Baricitinib for coRona Virus pnEumonia (COVID-19): a THerapeutic Trial

Study Overview
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Brief Summary
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The objective of the study is to assess the efficacy and safety of Baricitinib in the treatment of patients with COVID-19 pneumonia. This will be a proof-of-concept trial with an exploratory single-arm proof of concept Phase IIa study to assess the efficacy and safety profile of Baricitinib in a limited number of patients with severe acute respiratory syndrome (SARS)-CoV-2 pneumonia. If the initial proof of concept phase will lead to favourable results, an open-label, Phase II, randomized controlled trial will be then designed and performed to confirm the results obtained in the proof of concept phase. The proof-of-concept phase guarantees that no safety issues arise on a limited number of patients in the use of a drug new to the current condition being treated.

Detailed Description
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Baricitinib 4 mg/daily will be prescribed for 7 days to eligible patients showing signs of acute inflammatory response activation. The primary outcome of the study will be the response to treatment. A patient is considered responder in the absence of either moderate to severe oxygenation impairment or death, whichever occurs first, within 8 days from enrolment. The main secondary outcomes will include the responder rate and mortality at 15 days, the quantification of patients experiencing moderate to severe oxygenation impairment, rate of patients admitted to the intensive care unit, length of hospitalization, mortality at 28 days, rate of re-admission, and adverse events. The duration of the study will be 28 days. In the proof of concept phase, 13 patients will be enrolled; if the responders will be at least 4 patients without safety issues, Baricitinib will be considered for further studies.

Official Title
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A proof-of Concept Study of the Use of Janus Kinase 1 and 2 Inhibitor, Baricitinib, in the Treatment of COVID-19-related Pneumonia

Conditions
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Corona Virus Infection

Intervention / Treatment
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* Drug: Baricitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to obtain informed patient consent noting the limitations of existing knowledge regarding Baricitinib's efficacy and the labeled warning and precautions as the proposed use is outside the approved indication, as well as the presence of known risk of being treated with Baricitinib while the subject of an active infection informed Consent as documented by signature patients with a confirmed SARS-CoV-2 pneumonia adult patients aged 18-74 years old infiltrates at chest radiography c-reactive protein level greater than 10 mg/dl or ferritin level > 900 ug/L Lymphocyte count less than 1500/mmc > 200 PaO2/FiO2 ≤ 300 Exclusion Criteria: patients aged < 18 years old and ≥ 75 years old concomitant bacterial infection lymphopenia less than 500/mmc hemoglobin < 8 g/dl absolute neutrophil count < 1 x 109 cells/L requiring continuous positive airway pressure (C-PAP) or mechanical ventilation sudden clinical deterioration requiring intensive care unit access known hypersensitivity or allergy to the study drug Creatinine clearance < 30 mL/min; if the creatinine clearance is between 30 and 60 mL/min the dose of Baricitinib should be reduced to 2 mg/daily Severe hepatic impairment (no dose adjustment of Baricitinib is required in mild or moderate hepatic impairment) Pregnant or breast-feeding Active tuberculosis Evidence of active hepatitis B (HBV) (HbsAg positive) or with detectable hepatitis C virus (HCV)-RNA, human immunodeficiency virus (HIV) Ongoing, acute diagnosis of deep venous thrombosis/pulmonary embolism (DVT/PE) Previous diagnosis of DVT/PE

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 74 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
Intervention Model: Single Group Assignment
Interventional Model Description: Proof-of-concept trial with an exploratory single-arm proof of concept Phase IIa study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Baricitinib active treatment<br>Baricitinib 4 mg/day | Drug: Baricitinib<br>* 4 mg/day for 7 days<br>* Other names: Olumiant;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response to treatment: absence of moderate to severe oxygenation impairment (Berlin criteria) | A patient is consider responder in the absence of either moderate to severe oxygenation impairment according to Berlin criteria - measured as Partial pressure of oxygen/fraction inspired oxygen (PaO2/FiO2) | 8 days | 
| Response to treatment: survival | Absence of death within 8 days from enrollment | 8 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To quantify the rate of each of: moderate or severe oxygenation impairment within 8 days | Moderate to severe oxygenation impairment according to Berlin criteria (measured as PaO2/FiO2) | 8 days | 
| To quantify the rate of each of: moderate or severe oxygenation impairment within 15 days | Moderate to severe oxygenation impairment according to Berlin criteria (measured as PaO2/FiO2) | 15 days | 
| Mortality | To quantify mortality within 8 and 15 days | 8 days and 15 days | 
| Peripheral capillary oxygen saturation (SpO2) | SpO2 will be assessed with the median and 25th-75th percentiles | 8 days; 15 days | 
| Partial pressure of oxygen/fraction inspired oxygen (PaO2/FiO2) | PaO2/FiO2 will be assessed with the median and 25th-75th percentiles | 8 days; 15 days | 
| To assess the rate of patients admitted to the intensive care unit | Number of patients over the number of patients enrolled | 8 days; 15 days | 
| To measure the length of hospital stay | Median number of days and 25th-75th percentiles | 8 days; 15 days | 
| 28-day mortality | To quantify 28-day mortality | 28 days | 
| To quantify the rate of re-admission within 28 days | Number of patients readmitted over the number patients enrolled | 28 days | 
| To quantify the cumulative incidence and severity of adverse events | Number, type, and severity of adverse events | 28 days | 
| Interleukin (IL)-1; IL-2; IL-10; IL-6; IL-8; IL-17; IL-2 receptor levels; | Serial serum assessments from baseline up to 15 days | 15 days | 
| TNFalpha; vascular endothelial growth factor (VEGF); interferon gamma (IFNgamma) levels | Serial serum assessments from baseline up to 15 days | 15 days | 
| Viral load analyses | Serial assessments from baseline up to 15 days for viral load persistence | 15 days |