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Baricitinib Compared to Standard Therapy in Patients With COVID-19 (BARICIVID-19)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04393051
Recruitment Status : Not yet recruiting
First Posted : May 19, 2020
Last Update Posted : May 20, 2020
Sponsor:
Information provided by (Responsible Party):
Francesco Menichetti, Azienda Ospedaliero, Universitaria Pisana

Tracking Information
First Submitted Date  ICMJE May 16, 2020
First Posted Date  ICMJE May 19, 2020
Last Update Posted Date May 20, 2020
Estimated Study Start Date  ICMJE May 20, 2020
Estimated Primary Completion Date June 30, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 16, 2020)
Need of invasive mechanical ventilation [ Time Frame: after 7 and 14 days of treatment ]
Reduction of the number of patients requiring invasive ventilation
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 16, 2020)
  • Mortality [ Time Frame: 14- and 28-days from randomization ]
    Proportion of any cause deaths
  • Time to invasive mechanical ventilation [ Time Frame: 30 days ]
    Days from randomization to invasive mechanical ventilation
  • Time to independence from non-invasive mechanical ventilation [ Time Frame: 30 days ]
    Days from randomization to independence from non-invasive mechanical ventilation
  • Time to independence from oxygen therapy [ Time Frame: 30 days ]
    Days from randomization to independence from oxygen therapy
  • Time to improvement in oxygenation for at least 48 hours [ Time Frame: 30 days ]
    Days from randomization to improvement in oxygenation for at least 48 hours
  • Length of hospital stay [ Time Frame: 30 days ]
    Days of hospital stay
  • Length of ICU stay [ Time Frame: 30 days ]
    Days of ICU stay
  • Instrumental response [ Time Frame: 30 days ]
    Changes in pulmonary echography
  • Proportion of adverse events [ Time Frame: 30 days ]
    Rate of adverse events codified by Common Terminology Criteria for Adverse Events (CTCAE) v. 5.0
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Baricitinib Compared to Standard Therapy in Patients With COVID-19
Official Title  ICMJE BARICIVID-19 STUDY: MultiCentre, Randomised, Phase IIa Clinical Trial Evaluating Efficacy and Tolerability of Baricitinib as add-on Treatment of In-patients With COVID-19 Compared to Standard Therapy
Brief Summary

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.

Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Phase II randomized clinical trial to evaluate the efficacy and safety of baricitinib in patients with SARS-CoV2 pneumonia
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Covid-19
  • SARS-CoV 2
  • SARS Pneumonia
Intervention  ICMJE Drug: Baricitinib Oral Tablet
Baricitinib will be administered by oral route at different dosages according to age and kidney function. The drug will be administered for 14 days, unless occurrence of discontinuation criteria.
Study Arms  ICMJE
  • Experimental: BAR group

    Patients who will be assigned (after a computerized randomization) to the BAR group will. receive baricitinib as adjunctive therapy.

    Baricitinib will be administered at 4 mg daily via oral route for 14 days as add-on therapy or 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

    Intervention: Drug: Baricitinib Oral Tablet
  • No Intervention: Control group
    Patients in the control group will continue to receive standard therapy.
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: May 16, 2020)
126
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 30, 2020
Estimated Primary Completion Date June 30, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Marco Falcone, MD 050996735 marco.falcone@unipi.it
Contact: Giusy Tiseo, MD 050996343 tiseogiusy@gmail.com
Listed Location Countries  ICMJE Italy
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04393051
Other Study ID Numbers  ICMJE BARICIVID-19
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Francesco Menichetti, Azienda Ospedaliero, Universitaria Pisana
Study Sponsor  ICMJE Azienda Ospedaliero, Universitaria Pisana
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Francesco Menichetti, MD Azienda Ospedaliero, Universitaria Pisana
PRS Account Azienda Ospedaliero, Universitaria Pisana
Verification Date May 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP