The Effects of Interferon-gamma on Sepsis-induced Immunoparalysis

This study is currently recruiting participants.
Verified April 2014 by Radboud University
Sponsor:
Information provided by (Responsible Party):
Radboud University
ClinicalTrials.gov Identifier:
NCT01649921
First received: July 23, 2012
Last updated: April 11, 2014
Last verified: April 2014

July 23, 2012
April 11, 2014
November 2012
December 2016   (final data collection date for primary outcome measure)
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 ] [ Designated as safety issue: No ]
The primary endpoint is the TNF-α secretion by ex vivo LPS-stimulated leukocytes as a marker of immunosuficiency/antimicrobial response. [ Time Frame: at admission and at days 0, 2, 7, 14 and 28 ] [ Designated as safety issue: No ]
Complete list of historical versions of study NCT01649921 on ClinicalTrials.gov Archive Site
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Mortality (including time to death) at week 2 and week 6 after end of treatment (all causes) [ Time Frame: At days 14 and 28 ] [ Designated as safety issue: Yes ]
  • Length of stay at ICU and duration of hospitalization [ Time Frame: At days 28 and 56 ] [ Designated as safety issue: No ]
  • Organ function [ Time Frame: at days 0, 14, and 28 ] [ Designated as safety issue: Yes ]
    • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • reversibility of monocytes tolerance [ Time Frame: Day 0 ] [ Designated as safety issue: No ]
    the reversibility of monocytes tolerance by the mean of innate immune training (cytokines production such as TNF and Interleukin (IL)-6 will be assessed).
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Mortality (including time to death) at week 2 and week 6 after end of treatment (all causes) [ Time Frame: At days 14 and 28 ] [ Designated as safety issue: Yes ]
  • Length of stay at ICU and duration of hospitalization [ Time Frame: At days 28 and 56 ] [ Designated as safety issue: No ]
  • Organ function [ Time Frame: at days 0, 14, and 28 ] [ Designated as safety issue: Yes ]
    • 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) [ Time Frame: At admission, at days 0, 2, 7, 14, and 28 ] [ Designated as safety issue: No ]
  • Markers of "immune status" (including mHLA-DR and PD-1 expression, IL-6 plasma concentration) [ Time Frame: At admission and at days 0, 2, 7, 14, and 28 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
Not Provided
Not Provided
 
The Effects of Interferon-gamma on Sepsis-induced Immunoparalysis
The Effects of Interferon-gamma on Sepsis-induced Immunoparalysis, a Randomised Double-blind Placebo-controlled Pilot (Phase IIIb) Study

The primary aim of this study is to assess the effects of adjunctive therapy with Interferon (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. With use of the results the investigators will obtain in this pilot study, the investigators will conduct a large multicentre clinical trial with IFN-γ.

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.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
  • Sepsis
  • Septic Shock
  • 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
  • Other: Saline 0.9%
    subcutaneous administration on days 0, 2, 4, 7, 9, and 11.
  • Active Comparator: Interferon-gamma
    Intervention: Drug: Interferon-gamma, Recombinant
  • Placebo Comparator: Saline 0.9%
    Intervention: Other: Saline 0.9%
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
20
December 2016
December 2016   (final data collection date for primary outcome measure)

Inclusion criteria:

  • Written informed consent from patient of legal representative
  • Age >18 years
  • Presence of septic shock of bacterial origin with evidence of bacterial infection (last 96 hours, with 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), Two SIRS criteria (last 24 hours, fever (>38.3 ˚C), hypothermia (<35.6 ˚C), tachycardia (>90bpm), tachypnea (>20/min), or partial pressure of arterial carbon dioxide (PaCO2) <32 mmHg, or mechanical ventilation, leukocytosis (>12,000/μl), leucopenia (<4,0000/μl), or >10% immature forms), and presence of shock with need for vasopressor therapy to maintain systolic blood pressure (SBP) ≥ 90 mmHg.

Exclusion Criteria:

  • Pregnancy or lactating
  • Subjects with a history of allergy or intolerance to IFN-gamma
  • Systemic autoimmune disease, hematologic disease (neoplasma, acute leukemia), transplant patients, or patients on steroid medication receiving a prednisolone equivalent of > 5 mg per day
  • Human immunodeficiency virus positivity
  • Presence of an advanced directive to withhold or to withdraw life sustaining treatment
  • Underlying disease with a prognosis for survival < 3 months, or moribund patient highly likely to die within 24 hours.
  • Cardiopulmonary resuscitation (<72 hours) before enrollment
  • Acute myocardial infarction or pulmonary embolization (<72 hours)
  • Participation in a clinical trial until 30 days prior to inclusion
  • Subjects with a history of documented epileptic seizures
  • Subjects with severe renal impairment (creatinine clearance less than 30 mL/min)
  • Subjects with severe liver failure (impaired synthesis of proteins such as coagulation factors manifested by increased prothrombin time)
  • Subjects with an absolute neutrophil count of less than 500/mm3 at study entry
Both
18 Years and older
No
Not Provided
Netherlands
 
NCT01649921
IFN_sepsis
Yes
Radboud University
Radboud University
Not Provided
Principal Investigator: Peter Pickkers, MD, PhD Radboud University
Radboud University
April 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP