Nebulized Heparin for the Treatment of COVID-19 Induced Lung Injury

April 2, 2024 updated by: Thomas Smoot, PharmD, Frederick Health

Nebulized Heparin vs. Placebo for the Treatment of COVID-19 Induced Lung Injury

Randomized, placebo controlled study to determine if nebulized heparin may reduce the severity of lung injury caused by the novel coronavirus, also known as COVID-19

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

13

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 Locations

  • United States
    • Maryland
      • Frederick, Maryland, United States, 21701
        • Frederick Health Hospital

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

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Age ≥18 years
  • Admitted to the intensive care unit
  • Positive COVID-19 PCR
  • Mechanical Ventilation for ≤ 48 hours
  • PaO2/FiO2 ≤300

Exclusion Criteria:

  • Heparin allergy
  • Active bleeding
  • Death or withdraw of care anticipated by intensivist within 24 hours
  • Platelets< 50,000 cells/µL
  • Clinically significant coagulopathy, as decided by the intensivist
  • O2 dependent at baseline

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: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Nebulized Heparin
Heparin 5,000 units/mL Dose: 25,000 units Frequency: every 6 hours Duration: 10 days
Drug: Heparin
Nebulized Heparin
Placebo Comparator: Placebo
0.9% Sodium Chloride Dose: 5 mL Frequency: every 6 hours Duration: 10 days
Drug: 0.9% Sodium-chloride
Nebulized 0.9% Sodium Chloride
Other Names:
  • Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Mean daily PaO2 to FiO2 ratio
Time Frame: 10 days
10 days

Secondary Outcome Measures

Outcome Measure
Time Frame
Duration of mechanical ventilation
Time Frame: 30 days
30 days
ICU length of stay
Time Frame: 30 days
30 days
Mortality Rate
Time Frame: 30 days
30 days
Incidence of adverse drug events
Time Frame: 10 days
10 days

Collaborators and Investigators

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

Sponsor

Frederick Health

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 (Actual)

December 31, 2021

Study Completion (Actual)

December 31, 2021

Study Registration Dates

First Submitted

May 19, 2020

First Submitted That Met QC Criteria

May 20, 2020

First Posted (Actual)

May 21, 2020

Study Record Updates

Last Update Posted (Actual)

April 3, 2024

Last Update Submitted That Met QC Criteria

April 2, 2024

Last Verified

April 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • FHHep518

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

Yes

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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