Ignite Creation Date:
2024-05-06 @ 3:41 PM
Last Modification Date:
2024-10-26 @ 1:54 PM
Study NCT ID:
NCT04723563
Status:
COMPLETED
Last Update Posted:
2021-09-05
First Post:
2021-01-22
Brief Title:
Nebulized Heparin for the Treatment of COVID-19
Sponsor:
Frederick Health
Organization:
Frederick Health
Study Overview
Official Title:
INHALEd Unfractionated HEParin for the Treatment of Hospitalized Patients With COVID-19 Pneumonia
Status:
COMPLETED
Status Verified Date:
2021-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
INHALE-HEP
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
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 coronaviruses56 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 10000 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 25000 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
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 coronaviruses56 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 10000 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 25000 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
True
Is an FDA AA801 Violation?:
None