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.

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.

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.

SOFA (sequential organ failure assessment) on days of assessment, mean total SOFA and SOFA changes over time

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

Overall rate of adverse and severe adverse events. The the frequency of other typical side effects (diarrhea, mucositis, alopecia, nausea and vomiting).

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).

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.

For all catecholamines and inotropes the highest daily rate administerd for at least one hour will be documented.

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

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.

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.