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

Sponsor

Democritus University of Thrace (Other)

Overall Status

Recruiting

CT.gov ID

NCT05279391

Collaborator

(none)

150

Enrollment

Location

Arms

38.2

Anticipated Duration (Months)

3.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
COVID-19 Severe Respiratory Failure	Drug: Dexamethasone Drug: Low molecular weight heparin Drug: Anakinra 100Mg/0.67Ml Inj Syringe Drug: Tocilizumab Drug: Baricitinib Drug: Dornase Alfa Inhalant Product	N/A

Study Design

Study Type:

Interventional

Anticipated Enrollment :

150 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Oct 25, 2020

Actual Primary Completion Date :

Nov 30, 2021

Anticipated Study Completion Date :

Dec 31, 2023

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: SOC 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 Dexamethasone 6-8 mg once daily Drug: Low molecular weight heparin Therapeutic doses of LMWH (e.g. Tinzaparin 175IU/kg)
Active Comparator: TOCI Patients included in this arm treated with the SOC plus Tocilizumab (single IV dose: 8mg/kg)	Drug: Dexamethasone Dexamethasone 6-8 mg once daily Drug: Low molecular weight heparin Therapeutic doses of LMWH (e.g. Tinzaparin 175IU/kg) Drug: Tocilizumab IV administration of Tocilizumab as a single dose of 8mg/kg
Active Comparator: ANA 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 Dexamethasone 6-8 mg once daily Drug: Low molecular weight heparin Therapeutic doses of LMWH (e.g. Tinzaparin 175IU/kg) Drug: Anakinra 100Mg/0.67Ml Inj Syringe IV administration of Anakinra 200 mg/twice daily for 3-6 days, then 100 mg/twice daily, for up to 10 days in total.
Active Comparator: COMBI 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 Dexamethasone 6-8 mg once daily Drug: Low molecular weight heparin Therapeutic doses of LMWH (e.g. Tinzaparin 175IU/kg) Drug: Tocilizumab IV administration of Tocilizumab as a single dose of 8mg/kg Drug: Baricitinib 4 mg per os once daily, for up to 14 days (2 mg if GFR: 30 to <60 ml/min/1.73 m2) Drug: Dornase Alfa Inhalant Product Inh. 2,500 U/twice daily, for up to 14 days.

Outcome Measures

Primary Outcome Measures

In-hospital mortality rate [Through study completion, an average of 1 year]
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.

Secondary Outcome Measures

Intubation rate [Through study completion, an average of 1 year]
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.
Days of hospitalization [Through study completion, an average of 1 year]
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.
Overall mortality rate [Follow-up (max: 52 weeks)]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 100 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.