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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.
For both groups :
At inclusion visit :
At visit 1 to visit 10 ( Day1- day10)
At visit 11(Day 10-12 test-of-cure) :
At visit 12 :
At visit 13 (month 3) and visit 14 (month 6) :
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Baricitinib + Standard of care | Experimental | 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 |
|
| Standard of care alone | Sham Comparator | Same as described in arm 1 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Baricitinib 4 MG | Drug | Reference drug |
|
| 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 |
| 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 |
| 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) |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Astrid GARREAU | Contact | +33 (0) 2 53 48 28 40 | astrid.garreau@chu-nantes.fr |
| Name | Affiliation | Role |
|---|---|---|
| Antoine ROQUILLY | Nantes University Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| St-Luc Clinics | Brussels | Belgium |
|
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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 |
| 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 |
| Ghent University Hospital | Ghent | Belgium |
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| Groupe Jolimont | Haine-Saint-Paul | Belgium |
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| Clinique Saint-Pierre | Ottignies | Belgium |
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| University Hospital of UCL Namur | Yvoir | Belgium |
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| CHU Angers | Angers | France |
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| CHU de Brest | Brest | France |
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| CHU de Caen | Caen | France |
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| CHU Clermont-Ferrand | Clermont-Ferrand | France |
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| CHU de Clermont-Ferrand | Clermont-Ferrand | France |
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| CHU de Clermont-Ferrand | Clermont-Ferrand | France |
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| CH La Roche sur Yon | La Roche-sur-Yon | France |
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| CHU de Limoges | Limoges | France |
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| CHU de Marseille | Marseille | France |
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| CHU de Nancy | Nancy | France |
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| CHU de Nantes | Nantes | France |
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| CHU de Nantes | Nantes | France |
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| CHU de Nantes | Nantes | France |
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| CHU de Nantes | Nantes | France |
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| CHU de Beaujon | Paris | France |
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| CHU la Pitié-Salpétrière | Paris | France |
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| CHU Pitié-Salpétrière | Paris | France |
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| CHU de Poitiers | Poitiers | France |
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| CHU de Rennes | Rennes | France |
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| CHU de Rennes | Rennes | France |
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| University Medical Center Utrecht | Utrecht | Netherlands |
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| Hospital Clinic | Barcelona | Spain |
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| Hospital del Mar | Barcelona | Spain |
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| Hospital Vall d'Hebron | Barcelona | Spain |
|
| ID | Term |
|---|---|
| D000077299 | Healthcare-Associated Pneumonia |
| ID | Term |
|---|---|
| D003428 | Cross Infection |
| D007239 | Infections |
| D011014 | Pneumonia |
| D012141 | Respiratory Tract Infections |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D007049 | Iatrogenic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| C000596027 | baricitinib |
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