Ruxolitinib for Acute Respiratory Disorder Syndrome Due to COVID-19

Study Overview
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Brief Summary
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The COVID-19 pandemic has had a dramatic effect in public health worldwide. In Brazil, there have been more than 2 million confirmed cases and over 75,000 deaths since February 26, 2020. Based on reports of a hyperinflammatory state associated with COVID-19, the use of immunosuppressive drugs may be efficacious in the treatment of this disease. JAK inhibitors have been shown to harness inflammation in a number of different pathologic conditions. The aim of the present study is to evaluate the efficacy and safety of JAK inhibitor ruxolitinib in patients with acute respiratory distress syndrome due to COVID-19.

Official Title
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Randomized, Double-Blind Clinical Trial of Ruxolitinib in Patients With Acute Respiratory Disorder Syndrome Due to SARS-CoV-2 Infection

Conditions
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SARS-CoV2, Severe Acute Respiratory Syndrome Coronavirus 2

Intervention / Treatment
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* Drug: Janus Kinase Inhibitor (ruxolitinib)
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients hospitalized with SARS-CoV-2 pneumonia confirmed by RT-PCR or serology (IgA); PaO2/FiO2 < 300 (not fully explained by heart failure or volume overload) or SpO2 < 90% on room air. Exclusion Criteria: Symptom onset > 14 days; Neutrophil count < 1,000/mm3; Platelets < 50,000/mm3; ICU care at enrollment; On invasive mechanical ventilation at enrollment; Current use of experimental therapy for COVID-19 (except: azithromycin or corticosteroids) Uncontrolled arterial hypertension; Current or previous use of systemic immunosuppressive therapy in the last 30 days; Pregnancy or lactation; Estimated creatinine clearance < 30 mL/min or receiving CRRT or intermittent hemodialysis; Allergy to ruxolitinib; Active tuberculosis; HIV seropositivity; Prior history of progressive multifocal leukoencephalopathy; Use of any JAK inhibitor in the last 30 days before study enrollment; Not qualifying according to investigators' perception.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 95 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental Group - ruxolitinib<br>Ruxolitinib 5 mg PO b.i.d. for 14 days | Drug: Janus Kinase Inhibitor (ruxolitinib)<br>* 5 mg P.O. b.i.d. for 14 days. Dose reduction will occur if neutrophils < 500/mm3 or platelets <50,000/mm3.<br>|
| Placebo Comparator: Placebo Group<br> | Other: Placebo<br>* Placebo tablets P.O. b.i.d. for 14 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| A composite outcome of death or ICU admission or mechanical ventilation at day 14. |  | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| A composite outcome of death or ICU admission or mechanical ventilation at day 28 |  | 28 days | 
| Time to treatment failure | ICU admission, mechanical ventilation, death or consent withdrawal | 28 days | 
| Overall survival at days 14 and 28 |  | 14 and 28 days | 
| Cumulative incidence of ICU admission rate at days 14 and 28 |  | 14 and 28 days | 
| Cumulative incidence of mechanical ventilation at days 14 and 28 |  | 14 and 28 days | 
| Duration of hospital stay |  | 28 days | 
| Duration of ICU stay |  | 28 days | 
| Duration of mechanical ventilation |  | 28 days | 
| Duration of non-invasive ventilation |  | 28 days | 
| Secondary hemophagocytic syndrome rate |  | 28 days | 
| Cumulative incidence nosocomial infection rate at days 14 and 28 |  | 14 and 28 days | 
| Incidence of discontinuation of oxygen supplementation at days 14 and 28 |  | 14 and 28 days | 
| Rate of grade 1-2 and 3-5 emerging adverse events at day 28 |  | 28 days | 
| Cumulative dose of methylprednisolone at days 14 and 28 |  | 14 and 28 days | 
| Change in PaO2/FiO2 ratio from baseline to days 14 and 28 |  | 14 and 28 days | 
| Change in interleukin 6 levels [pg/mL] from baseline to days 14 and 28 |  | 14 and 28 days | 
| Change in d-dimer levels [ng/mL] from baseline to days 14 and 28 |  | 14 and 28 days | 
| Change in fibrinogen levels [mg/dL] from baseline to days 14 and 28 |  | 14 and 28 days | 
| Change in ferritin levels [ng/mL] from baseline to days 14 and 28 |  | 14 and 28 days | 
| Change in C reactive protein levels [mg/L] from baseline to days 14 and 28 |  | 14 and 28 days | 
| Change in alanine aminotransferase [U/L] from baseline to days 14 and 28 |  | 14 and 28 days | 
| Change in aspartate aminotransferase [U/L] from baseline to days 14 and 28 |  | 14 and 28 days | 
| Change in creatinine levels [mg/dL] from baseline to days 14 and 28 |  | 14 and 28 days | 
| Change in glucose levels [mg/dL] from baseline to days 14 and 28 |  | 14 and 28 days | 
| Change in hemoglobin levels [g/dL] from baseline to days 14 and 28 |  | 14 and 28 days | 
| Change in platelet count [x10ˆ3/mmˆ3] from baseline to days 14 and 28 |  | 14 and 28 days | 
| Change in absolute neutrophil count [x10ˆ3/mmˆ3] from baseline to days 14 and 28 |  | 14 and 28 days | 
| Change in absolute neutrophil count [/mmˆ3] from baseline to days 14 and 28 |  | 14 and 28 days | 
| Change in absolute lymphocyte count [/mmˆ3] from baseline to days 14 and 28 |  | 14 and 28 days | 
| Change in prothrombin time ratio from baseline to days 14 and 28 |  | 14 and 28 days | 
| Change in partial thromboplastin time ratio from baseline to days 14 and 28 |  | 14 and 28 days | 
| Change in bilirubin [mg/dl] from baseline to days 14 and 28 |  | 14 and 28 days | 
| Change in lactate dehydrogenase [U/L] from baseline to days 14 and 28 |  | 14 and 28 days | 
| Change in CPK-MB [ng/mL] from baseline to days 14 and 28 |  | 14 and 28 days | 
| Change in troponin [ng/mL] from baseline to days 14 and 28 |  | 14 and 28 days | 
| Change in von Willebrand factor antigen level (VWF:Ag) [%] from baseline to days 14 and 28 |  | 14 and 28 days | 
| Change in von Willebrand factor activity (ristocetin cofactor) [%] from baseline to days 14 and 28 |  | 14 and 28 days | 
| Change in ADAMTS-13 [%] from baseline to days 14 and 28 |  | 14 and 28 days | 
| Change in von Willebrand multimeters from baseline to days 14 and 28 |  | 14 and 28 days | 
| Change in plasminogen activator inhibitor-1 levels [ng/mL] from baseline to days 14 and 28 |  | 14 and 28 days | 
| Change in E-selectin levels [ng/mL] from baseline to days 14 and 28 |  | 14 and 28 days | 
| Change in P-selectin levels [ng/mL] from baseline to days 14 and 28 |  | 14 and 28 days | 
| Change in endothelin [fmol/mL] from baseline to days 14 and 28 |  | 14 and 28 days | 
| Change in circulating microparticles from baseline to days 14 and 28 |  | 14 and 28 days | 
| Change in thromboelastography from baseline to days 14 and 28 |  | 14 and 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Clinical Efficacy, Clinical Trial, SARS-CoV2, Severe Acute Respiratory Syndrome Coronavirus 2, Janus Kinase Inhibitors, Safety