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 Overview
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Brief Summary
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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
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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).

Official Title
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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

Conditions
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Critically Ill Patients

Intervention / Treatment
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* Drug: Recombinant Interferon gamma 1b (IMUKIN®)
* Drug: Recombinant Interferon gamma 1b placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Recombinant Interferon gamma 1b (IMUKIN®)<br> | Drug: Recombinant Interferon gamma 1b (IMUKIN®)<br>* 100 µg/0,5ml subcutaneous injections from day 1 to day 9 (5 injections, i.e. 1 injection of 100 µg every 48h)<br>|
| Placebo Comparator: Recombinant Interferon gamma 1b placebo<br> | Drug: Recombinant Interferon gamma 1b placebo<br>* 5 subcutaneous injections from day 1 to day 9 (i.e. 1 injection of 0,5ml every 48h).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause mortality [efficiency of rHu-IFN-γ, on pneumonia-associated morbidity and mortality reduction] | Rate of all-cause mortality at D28 and D90 | Day 28 and Day 90 | 
| Rate of HAP [efficiency] | Rate of HAP at D28 | Day 28 | 
| Bacterial ecology of the 1st episode of HAP [efficiency] | Bacterial ecology of the 1st episode of HAP (respiratory fluids) | Day 28 | 
| 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 | Day 28 | 
| Occurence of Acute Respiratory Distress Syndrome [efficiency] | Acute Respiratory Distress Syndrome within 28 days after randomization | Day 28 | 
| Duration of antimicrobial therapy [efficiency] | Duration of antimicrobial therapy at D28, antibiotic free days at D28 | Day 28 | 
| Duration of mechanical ventilation [efficiency] | Duration of mechanical ventilation at D90, mechanical ventilation free days at D90 | Day 90 | 
| Duration of ICU hospitalization [efficiency] | Duration of ICU hospitalization at D90, Duration of hospitalization at D90. | Day 90 | 
| Rate of SAEs and SUSARs [tolerance] | Rate of serious adverse effects and suspected unexpected serious adverse reaction (SUSAR) at D15 | Day 15 | 
| Rate of leukocytosis [tolerance] | Rate of leukocytosis at D15. | Day 15 | 
| Rate of neutropenia [tolerance] | Rate of neutropenia at D15. | Day 15 | 
| Rate of lymphopenia [tolerance] | Rate of lymphopenia at D15. | Day 15 | 
| Rate of thrombopenia [tolerance] | Rate of thrombopenia at D15. | Day 15 | 
| Rate of liver cytolysis [tolerance] | Rate of liver cytolysis (Increases in AST and/or ALT) at D15. | Day 15 | 
| Rate of pancreatitis [tolerance] | Rate of pancreatitis (Increase in Lipase) at D15. | Day 15 | 
| Rate of patients with episode of fever [tolerance] | Rate of patients with episode of fever (T° > 38.3°C) | Day 15 | 
| Rate of patients with episode of headache [tolerance] | Rate of patients with episode of headache | Day 15 | 
| Rate of patients with episode of nausea [tolerance] | Rate of patients with episode of nausea | Day 15 | 
| Rate of allergic reaction [tolerance] | Rate of major allergic reaction at D15 defined as systemic epidermic reaction, anaphylactic | Day 15 | 
| Incidence of injection site reaction [tolerance] | Occurence of injection site reaction at D15 | Day 15 | 
| Rate of myalgia [tolerance] | Rate of myalgia at D15 | Day 15 | 
| Rate of arthralgia [tolerance] | Rate of arthralgia at D15 | Day 15 | 
| Rate of back pain [tolerance] | Rate of back pain at D15 | Day 15 | 
| 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. | Day 90 | 
| 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. | Day 90 | 
| 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). | Day 90 | 
| 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). | Day 90 | 
| 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. | Day 90 |