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

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ClinicalTrials.gov Identifier: NCT05279391
Recruitment Status : Recruiting
First Posted : March 15, 2022
Last Update Posted : March 15, 2022
Sponsor:
Information provided by (Responsible Party):
Konstantinos Ritis, Democritus University of Thrace

Study Description
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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 Not Applicable

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated 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 : October 25, 2020
Actual Primary Completion Date : November 30, 2021
Estimated Study Completion Date : December 31, 2023

Resource links provided by the National Library of Medicine


Arms and Interventions
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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
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Primary Outcome Measures :
  1. In-hospital mortality rate [ Time Frame: 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 :
  1. Intubation rate [ Time Frame: 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.

  2. Days of hospitalization [ Time Frame: 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.

  3. Overall mortality rate [ Time Frame: 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
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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. adult patients ≥18 years old, of any gender
  2. positive polymerase-chain-reaction (PCR) test for SARS-CoV-2 RNA in nasopharyngeal swab
  3. pulmonary infiltrates suggestive of COVID-19
  4. severe respiratory failure (SRF) as defined by PaO2/FiO2<100 mm Hg
  5. written informed consent from the patients or legal representatives for the current compassionate therapeutic protocol.

Exclusion Criteria:

  1. need for intubation/IMV during the first 24 hours after the initiation of treatment
  2. multi-organ failure,
  3. systemic co-infection
  4. SRF due to cardiac failure or fluid overload
  5. glomerular filtration rate (GFR) <30 ml/min/1.73 m2)
  6. any stage IV solid tumor or immunosuppression due to hematological disorders
  7. any immunosuppressive therapy and/or chemotherapy during the last 30 days
  8. low patient's functional performance as defined by a Palliative Performance Scale (PPS) score ≤30%
  9. pregnancy.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05279391


Contacts
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Contact: Konstantinos Ritis, Professor +302551351103 kritis@med.duth.gr
Contact: Panagiotis Skendros, Associate Professor +302551351090 pskendro@med.duth.gr

Locations
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Greece
University Hospital of Alexandroupolis Recruiting
Alexandroupolis, Evros, Greece, 68100
Contact: Konstantinos Ritis, Professor    +302551351103    kritis@med.duth.gr   
Contact: Panagiotis Skendros, Associate Professor    +302551351091    pskendro@med.duth.gr   
Sub-Investigator: Efstratios Gavriilidis, MD, MSc         
Sub-Investigator: Christina Antoniadou, MD, MSc         
Sponsors and Collaborators
Democritus University of Thrace
More Information
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Responsible Party: Konstantinos Ritis, Professor of Internal Medicine, First Department of Internal Medicine, Democritus University of Thrace
ClinicalTrials.gov Identifier: NCT05279391    
Other Study ID Numbers: 87/08-04-2020
16210/20-04-2021 ( Other Identifier: University Hospital of Alexandroupolis, Greece )
First Posted: March 15, 2022    Key Record Dates
Last Update Posted: March 15, 2022
Last Verified: March 2022

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Konstantinos Ritis, Democritus University of Thrace:
COVID-19
Respiratory failure
Inhaled DNase
Baricitinib
 Tocilizumab
Low molecular weight heparin
Dexamethasone
Anakinra
Additional relevant MeSH terms:
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COVID-19
Respiratory Insufficiency
Respiratory Tract Infections
Infections
Pneumonia, Viral
Pneumonia
Virus Diseases
Coronavirus Infections
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Lung Diseases
Respiratory Tract Diseases
Respiration Disorders
Dexamethasone
 Interleukin 1 Receptor Antagonist Protein
Heparin
Heparin, Low-Molecular-Weight
Tinzaparin
Dalteparin
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal