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

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ClinicalTrials.gov Identifier: NCT04530578
Recruitment Status : Recruiting
First Posted : August 28, 2020
Last Update Posted : August 31, 2020
Sponsor:
Information provided by (Responsible Party):
DRA ALICIA BEATRIZ VILASECA, Clinica San Camilo, Argentina

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Covid19 Pneumonia Drug: Heparin sodium Drug: Enoxaparin Phase 4

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 .

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Controled, prospective, randomized, comparative against standard treatment.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Efficacy and Safety Study to Evaluate the Use of Nebulized Heparin in Patients With Severe Acute Respiratory Syndrome Covid-19 (SARS-CoV-2)
Actual Study Start Date : June 1, 2020
Estimated Primary Completion Date : October 30, 2020
Estimated Study Completion Date : June 1, 2021


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 Name: UNFRACTION HEPARIN

Drug: Enoxaparin
Subcutaneous Enoxaparine every 24 hours
Other Name: 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 Name: Low Molecular Weight Heparin




Primary Outcome Measures :
  1. 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)



Secondary Outcome Measures :
  1. Percentage of patients with PaO2 to Fi02 ratio > 300 [ Time Frame: 7 days ]
    Mean every 48 hours PaO2 to FiO2 ratio

  2. Lengths of hospital-stay [ Time Frame: Days 60 ]
    To compare the lengths of hospital-stay

  3. Mortality rate [ Time Frame: 30 days ]
    All cause mortality



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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:

  • 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

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): NCT04530578


Contacts
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Contact: ALICIA B VILASECA, DR +5401148588144 ext 244 avilaseca@clinicasancamilo.org.ar
Contact: Ruben F Barbera, DR +5401148588199 rbarbera@clinicasancamilo.org.ar

Locations
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Argentina
Clinica San Camilo Recruiting
Ciudad Autonoma de Buenos Aire, Buenos Aires, Argentina, 1405
Contact: ALICIA B VILASECA, DR    +54 91160993060    avilaseca@gmail.com   
Contact: RUBEN F BARBERA, DR    +541148588198    RBARBERA@CLINICASANCAMILO.ORG.AR   
Sponsors and Collaborators
Clinica San Camilo, Argentina
Investigators
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Principal Investigator: ALICIA B VILASECA, DR CLINICA SAN CAMILO
Publications:
Scazziota A. Pons S. Heparin effects beyond antithrombotic activity. Hematología Volumen 21 Nº Extraordinario: 166175 XXIII Congreso Argentino de Hematología Noviembre 2017
Courtney Mycroft-West, Dunhao Su, Stefano Elli , Scott Guimond,Gavin Miller, Jeremy Turnbull , Edwin Yates , Marco Guerrini , David Fernig , Marcelo Lima and Mark Skidmore. The 2019 coronavirus (SARS-CoV-2) surface protein (Spike) S1 Receptor Binding Domain undergoes conformational change upon heparin binding. bioRxiv preprint doi: https://doi.org/10.1101/2020.02.29.971093.This version posted March 2, 2020.

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Responsible Party: DRA ALICIA BEATRIZ VILASECA, CHIEF OF HEMATOLOGY SERVICE, Clinica San Camilo, Argentina
ClinicalTrials.gov Identifier: NCT04530578    
Other Study ID Numbers: CSanCamilo
First Posted: August 28, 2020    Key Record Dates
Last Update Posted: August 31, 2020
Last Verified: August 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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 DRA ALICIA BEATRIZ VILASECA, Clinica San Camilo, Argentina:
nebulized heparin pneumonia COVID 19
Additional relevant MeSH terms:
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Severe Acute Respiratory Syndrome
Pneumonia
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Coronavirus Infections
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Virus Diseases
Heparin
Calcium heparin
Enoxaparin
Heparin, Low-Molecular-Weight
Tinzaparin
Dalteparin
Anticoagulants
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action