thus aspire to optimize delivery of potential therapy and efficiently utilize available resources. This has been accomplished through the use of response adaptive randomization across different doses in phase 2, adaptive stopping for futility and success, the construction of trials which simultaneously monitor multiple endpoints, and seamless 2/3 designs.
Berry Examples and Case Studies
SEPSIS-ACT investigated selepressin for the treatment of sepsis. SEPSIS-ACT was a seamless 2/3 trial, initially consisting of a dose ranging portion exploring multiple doses of selepressin compared to a control arm. During this phase 2 dose ranging, response adaptive randomization was employed to increase allocation to more promising doses and lower allocation to less promising doses. This strategy increases the power of the dose ranging and increases the probability of selecting the correct dose. If selepressin had demonstrated sufficient promise in the phase 2 portion, SEPSIS-ACT would have selected a dose and seamlessly moved into a confirmatory phase 3 stage with continuing interim analyses allowing for the trial to stop early for both success or futility. Unfortunately, selepressin did not demonstrate sufficient promise to proceed to the phase 3 component of the trial.
VICTAS investigated Vitamin C, Thiamine, and Steroids (“HAT therapy”). While this regimen had been suggested based on a small study, significant doubt existed regarding its efficacy. As such, VICTAS was designed to both obtain high power should HAT therapy be effective while still declaring futility as early as possible if not. This was accomplished using multiple interim analyses. VICTAS also employed a novel methodology and monitored both days free from ventilator and vasopressors (VVFD) as well as mortality. While VVFD is more sensitive and more likely to generate a conclusive answer, significant interest remained on mortality. At the interim analyses in VICTAS, had efficacy been demonstrated on VVFD, the trial could “bypass” the early stop if the mortality data were sufficiently promising that a significant effect on mortality might be obtained. VICTAS stopped for futility, as did many other trials investigating HAT therapy.
RACE investigated L-Carnitine in phase 2. The trial employed response adaptive randomization across multiple doses, similar to SEPSIS-ACT, and also had a novel “go/no-go” definition of trial success, requiring a demonstration of success on SOFA score as well as a sufficiently high predictive probability of success on mortality in phase 3. In other words, the RACE primary analysis directly assessed the likelihood future trials would be successful. RACE also stopped early for futility.
While all three trials stopped early for futility, this represents a key point of their design. While it is unfortunate sepsis is so challenging, the ability to stop trials early and move on to more promising therapies as quickly as possible both saves resources and provides the best opportunity to eventually find an effective therapy for this high mortality condition.
