Hospital-acquired Pneumonia
Conditions
Brief summary
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
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)
Interventions
DRUGBaricitinib 4 MG
Reference drug
Sponsors
Nantes University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Day 28 | 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 |
| 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 | Day 28 | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To demonstrate the efficacy of baricitinib on pneumonia-associated morbidity | Month 3 and Month 6 | All-cause morbidity at Month 3 and Month 6 |
| To demonstrate the efficacy of baricitinib on pneumonia-associated mortality | Month 3 and Month 6 | All-cause mortality at Month 3 and Month 6 |
| To demonstrate the efficacy of baricitinib on pneumonia-associated morbidity reduction | Day 28 | In case of a non-significant difference in the rate of clinical cure, the co-primary outcome will be presented as a secondary outcome. |
| To demonstrate the efficacy of baricitinib on pneumonia-associated mortality reduction | Day 28 | In case of a non-significant difference in the rate of clinical cure, the co-primary outcome will be presented as a secondary outcome. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Determine if baricitinib increases the economic efficiency of the treatment of pneumonia | 6 months | Cost-effictiveness analysis (CEA) using QALYs (Quality-Adjusted Life-Years) will consist in estmating an incremental cost-effectiveness ratio (ICER) |
| Determine the suitability of baricitinib from the patient's perspectives | Up to 6 months | Changes in health-related quality of life after randomization measured with the Short Form-36 scale validated in French, Spanish, Flemish and Dutch. These questionnaires will be filled in by the patient (patient's perspective) or by one relative if the patient cannot respond for him/herself (patient's perspective). |
| To identify biomarkers for stratidication of patents into responders and non-responders to baricitinib | Day 10-12 | To capture the complexity of the host-pathogens interactions and to clinically validate biomarkers for the stratification of patients into low/high risk of poor outcomes of HAP and responders/non responders to immunotherapy |
| To identify a biobank of blood and respiratory samples collected from humans with hospital-acquired pneumonia | Day 10-12 | Collection of respiratory fluid and blood for biobank |
| Determine the safety of baricitinib | Day 10-12 | Rate of serious adverse effects and suspected unexpected serious adverse reaction (SUSAR) at Day 28. Rate of neutropenia, lymphopenia and trhombocytosis at the test-of-cure visit (Day 10-12). Rates of drug-induced liver injury defined by the International DILI Expert Working Groups as ALT greater than or equal to 5 or ALP greater than or equal to 2 and TBL inferior to 2 ULN (corresponding to grade 1, mild severity) Rate of acute kidney failure (KDIO 2-3) at the test-of-cure visit (Day 10-12) Rate of major trhombo-embolic events at the test-of-cure visit (Days 10-12), rate of EKG modification at the test-of-cure visit (Day10-12) |
Countries
Belgium, France, Netherlands, Spain
Contacts
Primary ContactAstrid GARREAU
Outcome results
None listed