Sepsis-induced immunoparalysis (SIRS, Sepsis, Septic shock) MedDRA version: 14.1 Level: LLT Classification code 10062357 Term: SIRS System Organ Class: 10018065 - General disorders and administration site conditions MedDRA version: 14.1 Level: PT Classification code 10061218 Term: Inflammation System Organ Class: 10018065 - General disorders and administration site conditions MedDRA version: 14.1 Level: PT Classification code 10040047 Term: Sepsis System Organ Class: 10021881 - Infections and
Conditions
Interventions
Trade Name: Immukine
Product Name: Recombinant human interferon-gamma
Product Code: L03A B03
Pharmaceutical Form: Powder for solution for injection
Pharmaceutical form of the placebo: Solution for inj
Sponsors
Radboud University Nijmegen Medical Centre
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Written informed consent from patient of legal representative 2. Age >18 years 3. Presence of septic shock of bacterial origin (A-C required): A. Evidence of bacterial infection (last 96 hours), at least one: pathogenic microorganism in blood, sputum, urine, normally sterile body fluid, or on central venous catheter; Focus of infection identified (e.g. ruptured bowel, purulent drainage/sputum); or leukocytes in normally sterile body fluid B. Two SIRS criteria (last 24 hours): fever (>38.3 °C), hypothermia (90bpm), tachypnea (>20/min), or PaCO2 12,000/µl), leucopenia (10% immature forms. C. Presence of shock with need for vasopressor therapy to maintain SBP = 90 mmHg. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 10 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 10
Exclusion criteria
Exclusion criteria: 1. Pregnancy or lactating 2. Subjects with a history of allergy or intolerance to IFN-? 3. Systemic autoimmune disease, hematologic disease (neoplasma, acute leukemia), transplant patients, or patients on steroid medication receiving a prednisolon equivalent of > 5 mg per day 4. Human immunodeficiency virus positivity 5. Presence of an advanced directive to withhold or to withdraw life sustaining treatment 6. Underlying disease with a prognosis for survival < 3 months, or moribund patient highly likely to die within 24 hours. 7. Cardiopulmonary resuscitation (<72 hours) before enrolment 8. Acute myocardial infarction or pulmonary embolisation (<72 hours) 9. Participation in a clinical trial until 30 days prior to inclusion 10. Subjects with a history of documented epileptic seizures 11. Subjects with severe renal impairment (creatinine clearance less than 30 mL/min) 12. Subjects with severe liver failure (impaired synthesis of proteins such as coagulation factors manifested by increased prothrombine time) 13. Subjects with an absolute neutrophil count of less than 500/mm3 at study entry
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the (preliminary) efficacy of IFN-? as adjunctive treatment in combination with standard therapy for the treatment of patients presenting with septic shock, by assessment of a series of surogate immunological parameters. ;Secondary Objective: A secondary aim will be to evaluate markers (including mHLA-DR expression) that are currently used to identify patients with immunoparalysis who will benefit from immunotherapy, and to monitor the patient’s immunological response to IFN-?.;Primary end point(s): The primary endpoint is the TNF-a secretion by ex vivo LPS-stimulated leukocytes as a marker of immunosuficiency/antimicrobial response. ;Timepoint(s) of evaluation of this end point: at admission and at days 0, 2, 7, 14, and 28 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - Outcome of bacterial infection (occurrence of secondary and/or opportunistic infections, duration of antibacterial treatment, microbiological evaluation) - Hemodynamic stability (noradrenalin infusion rate, amount of infused fluids per day, amount of urine produced per day, daily fluid balance) - Mortality (including time to death) at week 2 and week 6 after end of treatment (all causes) - Length of stay at ICU and duration of hospitalization - Organ function: * Cardiovascular function: lactate level, vasopressor usage, and cardiovascular Sequential Organ Failure Assessment (SOFA) score * Respiratory function: oxygenation index, PaO2/FiO2 (P/F) ratio, and respiratory SOFA score * Renal function: creatinin level, urine ouput, renal replacement therapy usage, and renal SOFA score * Hematologic function: hematologic SOFA score * Hepatic function: Hepatic SOFA score - Production of cytokines by leukocytes ex vivo stimulated with various stimuli (including LPS, peptidoglycan, candida) - Markers of “immune status” (including mHLA-DR and PD-1 expression, IL-6 plasma concentration) - To determine the correlation between the level of immunoparalysis (indicated by the commonly used marker mHLA-DR and new markers of “immune status” found), and effectiveness of IFN-? (indicated by TNF-a secretion by ex vivo LPS-stimulated PBMC’s). - Transcriptional activity of leukocytes, including microarrays with a focus on inflammatory pathways - Changes in phenotype or gene expression caused by mechanisms other than changes in the underlying DNA sequence (epigenetic modifications);Timepoint(s) of evaluation of this end point: at admission and at days 0, 2, 7, 14, and 28 | — |
Countries
Netherlands
Contacts
Public ContactPeter Pickkers
Radboud University Nijmegen Medical Centre
Outcome results
None listed