Epirubicin for the Treatment of Sepsis & Septic Shock (EPOS-1)

The study will assess the safety of low doses of epirubicin in sepsis patients. Therefore the study will look for side effects in patients treated with low dose epirubicin compared to control patients.

In animals, low dose epirubicin has been shown to induce tolerance to infection and increase survival in septic mice.

The study will also look for positive effects on organ function in humans. The investigators hypothesize that low-dose epirubicin can be used therapeutically to improve the disease course and lessen mortality of patients with sepsis. In a first step, the investigators aim at proving that low-dose epirubicin can safely be administered to sepsis patients and will perform a dose-escalation multi-center trial.

Study Overview

• Status: Recruiting
• Conditions: Sepsis
• Intervention / Treatment: Drug: Placebo; Drug: Epirubicin

Detailed Description

There are two ways for organism to deal with infection. Resistance, which means elimination of infectious microorganisms by the immune system, is widely recognized. It can be supported by antibiotic medication and surgical or interventional drainage of an infectious focus. The other response is tolerance, which means limiting organ damage without fighting the infection itself. Its importance has become more clearly recently, but so far there are no therapeutic interventions to support this mechanism.

Epirubicin is a chemotherapeutic substance used to treat cancer. In animal experiments, it has been shown that doses much lower than the ones used in oncology, can induce tolerance in infected animals. Animals treated with epirubicin survive an infectious dose that kills animals not treated with epirubicin. Before this approach can be studied in a large group of sepsis patients, it is necessary that epirubicin in low doses can be safely used in this population.

Therefore in this study, septic patients will be treated with low doses of epirubicin and systematically assessed for serious side effects. Some patients will be treated with placebo for comparison. The trial will be conducted as a dose escalation study with three groups. This means that the first group of patients will receive only a quarter of the dose shown to be effective in animal experiments. Only if no serious side effects are observed will the dose be increased in the second group and again in the third group.

In addition, the study will look for signs of beneficial effects on organ function in human patients with sepsis, pharmacokinetics of epirubicin in sepsis patients and changes in the inflammatory response.

The investigators hypothesize that low-dose epirubicin can be used therapeutically to improve the disease course and lessen mortality of patients with sepsis. In a first step, the investigators aim at proving that low-dose epirubicin can safely be administered to sepsis patients and will perform a phase IIa dose-escalation multi-center trial.

• Study Type: Interventional
• Enrollment (Estimated): 45
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Sebastian Weis, M.D.; Phone Number: 3100 +49 (0) 3641-932; Email: Sebastian.Weis@med.uni-jena.de
• Study Contact Backup: Name: Daniel O Thomas-Rüddel, M.D.; Phone Number: 3267 +49 (0) 3641-932; Email: Daniel.Thomas@med.uni-jena.de

Study Locations

• Germany
  • Bochum, Germany, 44892
    • Not yet recruiting
    • University Hospital Knappschafstkrankenhaus Bochum
    • Contact: Tim Rahmel, M.D.; Phone Number: 80025 +49 234 299; Email: Tim.Rahmel@kk-bochum.de
    • Contact: Hartmuth Nowak, M.D.; Phone Number: 80039 +49 (234) 299; Email: hartmuth.nowak@kk-bochum.de
    • Principal Investigator: Tim Rahmel, M.D.
    • Sub-Investigator: Hartmuth Nowak, M.D.
  • Greifswald, Germany, 17489
    • Not yet recruiting
    • University Medicine Greifswald
    • Contact: Matthias Gründling, M.D.; Phone Number: 5810 +49 (0) 3834 86; Email: matthias.gruendling@med.uni-greifswald.de
    • Contact: Sven-Olaf Kuhn, M.D.; Phone Number: 5801 +49 (0) 3834 86; Email: sven-olaf.kuhn@med.uni-greifswald.de
    • Principal Investigator: Matthias Gründling, M.D.
    • Sub-Investigator: Sven-Olaf Kuhn, M.D.
    • Sub-Investigator: Christian Fuchs, M.D.
  • Hamburg, Germany, 20251
    • Not yet recruiting
    • Universitatsklinikum Hamburg Eppendorf
    • Contact: Axel Nierhaus, M.D.; Phone Number: 55325 +49 (0) 40 7410; Email: nierhaus@uke.de
    • Contact: Grit Ringeis; Phone Number: 35315 +49 (0) 40 7410; Email: g.ringeis@uke.de
    • Principal Investigator: Axel Nierhaus, M.D.
  • Würzburg, Germany, 97080
    • Not yet recruiting
    • Universitatsklinikum Wurzburg
    • Contact: Patrick Meybohm, Prof.; Phone Number: 30000 +(49)931-201; Email: meybohm_p@ukw.de
    • Contact: Eva Kranke; Phone Number: 30024 +(49)931-201; Email: kranke_e@ukw.de
    • Principal Investigator: Patrick Meybohm, Prof.
    • Sub-Investigator: Peter Kranke, M.D.
  • Thuringia
    • Jena, Thuringia, Germany, 07747
      • Recruiting
      • Jena University Hospital
      • Contact: Sebastian Weis, M.D.; Phone Number: 3100 +49 (0) 3641-932; Email: Sebastian.Weis@med.uni-jena.de
      • Contact: Daniel O Thomas-Rüddel, M.D.; Phone Number: 3267 +49 (0) 3641-932; Email: Daniel.Thomas@med.uni-jena.de
      • Principal Investigator: Sebastian Weis, M.D.
      • Sub-Investigator: Daniel Thomas-Rüddel, M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• admitted to the ICU with sepsis or septic shock, diagnosed within the previous 24 hours

Exclusion Criteria:

• Leukopenia/Neutropenia/Thrombocytopenia-prior or upon inclusion (Leucocyte Count <4000/μL; Neutrophile/ platelets Count below Lower Limit of Normal).
• Weight >135 kg/BMI >45.
• Active neoplasia.
• History of chemotherapy.
• Hypersensitivity to epirubicin
• History of bone marrow or solid organ transplantation.
• Immunosuppressive therapy.
• Acute severe infection within 4 weeks prior to admission (Hospitalization or admission to higher level clinical care facility for infection).
• Chronic infection.
• Cardiomyopathy with a documented ejection fraction <30% or AICD (automatic internal cardioverter defibrillator) implantation.
• Acute liver failure following the European Association for the Study of the Liver definition as International Normalized Ratio (INR) >1.5 and elevation of transaminases > 3 times of the upper normal limit (2).
• Pregnancy during all trimesters/breast-feeding.
• Chronic mechanical ventilation dependency.
• Cystic fibrosis.
• Concomitant medication with Verapamil or Cimetidine.
• Prior enrollment in this study.
• Participation in another clinical intervention trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Administration of NaCl i.v. as placebo once.	Drug: Placebo; NaCl is given once over 15 Minutes via a central line
Experimental: Epirubicin Phase I; Administration of epirubicin i.v. 3.75 mg/m2 once.	Drug: Epirubicin; Epirubicin is given once over 15 Minutes via a central line
Experimental: Epirubicin Phase II; Administration of epirubicin i.v. 7.5 mg/m2 once.	Drug: Epirubicin; Epirubicin is given once over 15 Minutes via a central line
Experimental: Epirubicin Phase III; Administration of epirubicin i.v. 15 mg/m2 once.	Drug: Epirubicin; Epirubicin is given once over 15 Minutes via a central line

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with myelotoxicity	Neutropenia or thrombocytopenia of grade 3 or 4 (neutrophiles <1,000μL or platelets <50,000/μL) at two consecutive study visits up to day 14 accompanied by neutropenia or thrombocytopenia of grade 2, 3 or 4 (neutrophiles <1,500μL or platelets <75,000/μL) at both study visits and accompanied by an IPF (immature platelet fraction) below 2.5% at one or two of the consecutive study visits.	Up to 14 days after administration of study drug

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival at day 14, 28 and 90	Survival	14, 28 and 90 days
SOFA score	SOFA (sequential organ failure assessment) on days of assessment, mean total SOFA and SOFA changes over time	Up to 14 days after administration of study drug
Cardiotoxicity	Ejection fraction measured via TTE (trans-thoracic echocardiography)	7 days after administration of study drug
"Success" rate	Decrease of procalcitonin (PCT) serum concentration by 80% or more of its intra-individual peak value or to 0.5 μg/L or lower within 72 hours after randomization	3 days after administration of study drug
Adverse events	Overall rate of adverse and severe adverse events. The the frequency of other typical side effects (diarrhea, mucositis, alopecia, nausea and vomiting).	Up to 90 days after administration of study drug
Quality of life assesed by the SF-36 questionaire	The short Form 36 Health Questionnaire (SF-36) contains 36 questions on quality of life. From the answers a Physical Component Summary (PCS) and a Mental Component Summary (MCS) are calculated, both ranging approximately from 0 (severe disability) up to 80 (absence of disability).	At follow up 90 days after administration of study drug
Fluid balance and urine output	Assessment of fluid balance and urine output	Up to 14 days after administration of study drug
Need for renal replacement therapy	Use of renal replacement therapy for chronic or acute kidney failure	Up to 14 days after administration of study drug
Oxygenation index (paO2/FiO2)	The ratio of arterial oxygen partial pressure and the fraction of inhaled oxygen will be calculated. For patients receiving conventional low flow oxygen FiO2 will be estimated based on a predefined table.	Up to 14 days after administration of study drug
Need for respiratory support	The highest level of respiratory support will be documented.	Up to 14 days after administration of study drug
Need for catecholamines and inotropes	For all catecholamines and inotropes the highest daily rate administerd for at least one hour will be documented.	Up to 14 days after administration of study drug

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Epirubicin plasma concentrations	Epirubicin concentrations in the plasma will be measured using mass-spectrometry	At 15minutes and at 1, 2, 3, 6, 12, and 24 hours after administration of study drug
DNA damage	DNA damage in peripheral mononuclear blood cells (PBMC) will be assessed. Further assessment of molecular parameters from the PBMCs reflecting epirubicin effects on the DNA or damage control pathways will be performed subsequently	Up to 7 days after administration of study drug
Cytokines	Plasma cytokines will be determined in all patients using Luminex xMAP or alike multiplex technology	Up to 14 days after administration of study drug
Organ damage markers	Non-conventional sensitive organ damage markers (e.g. NGAL) will be measured	Up to 14 days after administration of study drug
Anti-PF4 anti-bodies	Determination of anti-PF4 (platelet factor 4) anti-bodies	Up to 14 days after administration of study drug
Mitochondrial function	Molecular parameters for mitochondrial function will be assessed from isolated PBMCs	Up to 7 days after administration of study drug

Collaborators and Investigators

• Sponsor: Jena University Hospital
• Collaborators: University Medicine Greifswald; Ruhr University of Bochum
• Investigators: Principal Investigator: Sebastian Weis, M.D., Jena University Hospital

Publications and helpful links

General Publications

• Figueiredo N, Chora A, Raquel H, Pejanovic N, Pereira P, Hartleben B, Neves-Costa A, Moita C, Pedroso D, Pinto A, Marques S, Faridi H, Costa P, Gozzelino R, Zhao JL, Soares MP, Gama-Carvalho M, Martinez J, Zhang Q, Doring G, Grompe M, Simas JP, Huber TB, Baltimore D, Gupta V, Green DR, Ferreira JA, Moita LF. Anthracyclines induce DNA damage response-mediated protection against severe sepsis. Immunity. 2013 Nov 14;39(5):874-84. doi: 10.1016/j.immuni.2013.08.039. Epub 2013 Oct 31.

Study record dates

Study Major Dates

• Study Start (Actual): October 19, 2022
• Primary Completion (Estimated): October 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: August 4, 2021
• First Submitted That Met QC Criteria: August 30, 2021
• First Posted (Actual): September 5, 2021

Study Record Updates

• Last Update Posted (Actual): March 12, 2024
• Last Update Submitted That Met QC Criteria: March 11, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: pilot study; epirubicin; disease tolerance; myelotoxicity
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Toxemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Epirubicin
• Other Study ID Numbers: EPOS_ZKSJ0134; 2021-002300-12 (EudraCT Number); 01EN2001 (Other Grant/Funding Number: German Federal Ministry of Education and Research); DRKS00025884 (Registry Identifier: German Clinical Trials Register)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No