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

Hospital-acquired Pneumonia Clinical Trial

— TREAT-HAP  

Official title:

"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.

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05914584
• Other study ID #: RC22_0522
• Status: Not yet recruiting
• Phase: Phase 2/Phase 3
• Start date: July 1, 2023
• Est. completion date: December 31, 2025

Study information

• Verified date: June 2023
• Source: Nantes University Hospital
• Contact: Astrid GARREAU
• Phone: +33 (0) 2 53 48 28 40
• Email: astrid.garreau[@]chu-nantes.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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)

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 450
• Est. completion date: December 31, 2025
• Est. primary completion date: August 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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

Related Conditions & MeSH terms

• Healthcare-Associated Pneumonia
• Hospital-acquired Pneumonia
• Pneumonia

Intervention

Drug:
• Baricitinib 4 MG
Reference drug

Locations

Country	Name	City	State
Belgium	St-Luc Clinics	Bruxelles
Belgium	Ghent University Hospital	Ghent
Belgium	Groupe Jolimont	Haine-Saint-Paul
Belgium	Clinique Saint-Pierre	Ottignies
Belgium	University Hospital of UCL Namur	Yvoir
France	CHU Angers	Angers
France	CHU de Brest	Brest
France	CHU de Caen	Caen
France	CHU Clermont-Ferrand	Clermont-Ferrand
France	CHU de Clermont-Ferrand	Clermont-Ferrand
France	CHU de Clermont-Ferrand	Clermont-Ferrand
France	CH La Roche sur Yon	La Roche-sur-Yon
France	CHU de Limoges	Limoges
France	CHU de Marseille	Marseille
France	CHU de Nancy	Nancy
France	CHU de Nantes	Nantes
France	CHU de Nantes	Nantes
France	CHU de Nantes	Nantes
France	CHU de Nantes	Nantes
France	CHU de Beaujon	Paris
France	CHU la Pitié-Salpétrière	Paris
France	CHU Pitié-Salpétrière	Paris
France	CHU de Poitiers	Poitiers
France	CHU de Rennes	Rennes
France	CHU de Rennes	Rennes
Netherlands	University Medical Center Utrecht	Utrecht
Spain	Hospital del Mar	Barcelona
Spain	Hospital Vall d'Hebron	Barcelona
Spain	Hospital Clinic	Barcelone

Sponsors (1)

Lead Sponsor	Collaborator
Nantes University Hospital

Countries where clinical trial is conducted

Belgium,  France,  Netherlands,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Determine the safety of baricitinib	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)	Day 10-12
Other	Determine if baricitinib increases the economic efficiency of the treatment of pneumonia	Cost-effictiveness analysis (CEA) using QALYs (Quality-Adjusted Life-Years) will consist in estmating an incremental cost-effectiveness ratio (ICER)	6 months
Other	Determine the suitability of baricitinib from the patient's perspectives	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).	Up to 6 months
Other	Determine the suitability of baricitinib from the patient's perspectives	Changes in anxiety and depression measured with the Hospital and Aanxiety Depression 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).	Up to 6 months
Other	Determine the suitability of baricitinib from the patient's perspectives	Changes in subjective well-being measured with the Satisfaction With Life Scale (SWLS) validated in French, Spanish, Flemish and Dutch.	Up to 6 months
Other	To identify biomarkers for stratidication of patents into responders and non-responders to baricitinib	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	Day 10-12
Other	To identify a biobank of blood and respiratory samples collected from humans with hospital-acquired pneumonia	Collection of respiratory fluid and blood for biobank	Day 10-12
Other	Determine the safety of baricitinib	Rate of serious adverse effects and suspected unexpected serious adverse reaction (SUSAR) at Day 28.	Day 28
Other	Determine the safety of baricitinib	Rate of neutropenia, lymphopenia and thrombocytosis at the test-of-cure visit	Day 10-12
Other	Determine the safety of baricitinib	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)	Day 10-12
Other	Determine the safety of baricitinib	Rate of acute kidney failure (KDIO 2-3) at the test-of-cure visit	Day 10-12
Other	Determine the safety of baricitinib	Rate of major thrombo-embolic events at the test-of-cure visit	Day 10-12
Other	Determine the safety of baricitinib	Rate of EKG modification at the test-of-cure visit	Day 10-12
Primary	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
Primary	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	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
Secondary	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
Secondary	To demonstrate the efficacy of baricitinib on pneumonia-associated morbidity	All-cause morbidity at Month 3 and Month 6	Month 3 and Month 6
Secondary	To demonstrate the efficacy of baricitinib on pneumonia-associated mortality	All-cause mortality at Month 3 and Month 6	Month 3 and Month 6
Secondary	To demonstrate the efficacy of baricitinib on pneumonia-associated morbidity reduction	Rate of pleural empyema at Day 28.	Day 28
Secondary	To demonstrate the efficacy of baricitinib on pneumonia-associated mortality reduction	Presence of pleural empyema at Day 28.	Day 28
Secondary	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
Secondary	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
Secondary	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
Secondary	To demonstrate the efficacy of baricitinib on pneumonia-associated mortality reduction	Rate of pneumonia relapse	Up to 28 days
Secondary	To demonstrate the efficacy of baricitinib on pneumonia-associated mortality reduction	Time course of body temperature	Up to Day 28
Secondary	To demonstrate the efficacy of baricitinib on pneumonia-associated mortality reduction	Cardiac pulse rate	Up to Day 28
Secondary	To demonstrate the efficacy of baricitinib on pneumonia-associated mortality reduction	Oxygen saturation	Up to Day 28
Secondary	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
Secondary	To demonstrate the efficacy of baricitinib on pneumonia-associated mortality reduction	Leukocyte counts (every 48 hours) for 12 days	Up to Day 12
Secondary	To demonstrate the efficacy of baricitinib on pneumonia-associated mortality reduction	Pa02/FiO2	Day 28
Secondary	To demonstrate the efficacy of baricitinib on pneumonia-associated mortality reduction	Rates of non respiratory hospital-acquired infections	Day 28
Secondary	To demonstrate the efficacy of baricitinib on pneumonia-associated morbidity reduction	Rates of nonrespiratory hospital-acquired infections	Day 28
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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