Human Recombinant Interferon Gamma in the Treatment of Ventilator-acquired Pneumonia in ICU Patients (IGNORANT)

Clinical presentation of patients after severe injury such as a severe infection, trauma or extensive burns is characterized by the simultaneous occurrence of dysregulation of the initial inflammatory response and immunosuppression associating quantitative and functional alterations of innate and adaptive immune cells. These acquired immune dysfunctions have been associated with an increased susceptibility to nosocomial infections, foremost among which are ventilator-associated pneumonia (VAP). Despite the implementation of a set of preventive measures, the incidence of these VAP remains high in intensive care, with rates in Europe of 1.5% per day of ventilation.

Post-aggressive immunosuppression is characterized by the decrease in the expression of HLA-DR (belonging to the type II major histocompatibility complex, MHC-II) on the surface of monocytes (mHLA-DR). The administration of interferon gamma (IFNγ) can restore the level of mHLA-DR and may possibly improve the prognosis as an adjuvant therapy associated to antibiotics. However, the level of proof of this therapeutic strategy is low, limited to small cohorts of patients, or clinical studies without prior immunodepression assessment. The objective of this study is to conduct a randomized, double-blind, placebo-controlled superiority trial to assess the effect of IFNγ administration on the duration of mechanical ventilation following the first episode of VAP in patients having an HLA-DR < 8000 AB/C

All reported data about recombinant human IFNγ 1b for the control of secondary infections in patients with septic shock used the dose of 100 micrograms per day by subcutaneous route for 3 to 5 days . At this dose, no retrospective study has reported any serious adverse effects and recombinant human IFNγ 1b allows an increase in monocyte membrane expression of mHLA-DR.

Study Overview

• Status: Recruiting
• Conditions: Pneumonia, Ventilator-Associated
• Intervention / Treatment: Drug: Interferon gamma; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 132
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Anne-Claire LUKASZEWICZ, Pr; Phone Number: +33 472 11 13 27; Email: anne-claire.lukaszewicz@chu-lyon.fr
• Study Contact Backup: Name: Camille BOUCHENY; Phone Number: +33 4 26 73 27 39; Email: Camille.boucheny@chu-lyon.fr

Study Locations

• France
  • Lyon, France, 69003
    • Recruiting
    • Service civilo-militaire d'Anesthésie-Réanimation et Médecine Périopératoire
    • Contact: Anne-Claire LUKASZEWICZ, Pr
    • Principal Investigator: Anne-Claire LUKASZEWICZ, Pr
  • Lyon, France, 69004
    • Not yet recruiting
    • Service de reanimation chirurgicale Hopital Croix-Rousse
    • Contact: Marie-Charlotte DELIGNETTE, MD; Phone Number: +33 4 72 11 89 47; Email: marie-charlotte.delignette@chu-lyon.fr
    • Principal Investigator: Marie-Charlotte DELIGNETTE, MD
  • Lyon, France, 69004
    • Recruiting
    • Service de reanimation médicale hôpital de la Croix-Rousse
    • Contact: Jean-Christophe RICHARD, Pr; Phone Number: +33 4 26 10 92 72; Email: j-christophe.richard@chu-lyon.fr
    • Principal Investigator: Jean-Christophe RICHARD, Pr
  • Nancy, France, 54511
    • Not yet recruiting
    • Service d'anesthésie-réanimation, unité de réanimation chirurgicale Picard
    • Contact: Marie-Reine Marie-Reine LOSSER, Pr; Phone Number: +33 3 83 15 41 66; Email: mr.losser@chru-nancy.fr
    • Principal Investigator: Marie-Reine LOSSER, Pr
  • Paris, France, 75014
    • Not yet recruiting
    • Médecine intensive- Réanimation
    • Contact: Frederic PENE, Pr; Phone Number: +33 1 58 41 25 36; Email: frederic.pene@aphp.fr
    • Principal Investigator: Frederic PENE, Pr
  • Pierre-Bénite, France, 69395
    • Recruiting
    • Service d'Anesthésie-réanimation-médecine intensive Hôpital Lyon Sud
    • Principal Investigator: Florent WALLET, MD
    • Contact: Florent WALLET, MD; Phone Number: +33 4 78 86 19 21; Email: florent.wallet@chu-lyon.fr
  • Saint-Étienne, France, 42055
    • Not yet recruiting
    • Département Anesthésie-Réanimation
    • Contact: Ludivine PETIT, MD; Phone Number: +33 6 77 81 86 87; Email: Ludivine.Petit@chu-st-etienne.fr
    • Principal Investigator: Ludivine PETIT, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• adult patients hospitalized in intensive care unit
• under mechanical ventilation for more than 5 days
• having a first episode of VAP (with a Clinical Pulmonary Infectious Score (CPIS score) >6)
• treated with antibiotics for less than 24 hours
• with monocyte HLA-DR < 8000 AB/C

Exclusion Criteria:

• Noradrenaline > 0.25 mcg/kg/min

• Immunosuppression, defined by:

  • solid tumor with chemotherapy in the last 3 months
  • progressive metastatic disease
  • hematological disease
  • solid organ transplantation
  • HIV infection (AIDS stage or not)
  • corticosteroid therapy at any dose for more than 3 months
  • ≥ 1 mg/kg of Prednisone equivalent for more than 7 days
  • immunosuppressive therapy
• Head and/or cervical spine trauma
• Cardiocirculatory arrest
• Burn patient
• Cirrhosis with Child B or C score
• Infection with Aspergillus spp.
• Refusal to participate
• Patient participating in another interventional research in progress or including an exclusion period still in progress at pre-inclusion (excluding interventional research of 2° not interfering with the endpoints of the study according to the judgment of the principal investigator)
• Lack of social coverage
• Patient under curatorship or guardianship
• Pregnant or breastfeeding women
• Patient admitted to intensive care for SARS-Cov2 pneumonia
• Known allergy to latex
• Hypersensitivity to the active substance (interferon gamma-1b) or known hypersensitivity to related products, such as another interferon, or to any of the following excipients: Mannitol, Disodium succinate hexahydrate, Succinic acid, polysorbate 20
• Existence of chronic heart disease with FeVG<45%
• Major hepatic impairment (total bilirubin>60 mg/L or 102 mcmol/L, equivalent to 3 SOFA points)
• thrombocytopenia <50000/mm3 (equivalent to 3 SOFA points) AST and/or ALT > 5N Lipase > 3N Severe chronic renal failure (creatinine clearance MDRD< 10 ml/min/1.73m2)
• Thrombocytopenia <50,000/mm3 (equivalent to 3 SOFA points)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Interferon gamma treatment; Interferon gamma treatment (100 micrograms /day during 5 days)	Drug: Interferon gamma; Daily subcutaneous administration of Interferon gamma during 5 days
Placebo Comparator: Placebo; The comparator drug (placebo) is an injectable solution of sodium chloride 0.9%	Drug: Placebo; Placebo during 5 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
duration of mechanical ventilation assessed from the first day of VAP diagnosis	mechanical ventilation-free days (VFD) from extubation through D28. A beneficial effect of using recombinant human interferon gamma-1b would be a statistically significant increase in VFD in patients receiving study drug in this setting compared to the group receiving placebo.	Day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause mortality in intensive care		Day 28
Previous positive microbiological sample at inclusion becomes negative	Previous positive microbiological sample at inclusion becomes negative, i.e. pulmonary, urinary, blood cultures	Day 5
Length of stay in intensive care unit		Day 28
length of stay at hospital		Day 28
occurrence of another episode of VAP before extubation		Day 28
occurrence of another episode of infection acquired in intensive care unit		Day 28
increase of monocytic HLA-DR expression above 8000 AB/C the day after the last dose of treatment (J5)		Day 28
increase or decrease of blood leucocyte count at the day after the last dose of treatment (J5) in comparison to baseline		Day 28
Evaluation of the economic efficiency of the administration of IFN-γ (assessed by the ACER (average cost-effectiveness ratio) method)	Evaluation of the cost-effectiveness of IFN-γ administration (assessed by the ACER (average cost-effectiveness ratio) method)	Day 28

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon
• Investigators: Principal Investigator: Anne-Claire LUKASZEWICZ, Pr, Hospices Civils de Lyon

Study record dates

Study Major Dates

• Study Start (Actual): June 30, 2023
• Primary Completion (Estimated): July 30, 2025
• Study Completion (Estimated): July 30, 2025

Study Registration Dates

• First Submitted: April 12, 2023
• First Submitted That Met QC Criteria: May 2, 2023
• First Posted (Actual): May 6, 2023

Study Record Updates

• Last Update Posted (Estimated): February 26, 2024
• Last Update Submitted That Met QC Criteria: February 22, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Sepsis; Critical Illness; Trauma; Interferon-gamma; immunostimulation; Immunodepression; Monocyte HLA-DR
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Disease Attributes; Cross Infection; Iatrogenic Disease; Healthcare-Associated Pneumonia; Pneumonia; Pneumonia, Ventilator-Associated; Anti-Infective Agents; Antiviral Agents; Antineoplastic Agents; Interferons; Interferon-gamma
• Other Study ID Numbers: 69HCL22_0851; 2022-502229-16-00 (Other Identifier: EUCT number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No