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INHALE-HEP: Nebulized Heparin for the Treatment of COVID-19

Sponsor
Frederick Health (Other)
Overall Status
Completed
CT.gov ID
NCT04723563
Collaborator
(none)
50
Enrollment
1
Location
2
Arms
6
Actual Duration (Months)
8.4
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Randomized, placebo controlled study to determine if nebulized heparin may reduce the need for mechanical ventilation in hospitalized patients with the novel coronavirus, also known as COVID-19. This will be a part of a larger meta-trial.

Condition or Disease Intervention/Treatment Phase
Phase 4

Detailed Description

COVID-19 is a novel coronavirus that can cause severe and potentially fatal respiratory infections. COVID-19 has many similarities to previously seen coronaviruses, such as those that caused the Middle Eastern Respiratory Syndrome (MERS) that emerged in 2011 and the Severe Acute Respiratory Syndrome (SARS) in 2002-2003. Based on early reports, many patients may present with mild to moderate respiratory symptoms, but approximately 20% developed severe symptoms. These severe cases developed a multitude of life threatening complications, like acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and shock.

An early investigation into the patients with severe presentations, revealed high levels of inflammatory cytokines like interleukin 2 (IL-2), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), and monocyte chemoattractant protein 1 (MCP-1). This upregulation of inflammatory cytokines, also referred to as a cytokine storm, is similar to the innate immune response triggered by the previous coronaviruses.5,6 The increased production of these cytokines is the expected anti-viral response of the innate immune system, which is trigged by viral RNA replication. Viral replication triggers downstream inflammatory signaling cascades like NF-κB and IRF3 leading to increased neutrophil and monocyte-macrophages infiltrating the tissue. While effective against viral infection, this process is also believed to be responsible for the development of the significant respiratory complications associated with COVID-19.

ALI and ARDS are not unique to COVID-19 and develop with many viral respiratory infections. Several therapeutic strategies have been evaluated in ALI and ARDS and demonstrated benefit outside of the current pandemic. Heparin, a commonly used anticoagulant, has been shown to exhibit anti-inflammatory properties within the respiratory system. An in vitro study of heparin in a pulmonary cell model of ALI found that heparin significantly inhibited the NF-κB pathway. This inhibition led to a reduced levels of IL-6 and TNF-α in human alveolar macrophages exposed to an E. coli lipopolysaccharide to simulate inflammatory ALI. Additionally, heparin significantly reduced IL-6, TNF-α, and MCP-1 in human alveolar type II cell models. No increases in necrosis or apoptosis were observed.

In addition to these immunomodulation effects, heparin is primarily an anticoagulant and systemic administration carries a risk of bleeding. Due to this, several investigations were conducted in animal models and in humans to determine if administering the heparin via nebulization could take advantage of the immunomodulation, without increasing the risk of bleeding. Nebulized heparin was studied in a rat model of ARDS and was observed to attenuate ALI through reduction of pro-coagulant and pro-inflammatory pathways. Significant reductions in IL-6 and TNF-α were observed. Additionally, reductions in the expression of NF-κB were observed in the alveolar macrophages.

Several clinical investigations in humans with ARDS have also been completed. In a randomized, placebo controlled study of 60 patients with severe ARDS, patients were randomized to nebulized heparin, streptokinase and placebo. Patients in the heparin group received 10,000 units via nebulizer every 4 hours and had significant improvements in their ARDS by day 8. No effect on systemic coagulation markers like APTT and INR were observed. Additionally, no major bleeding events or blood transfusions were observed. A second, randomized placebo controlled trial of 50 patients requiring more than 48 hours of mechanical ventilation was conducted to determine the possible benefit of nebulized heparin. Patients with ALI that received nebulized heparin had a significant reduction in the time on the ventilator as compared to placebo. Patients that received heparin had higher APTT values than those that received placebo, but no significant bleeding events occurred. This study utilized a heparin dose of 25,000 units every 4 hours, which may explain the difference between the laboratory effects in the two human studies.

Heparin has demonstrated the ability to reduce the inflammatory cytokines believed to be responsible for the development of ALI and ARDS in COVID-19 and it may prove to be beneficial in this patient population. When administered via nebulization, no adverse effects were observed in the previously conducted studies and may provide a safe therapeutic option to improve the outcomes of patients with COVID-19 related ALI and ARDS.

This study will be a randomized, double-blind, placebo controlled trial to determine if nebulized heparin administered for the duration of hospitalization will reduce the need for mechanical ventilation and the overall length of stay.

Study Design

Study Type:
Interventional
Actual Enrollment :
50 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
INHALEd Unfractionated HEParin for the Treatment of Hospitalized Patients With COVID-19 Pneumonia
Actual Study Start Date :
Feb 22, 2021
Actual Primary Completion Date :
Aug 23, 2021
Actual Study Completion Date :
Aug 23, 2021

Arms and Interventions

Arm Intervention/Treatment
Experimental: Nebulized Heparin

Heparin 5,000 units/mL Dose: 25,000 units Frequency: Four times per day Duration: until hospital discharge

Drug: Heparin
25,000 units of unfractionated heparin nebulized 4 times daily for the duration of hospitalization
Placebo Comparator: Placebo

0.9% Sodium Chloride Dose: 5 mL Frequency: Four times per day Duration: until hospital discharge

Drug: 0.9%sodium chloride
5 mL of 0.9% sodium chloride nebulized 4 times daily for the duration of hospitalization
Other Names:
  • Placebo

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Need for mechanical ventilation at day 28 [28 days]

      proportion of patients needed mechanical ventilation by day 28

    Secondary Outcome Measures

    1. Hospital length of stay [60 days]

      Days of hospital admission

    2. Average daily SaO2/FiO2 [28 days]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Admitted to the hospital

    • There is a PCR positive sample for SARS-CoV-2 within the past 21 days. The sample can be a nasal orpharyngeal swab, sputum, tracheal aspirate, bronchoalveolar lavage, or another sample from the patient

    • Modified Ordinal Clinical Scale for COVID-19 of 3-5

    Exclusion Criteria:

    • Intubated and on mechanical ventilation, or requiring immediate intubation as per the treating clinician's assessment

    • Heparin allergy or heparin-induced thrombocytopaenia

    • APTT > 120 seconds, not due to anticoagulant therapy and does not correct with administration of fresh frozen plasma

    • Platelet count < 20 x 109 per L

    • Pulmonary bleeding or uncontrolled bleeding

    • Pregnant or might be pregnant

    • Acute brain injury that may result in long-term disability

    • Myopathy, spinal cord injury, or nerve injury or disease with a likely prolonged incapacity to breathe independently e.g. Guillain-Barre syndrome

    • Treatment limitations in place, i.e. not for intubation, not for ICU admission

    • Death is imminent or inevitable within 24 hours

    • Clinician objection

    • Refusal of participant (person responsible) consent

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Frederick Health Hospital Frederick Maryland United States 21701

    Sponsors and Collaborators

    • Frederick Health

    Investigators

    None specified.

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Thomas Smoot, PharmD, Primary Investigator, Frederick Health
    ClinicalTrials.gov Identifier:
    NCT04723563
    Other Study ID Numbers:
    • FHHep2121
    First Posted:
    Jan 25, 2021
    Last Update Posted:
    Sep 5, 2021
    Last Verified:
    Sep 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Undecided
    Plan to Share IPD:
    Undecided
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Product Manufactured in and Exported from the U.S.:
    Yes
    Keywords provided by Thomas Smoot, PharmD, Primary Investigator, Frederick Health
    heparin
    COVID-19
    Additional relevant MeSH terms:
    COVID-19
    Pneumonia
    Pneumonia, Viral
    Heparin

    Study Results

    No Results Posted as of Sep 5, 2021