# Effect of early administration of tetracosactide on mortality and host response in critically ill patients requiring rescue surgery: a sensitivity analysis of the STOPSHOCK phase 3 randomized controlled trial

## TL;DR

A drug called tetracosactide reduced 30-day mortality and bleeding in critically ill patients needing emergency surgery, according to a sensitivity analysis.

## Contribution

The study demonstrates tetracosactide's potential to improve outcomes in undifferentiated shock through a novel sensitivity analysis approach.

## Key findings

- Tetracosactide reduced 30-day mortality from 8 deaths in the control group to 0 deaths in the treatment group.
- Tetracosactide significantly reduced blood transfusion episodes and bleeding cases in critically ill patients.
- Baseline Flt3L levels were associated with lower bleeding rates in tetracosactide-treated patients.

## Abstract

Undifferentiated shock is recognized as a criticality state that is transitional in immune-mediated topology for casual risk of lethal microcirculatory dysfunction. This was a sensitivity analysis of a drug (tetracosactide; TCS10) targeting melanocortin receptors (MCRs) in a phase 3 randomized controlled trial to improve cardiovascular surgical rescue outcome by reversing mortality and hemostatic disorders.

Sensitivity analysis was based on a randomized, two-arm, multicenter, double-blind, controlled trial. The Naïve Bayes classifier was performed by density-based sensitivity index for principal strata as proportional hazard model of 30-day surgical risk mortality according to European System for Cardiac Operative Risk Evaluation inputs-outputs in 100 consecutive cases (from August to September 2013 from Emilia Romagna region, Italy). Patients included an agent-based TCS10 group (10 mg, single intravenous bolus before surgery; n = 56) and control group (n = 44) and the association with cytokines, lactate, and bleeding-blood transfusion episodes with the prior-risk log-odds for mortality rate in time-to-event was analyzed.

Thirty-day mortality was significantly improved in the TCS10 group vs. control group (0 vs. 8 deaths, P < 0.0001). Baseline levels of interleukin (IL)-6, IL-10, and lactate were associated with bleeding episodes, independent of TCS10 treatment [odds ratio (OR) = 1.90, 95% confidence interval (CI) 1.39–2.79; OR = 1.53, 95%CI 1.17–2.12; and OR = 2.92, 95%CI 1.40–6.66, respectively], while baseline level of Fms-like tyrosine kinase 3 ligand (Flt3L) was associated with lower bleeding rates in TCS10-treated patients (OR = 0.31, 95%CI 0.11–0.90, P = 0.03). For every 8 TCS10-treated patients, 1 bleeding case was avoided. Blood transfusion episodes were significantly reduced in the TCS10 group compared to the control group (OR = 0.32, 95%CI 0.14–0.73, P = 0.01). For every 4 TCS10-treated patients, 1 transfusion case was avoided.

Sensitivity index underlines the quality target product profile of TCS10 in the runway of emergency casualty care. To introduce the technology readiness level in real-life critically ill patients, further large-scale studies are required.

European Union Drug Regulating Authorities Clinical Trials Database (EudraCT Number: 2007-006445-41).

The online version contains supplementary material available at 10.1186/s40779-024-00555-2.