Ignite Creation Date:
2024-05-06 @ 6:36 PM
Last Modification Date:
2024-10-26 @ 2:50 PM
Study NCT ID:
NCT05713019
Status:
NOT_YET_RECRUITING
Last Update Posted:
2023-02-06
First Post:
2023-01-12
Brief Title:
ATP and P2X3 Receptor in Chronic Cough
Sponsor:
Imperial College London
Organization:
Imperial College London
Study Overview
Official Title:
Neuroinflammatory Interactions of ATP and P2X3 Receptor in the Airways of Chronic Cough Patients an Exploratory Study
Status:
NOT_YET_RECRUITING
Status Verified Date:
2023-01
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:
This is a laboratory-based study that will be performed at the Clinical Research Centre at the Royal Brompton HospitalLondon The objectives are
1 Determine whether adenosine triphosphate ATP is present or released in airways of idiopathic chronic cough patients
2 Determine whether there is an increase in cough sensitivity and laryngeal sensitivity to exogenous ATP
3 Examine the effects of exogenous ATP on the inflammatory response in the upper and lower airways
The participants will be i Healthy subjects non-smoker 8 subjects and ii Chronic cough subjects attending Chronic Cough clinic 12 subjects Each will be involved in
Study 1 Following recruitment subjects will attend for a fiberoptic bronchoscopy
Study 2 Subjects will take part in a study of the effect of inhaling nebulized ATP Subjects will be studied on 2 days separated by at least 5 days On each day after measurements of lung function FeNO and cough questionnaires the subject will inhale either saline or ATP solution from a nebulizer following which laryngeal hypersensitivity capsaicin cough challenge and sputum induction will be performed
Results will be expressed as mean standard error of the mean SEM Study data will be analysed by the Investigators at the completion of the study Planned analyses will be done by comparing chronic cough patients to the healthy controls The Spearman rank-correlation test will be used to determine correlations
1 Determine whether adenosine triphosphate ATP is present or released in airways of idiopathic chronic cough patients
2 Determine whether there is an increase in cough sensitivity and laryngeal sensitivity to exogenous ATP
3 Examine the effects of exogenous ATP on the inflammatory response in the upper and lower airways
The participants will be i Healthy subjects non-smoker 8 subjects and ii Chronic cough subjects attending Chronic Cough clinic 12 subjects Each will be involved in
Study 1 Following recruitment subjects will attend for a fiberoptic bronchoscopy
Study 2 Subjects will take part in a study of the effect of inhaling nebulized ATP Subjects will be studied on 2 days separated by at least 5 days On each day after measurements of lung function FeNO and cough questionnaires the subject will inhale either saline or ATP solution from a nebulizer following which laryngeal hypersensitivity capsaicin cough challenge and sputum induction will be performed
Results will be expressed as mean standard error of the mean SEM Study data will be analysed by the Investigators at the completion of the study Planned analyses will be done by comparing chronic cough patients to the healthy controls The Spearman rank-correlation test will be used to determine correlations
Detailed Description:
These are the objectives of this study
1 Determine whether ATP is present or released in airways of idiopathic chronic cough patients
2 Determine whether there is an increase in cough sensitivity and laryngeal sensitivity to exogenous ATP
3 Examine the effects of exogenous ATP on the inflammatory response in the upper and lower airways
Outcome measures
These are all primary outcome measures of this study
1 Presence of ATP in airways of idiopathic chronic cough patients and the localisation of P2X23 receptors in the airways
2 Cough sensitivity and laryngeal sensitivity to exogenous ATP
3 Inflammatory response in the upper and lower airways to exogenous ATP
Study Design Consent will be obtained prior to screening Screening Participants will be screened prior to engagement in Studies Normal non-coughing patients will be asked whether they have a history of cough and they should not have had a chronic cough for 8 weeks or more Those participants with chronic cough need to satisfy the definition of a chronic cough having lasted for more than 8 weeks These participants will be recruited from the Royal Brompton Hospital Cough clinic We will use the inclusion and exclusion criteria noted below with regard to eligibility confirmation
Study 1 and 2 Participants will be in this research project for a total of 3 months
This study will be in two parts which may not be chronological in order
Study 1 Following recruitment subjects will attend for a fiberoptic bronchoscopy
Study 2 Subjects will take part in a study of the effect of inhaling nebulized ATP Subjects will be studied on 2 days separated by at least 5 days On each day after measurements of lung function FeNO and cough questionnaires the subject will inhale either saline or ATP solution from a nebulizer following which laryngeal hypersensitivity capsaicin cough challenge and sputum induction will be performed The order of the ATP or saline challenge will be randomized and the administration of either will be blinded to the patients and investigators measuring the response to the challenge
Subject population
This will be a single site study The investigators will recruit 12 patients with chronic cough attending our Cough Clinic at the Royal Brompton Hospital and 8 control healthy subjects age and gender matched
The participants of either gender with idiopathic chronic cough will be studied and should have had a chronic cough of at least 8 weeks duration and should have been followed in the Cough Clinic for at least 6 months These participants will have undergone a protocol with a diagnostic pathway as recommended by the European Respiratory Society guidelines for management of cough Participants would have either an identifiable cause for their cough that have failed therapies targeted towards the identified cause or classed as having chronic idiopathic cough where no identifiable cause has been found
The control non-coughing subjects will be recruited through advertisement within the hospital and local newspaper services
Research Intervention and procedures Fiberoptic bronchoscopy Bronchoscopy is a standard diagnostic procedure and will be undertaken by an experienced doctor of the research team
The fibre-optic bronchoscope will be passed through either the nasal passages or the oropharynx before passing into the trachea The nasal passages will be the preferential route but in case this cannot be done through the nasal passages the oropharynx will be used Bronchoalveolar lavage BAL will be performed from the right middle lobe using warmed 09 saline with 4 successive aliquots of 60ml The bronchoscopist will then take samples of the cells lining the airways using a brush and forceps the latter allowing small pieces of tissue to be obtained
Post-procedure the participant will be moved from the procedure room to the recovery area where heshe will be monitored by nursing staff In case of any bronchoconstriction heshe will be treated with nebulized salbutamol and if required corticosteroid therapy will be given Once stable and no longer requiring oxygen and no longer drowsy heshe will be discharged following review by the research doctors The doctor may however determine that you need to be kept under observation until fit to be discharged home Any patient given midazolam during the procedure will be asked to have a responsible adult to accompany them home on that day
Local anaesthetic is used prior to the procedure and participants may experience a numb mouth or throat In some patients if safe to do so an anxiolytic drug midazolam will be given in small doses through the cannula This is usually tolerated without problem
After the procedure participants may experience a sore throat hoarse voice or cough due to irritation to the airways but this usually settles within a few hours Other symptoms can include the increased production of sputum sometimes with blood streaking of the mucus and a transient fever which can occur after a few hours after the procedure This usually settles within a few hours and can be helped by taking paracetamol There should be no long-lasting sequelae
Serious risks are rare but include a pneumothorax 1 in 2000 cases and significant bleeding Participants will be closely monitored following the procedure and should any serious complication arise they will be given the appropriate treatment in hospital
Exhaled breath condensate EBC collection EBC will be collected by asking the subject to breathe normally onto a handheld breath collection apparatus from Respire Diagnostics Imperial College that will cool the exhaled breath to allow for condensation of the exhaled air The subject will breathe for 2 periods of 5 minutes each separated by a 3-4 min rest to allow the collection of up to 500 microlitre uL of liquid The liquid will be stored for later analysis
Blood sample collection Venous blood 30 cc will be taken from a vein in the forearm This test causes a transient discomfort as a needle is used to obtain the blood sample The blood sample will be used for measuring various proteins and for getting white blood cells to obtain some types of stem cells
Continuous laryngoscopic examination Continuous laryngoscopy testing is performed based on previous methodology Continuous laryngoscopy testing is performed by placing a fibreoptic nasendoscope in the posterior nasopharynx and securing it using specialist headgear A small quantity of lubricating jelly is used to ease passage of the scope Video images of the laryngeal inlet are thereafter continuously recorded whilst a subject performs various manoeuvres including respiratory movements and cough These movements will be observed and recorded before and following the various aspects of the challenge protocol and thus allow us to evaluate laryngeal movement abnormalities and for example position of the vocal folds The size and change in size of the glottic aperture will be evaluated
Capsaicin cough challenge Capsaicin challenge is performed as established in our laboratory
The Leicester Cough Questionnaire This will be used to assess the impact of chronic cough on the patients quality of life
Measurement of cough frequency Cough frequency will be measured objectively with a Hyfe cough recording monitor for 48 hours
All enrolled study participants will be provided with a dedicated Android phone or watch loaded with the Hyfe Research application to monitor and record their cough sounds
Cough recording will include 5 solicited coughs at the time of study enrolment for calibration Study personnel will have the ability to remotely monitor the accrual of coughs for each participant in real time with the Hyfe Research Platform Dashboard - thus verifying as needed that the phones are on and functioning appropriately
Upon study completion a trained study staff member will retrieve the phones and ensure that data has been automatically uploaded to the Hyfe server
Assessment of laryngeal function by questionnaire We will use the Laryngeal Hypersensitivity Questionnaire for assessing laryngeal dysfunction
Induction of sputum Sputum is induced by inhalation of an aerosol of sterile 3 saline solution and subsequently increasing to 4 and 5 during 3 periods of 5 minutes each Sputum samples are collected into sterile pots
Sputum plugs are selected and one portion is used to perform differential cell counts To perform differential cell counts dithiothreitol is added to the sputum plug and mixed vigorously on a plate shaker to solubilize the sputum Cytospins are then prepared and differential cell counts obtained
In addition some of the cells will be placed in RNA later for RNAseq analysis The supernatant will be kept for later assay of neuroimmune biomarkers
Spirometric measurements Spirometry FEV1 and forced vital capacity FVC is measured using a dry wedge spirometer Vitalograph Buckinghamshire UK
Fractional exhaled nitric oxide FeNO Fractional exhaled nitric oxide FeNO level is measured using a portable FeNO monitor NObreath Bedfont Scientific Ltd Rochester UK at a constant expiratory flow of 005 Ls
Specimens from bronchoscopy i Bronchial brushings a slides with cells attached will be obtained and preserved for later immunohistochemical analysis b cells will be placed in RNA later for later extraction for RNAseq analysis c cells will be placed in culture
ii Bronchial biopsies Five μm sections will be cut and stained with haematoxylin and eosin to assess morphology Investigators will measure the extent of inflammation and remodeling in these biopsies as previously described In addition these sections will be used for a series of immunohistochemical investigations for localization of ATP and other associated neuroimmune biomarkers of interest
iii Bronchoalveolar lavage Bronchoalveolar lavage cells will be placed in cytospin for counting of differential cells Some of the cells will be kept in RNAlater for RNAseq The supernatant BAL fluid will be kept for later assay of neuroimmune markers including ATP
1 Determine whether ATP is present or released in airways of idiopathic chronic cough patients
2 Determine whether there is an increase in cough sensitivity and laryngeal sensitivity to exogenous ATP
3 Examine the effects of exogenous ATP on the inflammatory response in the upper and lower airways
Outcome measures
These are all primary outcome measures of this study
1 Presence of ATP in airways of idiopathic chronic cough patients and the localisation of P2X23 receptors in the airways
2 Cough sensitivity and laryngeal sensitivity to exogenous ATP
3 Inflammatory response in the upper and lower airways to exogenous ATP
Study Design Consent will be obtained prior to screening Screening Participants will be screened prior to engagement in Studies Normal non-coughing patients will be asked whether they have a history of cough and they should not have had a chronic cough for 8 weeks or more Those participants with chronic cough need to satisfy the definition of a chronic cough having lasted for more than 8 weeks These participants will be recruited from the Royal Brompton Hospital Cough clinic We will use the inclusion and exclusion criteria noted below with regard to eligibility confirmation
Study 1 and 2 Participants will be in this research project for a total of 3 months
This study will be in two parts which may not be chronological in order
Study 1 Following recruitment subjects will attend for a fiberoptic bronchoscopy
Study 2 Subjects will take part in a study of the effect of inhaling nebulized ATP Subjects will be studied on 2 days separated by at least 5 days On each day after measurements of lung function FeNO and cough questionnaires the subject will inhale either saline or ATP solution from a nebulizer following which laryngeal hypersensitivity capsaicin cough challenge and sputum induction will be performed The order of the ATP or saline challenge will be randomized and the administration of either will be blinded to the patients and investigators measuring the response to the challenge
Subject population
This will be a single site study The investigators will recruit 12 patients with chronic cough attending our Cough Clinic at the Royal Brompton Hospital and 8 control healthy subjects age and gender matched
The participants of either gender with idiopathic chronic cough will be studied and should have had a chronic cough of at least 8 weeks duration and should have been followed in the Cough Clinic for at least 6 months These participants will have undergone a protocol with a diagnostic pathway as recommended by the European Respiratory Society guidelines for management of cough Participants would have either an identifiable cause for their cough that have failed therapies targeted towards the identified cause or classed as having chronic idiopathic cough where no identifiable cause has been found
The control non-coughing subjects will be recruited through advertisement within the hospital and local newspaper services
Research Intervention and procedures Fiberoptic bronchoscopy Bronchoscopy is a standard diagnostic procedure and will be undertaken by an experienced doctor of the research team
The fibre-optic bronchoscope will be passed through either the nasal passages or the oropharynx before passing into the trachea The nasal passages will be the preferential route but in case this cannot be done through the nasal passages the oropharynx will be used Bronchoalveolar lavage BAL will be performed from the right middle lobe using warmed 09 saline with 4 successive aliquots of 60ml The bronchoscopist will then take samples of the cells lining the airways using a brush and forceps the latter allowing small pieces of tissue to be obtained
Post-procedure the participant will be moved from the procedure room to the recovery area where heshe will be monitored by nursing staff In case of any bronchoconstriction heshe will be treated with nebulized salbutamol and if required corticosteroid therapy will be given Once stable and no longer requiring oxygen and no longer drowsy heshe will be discharged following review by the research doctors The doctor may however determine that you need to be kept under observation until fit to be discharged home Any patient given midazolam during the procedure will be asked to have a responsible adult to accompany them home on that day
Local anaesthetic is used prior to the procedure and participants may experience a numb mouth or throat In some patients if safe to do so an anxiolytic drug midazolam will be given in small doses through the cannula This is usually tolerated without problem
After the procedure participants may experience a sore throat hoarse voice or cough due to irritation to the airways but this usually settles within a few hours Other symptoms can include the increased production of sputum sometimes with blood streaking of the mucus and a transient fever which can occur after a few hours after the procedure This usually settles within a few hours and can be helped by taking paracetamol There should be no long-lasting sequelae
Serious risks are rare but include a pneumothorax 1 in 2000 cases and significant bleeding Participants will be closely monitored following the procedure and should any serious complication arise they will be given the appropriate treatment in hospital
Exhaled breath condensate EBC collection EBC will be collected by asking the subject to breathe normally onto a handheld breath collection apparatus from Respire Diagnostics Imperial College that will cool the exhaled breath to allow for condensation of the exhaled air The subject will breathe for 2 periods of 5 minutes each separated by a 3-4 min rest to allow the collection of up to 500 microlitre uL of liquid The liquid will be stored for later analysis
Blood sample collection Venous blood 30 cc will be taken from a vein in the forearm This test causes a transient discomfort as a needle is used to obtain the blood sample The blood sample will be used for measuring various proteins and for getting white blood cells to obtain some types of stem cells
Continuous laryngoscopic examination Continuous laryngoscopy testing is performed based on previous methodology Continuous laryngoscopy testing is performed by placing a fibreoptic nasendoscope in the posterior nasopharynx and securing it using specialist headgear A small quantity of lubricating jelly is used to ease passage of the scope Video images of the laryngeal inlet are thereafter continuously recorded whilst a subject performs various manoeuvres including respiratory movements and cough These movements will be observed and recorded before and following the various aspects of the challenge protocol and thus allow us to evaluate laryngeal movement abnormalities and for example position of the vocal folds The size and change in size of the glottic aperture will be evaluated
Capsaicin cough challenge Capsaicin challenge is performed as established in our laboratory
The Leicester Cough Questionnaire This will be used to assess the impact of chronic cough on the patients quality of life
Measurement of cough frequency Cough frequency will be measured objectively with a Hyfe cough recording monitor for 48 hours
All enrolled study participants will be provided with a dedicated Android phone or watch loaded with the Hyfe Research application to monitor and record their cough sounds
Cough recording will include 5 solicited coughs at the time of study enrolment for calibration Study personnel will have the ability to remotely monitor the accrual of coughs for each participant in real time with the Hyfe Research Platform Dashboard - thus verifying as needed that the phones are on and functioning appropriately
Upon study completion a trained study staff member will retrieve the phones and ensure that data has been automatically uploaded to the Hyfe server
Assessment of laryngeal function by questionnaire We will use the Laryngeal Hypersensitivity Questionnaire for assessing laryngeal dysfunction
Induction of sputum Sputum is induced by inhalation of an aerosol of sterile 3 saline solution and subsequently increasing to 4 and 5 during 3 periods of 5 minutes each Sputum samples are collected into sterile pots
Sputum plugs are selected and one portion is used to perform differential cell counts To perform differential cell counts dithiothreitol is added to the sputum plug and mixed vigorously on a plate shaker to solubilize the sputum Cytospins are then prepared and differential cell counts obtained
In addition some of the cells will be placed in RNA later for RNAseq analysis The supernatant will be kept for later assay of neuroimmune biomarkers
Spirometric measurements Spirometry FEV1 and forced vital capacity FVC is measured using a dry wedge spirometer Vitalograph Buckinghamshire UK
Fractional exhaled nitric oxide FeNO Fractional exhaled nitric oxide FeNO level is measured using a portable FeNO monitor NObreath Bedfont Scientific Ltd Rochester UK at a constant expiratory flow of 005 Ls
Specimens from bronchoscopy i Bronchial brushings a slides with cells attached will be obtained and preserved for later immunohistochemical analysis b cells will be placed in RNA later for later extraction for RNAseq analysis c cells will be placed in culture
ii Bronchial biopsies Five μm sections will be cut and stained with haematoxylin and eosin to assess morphology Investigators will measure the extent of inflammation and remodeling in these biopsies as previously described In addition these sections will be used for a series of immunohistochemical investigations for localization of ATP and other associated neuroimmune biomarkers of interest
iii Bronchoalveolar lavage Bronchoalveolar lavage cells will be placed in cytospin for counting of differential cells Some of the cells will be kept in RNAlater for RNAseq The supernatant BAL fluid will be kept for later assay of neuroimmune markers including ATP
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