Baricitinib Compared to Standard Therapy in Patients With COVID-19
Baricitinib Compared to Standard Therapy in Patients With COVID-19
There is urgent need of an effective therapy for Covid-19. To date, the best treatment of
 SARS-CoV-2 infection is unknown. Baricitinib has been identified as potential treatment for
 2019-nCoV acute respiratory disease, because of its immunomodulating and hypothesized
 antiviral activity.

 This is a multicenter randomized clinical trial that aims to evaluate the efficacy and safety
 of baricitinib in patients with SARS-CoV2 pneumonia. Patients will be randomized to receive
 or not baricitinib as adjunctive therapy. All patients will continue to receive the ongoing
 standard therapy: chloroquine/idrossichloroquine and low-molecular weight heparin (LMWH)
 eventually associated with ritonavir/lopinavir or darunavir/ritonavir will be allowed for all
 included patients.

 The primary endpoint measure is the efficacy of baricitinib in reducing the number of
 patients requiring invasive ventilation after 7 and 14 days of treatment.

 Secondary endpoints will be mortality rates and toxicity of baricitinib.
There is urgent need of an effective therapy for Covid-19. To date, the best treatment of
 SARS-CoV-2 infection is unknown. Multiple strategies have been proposed and several
 randomized clinical trials are ongoing. Recently, data extracted from scientific literature
 by machine learning suggested a potential role of baricitinib, a Janus kinases (JAKs)
 inhibitor, that induces an anti-inflammatory effect and a dose dependent inhibition of IL-6.
 This drug is currently approved for the treatment of rheumatoid arthritis. However, it has
 been suggested that this drug may act against SARS-CoV-2 by inhibiting of the AP2-associated
 protein kinase 1 (AAK1), a regulator of the endocytosis pathway exploited by SARS-CoV-2 to
 infect lung cells through binding with ACE2. Disruption of AAK1 might interrupt the passage
 of the virus into cells and also the intracellular assembly of virus particles.

 The aim of this study is to evaluate the efficacy and safety of baricitinib in patients with
 SARS-CoV2 pneumonia.

 This is a multicenter randomized controlled clinical trial for evaluating efficacy, safety
 and tolerability of baricitinib added to the usual care treatments in comparison with the
 usual care treatments, enrolling patients with COVID-19 /SARS-CoV2 pneumonia.

 The primary endpoint measure is the efficacy of baricitinib in reducing the number of
 patients requiring invasive ventilation after 7 and 14 days of treatment.

 Secondary endpoints will be: mortality rate after 14- and 28-days from randomization; time to
 invasive mechanical ventilation (days); time to independence from non-invasive mechanical
 ventilation (days); time to independence from oxygen therapy (days); time to improvement in
 oxygenation for at least 48 hours (days); length of hospital stay (days); length of ICU stay
 (days); instrumental response (pulmonary echography); toxicity of baricitinib.

 All patients included in the study will be treated with the usual care treatments. One group
 will receive baricitinib by oral route, while the control group will continue the usual care
 treatments. In the intervention group, baricitinib will be administered at the dosage of 4 mg
 daily by oral route for 14 consecutive days. For patients with eGFR between 30 and 60 ml/min
 and for patients with age >75 years old, the dosage will be half a tablet a day (2 mg/day)
 for 14 days.

 Inclusion criteria are the following

 -  Any gender

 -  Age > 18 years on day of signing informed consent

 -  Informed written consent for participation in the study

 -  Virological diagnosis of SARS-CoV-2 infection (real-time PCR)

 -  Hospitalized due to clinical instrumental diagnosis of pneumonia

 -  Oxygen saturation at rest in ambient air ≤93% or P/F ratio <250

 -  Able to be administered by oral route drugs

 -  Patients who receive O2 therapy or who need non-invasive mechanical ventilation

 -  In case of female patients at childbearing potential, they should agree to use highly
 effective methods of birth control at least till 7 days after the termination of the
 treatments

 Exclusion criteria are the following:

 -  Known hypersensitivity to Baricitinib or its excipients

 -  Patients with Creatinine Clearance < 30 ml/min

 -  Patients with active Tuberculosis (TBC)

 -  Patients with known HBV or HCV infection

 -  Patients with deep vein thrombosis (DVP) or Pulmonary Embolism (PE)

 -  Patients with ALT or AST> 5 times the upper limit of the normality

 -  Neutrophils <1000/mmc

 -  Platelets <50.000/mmc

 -  Hb< 8g/dl

 -  Bowel diverticulitis or perforation

 -  Patients who receive invasive mechanical ventilation

 -  Documented bacterial infection at time of randomization

 -  Patients with "do not resuscitate order"

 -  Patients receiving immunosuppressants or anti-rejection drugs

 -  Pregnancy or breastfeeding

 All patients, required by the assignment arm, will continue to receive therapy already in
 place, including that for Sars-CoV2 infection. Chloroquine/idrossichloroquine and
 low-molecular weight heparin (LMWH) eventually associated with ritonavir/lopinavir or
 darunavir/ritonavir will be allowed for all included patients.

 For the duration of the study, the following will not be allowed:

 -  the concomitant use of IL-1 or IL-6 blockers, JAK inhibitors and TNF inhibitors

 -  the start of the steroid in the two weeks of study. The steroid will be continued if the
 patient already takes steroid at the time of admission

 Intervention:

 Intervention arm:

 -  BARICITINIB 4 mg daily via oral route for 14 days as add-on therapy

 -  BARICITINIB 2 mg daily via oral route (eGFR between 30 and 60 ml/min and for patients
 with age >75 years old) for 14 days as add-on therapy

 Control arm:

 - patients in the control group will continue to receive standard therapy

 Sample size calculation:

 Expected 7-days and 14-days invasive ventilation (P0):30% Auspicated 7-days and 14-days
 invasive ventilation (P1):12% Statistical power: 80% Bilateral alpha error: 5% Sample size
 needed: 63 patients for each group (126 total patients)

 The statistical analysis plan will be developed and finalized before database lock and will
 describe the participant populations to be included in the analyses, and procedures for
 accounting for missing, unused, and spurious data.

 An intention-to-treat (ITT) and per-protocol (PP) analysis will be performed on randomized
 patients and on the overall population, respectively.
Inclusion Criteria:

 -  Any gender

 -  Age > 18 years on day of signing informed consent

 -  Informed written consent for participation in the study

 -  Virological diagnosis of SARS-CoV-2 infection (real-time PCR)

 -  Hospitalized due to clinical instrumental diagnosis of pneumonia.

 -  Oxygen saturation at rest in ambient air ≤93% or P/F ratio <250

 -  Able to be administered by oral route drugs

 -  Patients who receive O2 therapy or who need non-invasive mechanical ventilation

 -  In case of female patients at childbearing potential, they should agree to use highly
 effective methods of birth control at least till 7 days after the termination of the
 treatments

 Exclusion Criteria:

 -  Known hypersensitivity to Baricitinib or its excipients

 -  Patients with Creatinine Clearance < 30 ml/min

 -  Patients with active Tuberculosis (TBC)

 -  Patients with known HBV or HCV infection

 -  Patients with deep vein thrombosis (DVP) or Pulmonary Embolism (PE)

 -  Patients with ALT or AST> 5 times the upper limit of the normality

 -  Neutrophils <1000/mmc

 -  Platelets <50.000/mmc

 -  Hb< 8g/dl

 -  Bowel diverticulitis or perforation

 -  Patients who receive invasive mechanical ventilation

 -  Documented bacterial infection at time of randomization

 -  Patients with "do not resuscitate order"

 -  Patients receiving immunosuppressants or anti-rejection drugs

 -  Pregnancy or breastfeeding