Baricitinib for Treating Hospital-acquired Pneumonia in Critically Ill Patients With a Proinflammatory Phenotype.

Study Overview
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Brief Summary
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The goal of this clinical trial is to determine the safety (phase II), then efficacy (phase III) of baricitinib plus standard of care (SOC) as compared to SOC alone for the treatment of hospital-acquired pneumonia in patients with a pro-inflammatory profile.

Detailed Description
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For both groups : At inclusion visit : Verification of inclusion and non-inclusion criteria Patient information and signature of consent form Pregnancy test (urine ou blood) Randomization Clinical evaluation (cardiac frequency, saturation, tracheal secretions, PaO2/FiO2 ratio, body temperature, mechanical ventilation support) Collection of respiratory fluid and blood for biobank Liver function test (AST, ALT, bilirubin), blood white cells count and EKG Treatment compliance Concomitant medications (antimicrobial therapy and steriods) Survival and EQ-5D-5L At visit 1 to visit 10 ( Day1- day10) Clinical evaluation (cardiac frequency, saturation, tracheal secretions, PaO2/FiO2 ratio, body temperature, mechanical ventilation support) Study drug administration (daily) Collection of respiratory fluid and blood for biobank (day 3 and day 7) Liver function test (AST, ALT, bilirubin), blood white cells count and EKG (Liver, day 3 and day 7) Treatment compliance Adverse event Concomitant medications (antimicrobial therapy and steriods) At visit 11(Day 10-12 test-of-cure) : Clinical evaluation (cardiac frequency, saturation, tracheal secretions, PaO2/FiO2 ratio, body temperature, mechanical ventilation support) Collection of respiratory fluid and blood for biobank Collection of the respiratory fluid for bacterial cure Liver function test (AST, ALT, bilirubin), blood white cells count and EKG Adverse event Concomitant medications (antimicrobial therapy and steriods) At visit 12 : Adverse event Survival and EQ-5D-5L At visit 13 (month 3) and visit 14 (month 6) : Query in NHI Database (SNDS) for consumption of Health resources (pharmaceuticals, consultations...) Survival and EQ-5D-5L Health -related quality of the life (SF-36), anxiety/depression (HADS), subjective well-being (SWLS) Interview with a researcher in pshychology (20 patients and their relatives - only in France)

Official Title
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Baricitinib for Treating Hospital-acquired Pneumonia in Critically Ill Patients With a Proinflammatory Phenotype, an International Phase II/Phase III, Randomized, Controlled Trial - TREAT-HAP Study.

Conditions
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Hospital-acquired Pneumonia

Intervention / Treatment
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* Drug: Baricitinib 4 MG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ventilators-associated pneumonia (VAP) or hospital -acquired pneumonia requiring invasive ventilation (V-HAP) Diagnosis of HAP according to European guidelines : association of two clinical criteria (body temperature > 38°c and purulent pulmonary secretions), the appearance of a new infiltrate or change in an existing infiltrate on chest radography, and respiratory sample (AET, BAL, mini-BAL or blind BAL) collected for bacteriological diagnosis (results can be pending at inclusion). The diagnosis of HAP can have been made outside of ICU VAP : patients should have received machenical ventilation via an endotracheal or nasotracheal tube for the least 48h at the time of HAP diagnosis. V-HAP : patients should have been hospitalized for the least 48 hours before the onset of the first signs or symptoms and required invasive mechanical ventilation during HAP treatment Biological systemic inflammatory response defined according to the on-site standard of acre (CPR > 125 mg/L and/or PCT > 2µg/L and/or ferritin blood level > 650 ng/mL Receiving antimicrobal therapy for the current episode of HAP pneumonia for less than 72 hours Informed consent from legal representative or emergency procedure (when possible according to national regulation). If it's impossible to obtain patient consent before the inclusion (comatose patients), patient consent for the study continuation will be obtained as soon as deemed possible Person insured under a helth insurance scheme Exclusion Criteria: Pregnant women (serum or urine test), breastfeeding woment Patient under legal protection (inc. under guardianship or trusteesheep) Hypersensitivity to baricitinib Uncontrolled herpes zoster, viral hepatitis, infection with human immunodeficiency virus, fungal infections or tuberculosis Severe hepatic insufficiency (child-Pugh B or C) Acute or chronic renal insufficiency (modification of diet in renal disease (MDRD) creatinine clearance < 30 ml/min/1.73 m²) Persistent anemia (haemoglobin < 8 g/L), lymphopenia (absolute lymphocyte < 500 cells/mm3) Immunosuppression (hematologic cancer, aplasia, chemotherapy/radiotherapy for cancer within 3 months prior to the inclusion or anti-graft rejection drug) Recent (<90 days) trhomboembolic event (venous trhombosis, pulmonary embolism, myocardial infarction, and/or stroke) Participation to an interventional drug study within 1 month prior to the inclusion

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Baricitinib + Standard of care<br>Baricitinib injected per os for 10 days (4mg/day). the first administration of this treatment is performed within the 6 hours following the randomization, followed by daily administration for a total of 10 days. The standard of care : for treating HAP will comply with international guidelines. For all patients, empiri antimicrobial therapy is initiated imedialty after collecting the respiratory sample and can thus be started before the randomization to avoid delayed antimicrobial therapy. Its recommanded to broaden the spectrum in case of resistant bacteria resistant to the empirical antimicrobial therapy but il is not recommanded to prolong the antibiotic tratment for more than 7-8 days | Drug: Baricitinib 4 MG<br>* Reference drug<br>|
| Sham Comparator: Standard of care alone<br>Same as described in arm 1 | Drug: Baricitinib 4 MG<br>* Reference drug<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the safety (phase II), of baricitinib plus standard of care (SOC) as compared to (SOC) alone for the treatment of hospital-acquired pneumonia in patients with a pro-inflammatory profile | Using a hierarchic procedure. We will test the baricitinib superiority on the clinical cure rate at the test-of-cure visit realized 10-12 days after randomization or at the ICU discharge. If the superiority criterion is met at the test-of-cure visit, we will test the baricitinib superiority on the rate of all-cause mortality on Day 28 | Day 28 | 
| Determine the efficacy (phase III) of baricitinib plus standard of care (SOC) as compared to (SOC) alone for the treatment of hospital-acquired pneumonia in patients with a pro-inflammatory profile | Using a hierarchic procedure. We will test the baricitinib superiority on the clinical cure rate at the test-of-cure visit realized 10-12 days after randomization or at the ICU discharge. If the superiority criterion is met at the test-of-cure visit, we will test the baricitinib superiority on the rate of all-cause mortality on Day 28 | Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To demonstrate the efficacy of baricitinib on pneumonia-associated morbidity reduction | In case of a non-significant difference in the rate of clinical cure, the co-primary outcome will be presented as a secondary outcome. | Day 28 | 
| To demonstrate the efficacy of baricitinib on pneumonia-associated mortality reduction | In case of a non-significant difference in the rate of clinical cure, the co-primary outcome will be presented as a secondary outcome. | Day 28 | 
| To demonstrate the efficacy of baricitinib on pneumonia-associated morbidity | All-cause morbidity at Month 3 and Month 6 | Month 3 and Month 6 | 
| To demonstrate the efficacy of baricitinib on pneumonia-associated mortality | All-cause mortality at Month 3 and Month 6 | Month 3 and Month 6 | 
| To demonstrate the efficacy of baricitinib on pneumonia-associated morbidity reduction | Rate of pleural empyema at Day 28. | Day 28 | 
| To demonstrate the efficacy of baricitinib on pneumonia-associated mortality reduction | Presence of pleural empyema at Day 28. | Day 28 | 
| To demonstrate the efficacy of baricitinib on pneumonia-associated morbidity reduction | Rate of microbial failure (defined as a positive respiratory culture at the ToC visit) | Day 28 | 
| To demonstrate the efficacy of baricitinib on pneumonia-associated mortality reduction | Rate of microbial failure (defined a a positive respiratory culture at the ToC visit) | Day 28 | 
| To demonstrate the efficacy of baricitinib on pneumonia-associated morbidity reduction | Rate of pneumonia relapse (defined as a second episode of HAP with one r more identical pathogens, rate of pneumonia recurrence (defined as a second epsode of AP with different pathogens) | Up to 28 days | 
| To demonstrate the efficacy of baricitinib on pneumonia-associated mortality reduction | Rate of pneumonia relapse | Up to 28 days | 
| To demonstrate the efficacy of baricitinib on pneumonia-associated mortality reduction | Time course of body temperature | Up to Day 28 | 
| To demonstrate the efficacy of baricitinib on pneumonia-associated mortality reduction | Cardiac pulse rate | Up to Day 28 | 
| To demonstrate the efficacy of baricitinib on pneumonia-associated mortality reduction | Oxygen saturation | Up to Day 28 | 
| To demonstrate the efficacy of baricitinib on pneumonia-associated mortality reduction | Type of mechanical ventilation support (invasive, noninvasive, none) (daily evaluation at 8.00am and 8.00pm) | Up to Day 28 | 
| To demonstrate the efficacy of baricitinib on pneumonia-associated mortality reduction | Leukocyte counts (every 48 hours) for 12 days | Up to Day 12 | 
| To demonstrate the efficacy of baricitinib on pneumonia-associated mortality reduction | Pa02/FiO2 | Day 28 | 
| To demonstrate the efficacy of baricitinib on pneumonia-associated mortality reduction | Rates of non respiratory hospital-acquired infections | Day 28 | 
| To demonstrate the efficacy of baricitinib on pneumonia-associated morbidity reduction | Rates of nonrespiratory hospital-acquired infections | Day 28 | 
| To demonstrate the efficacy of baricitinib on pneumonia-associated morbidity reduction | Antibiotic-free days (the number of antibiotic-free days is defined as the number of days between Day 1 and Day 28 for which living patients do not receive antibiotics. | Day 28 | 
| To demonstrate the efficacy of baricitinib on pneumonia-associated mortality reduction | Antibiotic-free days (the number of antibiotic-free days is defined as the number of days between Day 1 and Day 28). Dead patients will be ascribed 0 antibiotic-free days. | Day 28 | 
| To demonstrate the efficacy of baricitinib on pneumonia-associated morbidity reduction | Duration of invasive mechanical ventilation and invasive mechanical ventilation-free days (defined as the number of days between Day 1 and Month 3 for which living patients breath spontaneously. | Up to Month 3 | 
| To demonstrate the efficacy of baricitinib on pneumonia-associated mortality reduction | Duration of invasive mechanical ventilation and invasive mechanical ventilation-free days (defined as the number of days between Day 1 and Month 3). Dead patients will be ascribed 0 mechanical ventilation-free days. | Up to Month 3 | 
| To demonstrate the efficacy of baricitinib on pneumonia-associated mortality reduction | Duration ogf hospitalization and hospital-free days (the number of hospital-free days is defined as the number of days between Day 1 and Month 3 which living patients are outside of a hospital. | Up to Month 3 | 
| To demonstrate the efficacy of baricitinib on pneumonia-associated morbidity reduction | Duration ogf hospitalization and hospital-free days (the number of hospital-free days is defined as the number of days between Day 1 and Month 3). Dead patients will be ascribed 0 hospital-fre days) | Up to Month 3 |