Ignite Creation Date:
2024-07-17 @ 11:25 AM
Last Modification Date:
2024-10-26 @ 3:34 PM
Study NCT ID:
NCT06488118
Status:
RECRUITING
Last Update Posted:
2024-07-10
First Post:
2024-06-28
Brief Title:
Lung Immune Challenge Study Controlled Exposure to Inhaled Resiquimod R848
Sponsor:
Akhilesh Jha
Organization:
Cambridge University Hospitals NHS Foundation Trust
Study Overview
Official Title:
Lung Immune Challenge Study Controlled Exposure to Inhaled Resiquimod R848 to Study Mechanisms of Inflammation
Status:
RECRUITING
Status Verified Date:
2024-07
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:
None
Brief Summary:
Respiratory viral infections can be a cause of significant illness particularly in vulnerable individuals as seen in the COVID-19 pandemic An underactive or overactive immune response can lead to ineffective resolution of inflammation after an infection especially in people with airway diseases such as asthma A better understanding of immune responses to infection that does not rely on cell or animal models is crucial to help develop better treatments for lung inflammation
An established method of studying inflammation in humans is through careful and controlled exposure or challenge with a mimic of a virus to simulate an infection in a similar manner to that of a virus but with the advantage of not causing an infection The investigators have already developed a well-tolerated mimic of human viral infection using a sterile substance called Resiquimod or R848 Since it does not contain living organisms there is no possibility of being infected This has been used previously as a nasal spray to cause a mild short-lived inflammation that mimics a mild cold This has been used safely in a range of people of different ages including those who have asthma
There are differences however in how the nose and lungs respond to viral infections This is particularly true in those with airway diseases such as asthma who have cells in the airways of their lungs that respond in a different way to inflammatory triggers such as viruses
The current study aims to build on previous research by developing a new approach of studying inflammation in the lungs using a small volume of Resiquimod This will be done by gently inhaling a fine mist through a mouthpiece into the lungs Blood and phlegm samples would then be collected to assess inflammation and how well people tolerate the procedure
An established method of studying inflammation in humans is through careful and controlled exposure or challenge with a mimic of a virus to simulate an infection in a similar manner to that of a virus but with the advantage of not causing an infection The investigators have already developed a well-tolerated mimic of human viral infection using a sterile substance called Resiquimod or R848 Since it does not contain living organisms there is no possibility of being infected This has been used previously as a nasal spray to cause a mild short-lived inflammation that mimics a mild cold This has been used safely in a range of people of different ages including those who have asthma
There are differences however in how the nose and lungs respond to viral infections This is particularly true in those with airway diseases such as asthma who have cells in the airways of their lungs that respond in a different way to inflammatory triggers such as viruses
The current study aims to build on previous research by developing a new approach of studying inflammation in the lungs using a small volume of Resiquimod This will be done by gently inhaling a fine mist through a mouthpiece into the lungs Blood and phlegm samples would then be collected to assess inflammation and how well people tolerate the procedure
Detailed Description:
Background The initial immune response to respiratory viral infections is key to determining what kind of clinical outcome is experienced The COVID-19 pandemic highlights the key importance of gaining a thorough understanding of these immune mechanisms
People with chronic lung conditions such as asthma often experience more severe and prolonged symptoms in response to external triggers This can be due to ongoing inflammation in their airways and lungs Animal and cell models fail to accurately recapitulate the disease which limit its usefulness in developing new treatments
Observational human studies of asthma attacks can be useful but have several confounding factors which significantly influence the outcomes being assessed For example one issue may be the significant variability in time between exposure to a pathogen to the point at which they present to hospital
One important method for understanding mechanisms of inflammation in humans is to perform controlled and careful exposure to an inflammatory stimulus to assess why and how differences occur between individuals This is already established using live viral infection studies - however these studies are technically difficult resource intensive may make participants feel unwell for several days and can be inconvenient for them due to the need for prolonged quarantine
An alternative approach for studying the first line of immune defence or innate immunity is to use a mimic of a virus that binds to the same receptors as respiratory viruses such as influenza and SARS-CoV-2 The study team have already established and published this research using a nasal spray with a synthetic compound called Resiquimod R848 It generates an inflammatory response with the release of molecules such as interferons and cytokines in the nose in a very similar manner to what we see with live viral infections This approach has been used to demonstrate differences in immune responses between healthy individuals and people with asthma
However there are important differences between how the nose and lungs may respond to an inflammatory stimulus This is due to many reasons including differences in the types of cells present between the upper and lower airways which is especially the case in people who have airway diseases such as asthma
Lung Challenge Model A lung immune challenge model using Resiquimod would therefore represent an important approach for studying differences in innate immune responses between individuals enable an understanding of which cells are responsible for driving inflammation and have the potential to be a platform for testing new anti-inflammatory therapies
The first step of this approach and the focus of the current study is to define what dose is the most suitable for generating an appropriate innate immune response whilst also being clinically tolerable for volunteers The dose has already been established in the respiratory tract using nasal challenge so this is a very good starting point when designing the current study The initial dose for lung challenge will be 100-fold lower than with nasal challenge and therefore it is not anticipated to generate an immune response The subsequent doses will then be escalated and reach a maximum dose that has already been administered via the intranasal route in clinical trials
Identifying whether an appropriate immune response has been generated will be done by measuring the inflammatory molecule CXCL10 It is known that CXCL10 is an excellent biomarker for immune activation as it is increased after nasal challenge with Resiquimod as well as after natural viral infections CXCL10 will be measured in the blood and in the lungs by analysing sputum samples
The dose cohort design with 6 participants in each dose cohort and 4 participants being randomised to Resiquimod whilst 2 participants being randomised to saline is based on an already published AstraZeneca trial of a similar compound used for inhaled challenge This will enable an accurate comparison of responses between saline and active groups
An important aspect of this study is to ensure it is clinically tolerable for volunteers They will have been informed in the PIS that they may experience flu-like symptoms as the purpose of the study is to mimic flu and therefore they may have transient inflammation and cold symptoms To ensure their safety - their symptoms physiological observations and airway function will be closely monitored for the first 24 hours of the study directly within the research facility with access to full healthcare resources and staff Individuals with asthma will only undergo inhaled challenge once an appropriate dose has been established in healthy participants
People with chronic lung conditions such as asthma often experience more severe and prolonged symptoms in response to external triggers This can be due to ongoing inflammation in their airways and lungs Animal and cell models fail to accurately recapitulate the disease which limit its usefulness in developing new treatments
Observational human studies of asthma attacks can be useful but have several confounding factors which significantly influence the outcomes being assessed For example one issue may be the significant variability in time between exposure to a pathogen to the point at which they present to hospital
One important method for understanding mechanisms of inflammation in humans is to perform controlled and careful exposure to an inflammatory stimulus to assess why and how differences occur between individuals This is already established using live viral infection studies - however these studies are technically difficult resource intensive may make participants feel unwell for several days and can be inconvenient for them due to the need for prolonged quarantine
An alternative approach for studying the first line of immune defence or innate immunity is to use a mimic of a virus that binds to the same receptors as respiratory viruses such as influenza and SARS-CoV-2 The study team have already established and published this research using a nasal spray with a synthetic compound called Resiquimod R848 It generates an inflammatory response with the release of molecules such as interferons and cytokines in the nose in a very similar manner to what we see with live viral infections This approach has been used to demonstrate differences in immune responses between healthy individuals and people with asthma
However there are important differences between how the nose and lungs may respond to an inflammatory stimulus This is due to many reasons including differences in the types of cells present between the upper and lower airways which is especially the case in people who have airway diseases such as asthma
Lung Challenge Model A lung immune challenge model using Resiquimod would therefore represent an important approach for studying differences in innate immune responses between individuals enable an understanding of which cells are responsible for driving inflammation and have the potential to be a platform for testing new anti-inflammatory therapies
The first step of this approach and the focus of the current study is to define what dose is the most suitable for generating an appropriate innate immune response whilst also being clinically tolerable for volunteers The dose has already been established in the respiratory tract using nasal challenge so this is a very good starting point when designing the current study The initial dose for lung challenge will be 100-fold lower than with nasal challenge and therefore it is not anticipated to generate an immune response The subsequent doses will then be escalated and reach a maximum dose that has already been administered via the intranasal route in clinical trials
Identifying whether an appropriate immune response has been generated will be done by measuring the inflammatory molecule CXCL10 It is known that CXCL10 is an excellent biomarker for immune activation as it is increased after nasal challenge with Resiquimod as well as after natural viral infections CXCL10 will be measured in the blood and in the lungs by analysing sputum samples
The dose cohort design with 6 participants in each dose cohort and 4 participants being randomised to Resiquimod whilst 2 participants being randomised to saline is based on an already published AstraZeneca trial of a similar compound used for inhaled challenge This will enable an accurate comparison of responses between saline and active groups
An important aspect of this study is to ensure it is clinically tolerable for volunteers They will have been informed in the PIS that they may experience flu-like symptoms as the purpose of the study is to mimic flu and therefore they may have transient inflammation and cold symptoms To ensure their safety - their symptoms physiological observations and airway function will be closely monitored for the first 24 hours of the study directly within the research facility with access to full healthcare resources and staff Individuals with asthma will only undergo inhaled challenge once an appropriate dose has been established in healthy participants
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?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| MRY0009351 | OTHER_GRANT | None | None |