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.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
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
Peter Pickkers, MD, PhD
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)