Sepsis
Conditions
Keywords
epirubicin, disease tolerance, myelotoxicity, pilot study
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.
Interventions
DRUGEpirubicin
Epirubicin is given once over 15 Minutes via a central line
DRUGPlacebo
NaCl is given once over 15 Minutes via a central line
Sponsors
Ruhr University of Bochum
University Medicine Greifswald
Jena University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Study medication is provided in colored infusion bags with additional covers
Intervention model description
Sequential dose escalation with three dosing groups and placebo.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of participants with myelotoxicity | Up to 14 days after administration of study drug | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Success rate | 3 days after administration of study drug | 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 |
| Quality of life assesed by the SF-36 questionaire | At follow up 90 days after administration of study drug | 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). |
| Fluid balance and urine output | Up to 14 days after administration of study drug | Assessment of fluid balance and urine output |
| Need for renal replacement therapy | Up to 14 days after administration of study drug | Use of renal replacement therapy for chronic or acute kidney failure |
| Oxygenation index (paO2/FiO2) | Up to 14 days after administration of study drug | 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. |
| Need for respiratory support | Up to 14 days after administration of study drug | The highest level of respiratory support will be documented. |
| Need for catecholamines and inotropes | Up to 14 days after administration of study drug | For all catecholamines and inotropes the highest daily rate administerd for at least one hour will be documented. |
| Survival at day 14, 28 and 90 | 14, 28 and 90 days | Survival |
| SOFA score | Up to 14 days after administration of study drug | SOFA (sequential organ failure assessment) on days of assessment, mean total SOFA and SOFA changes over time |
| Cardiotoxicity | 7 days after administration of study drug | Ejection fraction measured via TTE (trans-thoracic echocardiography) |
| Adverse events | Up to 90 days after administration of study drug | Overall rate of adverse and severe adverse events. The the frequency of other typical side effects (diarrhea, mucositis, alopecia, nausea and vomiting). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Cytokines | Up to 14 days after administration of study drug | Plasma cytokines will be determined in all patients using Luminex xMAP or alike multiplex technology |
| Organ damage markers | Up to 14 days after administration of study drug | Non-conventional sensitive organ damage markers (e.g. NGAL) will be measured |
| Anti-PF4 anti-bodies | Up to 14 days after administration of study drug | Determination of anti-PF4 (platelet factor 4) anti-bodies |
| Mitochondrial function | Up to 7 days after administration of study drug | Molecular parameters for mitochondrial function will be assessed from isolated PBMCs |
| DNA damage | Up to 7 days after administration of study drug | 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 |
| Epirubicin plasma concentrations | At 15minutes and at 1, 2, 3, 6, 12, and 24 hours after administration of study drug | Epirubicin concentrations in the plasma will be measured using mass-spectrometry |
Countries
Germany
Contacts
Primary ContactSebastian Weis, M.D.
Backup ContactDaniel O Thomas-Rüddel, M.D.
Outcome results
None listed