- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04723563
Nebulized Heparin for the Treatment of COVID-19 (INHALE-HEP)
INHALEd Unfractionated HEParin for the Treatment of Hospitalized Patients With COVID-19 Pneumonia
Study Overview
Status
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.
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 Type
Enrollment (Actual)
Phase
- Phase 4
Contacts and Locations
Study Locations
-
-
Maryland
-
Frederick, Maryland, United States, 21701
- Frederick Health Hospital
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
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: Four times per day Duration: until hospital discharge
|
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
|
5 mL of 0.9% sodium chloride nebulized 4 times daily for the duration of hospitalization
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Need for mechanical ventilation at day 28
Time Frame: 28 days
|
proportion of patients needed mechanical ventilation by day 28
|
28 days
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Hospital length of stay
Time Frame: 60 days
|
Days of hospital admission
|
60 days
|
Average daily SaO2/FiO2
Time Frame: 28 days
|
28 days
|
Collaborators and Investigators
Sponsor
Publications and helpful links
General Publications
- 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;:
- 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.
- 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.
- 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.
- 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. doi: 10.1111/j.1365-2249.2004.02415.x.
- Perlman S, Dandekar AA. Immunopathogenesis of coronavirus infections: implications for SARS. Nat Rev Immunol. 2005 Dec;5(12):917-27. doi: 10.1038/nri1732.
- 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.
- Camprubi-Rimblas M, Guillamat-Prats R, Lebouvier T, Bringue 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, Camprubi-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.
- van Haren FMP, Page C, Laffey JG, Artigas A, Camprubi-Rimblas M, Nunes Q, Smith R, Shute J, Carroll M, Tree J, Carroll M, Singh D, Wilkinson T, Dixon B. Nebulised heparin as a treatment for COVID-19: scientific rationale and a call for randomised evidence. Crit Care. 2020 Jul 22;24(1):454. doi: 10.1186/s13054-020-03148-2.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Coronavirus Infections
- Coronaviridae Infections
- Nidovirales Infections
- RNA Virus Infections
- Virus Diseases
- Infections
- Respiratory Tract Infections
- Respiratory Tract Diseases
- Lung Diseases
- COVID-19
- Pneumonia
- Pneumonia, Viral
- Molecular Mechanisms of Pharmacological Action
- Fibrinolytic Agents
- Fibrin Modulating Agents
- Anticoagulants
- Heparin
Other Study ID Numbers
- FHHep2121
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
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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