Ignite Creation Date:
2024-05-06 @ 3:40 PM
Last Modification Date:
2024-10-26 @ 1:54 PM
Study NCT ID:
NCT04718285
Status:
UNKNOWN
Last Update Posted:
2022-04-28
First Post:
2021-01-15
Brief Title:
Investigation the Effect of Montelukast in COVID-19
Sponsor:
Bahçeşehir University
Organization:
Bahçeşehir University
Study Overview
Official Title:
A National Multi-Center Open-Label Three-Arm Phase II Study to Investigate the Effect of Montelukast Between Emergency Room Visits and Hospitalizations in COVID-19 Pneumonia in Comparison With Standard Treatment
Status:
UNKNOWN
Status Verified Date:
2022-04
Last Known Status:
RECRUITING
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:
None
Brief Summary:
Small molecule inhibitors have previously been investigated in different studies as possible therapeutics in the treatment of SARS-CoV-2 In the current drug repurposing study the investigators identified the leukotriene D4 receptor antagonist Montelukast as a novel agent that simultaneously targets two important drug targets of SARS-CoV-2 The investigators initially demonstrated the dual inhibition main protease and SpikeACE2 profile of Montelukast through multiscale molecular modeling studies Next the investigators characterized its effect on both targets by different in vitro experiments including the Fluorescent Resonance Energy Transfer FRET-based main protease enzyme inhibition assay surface plasmon resonance SPR spectroscopy pseudovirus neutralization on HEK293T hACE2 and virus neutralization assay using xCELLigence MP real time cell analyzer
Detailed Description:
The 2019 new coronavirus SARS-CoV-2 was first reported in December 2019 in Wuhan Hubei China It has quickly spread to other countries all around the world and effected more than 67 million people worldwide becoming an urgent global pandemic Coronaviruses are enveloped non-segmented positive-sense RNA viruses belonging to the family of Coronaviridae the largest family in Nidovirales and widely distributed in humans other mammals and birds causing respiratory enteric hepatic and neurological diseases Seven species of coronavirus are known to cause disease in humans Four of them 229E OC43 NL63 and HKU1 are common and they mostly cause common cold symptoms in immunocompetent individuals while the other three SARS-CoV MERS-CoV and SARSCoV-2 cause serious symptoms and death
SARS-CoV-2 has four structural proteins which are nucleocapsid envelope membrane and spike These four proteins play a vital role during the viral infection The Spike glycoprotein S protein located on the external surface of coronaviruses are responsible for the connection and entry of the virus to host cells The S protein mediates receptor recognition cell attachment and fusion during viral infection While the virus is in its natural environment S protein of coronavirus is inactive During viral infection target cell proteases activate the S protein by cleaving it into S1 and S2 subunits which are required to activate the membrane fusion domain after viral entry into target cells The S1 subunit includes the receptor binding domain RBD This domain binds directly to the peptidase domain angiotensin converting enzyme 2 ACE-2 S2 functions during membrane fusion The chymotrypsin-like cysteine protease called 3C-like protease 3CLpro aka main protease Mpro in SARS-CoV-2 is a vital enzyme involved in processes such as the processing assembly and replication of the virus
One of the key characteristics of severe COVID-19 is increased cytokine production It is thought that the severity of the disease is primarily associated with the cytokine storm which is an aggressive immune response to the virus The number of white blood cells neutrophils and levels of procalcitonin C-reactive protein and other inflammatory indices like IL2 IL7 IL10 granulocyte-colony stimulating factor GSCF interferon inducible protein -10 IP10 monocyte chemotactic protein-1 MCP1 macrophage inflammatory protein-1α MIP1A and TNF are significantly higher in severe cases in patients with COVID-19 Specifically IL-1β IL-6 and IL-10 are the three most elevated cytokines in serious cases One result of the cytokine storm is lung injury that can develop into acute lung injury or its more severe type acute respiratory distress syndrome ARDS Studies have shown the relation between COVID-19 and the most common chronic conditions such as diabetes cardiovascular diseases respiratory system diseases immune system disorders etc Asthma and chronic obstructive pulmonary disease COPD are among the diseases of the respiratory system that are most emphasized Asthma is a chronic inflammatory airway condition There is significant evidence that represents the relation of asthmatic patients in the population with viral infections like rhinoviruses Virus infections cause upper respiratory tract infection like influenza A rhinovirus and respiratory syncytial virus RSV elevate local leukotriene levels Leukotrienes which play a role in the contraction of bronchial muscles are effective in initiating and amplifying many biological responses including mast cell cytokine secretion macrophage activation and dendritic cell maturation and migration Leukotrienes LTC4 LTD4 and LTE4 activated basophils eosinophils macrophages and products of mast cells are types of lipids conjugated with peptides LTD4 receptors belong to G protein-coupled receptor GPCR family Montelukast is a selective leukotriene D4 receptor antagonist which is a member of quinolines and it was approved by FDA as an oral tablet in 1998 It is a licensed drug used for allergic rhinitis exercise-induced bronchospasm and especially prophylaxis and chronic treatment of asthma As a result of LTD4 blockage NF-kB pathway activation and release of the proinflammatory mediators ie IL-68 and 10 TNF-a and MCP-1 decrease Considering these anti-inflammatory effects by leukotriene receptor inhibition and possible antiviral effects Montelukast maybe considered for the effective medication against SARS CoV-2
Here initially the investigators explored the potential role of Montelukast in the management of SARS-CoV-2 infection with multiscale molecular modeling approaches and its promising results both in main protease and SpikeACE2 interface encouraged the investigators to perform further detailed in vitro experiments The results of FRET-based biochemical assays surface plasmon resonance SPR pseudovirus neutralization and virus neutralization experiments demonstrated the effect of Montelukast on SARS-CoV-2
This study was designed as a national multi-center open-label randomized parallel three-arm phase-II study
SARS-CoV-2 has four structural proteins which are nucleocapsid envelope membrane and spike These four proteins play a vital role during the viral infection The Spike glycoprotein S protein located on the external surface of coronaviruses are responsible for the connection and entry of the virus to host cells The S protein mediates receptor recognition cell attachment and fusion during viral infection While the virus is in its natural environment S protein of coronavirus is inactive During viral infection target cell proteases activate the S protein by cleaving it into S1 and S2 subunits which are required to activate the membrane fusion domain after viral entry into target cells The S1 subunit includes the receptor binding domain RBD This domain binds directly to the peptidase domain angiotensin converting enzyme 2 ACE-2 S2 functions during membrane fusion The chymotrypsin-like cysteine protease called 3C-like protease 3CLpro aka main protease Mpro in SARS-CoV-2 is a vital enzyme involved in processes such as the processing assembly and replication of the virus
One of the key characteristics of severe COVID-19 is increased cytokine production It is thought that the severity of the disease is primarily associated with the cytokine storm which is an aggressive immune response to the virus The number of white blood cells neutrophils and levels of procalcitonin C-reactive protein and other inflammatory indices like IL2 IL7 IL10 granulocyte-colony stimulating factor GSCF interferon inducible protein -10 IP10 monocyte chemotactic protein-1 MCP1 macrophage inflammatory protein-1α MIP1A and TNF are significantly higher in severe cases in patients with COVID-19 Specifically IL-1β IL-6 and IL-10 are the three most elevated cytokines in serious cases One result of the cytokine storm is lung injury that can develop into acute lung injury or its more severe type acute respiratory distress syndrome ARDS Studies have shown the relation between COVID-19 and the most common chronic conditions such as diabetes cardiovascular diseases respiratory system diseases immune system disorders etc Asthma and chronic obstructive pulmonary disease COPD are among the diseases of the respiratory system that are most emphasized Asthma is a chronic inflammatory airway condition There is significant evidence that represents the relation of asthmatic patients in the population with viral infections like rhinoviruses Virus infections cause upper respiratory tract infection like influenza A rhinovirus and respiratory syncytial virus RSV elevate local leukotriene levels Leukotrienes which play a role in the contraction of bronchial muscles are effective in initiating and amplifying many biological responses including mast cell cytokine secretion macrophage activation and dendritic cell maturation and migration Leukotrienes LTC4 LTD4 and LTE4 activated basophils eosinophils macrophages and products of mast cells are types of lipids conjugated with peptides LTD4 receptors belong to G protein-coupled receptor GPCR family Montelukast is a selective leukotriene D4 receptor antagonist which is a member of quinolines and it was approved by FDA as an oral tablet in 1998 It is a licensed drug used for allergic rhinitis exercise-induced bronchospasm and especially prophylaxis and chronic treatment of asthma As a result of LTD4 blockage NF-kB pathway activation and release of the proinflammatory mediators ie IL-68 and 10 TNF-a and MCP-1 decrease Considering these anti-inflammatory effects by leukotriene receptor inhibition and possible antiviral effects Montelukast maybe considered for the effective medication against SARS CoV-2
Here initially the investigators explored the potential role of Montelukast in the management of SARS-CoV-2 infection with multiscale molecular modeling approaches and its promising results both in main protease and SpikeACE2 interface encouraged the investigators to perform further detailed in vitro experiments The results of FRET-based biochemical assays surface plasmon resonance SPR pseudovirus neutralization and virus neutralization experiments demonstrated the effect of Montelukast on SARS-CoV-2
This study was designed as a national multi-center open-label randomized parallel three-arm phase-II study
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None