1. Epirubicin for the Treatment of Sepsis and Septic Shock (EPOS-1): study protocol for a randomised, placebo-controlled phase IIa dose-escalation trial
- Author
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Peter Schlattmann, Thomas Lehmann, Tim Rahmel, Johannes Roth, Peter Kranke, Frank M Brunkhorst, Andreas Greinacher, Patrick Meybohm, Philipp Helmer, Stefan Hagel, Florian Rißner, Michael Bauer, Matthias Gründling, Sven-Olaf Kuhn, Christian Fuchs, Luis Ferreira Moita, Frank Bloos, Matthias Michael, Ulrike Schumacher, Matthias Unterberg, Daniel Thomas-Rüddel, Christiane Helbig, Johannes Ehler, Heiko Schenk, Thomas Köcher, Markus Gräler, Ann-Julika Heger, Sebastian Weis, Karen Dlubatz, Jakob Hammersen, Katja Leonhardt, René Markgraf, Franziska Röstel, Nicole Schwarze, Mariann Städtler, Wolfgang Vivas-Varela, Andre Hagedorn, Andrea Wittkowski, Florian Rumpf, Tobias Haas, Sebastian Hottenrott, Eva Kranke, Marianne Neuf, Anke Reppchen, Daniel Röder, and Julius Schmidt
- Subjects
Medicine - Abstract
Introduction Sepsis remains the major cause of death among hospitalised patients in intensive care. While targeting sepsis-causing pathogens with source control or antimicrobials has had a dramatic impact on morbidity and mortality of sepsis patients, this strategy remains insufficient for about one-third of the affected individuals who succumb. Pharmacological targeting of mechanisms that reduce sepsis-defining organ dysfunction may be beneficial. When given at low doses, the anthracycline epirubicin promotes tissue damage control and lessens the severity of sepsis independently of the host–pathogen load by conferring disease tolerance to infection. Since epirubicin at higher doses can be myelotoxic, a first dose–response trial is necessary to assess the potential harm of this drug in this new indication.Methods and analysis Epirubicin for the Treatment of Sepsis and Septic Shock-1 is a randomised, double-blind, placebo-controlled phase 2 dose-escalation phase IIa clinical trial to assess the safety of epirubicin as an adjunctive in patients with sepsis. The primary endpoint is the 14-day myelotoxicity. Secondary and explorative outcomes include 30-day and 90-day mortality, organ dysfunction, pharmacokinetic/pharmacodynamic (PK/PD) and cytokine release. Patients will be randomised in three consecutive phases. For each study phase, patients are randomised to one of the two study arms (epirubicin or placebo) in a 4:1 ratio. Approximately 45 patients will be recruited. Patients in the epirubicin group will receive a single dose of epirubicin (3.75, 7.5 or 15 mg/m2 depending on the study phase. After each study phase, a data and safety monitoring board will recommend continuation or premature stopping of the trial. The primary analyses for each dose level will report the proportion of myelotoxicity together with a 95% CI. A potential dose-toxicity association will be analysed using a logistic regression model with dose as a covariate. All further analyses will be descriptive.Ethics and dissemination The protocol is approved by the German Federal Institute for Drugs and Medical Devices. The results will be submitted for publication in peer-reviewed journals.Trial registration number NCT05033808.
- Published
- 2024
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