Ignite Creation Date:
2025-12-24 @ 9:24 PM
Ignite Modification Date:
2025-12-25 @ 7:10 PM
Study NCT ID:
NCT04990232
Status:
COMPLETED
Last Update Posted:
2025-03-19
First Post:
2021-07-29
Is NOT Gene Therapy:
False
Has Adverse Events:
False
Brief Title:
Personalized Immunotherapy in Sepsis
Sponsor:
Hellenic Institute for the Study of Sepsis
Organization:
Study Overview
Official Title:
Personalized Immunotherapy in Sepsis: a Multicentre and Multinational, Double-blind, Double-dummy Randomized Clinical Trial
Status:
COMPLETED
Status Verified Date:
2025-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
ImmunoSep
Brief Summary:
Αim of ImmunoSep is to assess whether personalized adjunctive immunotherapy directed against a state of either fulminant hyper-inflammation or immunoparalysis is able to change sepsis outcomes. Patients will be selected by a panel of biomarkers and laboratory findings and will be allocated to placebo or immunotherapy treatment according to their needs.
Detailed Description:
Sepsis is a life-threatening organ dysfunction that results from the dysregulated host response to an infection. Accumulating knowledge suggests that there is a spectrum of dysregulation in this response. On the one end of this spectrum there are patients whose immune response is characterized by fulminant hyper-inflammation. On the other end of this spectrum there are patients whose immune response is characterized by immunoparalysis. The majority of patients are situated between these two extremes. The primary hypothesis of the ImmunoSep trial is to recognize both ends of this spectrum and to administer adjunctive therapy aiming to modulate the sepsis-associated hyper-inflammation or immunoparalysis. It is anticipated that with this strategy patients' organ dysfunctions be improved.
During the last years the Hellenic Sepsis Study Group (HSSG) managed to develop ferritin as the diagnostic tool for the recognition of patients with fulminant sepsis-associated hyper-inflammation. This was done by analysis of 5,121 patients split into a test and a validation cohort and by also studying a confirmation cohort coming from Sweden. Patients were classified according to the criteria for the macrophage activation syndrome developed by the American College of Rheumatology; approximately 4% of patients with sepsis have fulminant hyper-inflammation or macrophage activation-like syndrome (MALS) that is an independent clinical condition associated with short-term 10-day mortality. Serum ferritin greater than 4,420 ng/ml had sensitivity 97.1% and negative predictive value 98% for the diagnosis. More than 25 years ago one randomized clinical trial (RCT) was conducted where patients with severe sepsis were randomly assigned to blind treatment with placebo or with the recombinant human interleukin-1 receptor antagonist anakinra. The trial failed to disclose any benefit of anakinra on 28-day mortality. However, a recent post-hoc analysis revealed that patients who had signs of macrophage activation syndrome had significant 30% survival benefit by anakinra treatment.
The immunoparalysis of sepsis is associated with at least 50% risk of death in the subsequent 28 days. There is evidence from preclinical studies and from the endotoxin challenge model in human volunteers that this can be reversed using recombinant human interferon gamma (rhIFNγ). rhIFNγ was administered in nine patients with septic shock in a small open-label clinical trial without placebo comparator; reversal of immunoparalysis was achieved.
It is important to recognize patients with sepsis complicated either with MALS or with immunoparalysis and administer anakinra or rhIFNγ respectively as a potentially beneficial intervention. To this end, a smaller-scale trial was conducted in Greece that was aiming to the personalized management of septic shock. The acronym of this trial was PROVIDE. PROVIDE was conducted between December 2017 and December 2019 in 14 study sites in Greece under the auspices of the European Shock Society. In the PROVIDE trial patients with septic shock due to lower respiratory tract infection, acute cholangitis, or primary bacteremia, were screened on two consecutive days for laboratory signs of fulminant hyper-inflammation or immunoparalysis. Results showed that one single measurement of serum ferritin and the number of human leukocyte antigen-DR (HLA-DR) on monocytes can efficiently classify patients. More precisely, ferritin 4,420 ng/ml diagnoses MALS; and a combination of ferritin \>4,420 ng/ml and HLA-DR less than 5000 molecules/monocyte diagnose imunoparalysis. Patients were randomized into double-dummy blind treatment with placebo if randomly assigned to the standard-of-care arm and with anakinra/recombinant human interferon-gamma (rhIFNγ) if randomly assigned to the immunotherapy arm. Thirty-six patients were enrolled and preliminary results derived from the PROVIDE trial further corroborate the use of anakira/rhIFNγ as an innovative, personalized adjunct therapy for sepsis but one larger-scale study with larger number of patients is needed in order to validate findings.
ImmunoSep is a randomized placebo-controlled phase 2 clinical trial with a double-dummy design where the effect of personalized immunotherapy in patients with sepsis and either fulminant hyper-inflammation or immunoparalysis is studied. Hyper-inflammation is considered as a more direct life-threatening manifestation of sepsis than immunoparalysis; for that reason patients with lab findings of both immune states are allocated to the hyper-inflammation treatment arm.
During the last years the Hellenic Sepsis Study Group (HSSG) managed to develop ferritin as the diagnostic tool for the recognition of patients with fulminant sepsis-associated hyper-inflammation. This was done by analysis of 5,121 patients split into a test and a validation cohort and by also studying a confirmation cohort coming from Sweden. Patients were classified according to the criteria for the macrophage activation syndrome developed by the American College of Rheumatology; approximately 4% of patients with sepsis have fulminant hyper-inflammation or macrophage activation-like syndrome (MALS) that is an independent clinical condition associated with short-term 10-day mortality. Serum ferritin greater than 4,420 ng/ml had sensitivity 97.1% and negative predictive value 98% for the diagnosis. More than 25 years ago one randomized clinical trial (RCT) was conducted where patients with severe sepsis were randomly assigned to blind treatment with placebo or with the recombinant human interleukin-1 receptor antagonist anakinra. The trial failed to disclose any benefit of anakinra on 28-day mortality. However, a recent post-hoc analysis revealed that patients who had signs of macrophage activation syndrome had significant 30% survival benefit by anakinra treatment.
The immunoparalysis of sepsis is associated with at least 50% risk of death in the subsequent 28 days. There is evidence from preclinical studies and from the endotoxin challenge model in human volunteers that this can be reversed using recombinant human interferon gamma (rhIFNγ). rhIFNγ was administered in nine patients with septic shock in a small open-label clinical trial without placebo comparator; reversal of immunoparalysis was achieved.
It is important to recognize patients with sepsis complicated either with MALS or with immunoparalysis and administer anakinra or rhIFNγ respectively as a potentially beneficial intervention. To this end, a smaller-scale trial was conducted in Greece that was aiming to the personalized management of septic shock. The acronym of this trial was PROVIDE. PROVIDE was conducted between December 2017 and December 2019 in 14 study sites in Greece under the auspices of the European Shock Society. In the PROVIDE trial patients with septic shock due to lower respiratory tract infection, acute cholangitis, or primary bacteremia, were screened on two consecutive days for laboratory signs of fulminant hyper-inflammation or immunoparalysis. Results showed that one single measurement of serum ferritin and the number of human leukocyte antigen-DR (HLA-DR) on monocytes can efficiently classify patients. More precisely, ferritin 4,420 ng/ml diagnoses MALS; and a combination of ferritin \>4,420 ng/ml and HLA-DR less than 5000 molecules/monocyte diagnose imunoparalysis. Patients were randomized into double-dummy blind treatment with placebo if randomly assigned to the standard-of-care arm and with anakinra/recombinant human interferon-gamma (rhIFNγ) if randomly assigned to the immunotherapy arm. Thirty-six patients were enrolled and preliminary results derived from the PROVIDE trial further corroborate the use of anakira/rhIFNγ as an innovative, personalized adjunct therapy for sepsis but one larger-scale study with larger number of patients is needed in order to validate findings.
ImmunoSep is a randomized placebo-controlled phase 2 clinical trial with a double-dummy design where the effect of personalized immunotherapy in patients with sepsis and either fulminant hyper-inflammation or immunoparalysis is studied. Hyper-inflammation is considered as a more direct life-threatening manifestation of sepsis than immunoparalysis; for that reason patients with lab findings of both immune states are allocated to the hyper-inflammation treatment arm.
Study Oversight
Has Oversight DMC:
False
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?: