The Effects of Interferon-gamma on Sepsis-induced Immunoparalysis

Phase 3

Completed

• Conditions: Sepsis; Septic Shock
• Interventions: Other: Saline 0.9%; Drug: Interferon-gamma, Recombinant

• Registration Number: NCT01649921
• Lead Sponsor: Radboud University Medical Center

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.

Study Timeline

• Study First Submitted: 2012-07-23
• Study First Submitted QC: 2012-07-24
• Study First Posted: 2012-07-25
• Study Start: 2012-11
• Status Verified: 2014-04
• Primary Completion: 2016-12
• Study Completion: 2016-12
• Last Update Submitted: 2017-09-28
• Last Update Posted: 2017-09-29

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 4

Inclusion Criteria

Not provided

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Saline 0.9%	Saline 0.9%	-
Interferon-gamma	Interferon-gamma, Recombinant	-

Primary Outcome Measures

Name	Time	Method
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.	at admission and at days 0, 2, 7, 14 and 28

Secondary Outcome Measures

Name	Time	Method
Outcome of bacterial infection (occurrence of secondary and/or opportunistic infections, duration of antibacterial treatment, microbiological evaluation)	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)	At days 0, 2, 7, 14 and 28
Production of other cytokines by leukocytes ex vivo stimulated with various stimuli (including LPS, peptidoglycan, candida)	At admission, 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)	At admission and at days 0, 7, and 28
Length of stay at ICU and duration of hospitalization	At days 28 and 56
Mortality (including time to death) at week 2 and week 6 after end of treatment (all causes)	At days 14 and 28
Organ function	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
Transcriptional activity of leukocytes, including microarrays with a focus on inflammatory pathways	At admission and 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)	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).	At days 0, 14, and 28
reversibility of monocytes tolerance	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).

Trial Locations

Locations (1)

Radboud University Nijmegen Medical Centre; 🇳🇱 Nijmegen, Netherlands