Nebulized Heparin in Severe Acute Respiratory Syndrome COVID-19 (NEBUHEPA)

August 27, 2020 updated by: DRA ALICIA BEATRIZ VILASECA, Clinica San Camilo, Argentina

Efficacy and Safety Study to Evaluate the Use of Nebulized Heparin in Patients With Severe Acute Respiratory Syndrome Covid-19 (SARS-CoV-2)

To evaluate the safety and efficacy of the use of inhalational heparin in patients with pulmonary compromise / pneumonia / SARS associated with COVID-19, laboratory with marked inflammation parameters, and prothrombotic state secondary to it (Fibrinogen, Ferritin and / or elevated D-Dimer) , from admission to hospitalization.

The combination of inhalation heparin combined with prophylactic doses of LMWH could reduce the progression to severe forms of the disease, and consequently the need for intensive care units and mechanical ventilation.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

The emergency of COVID-19 requires the urgent development of strategies to avoid the impact of the disease on our population, the saturation of the health system and the mortality of the disease.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in Wuhan, Hubei province, China and has subsequently spread to the world population. Factors associated with the development of SARS and its mortality include advanced age, lymphopenia, organ dysfunction, and bleeding disorders.

Different manifestations have been described (deep vein thrombosis, pulmonary thromboembolism, digital ischemia and cerebral infarcts), and different mechanisms, such as the presence of antiphospholipid antibodies in COVID-19. There is evidence of the presence of a hypercoagulable state in the majority of deaths from SARS associated with COVID -19.

Increased plasma D-dimer concentrations is a common finding and also appears to be an independent predictor of mortality. These patients and those who meet criteria for sepsis-induced coagulopathy (SIC) would benefit from anticoagulant therapy primarily with low molecular weight heparin (LMWH).

Antithrombotic therapies have been used in clinical practice for almost a century. In clinical practice, unfractionated heparin (UFH) and heparin derivatives remain the predominant antithrombotic therapies administered parenterally.

Heparin binds to antithrombin III (AT-III), a plasma glycoprotein, and to a small extent also to the heparin II cofactor. The result of this binding produces a conformational change and a strong increase in the inhibitory effect of thrombin, which becomes approximately 1000 times more potent than before. Other targets of heparin on coagulation are the inhibition or reduced activation of factors V, VIII and IX and the inhibition of thrombocyte function, due to a nonspecific binding of platelet factor IV.

However, heparin is a drug not only with anticoagulant properties, it has many other properties (interaction with growth factors, regulation of cell proliferation and angiogenesis, modulation of proteases and antiproteases), making it an interesting subject of research in the field of inflammation, allergy and immunology, interstitial lung fibrosis and oncology. Inhalation of heparin produces local anti-inflammatory and antifibrotic effects . In addition, possible effects have been described to prevent viral infection, including coronaviridae . It was describes the capacity of SARS-CoV-2 S1 RBD to bind heparin. Such binding capacity is an important prerequisite for research related to the development of SARS-CoV-2 unfractionated heparin therapeutic inhalation Experimental studies of inhaled UFH in healthy subjects showed that doses of less than 32,000 IU of UFH through the lower respiratory tract were safe. In a prospective cohort study in young adults, Harenberg determined that the inhaled dose of LMWH had to be 10 times greater than that administered subcutaneously to achieve similar levels of anti-factor Xa assay.

Considering the role of coagulopathy and inflammation in the induction of ventilator-induced lung injury, nebulized heparin improved lung function in ventilated patients, equivalent to the use of corticosteroids. It has also been compared with other interventions to stimulate the fibrinolysis or block coagulation to suppress the inflammatory response and reduce lung injury in adult acute respiratory distress syndrome .

Study Type

Interventional

Enrollment (Anticipated)

200

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Argentina
    • Buenos Aires
      • Ciudad Autonoma de Buenos Aire, Buenos Aires, Argentina, 1405

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 98 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Persons over 18 years of age of any sex admitted with a diagnosis of a suspected case of COVID-19, in accordance with the definition of the Ministry of Health of the Nation (MSal) as of May 20, 2020, who present at the time of admission or in its evolution pulmonary infiltrates compatible with imaging studies (chest X-ray or chest CT) and at least one of the following biochemical parameters of systemic inflammation:

    • D DIMER over 1.0 ug/dl
    • Ferritin over 500 ng/ml
    • Fibrinogen over 500 mg/dl

Exclusion Criteria:

  • Under 18 years old
  • Pregnant women
  • Known allergy to Heparin
  • Participant in another clinical trial that is not approved for joint enrollment.
  • APTT> 120 seconds, not due to anticoagulant therapy.
  • Platelet count <20 x 109 per L
  • Lung bleeding.
  • Uncontrolled bleeding
  • Advanced neurological impairment
  • Advanced oncological disease

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: NEBULIZED HEPARIN

Nebulized Heparin (UNF)5000 IU in Saline Solution1 ml every 8 hours plus Enoxaparine 40mg /d or 60mg/d, adjusted by BMI and calculated creatinine clearance .

Device to nebulize without producing aerosolization:

To nebulized heparin we have a modified a fullface snorkel mask, in which instead of the discharge valve a connector for the Venturi has been placed, and in the air outlet / inlet of the snorkel it has been adapted a connector made with 3D printing for the insertion of a disposable antiviral filter (filters commonly used in Mechanical Respiratory Assistance devices).

The mask is made of materials that allow its sterilization with the STERRAT Hydrogen Peroxide plasma system, available at the institution.
Drug: Heparin sodium
Nebulized Heparin every 8 hours plus Subcutaneous Enoxaparin every 24hours
Other Names:
  • UNFRACTION HEPARIN
Drug: Enoxaparin
Subcutaneous Enoxaparine every 24 hours
Other Names:
  • Low Molecular Weight Heparin
Active Comparator: Enoxaparine
Enoxaparin 40mg/d or 60mg/d adjusted by BMI and calculated creatinine clearance
Drug: Enoxaparin
Subcutaneous Enoxaparine every 24 hours
Other Names:
  • Low Molecular Weight Heparin

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percentage of patients requirement mechanical ventilation
Time Frame: 15 days

Blood Gas criteria :PaO2 / FiO2 <200 (or the inability to maintain an SpO2 of at least 92% with a reservoir mask).

Acute ventilatory failure (pH less than 7.35 with PaCO2 greater than 45 mmHg)
15 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percentage of patients with PaO2 to Fi02 ratio > 300
Time Frame: 7 days
Mean every 48 hours PaO2 to FiO2 ratio
7 days
Lengths of hospital-stay
Time Frame: Days 60
To compare the lengths of hospital-stay
Days 60
Mortality rate
Time Frame: 30 days
All cause mortality
30 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Clinica San Camilo, Argentina

Investigators

  • Principal Investigator: ALICIA B VILASECA, DR, Clínica San Camilo

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 1, 2020

Primary Completion (Anticipated)

October 30, 2020

Study Completion (Anticipated)

June 1, 2021

Study Registration Dates

First Submitted

August 17, 2020

First Submitted That Met QC Criteria

August 26, 2020

First Posted (Actual)

August 28, 2020

Study Record Updates

Last Update Posted (Actual)

August 31, 2020

Last Update Submitted That Met QC Criteria

August 27, 2020

Last Verified

August 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CSanCamilo

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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