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

Overview

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.

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

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: N/A
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: September 15, 2020

Detailed Description

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.

Interventions

  • Drug: Baricitinib
    • 4 mg/day for 7 days

Arms, Groups and Cohorts

  • Experimental: Baricitinib active treatment
    • Baricitinib 4 mg/day

Clinical Trial Outcome Measures

Primary Measures

  • Response to treatment: absence of moderate to severe oxygenation impairment (Berlin criteria)
    • Time Frame: 8 days
    • 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)
  • Response to treatment: survival
    • Time Frame: 8 days
    • Absence of death within 8 days from enrollment

Secondary Measures

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

Participating in This Clinical Trial

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

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 74 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • IRCCS Policlinico S. Matteo
  • Provider of Information About this Clinical Study
    • Principal Investigator: Carlomaurizio Montecucco, Prof – IRCCS Policlinico S. Matteo
  • Overall Official(s)
    • Carlomaurizio Montecucco, Prof, Principal Investigator, Rheumatology, IRCCS Fondazione Policlinico S. Matteo, Pavia, Italy
    • Raffaele Bruno, Prof, Study Chair, Infectious Diseases; IRCCS Fondazione Policlinico S. Matteo, Pavia, Italy
  • Overall Contact(s)
    • Sara Monti, MD, 0382501878, sara.saramonti@gmail.com

References

Richardson P, Griffin I, Tucker C, Smith D, Oechsle O, Phelan A, Rawling M, Savory E, Stebbing J. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. Lancet. 2020 Feb 15;395(10223):e30-e31. doi: 10.1016/S0140-6736(20)30304-4. Epub 2020 Feb 4. No abstract available. Erratum In: Lancet. 2020 Jun 20;395(10241):1906.

Stebbing J, Phelan A, Griffin I, Tucker C, Oechsle O, Smith D, Richardson P. COVID-19: combining antiviral and anti-inflammatory treatments. Lancet Infect Dis. 2020 Apr;20(4):400-402. doi: 10.1016/S1473-3099(20)30132-8. Epub 2020 Feb 27. No abstract available.

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