Effect of Gefapixant on Cough-related Brain Activity in Patients With Chronic Cough

Study Overview
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Brief Summary
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Recently, a new drug called Gefapixant passed phase III clinical trials for cough suppression in patients with chronic cough. The goal of this clinical trial is to investigate the effect of acute and prolonged administration of the drug Gefapixant on cough-related brain activity in patients with chronic cough. The main question it aims to answer is: does the mechanism of action of Gefapixant on the brainstem and brain circuits regulating cough differ between acute and prolonged therapy in people with chronic cough? Participants have their brain activity and their sensitivity to cough-inducing substances measured as well as complete questionnaires about their cough before and while taking daily Gefapixant.

Detailed Description
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Chronic cough is a distressing disorder experienced by 1 in 10 people worldwide. At its worst, individuals can cough hundreds of times every hour of their waking lives, and this can persist for decades without relief. Chronic cough sufferers also experience an ongoing feeling of needing to cough (urge-to-cough) that prompts coughing and throat clearing, but usually without resolution of the sensation. The clinical problem is extremely challenging to manage because the last dedicated cough suppressant drug to be approved for clinical use (dextromethorphan) was in 1958 and it offers no benefit for chronic cough patients. Recently, a new drug called Gefapixant passed phase III clinical trials for cough suppression in patients with chronic cough and is currently advancing to market globally. Gefapixant is extremely well-tolerated with minimal side effects - a reduction in taste acuity being the main adverse effect reported. This project will investigate further the mechanisms of action of Gefapixant, assessing for the first time the effects of Gefapixant therapy on the brain pathways involved in cough and urge-to-cough generation. The study will recruit 31 participants with existing chronic cough and investigate their brain responses using non-invasive magnetic resonance imaging while briefly breathing personally tailored stimuli that are just below threshold for triggering coughing (determined using inhaled cough challenge testing procedures). Brain scans will be performed before and at two time points (3 days and 12 weeks) after starting Gefapixant treatment, consisting of one 45mg tablet swallowed twice daily. Participants will also complete questionnaires and maintain a diary about their cough. After 12 weeks of treatment, participants will cease taking Gefapixant for 1 week and brain scans will be performed again to assess whether changes in brain activity are sustained. Participants will then have access to Gefapixant for a further 9 months during which time cough sensitivity and questionnaires and will be assessed on 2 additional occasions to determine whether longer term therapy leads to added changes in nerve pathways mediating cough. Significance: Understanding how the brain controls cough and the urge-to-cough, and the specific brain processes altered by Gefapixant therapy, will significantly advance the understanding of the biology and clinical management of this challenging clinical condition.

Official Title
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The Effect of Acute and Prolonged Administration of Gefapixant on Cough-related Brain Activity in Patients With Chronic Cough

Conditions
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Chronic Cough

Intervention / Treatment
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* Drug: Gefapixant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent to participate in the study. 18-65 years old; Male or female. Non-smokers for at least 5 years and have no history of neurological disease or any recent history (over 8 weeks) of acute respiratory infections. Presence of Refractory Chronic Cough (RCC) or Unexplained Chronic Cough (UCC) for ≥1 year, defined as cough unresponsive to treatment for underlying conditions including reflux disease, asthma and rhinitis. Presence of cough symptoms as determined by a self-reported cough severity of ≥40mm on 10-point scale on screening. Exclusion Criteria: Current smokers or recreational drug users. Women who are pregnant. People with contraindications to MRI scanning (i.e. metal implants, claustrophobia). Children and/or young people (ie. <18 years). People with an intellectual or mental impairment. People highly dependent on medical care. People in existing dependent or unequal relationships with any member of the research team. People with known allergy to chili (very rare). Non-English speakers (as English proficiency is required to accurately complete research tasks).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Interventional Model Description: Open label, single arm, mechanism of disease study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gefapixant treatment<br>Participants will asked to take an oral tablet containing 45mg Gefapixant twice daily (BID). | Drug: Gefapixant<br>* Purinergic (P2X3) Receptor antagonist. Film-coated tablet taken orally.<br>* Other names: Merck (MK)-7264;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in cough-related brain activity using brain imaging following Gefapixant administration | We will investigate the time-dependent effect of Gefapixant treatment on brain activity evoked by inhaled ATP and capsaicin as measured using functional Magnetic Resonance Imaging (fMRI). The principle endpoint is measured as the change in capsaicin and ATP evoked Blood Oxygen Level Dependent (BOLD) signal and the unit of measure is percentage. | Gefapixant administration will be for 12 weeks with brain scans to be performed before, 3 days after, and 12 weeks after dosing. | 
| Change in cough-related brain activity using brain imaging following Gefapixant withdrawal | We will follow up with participants 1 week after stopping Gefapixant dosing and investigate the time-dependent effect of Gefapixant treatment on brain activity evoked by inhaled ATP and capsaicin as measured using functional Magnetic Resonance Imaging (fMRI). The principle endpoint is measured as the change in capsaicin and ATP evoked Blood Oxygen Level Dependent (BOLD) signal and the unit of measure is percentage. | Brain imaging will be performed 1 week after Gefapixant withdrawal (Week 13). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in capsaicin and ATP cough challenge test sensitivity following Gefapixant administration | We will investigate participant's cough sensitivity thresholds by inhaled cough challenge testing. This involves participants inhaling single breaths of increasing concentrations of tussigenic stimuli (capsaicin and ATP) as well as saline control to determine threshold doses that elicit an urge to cough, two coughs (C2) and five coughs (C5). The principle endpoint is measured as the change in capsaicin and ATP concentration needed to elicit cough responses and the unit of measure is micromolar. | Cough thresholds will be determined before, 3 days after and 12 weeks after Gefapixant dosing. | 
| Change in Urge To Cough Visual Analogue Scale (UTCVAS) score after Gefapixant administration | Participants will be asked to self-report on their urge to cough severity using the Urge to Cough Visual Analogue Scale. The scale is 100 units with a minimum value of 0 labelled No urge to cough and a maximum value of 100 labelled Worst urge to cough ever. A higher score indicates a worse outcome. The principal endpoint is measured as the change in UTCVAS score and the unit of measure is points. | Participant self-reports using the UTCVAS will be collected before and 3 days, 4 weeks, 8 weeks and 12 weeks after Gefapixant dosing. | 
| Change in Cough Visual Analogue Scale (CVAS) score after Gefapixant administration | Participants will be asked to self-report on their cough severity using the Urge to Cough Visual Analogue Scale. The scale is 100 units with a minimum value of 0 labelled No cough and a maximum value of 100 labelled Worst cough ever. A higher score indicates a worse outcome. The principal endpoint is measured as the change in CVAS score and the unit of measure is points. | Participant self-reports using the CVAS will be collected before and 3 days, 4 weeks, 8 weeks and 12 weeks after Gefapixant dosing. | 
| Change in Leicester Cough Questionnaire (LCQ) score after Gefapixant administration | Participants will be asked to self-report on the impact of cough on their quality of life. Each item requires a rating on a 7-point Likert scale from 1 to 7 and is related to the impact of cough in one of three domains (physical, psychological social). The LCQ is scored by averaging the ratings in each domain and then adding the average domain scores (range 3-21). A higher score indicates a better outcome. The principal endpoint is measured as the change in LCQ score and the unit of measure is points. | Participant self-reports using the LCQ will be collected before and 3 days, 4 weeks, 8 weeks and 12 weeks after Gefapixant dosing. | 
| Change in Newcastle Laryngeal Hypersensitivity Questionnaire (NLHQ) score after Gefapixant administration | Participants will be asked to self-report on sensations related to laryngeal hypersensitivity. Each item requires a rating on a 7-point Likert scale from 1 to 7 and is related to an upper airway sensation in one of three domains (throat obstruction, throat pain/thermal), throat tickle). The NHLQ is scored by averaging the ratings in each domain and then adding the average domain scores (range 3-21). A higher score indicates a better outcome. The principal endpoint is measured as the change in NLHQ score and the unit of measure is points. | Participant self-reports using the NLHQ will be collected before and 3 days, 4 weeks, 8 weeks and 12 weeks after Gefapixant dosing. | 
| Change in Hull Airway Reflux Questionnaire (HARQ) score after Gefapixant administration | Participants will be asked to self-report on symptoms related to airway reflux. Each item requires a rating on a 6-point Likert scale from 0 to 5 and is related to an aspect of airway reflux. The HARQ is scored by adding the total ratings (range 0-70). A higher score indicates a worse outcome. The principal endpoint is measured as the change in HARQ score and the unit of measure is points. | Participant self-reports using the HARQ will be collected before and 3 days, 4 weeks, 8 weeks and 12 weeks after Gefapixant dosing. | 
| Change in Cough Severity Diary (CSD) score after Gefapixant administration | Participants will be asked to self-report on their daily cough severity. Each item requires a rating on an 11-point Likert scale from 0 to 10 and is related to an aspect of cough in one of three domains (frequency, intensity, disruption). The CSD is scored by averaging the ratings in each domain, as well as averaging across all items (range 1-10). A higher score indicates a worse outcome. The principal endpoint is measured as the change in CSD score and the unit of measure is points. | Participant self-reports using the CSD will be collected every day for 12 weeks after the start of Gefapixant administration. | 
| Change in capsaicin and ATP cough challenge test sensitivity following Gefapixant withdrawal | We will follow up with participants 1 week after stopping Gefapixant dosing and investigate participant's cough sensitivity thresholds by inhaled cough challenge testing. This involves participants inhaling single breaths of increasing concentrations of tussigenic stimuli (capsaicin and ATP) as well as saline control to determine threshold doses that elicit an urge to cough, two coughs (C2) and five coughs (C5). The principle endpoint is measured as the change in capsaicin and ATP concentration needed to elicit cough responses and the unit of measure is micromolar. | Cough thresholds will be determined 1 week after Gefapixant withdrawal (Week 13). | 
| Change in Urge To Cough Visual Analogue Scale (UTCVAS) score following Gefapixant withdrawal | We will follow up with participants 1 week after stopping Gefapixant dosing. Participants will be asked to self-report on their urge to cough severity using the Urge to Cough Visual Analogue Scale. The scale is 100 units with a minimum value of 0 labelled No urge to cough and a maximum value of 100 labelled Worst urge to cough ever. A higher score indicates a worse outcome. The principal endpoint is measured as the change in UTCVAS score and the unit of measure is points. | Participant self-report using the UTCVAS will be collected 1 week after Gefapixant withdrawal (Week 13). | 
| Change in Cough Visual Analogue Scale (CVAS) score following Gefapixant withdrawal | We will follow up with participants 1 week after stopping Gefapixant dosing. Participants will be asked to self-report on their cough severity using the Urge to Cough Visual Analogue Scale. The scale is 100 units with a minimum value of 0 labelled No cough and a maximum value of 100 labelled Worst cough ever. A higher score indicates a worse outcome. The principal endpoint is measured as the change in CVAS score and the unit of measure is points. | Participant self-report using the CVAS will be collected 1 week after Gefapixant withdrawal (Week 13). | 
| Change in Leicester Cough Questionnaire (LCQ) score following Gefapixant withdrawal | We will follow up with participants 1 week after stopping Gefapixant dosing. Participants will be asked to self-report on the impact of cough on their quality of life. Each item requires a rating on a 7-point Likert scale from 1 to 7 and is related to the impact of cough in one of three domains (physical, psychological social). The LCQ is scored by averaging the ratings in each domain and then adding the average domain scores (range 3-21). A higher score indicates a better outcome. The principal endpoint is measured as the change in LCQ score and the unit of measure is points. | Participant self-report using the LCQ will be collected 1 week after Gefapixant withdrawal (Week 13). | 
| Change in Newcastle Laryngeal Hypersensitivity Questionnaire (NLHQ) score following Gefapixant withdrawal | We will follow up with participants 1 week after stopping Gefapixant dosing. Participants will be asked to self-report on sensations related to laryngeal hypersensitivity. Each item requires a rating on a 7-point Likert scale from 1 to 7 and is related to an upper airway sensation in one of three domains (throat obstruction, throat pain/thermal), throat tickle). The NHLQ is scored by averaging the ratings in each domain and then adding the average domain scores (range 3-21). A higher score indicates a better outcome. The principal endpoint is measured as the change in NLHQ score and the unit of measure is points. | Participant self-report using the NHLQ will be collected 1 week after Gefapixant withdrawal (Week 13). | 
| Change in Hull Airway Reflux Questionnaire (HARQ) score following Gefapixant withdrawal | We will follow up with participants 1 week after stopping Gefapixant dosing. Participants will be asked to self-report on symptoms related to airway reflux. Each item requires a rating on a 6-point Likert scale from 0 to 5 and is related to an aspect of airway reflux. The HARQ is scored by adding the total ratings (range 0-70). A higher score indicates a worse outcome. The principal endpoint is measured as the change in HARQ score and the unit of measure is points. | Participant self-report using the HARQ will be collected 1 week after Gefapixant withdrawal (Week 13). | 
| Change in Cough Severity Diary (CSD) score following Gefapixant withdrawal | We will follow up with participants 1 week after stopping Gefapixant dosing. Participants will be asked to self-report on their daily cough severity. Each item requires a rating on an 11-point Likert scale from 0 to 10 and is related to an aspect of cough in one of three domains (frequency, intensity, disruption). The CSD is scored by averaging the ratings in each domain, as well as averaging across all items (range 1-10). A higher score indicates a worse outcome. The principal endpoint is measured as the change in CSD score and the unit of measure is points. | Participant self-report using the CSD will be collected every day in the 1 week after Gefapixant withdrawal (Week 13). | 
| Sustainability of Gefapixant treatment effects on cough challenge sensitivity. | Participants can opt to resume Gefapixant administration for another 9 months after completion of the withdrawal assessments. We will investigate participant's cough sensitivity thresholds by inhaled cough challenge testing. This involves participants inhaling single breaths of increasing concentrations of tussigenic stimuli (capsaicin and ATP) as well as saline control to determine threshold doses that elicit an urge to cough, two coughs (C2) and five coughs (C5). The principle endpoint is measured as the change in capsaicin and ATP concentration needed to elicit cough responses and the unit of measure is micromolar. | Cough thresholds will be determined at 6 and 12 months (relative to start of study). | 
| Sustainability of Gefapixant treatment effects on Urge To Cough Visual Analogue Scale (UTCVAS) score | Participants can opt to resume Gefapixant administration for another 9 months after completion of the withdrawal assessments. Participants will be asked to self-report on their urge to cough severity using the Urge to Cough Visual Analogue Scale. The scale is 100 units with a minimum value of 0 labelled No urge to cough and a maximum value of 100 labelled Worst urge to cough ever. A higher score indicates a worse outcome. The principal endpoint is measured as the change in UTCVAS score and the unit of measure is points. | Participant self-report using the UTCVAS will be collected at 6 and 12 months (relative to start of study). | 
| Sustainability of Gefapixant treatment effects on Cough Visual Analogue Scale (CVAS) score | Participants can opt to resume Gefapixant administration for another 9 months after completion of the withdrawal assessments. Participants will be asked to self-report on their cough severity using the Urge to Cough Visual Analogue Scale. The scale is 100 units with a minimum value of 0 labelled No cough and a maximum value of 100 labelled Worst cough ever. A higher score indicates a worse outcome. The principal endpoint is measured as the change in CVAS score and the unit of measure is points. | Participant self-report using the CVAS will be collected at 6 and 12 months (relative to start of study). | 
| Sustainability of Gefapixant treatment effects on Leicester Cough Questionnaire (LCQ) score | Participants can opt to resume Gefapixant administration for another 9 months after completion of the withdrawal assessments. Participants will be asked to self-report on the impact of cough on their quality of life. Each item requires a rating on a 7-point Likert scale from 1 to 7 and is related to the impact of cough in one of three domains (physical, psychological social). The LCQ is scored by averaging the ratings in each domain and then adding the average domain scores (range 3-21). A higher score indicates a better outcome. The principal endpoint is measured as the change in LCQ score and the unit of measure is points. | Participant self-report using the LCQ will be collected at 6 and 12 months (relative to start of study). | 
| Sustainability of Gefapixant treatment effects on Newcastle Laryngeal Hypersensitivity Questionnaire (NLHQ) score | Participants can opt to resume Gefapixant administration for another 9 months after completion of the withdrawal assessments. Participants will be asked to self-report on sensations related to laryngeal hypersensitivity. Each item requires a rating on a 7-point Likert scale from 1 to 7 and is related to an upper airway sensation in one of three domains (throat obstruction, throat pain/thermal), throat tickle). The NHLQ is scored by averaging the ratings in each domain and then adding the average domain scores (range 3-21). A higher score indicates a better outcome. The principal endpoint is measured as the change in NLHQ score and the unit of measure is points. | Participant self-report using the NLHQ will be collected at 6 and 12 months (relative to start of study). | 
| Sustainability of Gefapixant treatment effects on Hull Airway Reflux Questionnaire (HARQ) score | Participants can opt to resume Gefapixant administration for another 9 months after completion of the withdrawal assessments. Participants will be asked to self-report on symptoms related to airway reflux. Each item requires a rating on a 6-point Likert scale from 0 to 5 and is related to an aspect of airway reflux. The HARQ is scored by adding the total ratings (range 0-70). A higher score indicates a worse outcome. The principal endpoint is measured as the change in HARQ score and the unit of measure is points. | Participant self-report using the HARQ will be collected at 6 and 12 months (relative to start of study). | 
| Sustainability of Gefapixant treatment effects on Cough Severity Diary (CSD) score | Participants can opt to resume Gefapixant administration for another 9 months after completion of the withdrawal assessments. Participants will be asked to self-report on their daily cough severity. Each item requires a rating on an 11-point Likert scale from 0 to 10 and is related to an aspect of cough in one of three domains (frequency, intensity, disruption). The CSD is scored by averaging the ratings in each domain, as well as averaging across all items (range 1-10). A higher score indicates a worse outcome. The principal endpoint is measured as the change in CSD score and the unit of measure is points. | Participant self-report using the CSD will be collected every day from Week 14 until 12 months (relative to start of study). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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functional brain imaging, ATP, Capsaicin, Refractory chronic cough, Mechanism of Disease