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

Phase 3
18 Years
Open (Enrolling)
Sepsis, Septic Shock

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Trial Information

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

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.

Inclusion 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

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

- 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

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

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.

Outcome Time Frame:

at admission and at days 0, 2, 7, 14 and 28

Safety Issue:


Principal Investigator

Peter Pickkers, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Radboud University


Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Study ID:




Start Date:

November 2012

Completion Date:

December 2013

Related Keywords:

  • Sepsis
  • Septic Shock
  • Sepsis
  • SIRS
  • Septic shock
  • Immunoparalysis
  • Interferon-gamma
  • Sepsis
  • Toxemia
  • Shock
  • Shock, Septic