Epirubicin for the Treatment of Sepsis & Septic Shock

Sepsis Clinical Trial

— EPOS-1  

Official title:

Epirubicin for the Treatment of Sepsis & Septic Shock

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05033808
• Other study ID #: EPOS_ZKSJ0134
• Secondary ID: 2021-002300-1201
• Status: Recruiting
• Phase: Phase 2
• Start date: October 19, 2022
• Est. completion date: December 2024

Study information

• Verified date: February 2024
• Source: Jena University Hospital
• Contact: Sebastian Weis, M.D.
• Phone: +49 (0) 3641-932
• Email: Sebastian.Weis[@]med.uni-jena.de
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 45
• Est. completion date: December 2024
• Est. primary completion date: October 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Sepsis
• Toxemia

Intervention

Drug:
• Epirubicin
Epirubicin is given once over 15 Minutes via a central line
• Placebo
NaCl is given once over 15 Minutes via a central line

Locations

Country	Name	City	State
Germany	University Hospital Knappschafstkrankenhaus Bochum	Bochum
Germany	University Medicine Greifswald	Greifswald
Germany	Universitätsklinikum Hamburg Eppendorf	Hamburg
Germany	Jena University Hospital	Jena	Thuringia
Germany	Universitätsklinikum Würzburg	Würzburg

Sponsors (3)

Lead Sponsor	Collaborator
Jena University Hospital	Ruhr University of Bochum, University Medicine Greifswald

Country where clinical trial is conducted

Germany, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	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
Other	Organ damage markers	Non-conventional sensitive organ damage markers (e.g. NGAL) will be measured	Up to 14 days after administration of study drug
Other	Anti-PF4 anti-bodies	Determination of anti-PF4 (platelet factor 4) anti-bodies	Up to 14 days after administration of study drug
Other	Mitochondrial function	Molecular parameters for mitochondrial function will be assessed from isolated PBMCs	Up to 7 days after administration of study drug
Primary	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	Survival at day 14, 28 and 90	Survival	14, 28 and 90 days
Secondary	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
Secondary	Cardiotoxicity	Ejection fraction measured via TTE (trans-thoracic echocardiography)	7 days after administration of study drug
Secondary	"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
Secondary	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
Secondary	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
Secondary	Fluid balance and urine output	Assessment of fluid balance and urine output	Up to 14 days after administration of study drug
Secondary	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
Secondary	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
Secondary	Need for respiratory support	The highest level of respiratory support will be documented.	Up to 14 days after administration of study drug
Secondary	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