The Effects of Interferon-gamma on Sepsis-induced Immunoparalysis

NCT ID: NCT01649921

Last Updated: 2017-09-29

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 4 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-11-30
• Study Completion Date: 2016-12-31

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.

Conditions

Sepsis; Septic Shock

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Interferon-gamma

Group Type: ACTIVE_COMPARATOR

Interferon-gamma, Recombinant

Intervention Type: DRUG

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

Saline 0.9%

Group Type: PLACEBO_COMPARATOR

Saline 0.9%

Intervention Type: OTHER

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

Interventions

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

Intervention Type: DRUG

Saline 0.9%

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

Intervention Type: OTHER

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Radboud University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Peter Pickkers, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Radboud University Medical Center

Locations

Radboud University Nijmegen Medical Centre

Nijmegen, , Netherlands

Countries

Netherlands

Other Identifiers

IFN_sepsis

Identifier Type: -

Identifier Source: org_study_id