Combination of Inhaled DNase, Baricitinib and Tocilizumab in Severe COVID-19

Study Overview
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Brief Summary
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In patients with COVID-19, severe hypoxemic respiratory failure (SRF) leading to invasive mechanical ventilation (IMV), raises the mortality rate substantially. Thus, the management of patients with SRF to avoid intubation and intensive care admission is a challenging and crucial issue. This study describes, as rescue/compassionate treatment, a therapeutic protocol based on the multi-mechanistic nature of severe COVID-19, using the combination of inhaled DNase, Baricitinib and Tocilizumab on top of standard of care (SOC) consisting of heparin and dexamethasone. COVID-19 patients with SRF who were treated with SOC, SOC plus Anakinra (ANA), and SOC plus Tocilizumab (TOCI) will be studied as comparators. Primary endpoint will be the reduction of the in-hospital mortality rate, whereas secondary endpoints concern intubation rate, days of hospitalization and overall survival as derived from the last follow-up visit, either in-office or remote. This is a non-randomized, open-label, study, conducted in the First Department of Internal Medicine, University Hospital of Alexandroupolis, Greece.

Official Title
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Combined Administration of Inhaled DNase, Baricitinib and Tocilizumab as Rescue Treatment in Severe COVID-19 Patients

Conditions
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COVID-19 Severe Respiratory Failure

Intervention / Treatment
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* Drug: Dexamethasone
* Drug: Low molecular weight heparin
* Drug: Anakinra 100Mg/0.67Ml Inj Syringe
* Drug: Tocilizumab
* Drug: Baricitinib
* Drug: Dornase Alfa Inhalant Product


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: adult patients ≥18 years old, of any gender positive polymerase-chain-reaction (PCR) test for SARS-CoV-2 RNA in nasopharyngeal swab pulmonary infiltrates suggestive of COVID-19 severe respiratory failure (SRF) as defined by PaO2/FiO2<100 mm Hg written informed consent from the patients or legal representatives for the current compassionate therapeutic protocol. Exclusion Criteria: need for intubation/IMV during the first 24 hours after the initiation of treatment multi-organ failure, systemic co-infection SRF due to cardiac failure or fluid overload glomerular filtration rate (GFR) <30 ml/min/1.73 m2) any stage IV solid tumor or immunosuppression due to hematological disorders any immunosuppressive therapy and/or chemotherapy during the last 30 days low patient's functional performance as defined by a Palliative Performance Scale (PPS) score ≤30% pregnancy.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: SOC<br>Patients included in this arm treated with the standard of care (SOC), including dexamethasone plus heparin, with or without the addition of antibiotics and remdesivir | Drug: Dexamethasone<br>* Dexamethasone 6-8 mg once daily<br>Drug: Low molecular weight heparin<br>* Therapeutic doses of LMWH (e.g. Tinzaparin 175IU/kg)<br>|
| Active Comparator: TOCI<br>Patients included in this arm treated with the SOC plus Tocilizumab (single IV dose: 8mg/kg) | Drug: Dexamethasone<br>* Dexamethasone 6-8 mg once daily<br>Drug: Low molecular weight heparin<br>* Therapeutic doses of LMWH (e.g. Tinzaparin 175IU/kg)<br>Drug: Tocilizumab<br>* IV administration of Tocilizumab as a single dose of 8mg/kg<br>|
| Active Comparator: ANA<br>Patients included in this arm treated with the SOC plus Anakinra (200mg twice daily IV for 3-6 days, then 100 mg/twice daily, for up to 10 days in total) | Drug: Dexamethasone<br>* Dexamethasone 6-8 mg once daily<br>Drug: Low molecular weight heparin<br>* Therapeutic doses of LMWH (e.g. Tinzaparin 175IU/kg)<br>Drug: Anakinra 100Mg/0.67Ml Inj Syringe<br>* IV administration of Anakinra 200 mg/twice daily for 3-6 days, then 100 mg/twice daily, for up to 10 days in total.<br>|
| Active Comparator: COMBI<br>Patients included in this arm treated with the SOC plus the combination of Tocilizumab, Baricitinib and inhaled DNase (COMBI) as a rescue treatment. | Drug: Dexamethasone<br>* Dexamethasone 6-8 mg once daily<br>Drug: Low molecular weight heparin<br>* Therapeutic doses of LMWH (e.g. Tinzaparin 175IU/kg)<br>Drug: Tocilizumab<br>* IV administration of Tocilizumab as a single dose of 8mg/kg<br>Drug: Baricitinib<br>* 4 mg per os once daily, for up to 14 days (2 mg if GFR: 30 to <60 ml/min/1.73 m2)<br>Drug: Dornase Alfa Inhalant Product<br>* Inh. 2,500 U/twice daily, for up to 14 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| In-hospital mortality rate | To investigate whether the combined administration of inhaled DNase, Baricitinib and Tocilizumab, as a rescue treatment, reduces the in-hospital mortality rate in COVID-19 patients with severe respiratory failure compared to standard of care and other immunomodulatory treatments. | Through study completion, an average of 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intubation rate | To investigate whether the combined administration of inhaled DNase, Baricitinib and Tocilizumab, as a rescue treatment, reduces the intubation rate in COVID-19 patients with severe respiratory failure compared to standard of care and other immunomodulatory treatments. | Through study completion, an average of 1 year | 
| Days of hospitalization | To investigate whether the combined administration of inhaled DNase, Baricitinib and Tocilizumab, as a rescue treatment, reduces the days of hospitalization in COVID-19 patients with severe respiratory failure compared to standard of care and other immunomodulatory treatments. | Through study completion, an average of 1 year | 
| Overall mortality rate | To investigate whether the combined administration of inhaled DNase, Baricitinib and Tocilizumab, as a rescue treatment, affects overall survival in a follow up of a maximum 52 weeks in COVID-19 patients with severe respiratory failure compared to standard of care and other immunomodulatory treatments. | Follow-up (max: 52 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, Respiratory failure, Inhaled DNase, Baricitinib, Tocilizumab, Low molecular weight heparin, Dexamethasone, Anakinra