Clinical trial NCT05033808: Epirubicin for the Treatment of Sepsis & Septic Shock
Official title: Epirubicin for the Treatment of Sepsis & Septic Shock
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Sepsis
Keywords: epirubicin
disease tolerance
myelotoxicity
pilot study
Lead sponsor: Jena University Hospital
Sponsor class: OTHER
Collaborators: name: Ruhr University of Bochum
name: University Medicine Greifswald
First posted: 2021-09-05
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Sequential dose escalation with three dosing groups and placebo.
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of participants with myelotoxicity
timeFrame: Up to 14 days after administration of study drug
Secondary outcomes:
measure: Survival at day 14, 28 and 90
timeFrame: 14, 28 and 90 days
measure: SOFA score
timeFrame: Up to 14 days after administration of study drug
measure: Cardiotoxicity
timeFrame: 7 days after administration of study drug
measure: "Success" rate
timeFrame: 3 days after administration of study drug
measure: Adverse events
timeFrame: Up to 90 days after administration of study drug
measure: Quality of life assesed by the SF-36 questionaire
timeFrame: At follow up 90 days after administration of study drug
measure: Fluid balance and urine output
timeFrame: Up to 14 days after administration of study drug
measure: Need for renal replacement therapy
timeFrame: Up to 14 days after administration of study drug
measure: Oxygenation index (paO2/FiO2)
timeFrame: Up to 14 days after administration of study drug
measure: Need for respiratory support
timeFrame: Up to 14 days after administration of study drug
measure: Need for catecholamines and inotropes
timeFrame: Up to 14 days after administration of study drug
Other outcomes:
measure: Epirubicin plasma concentrations
timeFrame: At 15minutes and at 1, 2, 3, 6, 12, and 24 hours after administration of study drug
measure: DNA damage
timeFrame: Up to 7 days after administration of study drug
measure: Cytokines
timeFrame: Up to 14 days after administration of study drug
measure: Organ damage markers
timeFrame: Up to 14 days after administration of study drug
measure: Anti-PF4 anti-bodies
timeFrame: Up to 14 days after administration of study drug
measure: Mitochondrial function
timeFrame: Up to 7 days after administration of study drug
Locations:
city: Jena
country: Germany
facility: Jena University Hospital
state: Thuringia
city: Bochum
country: Germany
facility: University Hospital Knappschafstkrankenhaus Bochum
city: Greifswald
country: Germany
facility: University Medicine Greifswald
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg Eppendorf
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg
Study officials:
affiliation: Jena University Hospital
name: Sebastian Weis, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.