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

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

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.

Study Overview

• Status: Unknown
• Conditions: Corona Virus Infection
• Intervention / Treatment: Drug: Baricitinib

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.

• Study Type: Interventional
• Enrollment (Anticipated): 13
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Sara Monti, MD; Phone Number: 0382501878; Email: sara.saramonti@gmail.com
• Study Contact Backup: Name: Valentina Zuccaro, MD; Phone Number: 0382501080; Email: V.Zuccaro@smatteo.pv.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 74 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Baricitinib active treatment; Baricitinib 4 mg/day	Drug: Baricitinib; 4 mg/day for 7 days; Other Names: Olumiant

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: IRCCS Policlinico S. Matteo
• Investigators: Principal Investigator: Carlomaurizio Montecucco, Prof, Rheumatology, IRCCS Fondazione Policlinico S. Matteo, Pavia, Italy; Study Chair: Raffaele Bruno, Prof, Infectious Diseases; IRCCS Fondazione Policlinico S. Matteo, Pavia, Italy

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): May 15, 2020
• Primary Completion (ANTICIPATED): September 15, 2020
• Study Completion (ANTICIPATED): November 15, 2020

Study Registration Dates

• First Submitted: May 13, 2020
• First Submitted That Met QC Criteria: May 21, 2020
• First Posted (ACTUAL): May 22, 2020

Study Record Updates

• Last Update Posted (ACTUAL): May 22, 2020
• Last Update Submitted That Met QC Criteria: May 21, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Coronavirus Infections; Pneumonia
• Other Study ID Numbers: 2020-001185-11

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No