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

"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.

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Hospital-acquired Pneumonia
• Intervention / Treatment: Drug: Baricitinib 4 MG

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)

• Study Type: Interventional
• Enrollment (Estimated): 450
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Astrid GARREAU; Phone Number: +33 (0) 2 53 48 28 40; Email: astrid.garreau@chu-nantes.fr

Study Locations

• Belgium
  • Bruxelles, Belgium
    • St-Luc Clinics
    • Contact: Jean-Baptiste MESLAND; Phone Number: +32/2 764 27 51; Email: baptiste.mesland@saintluc.uclouvain.be
  • Ghent, Belgium
    • Ghent University Hospital
    • Contact: Pieter DEPUYDT; Phone Number: +32/9 332 28 08; Email: pieter.depuydt@ugent.be
  • Haine-Saint-Paul, Belgium
    • Groupe Jolimont
    • Contact: Vincent HUBERLANT; Phone Number: +32/6 423 40 40; Email: vincent.huberlant@jolimont.be
  • Ottignies, Belgium
    • Clinique Saint-Pierre
    • Contact: Nicolas DE SCHRYVER; Phone Number: +32/1 043 77 34; Email: nicolas.deschryver@cspo.be
  • Yvoir, Belgium
    • University Hospital of UCL Namur
    • Contact: Patrick HONORE; Phone Number: +32/4 781 22 50; Email: patrick.honore@chuuclnamur.uclouvain.be
• France
  • Angers, France
    • CHU Angers
    • Contact: Sigismond LASOCKI; Phone Number: +33 (0) 2 41 35 36 35; Email: silasocki@chu-angers.fr
  • Brest, France
    • CHU de Brest
    • Contact: Xavier CHAPALAIN; Phone Number: +33 (0) 2 98 22 33 33; Email: xavier.chapalain@chu-brest.fr
  • Caen, France
    • CHU de Caen
    • Contact: Clément GAKUBA; Phone Number: +33 (0)2 31 06 31 06; Email: gakuba-c@chu-caen.fr
  • Clermont-Ferrand, France
    • Chu Clermont-Ferrand
    • Contact: Pierre COUHAULT; Phone Number: +33 (0) 4 73 75 07 50; Email: couhault@chu-clermontferrand.fr
  • Clermont-Ferrand, France
    • CHU de Clermont-Ferrand
    • Contact: Russell CHABANNE; Phone Number: +33 (0)4 73 75 16 48; Email: rchabanne@chu-clermontferrand.fr
  • La Roche-sur-Yon, France
    • CH La Roche sur Yon
    • Contact: Maude MILLEREUX; Phone Number: +33 (0) 2 51 44 61 61; Email: maud.millereux@ght85.fr
  • Limoges, France
    • CHU de Limoges
    • Contact: Bruno FRANCOIS; Phone Number: +33 (0) 5 55 05 62 74; Email: bruno.francois@chu-limoges.fr
  • Marseille, France
    • CHU de Marseille
    • Contact: Marc LEONE; Phone Number: +33 (0)4 91 96 86 50; Email: marc.leone@ap-hm.fr
  • Nancy, France
    • CHU de NANCY
    • Contact: Gérard AUDIBERT; Phone Number: +33 (0)3 83 85 96 50; Email: g.audibert@chru-nancy.fr
  • Nantes, France
    • CHU de Nantes
    • Contact: Jean-Baptise LASCARROU; Phone Number: +33 (0) 2 40 08 73 76; Email: jeanbaptiste.lascarrou@chu-nantes.fr
  • Paris, France
    • CHU Pitié-Salpêtrière
    • Contact: Jean-Michel CONSTANTIN; Phone Number: +33 (0) 1 42 16 33 71; Email: jean-michel.constantin@aphp.fr
  • Paris, France
    • CHU de Beaujon
    • Contact: Emmanuel WEISS; Phone Number: +33 (0) 1 40 87 44 03; Email: emmanuel.weiss@aphp.fr
  • Paris, France
    • CHU la Pitié-Salpétrière
    • Contact: Vincent DEGOS; Phone Number: +33 (0) 1 42 16 33 71; Email: vincent.degos@inserm.fr
  • Poitiers, France
    • CHU de Poitiers
    • Contact: Claire DAHYOT FIZELIER; Phone Number: +33 (0) 5 49 44 44 44; Email: fizelier@chu-poitiers.fr
  • Rennes, France
    • CHU de Rennes
    • Contact: Jean-Marc TADIE; Phone Number: +33 (0) 2 99 28 42 48; Email: jeanmarc.tadie@chu-rennes.fr
• Netherlands
  • Utrecht, Netherlands
    • University Medical Center Utrecht
    • Contact: Lennie DERDE; Phone Number: +31/887 555 555; Email: lderde@umcutrecht.nl
• Spain
  • Barcelona, Spain
    • Hospital del Mar
    • Contact: Rosana MUNOZ; Phone Number: +34/93 248 30 41; Email: rmunozbermudez@psmar.cat
  • Barcelona, Spain
    • Hospital Vall d'Hebron
    • Contact: Ricard FERRER; Phone Number: +34/93 274 62 09; Email: r.ferrer@vhebron.net
  • Barcelone, Spain
    • Hospital Clinic
    • Contact: Antoni TORRES; Phone Number: +34/93 227 5549; Email: atorres@clinic.cat

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Baricitinib + Standard of care; 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; Reference drug
Sham Comparator: Standard of care alone; Same as described in arm 1	Drug: Baricitinib 4 MG; Reference drug

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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
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
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
Determine the safety of baricitinib	Rate of serious adverse effects and suspected unexpected serious adverse reaction (SUSAR) at Day 28.	Day 28
Determine the safety of baricitinib	Rate of neutropenia, lymphopenia and thrombocytosis at the test-of-cure visit	Day 10-12
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
Determine the safety of baricitinib	Rate of acute kidney failure (KDIO 2-3) at the test-of-cure visit	Day 10-12
Determine the safety of baricitinib	Rate of major thrombo-embolic events at the test-of-cure visit	Day 10-12
Determine the safety of baricitinib	Rate of EKG modification at the test-of-cure visit	Day 10-12

Collaborators and Investigators

• Sponsor: Nantes University Hospital
• Investigators: Principal Investigator: Antoine ROQUILLY, CHU de Nantes

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2023
• Primary Completion (Estimated): August 31, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: April 19, 2023
• First Submitted That Met QC Criteria: June 13, 2023
• First Posted (Actual): June 22, 2023

Study Record Updates

• Last Update Posted (Actual): June 22, 2023
• Last Update Submitted That Met QC Criteria: June 13, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Disease Attributes; Cross Infection; Iatrogenic Disease; Healthcare-Associated Pneumonia; Pneumonia
• Other Study ID Numbers: RC22_0522

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No