Clinical trial NCT04793568: 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
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
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Critically Ill Patients
Lead sponsor: Nantes University Hospital
Sponsor class: OTHER
First posted: 2021-03-11
Enrollment: 109
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

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.

Primary outcomes:
measure: To demonstrate the efficiency of rHuIFN-γ for the prevention of hospital-acquired pneumonia
timeFrame: Day 28
Secondary outcomes:
measure: All-cause mortality [efficiency of rHu-IFN-γ, on pneumonia-associated morbidity and mortality reduction]
timeFrame: Day 28 and Day 90
measure: Rate of HAP [efficiency]
timeFrame: Day 28
measure: Bacterial ecology of the 1st episode of HAP [efficiency]
timeFrame: Day 28
measure: Rate of ventilator-associated tracheobronchitis [efficiency]
timeFrame: Day 28
measure: Occurence of Acute Respiratory Distress Syndrome [efficiency]
timeFrame: Day 28
measure: Duration of antimicrobial therapy [efficiency]
timeFrame: Day 28
measure: Duration of mechanical ventilation [efficiency]
timeFrame: Day 90
measure: Duration of ICU hospitalization [efficiency]
timeFrame: Day 90
measure: Rate of SAEs and SUSARs [tolerance]
timeFrame: Day 15
measure: Rate of leukocytosis [tolerance]
timeFrame: Day 15
measure: Rate of neutropenia [tolerance]
timeFrame: Day 15
measure: Rate of lymphopenia [tolerance]
timeFrame: Day 15
measure: Rate of thrombopenia [tolerance]
timeFrame: Day 15
measure: Rate of liver cytolysis [tolerance]
timeFrame: Day 15
measure: Rate of pancreatitis [tolerance]
timeFrame: Day 15
measure: Rate of patients with episode of fever [tolerance]
timeFrame: Day 15
measure: Rate of patients with episode of headache [tolerance]
timeFrame: Day 15
measure: Rate of patients with episode of nausea [tolerance]
timeFrame: Day 15
measure: Rate of allergic reaction [tolerance]
timeFrame: Day 15
measure: Incidence of injection site reaction [tolerance]
timeFrame: Day 15
measure: Rate of myalgia [tolerance]
timeFrame: Day 15
measure: Rate of arthralgia [tolerance]
timeFrame: Day 15
measure: Rate of back pain [tolerance]
timeFrame: Day 15
measure: Economic efficiency of rHu-IFN-γ in the prevention of pneumonia
timeFrame: Day 90
measure: To determine the suitability of rHu-IFN-γ from the patients' and relatives' perspectives using The Short Form (36) Health Survey
timeFrame: Day 90
measure: To determine the suitability of rHu-IFN-γ from the patients' and relatives' perspectives using the Hospital Anxiety and Depression scale (HADS)
timeFrame: Day 90
measure: To determine the suitability of rHu-IFN-γ from the patients' and relatives' perspectives using Satisfaction With Life Scale (SWLS)
timeFrame: Day 90
measure: To determine the acceptability of rHu-IFN-γ from the patients' and relatives' perspectives
timeFrame: Day 90
Other outcomes:
Locations:
city: Angers
country: France
facility: Angers University Hospital
city: Argenteuil
country: France
facility: Argenteuil Hospital
city: Brest
country: France
facility: Brest University Hospital
city: Clichy
country: France
facility: Beaujon University Hospital
city: Limoges
country: France
facility: Limoges University Hospital
city: Nantes
country: France
facility: Nantes University Hospital
city: Rennes
country: France
facility: Rennes University Hospital
city: Athens
country: Greece
facility: Aghioi Anargyroi General Oncology Hospital
city: Athen
country: Greece
facility: Attikon University General Hospital
city: Heraklion
country: Greece
facility: General University Hospital of Heraklion
city: Ioannina
country: Greece
facility: University General Hospital of Ioannina
city: Larissa
country: Greece
facility: General University Hospital of Larissa
city: Larissa
country: Greece
facility: Koutlimbaneio & Triantafylleio General Hospital of Larissa
city: Barcelona
country: Spain
facility: Hospital Clínic Barcelona
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebron
city: Lleida
country: Spain
facility: Hôpital universitaire Arnau de Vilanova
city: Madrid
country: Spain
facility: Hospital Clínico San Carlos
city: Palma
country: Spain
facility: Hospital Universitario de Son Llátzer
Study officials:
References: