The Senolytics To slOw Progression of Sepsis (STOP-Sepsis) trial is underway to evaluate the efficacy of senolytics in elderly patients diagnosed with sepsis. This study, detailed in Trials, aims to address the urgent need for effective treatments to combat sepsis, a life-threatening condition characterized by organ dysfunction resulting from a dysregulated host response to infection.
The STOP-Sepsis trial employs a Bayesian response-adaptive randomization design to efficiently explore different doses of the senolytic drug fisetin. This approach allows for interim monitoring and dose adjustments based on the predictive probability of success in a future Phase 3 clinical trial. The study focuses on elderly patients, a population particularly vulnerable to the severe consequences of sepsis.
Trial Design and Endpoints
The primary clinical endpoint is the difference in the composite cardiovascular, respiratory, and renal Sequential Organ Failure Assessment (CRR-SOFA) score at baseline compared to 7 days post-enrollment (ΔCRR-SOFA7). This score reflects the severity of organ dysfunction and is a critical indicator of sepsis progression. Secondary endpoints include organ failure-free days through 28 days (OFFD28), total SOFA score, Zubrod performance status, and SF-12 score, providing a comprehensive assessment of treatment effects.
The Bayesian probability model jointly analyzes ΔCRR-SOFA7 and OFFD28. Interim analyses, planned after enrolling approximately 100 and 180 participants, will assess the posterior probability that the mean ΔCRR-SOFA7 is lower in the treatment group compared to the control, as well as the predictive probability of success in a future Phase 3 trial using OFFD28 as the primary endpoint.
Statistical Analysis
The primary analysis will be based on ΔCRR-SOFA7, with the joint model incorporating OFFD28 used for interim monitoring. The posterior distributions for all model parameters will be approximated via Gibbs Sampling implemented in JAGS using the R package rjags. The trial may be terminated early for superiority if a dose is significantly different from the control and if there is confidence that the selected dose would be successful in a future Phase 3 clinical trial. Futility will be declared if the predictive probability of success is below a pre-defined threshold for all doses.
Secondary analyses will include linear regression models adjusting for age, race, sex, and other covariates. Biologic endpoints will also be considered, comparing the change from baseline to day 7 between patients randomized to each dose of fisetin versus those randomized to placebo. These analyses will be adjusted for potential confounders using ANCOVA and linear mixed models.
Subgroup and Sensitivity Analyses
Pre-planned subgroup analyses will examine the consistency of treatment effects across subgroups defined by age, race, sex, and SOFA score. Sensitivity analyses will address potential missing data using multiple chained imputation and data augmentation in the Gibbs sampler, ensuring the robustness of the trial's conclusions.
The STOP-Sepsis trial represents a significant effort to identify effective senolytic therapies for sepsis in elderly patients, utilizing a sophisticated Bayesian adaptive design to optimize dose selection and improve the efficiency of the clinical trial process.
