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

• ClinicalTrials.gov Identifier: NCT04397510
• Recruitment Status: Enrolling by invitation
• First Posted: May 21, 2020
• Last Update Posted: February 23, 2021
• Sponsor: Frederick Health
• Information provided by (Responsible Party): Thomas Smoot, PharmD, Frederick Health

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Covid-19; ARDS, Human; Acute Lung Injury	Drug: Heparin; Drug: 0.9% Sodium-chloride	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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 50 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Nebulized Heparin vs. Placebo for the Treatment of COVID-19 Induced Lung Injury
• Actual Study Start Date: June 1, 2020
• Estimated Primary Completion Date: December 31, 2021
• Estimated Study Completion Date: December 31, 2021

Arms and Interventions

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 Name: Placebo

Outcome Measures

Primary Outcome Measures :

1. Mean daily PaO2 to FiO2 ratio [ Time Frame: 10 days ]

Secondary Outcome Measures :

1. Duration of mechanical ventilation [ Time Frame: 30 days ]
2. ICU length of stay [ Time Frame: 30 days ]
3. Mortality Rate [ Time Frame: 30 days ]
4. Incidence of adverse drug events [ Time Frame: 10 days ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Maryland

Frederick Health Hospital

Frederick, Maryland, United States, 21701

Sponsors and Collaborators

Frederick Health

More Information

Publications:

Prompetchara E, Ketloy C, Palaga T. Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic. Asian Pac J Allergy Immunol. 2020 Mar;38(1):1-9. doi: 10.12932/AP-200220-0772. Review.

Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506. doi: 10.1016/S0140-6736(20)30183-5. Epub 2020 Jan 24. Erratum in: Lancet. 2020 Jan 30;:.

Liu B, Li M, Zhou Z, Guan X, Xiang Y. Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)? J Autoimmun. 2020 Jul;111:102452. doi: 10.1016/j.jaut.2020.102452. Epub 2020 Apr 10. Review.

Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J, Liu Y, Wei Y, Xia J, Yu T, Zhang X, Zhang L. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020 Feb 15;395(10223):507-513. doi: 10.1016/S0140-6736(20)30211-7. Epub 2020 Jan 30.

Mahallawi WH, Khabour OF, Zhang Q, Makhdoum HM, Suliman BA. MERS-CoV infection in humans is associated with a pro-inflammatory Th1 and Th17 cytokine profile. Cytokine. 2018 Apr;104:8-13. doi: 10.1016/j.cyto.2018.01.025. Epub 2018 Feb 2.

Wong CK, Lam CW, Wu AK, Ip WK, Lee NL, Chan IH, Lit LC, Hui DS, Chan MH, Chung SS, Sung JJ. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin Exp Immunol. 2004 Apr;136(1):95-103.

Perlman S, Dandekar AA. Immunopathogenesis of coronavirus infections: implications for SARS. Nat Rev Immunol. 2005 Dec;5(12):917-27. Review.

Darden DB, Hawkins RB, Larson SD, Iovine NM, Prough DS, Efron PA. The Clinical Presentation and Immunology of Viral Pneumonia and Implications for Management of Coronavirus Disease 2019. Crit Care Explor. 2020 Apr 29;2(4):e0109. doi: 10.1097/CCE.0000000000000109. eCollection 2020 Apr. Review.

Camprubí-Rimblas M, Guillamat-Prats R, Lebouvier T, Bringué J, Chimenti L, Iglesias M, Obiols C, Tijero J, Blanch L, Artigas A. Role of heparin in pulmonary cell populations in an in-vitro model of acute lung injury. Respir Res. 2017 May 10;18(1):89. doi: 10.1186/s12931-017-0572-3.

Chimenti L, Camprubí-Rimblas M, Guillamat-Prats R, Gomez MN, Tijero J, Blanch L, Artigas A. Nebulized Heparin Attenuates Pulmonary Coagulopathy and Inflammation through Alveolar Macrophages in a Rat Model of Acute Lung Injury. Thromb Haemost. 2017 Nov;117(11):2125-2134. doi: 10.1160/TH17-05-0347. Epub 2017 Nov 30.

Abdelaal Ahmed Mahmoud A, Mahmoud HE, Mahran MA, Khaled M. Streptokinase Versus Unfractionated Heparin Nebulization in Patients With Severe Acute Respiratory Distress Syndrome (ARDS): A Randomized Controlled Trial With Observational Controls. J Cardiothorac Vasc Anesth. 2020 Feb;34(2):436-443. doi: 10.1053/j.jvca.2019.05.035. Epub 2019 May 27.

Dixon B, Schultz MJ, Smith R, Fink JB, Santamaria JD, Campbell DJ. Nebulized heparin is associated with fewer days of mechanical ventilation in critically ill patients: a randomized controlled trial. Crit Care. 2010;14(5):R180. doi: 10.1186/cc9286. Epub 2010 Oct 11.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Flumignan RL, Tinôco JDS, Pascoal PI, Areias LL, Cossi MS, Fernandes MI, Costa IK, Souza L, Matar CF, Tendal B, Trevisani VF, Atallah ÁN, Nakano LC. Prophylactic anticoagulants for people hospitalised with COVID-19. Cochrane Database Syst Rev. 2020 Oct 2;10:CD013739. doi: 10.1002/14651858.CD013739.

• Responsible Party: Thomas Smoot, PharmD, Critical Care Pharmacy Specialist, Frederick Health
• ClinicalTrials.gov Identifier: NCT04397510
• Other Study ID Numbers: FHHep518
• First Posted: May 21, 2020
• Last Update Posted: February 23, 2021
• Last Verified: February 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Keywords provided by Thomas Smoot, PharmD, Frederick Health:

heparin; COVID-19; ARDS; Acute Lung Injury

Additional relevant MeSH terms:

Lung Injury; Acute Lung Injury; Respiratory Distress Syndrome, Adult; Wounds and Injuries; Lung Diseases; Respiratory Tract Diseases; Thoracic Injuries; Respiration Disorders; Heparin; Anticoagulants; Fibrinolytic Agents; Fibrin Modulating Agents; Molecular Mechanisms of Pharmacological Action