Ruxolitinib for Treatment of Covid-19 Induced Lung Injury ARDS

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of ruxolitinib in the treatment of patients with COVID-19 severe pneumonia.

Detailed Description
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This clinical trial is an open-label trial of ruxolitinib for the treatment of severe COVID-19 to assess its efficacy and safety. Ruxolitinib (INCB018424 phosphate, INC424, ruxolitinib phosphate) is a well established, potent and selective inhibitor of Janus kinase (JAK)1 and JAK2, with modest to marked selectivity against tyrosine kinase (TYK)2 and JAK3, respectively. Ruxolitinib interferes with the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. Ruxolitinib (JAKAVI®) is currently approved in the European Union (EU) for the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis (PMF) (also known as chronic idiopathic MF), post-polycythemia vera myelofibrosis (PPV-MF) or post-essential thrombocythemia myelofibrosis (PET-MF) and for the treatment of adult patients with PV who are resistant to or intolerant of hydroxyurea (HU). In the US, ruxolitinib has been approved in the treatment of steroid refractory graft versus host disease post allogeneic stem cell transplantation. Because many patients with severe respiratory disease due to COVID-19 have features consistent with the cytokine release syndrome (CRS) and increased activation of the JAK/STAT pathway, it is postulated that ruxolitinib might have a useful role in treating these patients.

Official Title
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Ruxolitinib for Treatment of Covid-19 Induced Lung Injury ARDS A Single-arm, Open-label, Proof of Concept Study

Conditions
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ARDS, Human, COVID

Intervention / Treatment
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* Drug: Ruxolitinib administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or non-pregnant female adult ≥18 years of age at time of enrollment. has laboratory-confirmed SARS-CoV-2 infection as determined by PCR or other commercial or public health assay (result of the PCR is not necessary for inclusion, but has to approved latest within 48-72 hours after registration) Willingness of men and women of childbearing potential to use highly effective contraceptive methods by abstinence or by using at least two contraceptive methods from the date of consent to the end of the study severe lung disease as defined by following: Recent intubation Requirement of invasive ventilation moderate to severe pulmonary oxygen exchange disturbance as defined by (PaO2/FiO2) ≤ 200 mmHg at a PEEP ≥ 5mm H2O Serum LDH > 283 U/l Ferritin above normal value CT-scan: pulmonary infiltration compatible with Covid-19 disease Patient or patient´s representative must provide written informed consent (and assent if applicable) before any study assessment is performed. Exclusion Criteria: Uncontrolled HIV infection Active tuberculosis (result of positive tuberculosis infection is not necessary for exclusion, but has to approved later on during patient´s intervention) Chronic kidney disease requiring dialysis ALT/AST > 5 times the upper limit of normal. Pregnancy or breast feeding. Allergy to study medication Simultaneous participation in another clinical trial with an experimental treatment

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Interventional Model Description: Ruxolitinib will be administered p.o. or by gavage feeding starting with 2 x 10mg or 2 x 15mg bid dose at day 1 according to the investigator's decision and can be increased up to 2 x 15mg bid from day 2 to day 28 (max) (depending on platelet counts and renal function). Ruxolitinib will be administered in the morning and evening. Dosing will be adjusted according to toxicity and kidney function; open design, single arm.If the patient is discharged before day 28, the therapy will be discontinued for discharge.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ruxolitinib treatment<br>Ruxolitinib will be administered p.o. or by gavage feeding for max 28 days | Drug: Ruxolitinib administration<br>* Ruxolitinib will be administered p.o. or by gavage feeding starting with 2 x 10mg or 2 x 15mg bid dose at day 1 according to the investigator's decision and can be increased up to 2 x 15mg bid from day 2 to day 28 (max) (depending on platelet counts and renal function). Ruxolitinib will be administered in the morning and evening. Dosing will be adjusted according to toxicity and kidney function.If the patient is discharged before day 28, the therapy will be discontinued for discharge.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | To determine the efficacy of ruxolitinib measured by overall survival | 28 days after registration into trial | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of the duration of ventilation support | Assessment of the duration of ventilation support | registration until 90 days after registration into trial | 
| cytokine storm | Assessment of the extent of cytokine storm reduction (IL-6, CRP, ferritin) | registration until 90 days after registration into trial | 
| time on ICU | To assess time on ICU | registration until 90 days after registration into trial | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 | In order to classify the severity of the AEs, number of participants with treatment-related adverse events will be assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 | registration until 90 days after registration into trial | 
| time frame for seroconversion under ruxolitinib treatment (SARS-Co-19- IgG) | To assess the timeframe for seroconversion under ruxolitinib treatment (SARS-Co-19- IgG) | registration until 90 days after registration into trial | 
| Rates of flow | To asses the rates of flow (liter/minute), in order to detect possible amelioration of pulmonary function after Covid-19 infection | Discharge from hospital (end of treatment) | 
| Gas exchange | To asses gas exchange (partial pressure of oxygen and carbon dioxide), in order to detect possible amelioration of pulmonary function after Covid-19 infection | Discharge from hospital (end of treatment) | 
| Forced expiratory volume in 1 second (FEV1) | To assess forced expiratory volume in 1 second (liters), in order to detect possible possible amelioration of pulmonary function after Covid-19 infection | Discharge from hospital (end of treatment) | 
| Forced vital capacity (FVC) | To assess forced vital capacity (liters), in order to detect possible possible amelioration of pulmonary function after Covid-19 infection | Discharge from hospital (end of treatment) | 
| Tiffeneau-Pinelli index | To assess Tiffeneau-Pinelli index (FEV1/FVC ratio in %), in order to detect possible possible amelioration of pulmonary function after Covid-19 infection | Discharge from hospital (end of treatment) | 
| Overall survival | To determine the efficacy of ruxolitinib measured by overall survival | 90 days after registration into trial | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Covid-19, Ruxolitinib, ARDS, Janus kinase, JAK1, JAK2