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Human Recombinant Interferon Gamma-1b for the Prevention of Hospital-acquired Pneumonia in Critically Ill Patients: a Double-blind, International, Phase 2, Randomized, Placebo-controlled Trial - the PREV-HAP Study (PREV-HAP)

Primary Purpose

Critically Ill Patients

Status
Active
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Recombinant Interferon gamma 1b (IMUKIN®)
Recombinant Interferon gamma 1b placebo
Sponsored by
Nantes University Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Critically Ill Patients

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Adult patients (18yr to 85yr).
  • Hospitalized in intensive care unit for less than 48 hours.
  • Receiving invasive mechanical ventilation at the time of inclusion.
  • One or more acute organ failure at the time of inclusion among: neurological (Glasgow coma scale <13 before sedation), hemodynamic (norepinephrine, epinephrine, or any other vasopressor at a dose of ≥ 0.1 μg per kilogram of body weight per minute or ≥0.5 mg per hour for at least 6 hours), respiratory (PaO2 / FiO2< 200) and/or renal (creatininemia > 2 fold higher than the basal value and/or oliguria < 0.5 mL/kg/hour for at less 12 hours).
  • Informed consent from a legal representative, or emergency procedure (when possible according to national regulation, see below). As is not possible to obtain the patient consent prior the inclusion (comatose patients), patient consent for the study continuation will be obtained as soon as deemed possible.
  • Person insured under a health insurance scheme.

Exclusion Criteria:

  • Pregnant women (serum or urine test), breastfeeding women
  • Patient under legal protection (incl. under guardianship or trusteeship)
  • 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
  • Severe hepatic insufficiency ( Child Pugh score B or C)
  • Liver cytolysis with hepatic enzymes (AST and/or ALT) > 5N
  • Severe chronic renal insufficiency (MDRD Creatinine Clearance < 10 ml/min/1.73m2)
  • Immunosuppression (hematologic cancer, aplasia, chemotherapy/radiotherapy for cancer within 3 months prior to the inclusion, known infection Human immunodeficiency virus, concomitant use of any anti-graft rejection drug).
  • Coma after resuscitated cardiac arrest
  • Cervical spinal cord injury
  • Participation to a drug interventional study within 1 month prior to the inclusion
  • Hospital-acquired pneumonia before inclusion in the study during the current hospitalization.
  • Sustained hyperlactatemia > 5 mmol/L.

Sites / Locations

  • Angers University Hospital
  • Argenteuil Hospital
  • Brest University Hospital
  • Beaujon University Hospital
  • Limoges University Hospital
  • Nantes University Hospital
  • Rennes University Hospital
  • Aghioi Anargyroi General Oncology Hospital
  • Attikon University General Hospital
  • General University Hospital of Heraklion
  • University General Hospital of Ioannina
  • General University Hospital of Larissa
  • Koutlimbaneio & Triantafylleio General Hospital of Larissa
  • Hospital Clínic Barcelona
  • Hospital Vall d'Hebron
  • Hôpital universitaire Arnau de Vilanova
  • Hospital Clínico San Carlos
  • Hospital Universitario de Son Llátzer

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Recombinant Interferon gamma 1b (IMUKIN®)

Recombinant Interferon gamma 1b placebo

Arm Description

Outcomes

Primary Outcome Measures

To demonstrate the efficiency of rHuIFN-γ for the prevention of hospital-acquired pneumonia
Rate of the composite outcome at day 28 made of at least one item among the following: all cause mortality and/or hospital-acquired pneumonia

Secondary Outcome Measures

All-cause mortality [efficiency of rHu-IFN-γ, on pneumonia-associated morbidity and mortality reduction]
Rate of all-cause mortality at D28 and D90
Rate of HAP [efficiency]
Rate of HAP at D28
Bacterial ecology of the 1st episode of HAP [efficiency]
Bacterial ecology of the 1st episode of HAP (respiratory fluids)
Rate of ventilator-associated tracheobronchitis [efficiency]
Rate of ventilator-associated tracheobronchitis at D28 defined as at least two of the following criteria: body temperature >38°C; leukocytosis>12000 cells/mL, leucopenia <4000 cells/mL, or purulent pulmonary secretions and a positive culture of a respiratory tract samples, without appearance of a new infiltrate or change in an existing infiltrate on chest radiography
Occurence of Acute Respiratory Distress Syndrome [efficiency]
Acute Respiratory Distress Syndrome within 28 days after randomization
Duration of antimicrobial therapy [efficiency]
Duration of antimicrobial therapy at D28, antibiotic free days at D28
Duration of mechanical ventilation [efficiency]
Duration of mechanical ventilation at D90, mechanical ventilation free days at D90
Duration of ICU hospitalization [efficiency]
Duration of ICU hospitalization at D90, Duration of hospitalization at D90.
Rate of SAEs and SUSARs [tolerance]
Rate of serious adverse effects and suspected unexpected serious adverse reaction (SUSAR) at D15
Rate of leukocytosis [tolerance]
Rate of leukocytosis at D15.
Rate of neutropenia [tolerance]
Rate of neutropenia at D15.
Rate of lymphopenia [tolerance]
Rate of lymphopenia at D15.
Rate of thrombopenia [tolerance]
Rate of thrombopenia at D15.
Rate of liver cytolysis [tolerance]
Rate of liver cytolysis (Increases in AST and/or ALT) at D15.
Rate of pancreatitis [tolerance]
Rate of pancreatitis (Increase in Lipase) at D15.
Rate of patients with episode of fever [tolerance]
Rate of patients with episode of fever (T° > 38.3°C)
Rate of patients with episode of headache [tolerance]
Rate of patients with episode of headache
Rate of patients with episode of nausea [tolerance]
Rate of patients with episode of nausea
Rate of allergic reaction [tolerance]
Rate of major allergic reaction at D15 defined as systemic epidermic reaction, anaphylactic
Incidence of injection site reaction [tolerance]
Occurence of injection site reaction at D15
Rate of myalgia [tolerance]
Rate of myalgia at D15
Rate of arthralgia [tolerance]
Rate of arthralgia at D15
Rate of back pain [tolerance]
Rate of back pain at D15
Economic efficiency of rHu-IFN-γ in the prevention of pneumonia
Economic endpoint at 3 months: Incremental cost effectiveness ratio (ICER). Analysis using QALYs (Quality-Adjusted Life-Years) as a measure of effectiveness. QALYs are a measure of effectiveness specifically designed for economic evaluations.
To determine the suitability of rHu-IFN-γ from the patients' and relatives' perspectives using The Short Form (36) Health Survey
Changes in health-related quality of life (HRQoL) from one (M1) to three months (M3) after randomization measured with the Short Form (SF)-36 scale validated in French, Greek, and Spanish he SF-36 is a 36-item self-report questionnaire with 8 domains = Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional, and Mental Health).The scores of each domain range from 0 to 100, a higher score indicating a better HRQoL.
To determine the suitability of rHu-IFN-γ from the patients' and relatives' perspectives using the Hospital Anxiety and Depression scale (HADS)
Changes in anxiety and depression from M1 to M3 measured with the HADS scale validated in French, Greek, and Spanish. The HADS is a 14-item self-report questionnaire with 2 domains (anxietyand depression). The scores for anxiety and depression range from 0 (no symptoms) to 21 (significant number of symptoms).
To determine the suitability of rHu-IFN-γ from the patients' and relatives' perspectives using Satisfaction With Life Scale (SWLS)
Changes in subjective well-being from M1 to M3 measured with the Satisfaction With Life Scale (SWLS) validated in French, Greek, and Spanish. The SWLS is a 5-item self-report questionnaire. The response scores to the five items are added together to provide a total score ranging from 5 (worst satisfaction level) to 35 (best level).
To determine the acceptability of rHu-IFN-γ from the patients' and relatives' perspectives
Adaptation of the patients to their health state and its evolution from M1 to M3 using differential item functioning and response shift analyses for HRQoL, anxiety and depression. Change in the meaning of patients' self-evaluation between groups (DIF) and over time (response shift) will be inferred by the change in the items' parameters of the Partial Credit Models.

Full Information

First Posted
February 24, 2021
Last Updated
February 1, 2022
Sponsor
Nantes University Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT04793568
Brief Title
Human Recombinant Interferon Gamma-1b for the Prevention of Hospital-acquired Pneumonia in Critically Ill Patients: a Double-blind, International, Phase 2, Randomized, Placebo-controlled Trial - the PREV-HAP Study
Acronym
PREV-HAP
Official Title
Human Recombinant Interferon Gamma-1b for the Prevention of Hospital-acquired Pneumonia in Critically Ill Patients: a Double-blind, International, Phase 2, Randomized, Placebo-controlled Trial - the PREV-HAP Study
Study Type
Interventional

2. Study Status

Record Verification Date
February 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
March 29, 2021 (Actual)
Primary Completion Date
November 7, 2021 (Actual)
Study Completion Date
June 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Nantes University Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
PREV-HAP study is part of a larger project entitled 'Host-targeted Approaches for the Prevention and the treatment of Hospital-Acquired Pneumonia' (HAP2), funded by the European Union's H2020 research and innovation programme under grant agreement N°847782. HAP2 aims to develop stratified host-directed drugs and biomarkers to enhance the prevention and the treatment of HAP and develop precision medicine in infectious diseases. Its ambition is to revolutionize the management of HAP: capitalising on the novel concept of critical-illness related immunosuppression altering the host-pathogens interactions, the aim is to propose a complete reappraisal of the physiopathology of HAP based on the concept of respiratory dysbiosis. The main hypothesis of the PREV-HAP study is that human recombinant Interferon gamma 1b (rHuIFN-γ, Imukin) treatment can restore immunity in critically ill patients and prevent Hospital-Acquired Pneumonia. The hypothesesis is that the in vivo investigations of the host-pathogens interactions can be used for the stratification of patients into high/low risk and responders/non-responders to host-targeted prevention of hospital-acquired infections. The involvement of a state of critical-illness related immunosuppression in the susceptibility to hospital-acquired pneumonia is widely accepted, and an emerging trend is that the development of drugs for the treatment of this acquired immunosuppression will prevent infection and enhance outcomes of hospitalized patients. It has been demonstrated that the productions of IFN-γ by immune cells are decreased in critically ill patients, and that these defects are associated with the susceptibility to HAP. rHuIFN-γ has neither been tested nor is recommended as adjunctive treatment of patients with HAP. Based on these specific factors identified in the host response, it is proposed in this study to use rHuIFN-γ as novel preventive approach for HAP.
Detailed Description
200 adult patients hospitalized in intensive care units, under mechanical ventilation in three European countries will be included in the trial, and will be randomized in 2 arms : Arm 1 (rHu-IFNγ): • Recombinant Interferon gamma 1b (IMUKIN®, from Clinigen®): 100 µg/0,5ml subcutaneous injections from day 1 to day 9 (5 injections, i.e. 1 injection of 100 µg every 48h), Arm 2 (Placebo): • Recombinant Interferon gamma 1b placebo: 5 subcutaneous injections from day 1 to day 9 (i.e. 1 injection of 0,5ml every 48h).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Critically Ill Patients

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
109 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Recombinant Interferon gamma 1b (IMUKIN®)
Arm Type
Experimental
Arm Title
Recombinant Interferon gamma 1b placebo
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
Recombinant Interferon gamma 1b (IMUKIN®)
Intervention Description
100 µg/0,5ml subcutaneous injections from day 1 to day 9 (5 injections, i.e. 1 injection of 100 µg every 48h)
Intervention Type
Drug
Intervention Name(s)
Recombinant Interferon gamma 1b placebo
Intervention Description
5 subcutaneous injections from day 1 to day 9 (i.e. 1 injection of 0,5ml every 48h).
Primary Outcome Measure Information:
Title
To demonstrate the efficiency of rHuIFN-γ for the prevention of hospital-acquired pneumonia
Description
Rate of the composite outcome at day 28 made of at least one item among the following: all cause mortality and/or hospital-acquired pneumonia
Time Frame
Day 28
Secondary Outcome Measure Information:
Title
All-cause mortality [efficiency of rHu-IFN-γ, on pneumonia-associated morbidity and mortality reduction]
Description
Rate of all-cause mortality at D28 and D90
Time Frame
Day 28 and Day 90
Title
Rate of HAP [efficiency]
Description
Rate of HAP at D28
Time Frame
Day 28
Title
Bacterial ecology of the 1st episode of HAP [efficiency]
Description
Bacterial ecology of the 1st episode of HAP (respiratory fluids)
Time Frame
Day 28
Title
Rate of ventilator-associated tracheobronchitis [efficiency]
Description
Rate of ventilator-associated tracheobronchitis at D28 defined as at least two of the following criteria: body temperature >38°C; leukocytosis>12000 cells/mL, leucopenia <4000 cells/mL, or purulent pulmonary secretions and a positive culture of a respiratory tract samples, without appearance of a new infiltrate or change in an existing infiltrate on chest radiography
Time Frame
Day 28
Title
Occurence of Acute Respiratory Distress Syndrome [efficiency]
Description
Acute Respiratory Distress Syndrome within 28 days after randomization
Time Frame
Day 28
Title
Duration of antimicrobial therapy [efficiency]
Description
Duration of antimicrobial therapy at D28, antibiotic free days at D28
Time Frame
Day 28
Title
Duration of mechanical ventilation [efficiency]
Description
Duration of mechanical ventilation at D90, mechanical ventilation free days at D90
Time Frame
Day 90
Title
Duration of ICU hospitalization [efficiency]
Description
Duration of ICU hospitalization at D90, Duration of hospitalization at D90.
Time Frame
Day 90
Title
Rate of SAEs and SUSARs [tolerance]
Description
Rate of serious adverse effects and suspected unexpected serious adverse reaction (SUSAR) at D15
Time Frame
Day 15
Title
Rate of leukocytosis [tolerance]
Description
Rate of leukocytosis at D15.
Time Frame
Day 15
Title
Rate of neutropenia [tolerance]
Description
Rate of neutropenia at D15.
Time Frame
Day 15
Title
Rate of lymphopenia [tolerance]
Description
Rate of lymphopenia at D15.
Time Frame
Day 15
Title
Rate of thrombopenia [tolerance]
Description
Rate of thrombopenia at D15.
Time Frame
Day 15
Title
Rate of liver cytolysis [tolerance]
Description
Rate of liver cytolysis (Increases in AST and/or ALT) at D15.
Time Frame
Day 15
Title
Rate of pancreatitis [tolerance]
Description
Rate of pancreatitis (Increase in Lipase) at D15.
Time Frame
Day 15
Title
Rate of patients with episode of fever [tolerance]
Description
Rate of patients with episode of fever (T° > 38.3°C)
Time Frame
Day 15
Title
Rate of patients with episode of headache [tolerance]
Description
Rate of patients with episode of headache
Time Frame
Day 15
Title
Rate of patients with episode of nausea [tolerance]
Description
Rate of patients with episode of nausea
Time Frame
Day 15
Title
Rate of allergic reaction [tolerance]
Description
Rate of major allergic reaction at D15 defined as systemic epidermic reaction, anaphylactic
Time Frame
Day 15
Title
Incidence of injection site reaction [tolerance]
Description
Occurence of injection site reaction at D15
Time Frame
Day 15
Title
Rate of myalgia [tolerance]
Description
Rate of myalgia at D15
Time Frame
Day 15
Title
Rate of arthralgia [tolerance]
Description
Rate of arthralgia at D15
Time Frame
Day 15
Title
Rate of back pain [tolerance]
Description
Rate of back pain at D15
Time Frame
Day 15
Title
Economic efficiency of rHu-IFN-γ in the prevention of pneumonia
Description
Economic endpoint at 3 months: Incremental cost effectiveness ratio (ICER). Analysis using QALYs (Quality-Adjusted Life-Years) as a measure of effectiveness. QALYs are a measure of effectiveness specifically designed for economic evaluations.
Time Frame
Day 90
Title
To determine the suitability of rHu-IFN-γ from the patients' and relatives' perspectives using The Short Form (36) Health Survey
Description
Changes in health-related quality of life (HRQoL) from one (M1) to three months (M3) after randomization measured with the Short Form (SF)-36 scale validated in French, Greek, and Spanish he SF-36 is a 36-item self-report questionnaire with 8 domains = Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional, and Mental Health).The scores of each domain range from 0 to 100, a higher score indicating a better HRQoL.
Time Frame
Day 90
Title
To determine the suitability of rHu-IFN-γ from the patients' and relatives' perspectives using the Hospital Anxiety and Depression scale (HADS)
Description
Changes in anxiety and depression from M1 to M3 measured with the HADS scale validated in French, Greek, and Spanish. The HADS is a 14-item self-report questionnaire with 2 domains (anxietyand depression). The scores for anxiety and depression range from 0 (no symptoms) to 21 (significant number of symptoms).
Time Frame
Day 90
Title
To determine the suitability of rHu-IFN-γ from the patients' and relatives' perspectives using Satisfaction With Life Scale (SWLS)
Description
Changes in subjective well-being from M1 to M3 measured with the Satisfaction With Life Scale (SWLS) validated in French, Greek, and Spanish. The SWLS is a 5-item self-report questionnaire. The response scores to the five items are added together to provide a total score ranging from 5 (worst satisfaction level) to 35 (best level).
Time Frame
Day 90
Title
To determine the acceptability of rHu-IFN-γ from the patients' and relatives' perspectives
Description
Adaptation of the patients to their health state and its evolution from M1 to M3 using differential item functioning and response shift analyses for HRQoL, anxiety and depression. Change in the meaning of patients' self-evaluation between groups (DIF) and over time (response shift) will be inferred by the change in the items' parameters of the Partial Credit Models.
Time Frame
Day 90

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Adult patients (18yr to 85yr). Hospitalized in intensive care unit for less than 48 hours. Receiving invasive mechanical ventilation at the time of inclusion. One or more acute organ failure at the time of inclusion among: neurological (Glasgow coma scale <13 before sedation), hemodynamic (norepinephrine, epinephrine, or any other vasopressor at a dose of ≥ 0.1 μg per kilogram of body weight per minute or ≥0.5 mg per hour for at least 6 hours), respiratory (PaO2 / FiO2< 200) and/or renal (creatininemia > 2 fold higher than the basal value and/or oliguria < 0.5 mL/kg/hour for at less 12 hours). Informed consent from a legal representative, or emergency procedure (when possible according to national regulation, see below). As is not possible to obtain the patient consent prior the inclusion (comatose patients), patient consent for the study continuation will be obtained as soon as deemed possible. Person insured under a health insurance scheme. Exclusion Criteria: Pregnant women (serum or urine test), breastfeeding women Patient under legal protection (incl. under guardianship or trusteeship) 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 Severe hepatic insufficiency ( Child Pugh score B or C) Liver cytolysis with hepatic enzymes (AST and/or ALT) > 5N Severe chronic renal insufficiency (MDRD Creatinine Clearance < 10 ml/min/1.73m2) Immunosuppression (hematologic cancer, aplasia, chemotherapy/radiotherapy for cancer within 3 months prior to the inclusion, known infection Human immunodeficiency virus, concomitant use of any anti-graft rejection drug). Coma after resuscitated cardiac arrest Cervical spinal cord injury Participation to a drug interventional study within 1 month prior to the inclusion Hospital-acquired pneumonia before inclusion in the study during the current hospitalization. Sustained hyperlactatemia > 5 mmol/L.
Facility Information:
Facility Name
Angers University Hospital
City
Angers
Country
France
Facility Name
Argenteuil Hospital
City
Argenteuil
Country
France
Facility Name
Brest University Hospital
City
Brest
Country
France
Facility Name
Beaujon University Hospital
City
Clichy
Country
France
Facility Name
Limoges University Hospital
City
Limoges
Country
France
Facility Name
Nantes University Hospital
City
Nantes
ZIP/Postal Code
44093
Country
France
Facility Name
Rennes University Hospital
City
Rennes
Country
France
Facility Name
Aghioi Anargyroi General Oncology Hospital
City
Athens
Country
Greece
Facility Name
Attikon University General Hospital
City
Athen
Country
Greece
Facility Name
General University Hospital of Heraklion
City
Heraklion
Country
Greece
Facility Name
University General Hospital of Ioannina
City
Ioannina
Country
Greece
Facility Name
General University Hospital of Larissa
City
Larissa
Country
Greece
Facility Name
Koutlimbaneio & Triantafylleio General Hospital of Larissa
City
Larissa
Country
Greece
Facility Name
Hospital Clínic Barcelona
City
Barcelona
Country
Spain
Facility Name
Hospital Vall d'Hebron
City
Barcelona
Country
Spain
Facility Name
Hôpital universitaire Arnau de Vilanova
City
Lleida
Country
Spain
Facility Name
Hospital Clínico San Carlos
City
Madrid
Country
Spain
Facility Name
Hospital Universitario de Son Llátzer
City
Palma
Country
Spain

12. IPD Sharing Statement

Learn more about this trial

Human Recombinant Interferon Gamma-1b for the Prevention of Hospital-acquired Pneumonia in Critically Ill Patients: a Double-blind, International, Phase 2, Randomized, Placebo-controlled Trial - the PREV-HAP Study

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