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The Effects of Interferon-gamma on Sepsis-induced Immunoparalysis

Primary Purpose

Sepsis, Septic Shock

Status

Completed

Phase

Phase 3

Locations

Netherlands

Study Type

Interventional

Intervention

Interferon-gamma, Recombinant

Saline 0.9%

About this trial

This is an interventional treatment trial for Sepsis focused on measuring Sepsis, SIRS, Septic shock, Immunoparalysis, Interferon-gamma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Radboud University Nijmegen Medical Centre

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Interferon-gamma

Saline 0.9%

Arm Description

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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, 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)

Markers of "immune status" (including human leukocyte antigen expression on monocytes (mHLA)-DR and programmed death (PD)-1 expression, interleukin (IL)-6 plasma concentration)

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).

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)

reversibility of monocytes tolerance

the reversibility of monocytes tolerance by the mean of innate immune training (cytokines production such as TNF and Interleukin (IL)-6 will be assessed).

Full Information

NCT ID

NCT01649921

First Posted

July 23, 2012

Last Updated

September 28, 2017

Sponsor

Radboud University Medical Center

1. Study Identification

Unique Protocol Identification Number

NCT01649921

Brief Title

The Effects of Interferon-gamma on Sepsis-induced Immunoparalysis

Official Title

The Effects of Interferon-gamma on Sepsis-induced Immunoparalysis, a Randomised Double-blind Placebo-controlled Pilot (Phase IIIb) Study

Study Type

Interventional

2. Study Status

Record Verification Date

April 2014

Overall Recruitment Status

Completed

Study Start Date

November 2012 (Actual)

Primary Completion Date

December 2016 (Actual)

Study Completion Date

December 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Radboud University Medical Center

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

Detailed Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Sepsis, Septic Shock

Keywords

Sepsis, SIRS, Septic shock, Immunoparalysis, Interferon-gamma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Single Group Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

4 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Interferon-gamma

Arm Type

Active Comparator

Arm Title

Saline 0.9%

Arm Type

Placebo Comparator

Intervention Type

Drug

Intervention Name(s)

Interferon-gamma, Recombinant

Intervention Description

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

Intervention Type

Other

Intervention Name(s)

Saline 0.9%

Intervention Description

subcutaneous administration on days 0, 2, 4, 7, 9, and 11.

Primary Outcome Measure Information:

Title

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

Secondary Outcome Measure Information:

Title

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

Title

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

Title

Mortality (including time to death) at week 2 and week 6 after end of treatment (all causes)

Time Frame

At days 14 and 28

Title

Length of stay at ICU and duration of hospitalization

Time Frame

At days 28 and 56

Title

Organ function

Description

Time Frame

at days 0, 14, and 28

Title

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

Title

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

Title

Time Frame

At days 0, 14, and 28

Title

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

Title

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

Title

reversibility of monocytes tolerance

Description

the reversibility of monocytes tolerance by the mean of innate immune training (cytokines production such as TNF and Interleukin (IL)-6 will be assessed).

Time Frame

Day 0

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Peter Pickkers, MD, PhD

Organizational Affiliation

Radboud University Medical Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

Radboud University Nijmegen Medical Centre

City

Nijmegen

Country

Netherlands

12. IPD Sharing Statement

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The Effects of Interferon-gamma on Sepsis-induced Immunoparalysis

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