Clinical trial NCT04399798: Baricitinib for coRona Virus pnEumonia (COVID-19): a THerapeutic Trial
Official title: 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: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Corona Virus Infection
Lead sponsor: Fondazione IRCCS Policlinico San Matteo di Pavia
Sponsor class: OTHER
First posted: 2020-05-22
Enrollment: 13
Sex: ALL
Minimum age (years): 18
Maximum age (years): 74
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Proof-of-concept trial with an exploratory single-arm proof of concept Phase IIa study
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Response to treatment: absence of moderate to severe oxygenation impairment (Berlin criteria)
timeFrame: 8 days
measure: Response to treatment: survival
timeFrame: 8 days
Secondary outcomes:
measure: To quantify the rate of each of: moderate or severe oxygenation impairment within 8 days
timeFrame: 8 days
measure: To quantify the rate of each of: moderate or severe oxygenation impairment within 15 days
timeFrame: 15 days
measure: Mortality
timeFrame: 8 days and 15 days
measure: Peripheral capillary oxygen saturation (SpO2)
timeFrame: 8 days; 15 days
measure: Partial pressure of oxygen/fraction inspired oxygen (PaO2/FiO2)
timeFrame: 8 days; 15 days
measure: To assess the rate of patients admitted to the intensive care unit
timeFrame: 8 days; 15 days
measure: To measure the length of hospital stay
timeFrame: 8 days; 15 days
measure: 28-day mortality
timeFrame: 28 days
measure: To quantify the rate of re-admission within 28 days
timeFrame: 28 days
measure: To quantify the cumulative incidence and severity of adverse events
timeFrame: 28 days
measure: Interleukin (IL)-1; IL-2; IL-10; IL-6; IL-8; IL-17; IL-2 receptor levels;
timeFrame: 15 days
measure: TNFalpha; vascular endothelial growth factor (VEGF); interferon gamma (IFNgamma) levels
timeFrame: 15 days
measure: Viral load analyses
timeFrame: 15 days
Other outcomes:
Locations:
Study officials:
affiliation: Rheumatology, IRCCS Fondazione Policlinico S. Matteo, Pavia, Italy
name: Carlomaurizio Montecucco, Prof
role: PRINCIPAL_INVESTIGATOR
affiliation: Infectious Diseases; IRCCS Fondazione Policlinico S. Matteo, Pavia, Italy
name: Raffaele Bruno, Prof
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.