Epirubicin for the Treatment of Sepsis & Septic Shock

Study Overview
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Brief Summary
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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
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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.

Official Title
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Epirubicin for the Treatment of Sepsis & Septic Shock

Conditions
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Sepsis

Intervention / Treatment
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* Drug: Epirubicin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Sequential dose escalation with three dosing groups and placebo.
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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epirubicin, disease tolerance, myelotoxicity, pilot study