The Effects of Interferon-gamma on Sepsis-induced Immunoparalysis
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|ClinicalTrials.gov Identifier: NCT01649921|
Recruitment Status : Completed
First Posted : July 25, 2012
Last Update Posted : September 29, 2017
|Condition or disease||Intervention/treatment||Phase|
|Sepsis Septic Shock||Drug: Interferon-gamma, Recombinant Other: Saline 0.9%||Phase 3|
Sepsis is the leading cause of death in the ICU with an estimated 6 million victims per year worldwide. Although septic shock is traditionally viewed as an excessive systemic inflammatory reaction to invasive microbial pathogens, pharmacological suppression of the innate immune response in sepsis has proved to be unsuccessful. An important reason for this might be that the vast majority of septic patients survive the initial pro-inflammatory hit, but die in the subsequent immunosuppressed state due to secondary/opportunistic infections. This so-called 'immunoparalysis' is increasingly recognized as the overriding immune dysfunction in septic patients. Reversal of sepsis-induced immunoparalysis is therefore a promising adjunctive treatment for patients presenting with septic shock.
It was demonstrated that interferon-gamma (IFN)-gamma can reverse immunoparalysis in vitro and in vivo in animals and in healthy volunteers. Moreover, in a case-series of septic patients interferon-gamma treatment leaded to reversal of immunoparalysis, reduction in mechanical ventilation time and length of stay with no relevant side-effects.
The primary aim of this study is to assess the effects of adjunctive therapy with IFN-gamma on immune function in patients with septic shock in a placebo-controlled manner. Moreover, the investigators want to evaluate new markers that could be used to identify patients with immunoparalysis, and to monitor the patient's immunological response to IFN-γ. In addition, mechanistic studies will be performed to further elucidate mechanisms (such as epigenetic modifications) behind immunoparalysis and the effects of IFN-γ on these mechanisms.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||4 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|Official Title:||The Effects of Interferon-gamma on Sepsis-induced Immunoparalysis, a Randomised Double-blind Placebo-controlled Pilot (Phase IIIb) Study|
|Actual Study Start Date :||November 2012|
|Actual Primary Completion Date :||December 2016|
|Actual Study Completion Date :||December 2016|
|Active Comparator: Interferon-gamma||
Drug: Interferon-gamma, Recombinant
Interferon-gamma (Immukine, Boehringer-Ingelheim, Alkmaar, the Netherlands), 100mcg subcutaneously, on days 0-2-4-7-9-11. Interferon-gamma treatment will be initiated when the noradrenalin dose is reduced to 50% of maximum dose, ensuring that the sepsis-induced pro-inflammatory phase has passed
|Placebo Comparator: Saline 0.9%||
Other: Saline 0.9%
subcutaneous administration on days 0, 2, 4, 7, 9, and 11.
- The primary endpoint is the tumor necrosis factor (TNF)-α secretion by ex vivo lipopolysaccharide (LPS)-stimulated leukocytes as a marker of immunosufficiency/antimicrobial response. [ Time Frame: at admission and at days 0, 2, 7, 14 and 28 ]
- Outcome of bacterial infection (occurrence of secondary and/or opportunistic infections, duration of antibacterial treatment, microbiological evaluation) [ Time Frame: At days 0, 2, 7, 14 and 28 ]
- Hemodynamic stability (noradrenalin infusion rate, amount of infused fluids per day, amount of urine produced per day, daily fluid balance) [ Time Frame: At days 0, 2, 7, 14 and 28 ]
- Mortality (including time to death) at week 2 and week 6 after end of treatment (all causes) [ Time Frame: At days 14 and 28 ]
- Length of stay at ICU and duration of hospitalization [ Time Frame: At days 28 and 56 ]
- Organ function [ Time Frame: at days 0, 14, and 28 ]
- Cardiovascular function: lactate level, vasopressor usage, and cardiovascular Sequential Organ Failure Assessment (SOFA) score
- Respiratory function: oxygenation index, Pulmonary Arterial Oxygen Tension (PaO2) / fraction of inspired oxygen (FiO2) (P/F) ratio, and respiratory SOFA score
- Renal function: creatinine level, urine output, renal replacement therapy usage, and renal SOFA score
- Hematologic function: hematologic SOFA score
- Hepatic function: Hepatic SOFA score
- Production of other cytokines by leukocytes ex vivo stimulated with various stimuli (including LPS, peptidoglycan, candida) [ Time Frame: At admission, at days 0, 2, 7, 14, and 28 ]
- Markers of "immune status" (including human leukocyte antigen expression on monocytes (mHLA)-DR and programmed death (PD)-1 expression, interleukin (IL)-6 plasma concentration) [ Time Frame: At admission and at days 0, 2, 7, 14, and 28 ]
- 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-γ (indicated by TNF-α secretion by ex vivo LPS-stimulated PBMC's). [ Time Frame: At days 0, 14, and 28 ]
- Transcriptional activity of leukocytes, including microarrays with a focus on inflammatory pathways [ Time Frame: At admission and at days 0, 2, 7, 14, and 28 ]
- Changes in phenotype or gene expression caused by mechanisms other than changes in the underlying DNA sequence (epigenetic modifications) [ Time Frame: At admission and at days 0, 7, and 28 ]
- reversibility of monocytes tolerance [ Time Frame: Day 0 ]the reversibility of monocytes tolerance by the mean of innate immune training (cytokines production such as TNF and Interleukin (IL)-6 will be assessed).
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01649921
|Radboud University Nijmegen Medical Centre|
|Principal Investigator:||Peter Pickkers, MD, PhD||Radboud University|