Chronic CoughEarly Phase 1NCT05813223
Effect of Gefapixant on Cough-related Brain Activity in Patients With Chronic Cough
A Early Phase 1 study testing Gefapixant in people with Chronic Cough, run by Stuart Mazzone at 1 site in Australia.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Chronic Cough
- What is being tested?
- Gefapixant
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 31 participants
- Where
- 1 siteAustralia
- Study dates
- 1 Jan 2024to 30 Jun 2026
- Phase
- Early Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Show all 9Show fewer
- 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).
Trial locations and contacts
1 site in 1 country.
Australia1 site, 1 recruiting
- Recruiting
The University of Melbourne
Parkville, Victoria, 3010
Stuart B Mazzone, PhD, +61383446457, stuart.mazzone@unimelb.edu.au
About this study
Official title: The Effect of Acute and Prolonged Administration of Gefapixant on Cough-related Brain Activity in Patients With Chronic Cough
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.
Read the detailed description
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.
- Conditions
- Chronic Cough
- Being tested
- Gefapixant
- Keywords
- functional brain imaging, ATP, Capsaicin, Refractory chronic cough, Mechanism of Disease
- Medical subject headings
- Chronic Cough
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
GefapixantDrug
Also called Merck (MK)-7264
Purinergic (P2X3) Receptor antagonist. Film-coated tablet taken orally.
| Study group | Role | What they receive |
|---|---|---|
| Gefapixant treatment | Experimental | Participants will asked to take an oral tablet containing 45mg Gefapixant twice daily (BID). Receives: Drug: Gefapixant |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: Brain imaging will be performed 1 week after Gefapixant withdrawal (Week 13).
Secondary outcomes (21)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Participant self-report using the CSD will be collected every day from Week 14 until 12 months (relative to start of study).
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Apr 2023
- Study start1 Jan 2024
- Primary completion31 Oct 2025 (estimated)
- Study completion30 Jun 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (10)Papers the sponsor has linked to this study.
- Other trials for Chronic CoughStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Early Phase 1
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- Open label, single arm, mechanism of disease study
- Masking
- None (open label)
- Enrolment
- 31 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Stuart Mazzone
- Sponsor type
- University, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC, Melbourne Health, Monash University
- Responsible party
- Sponsor-investigator, Stuart Mazzone, University of Melbourne
- Investigators
- Stuart B Mazzone, PhD, Principal investigator, +61383446457
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05813223
- Sponsor's protocol ID
- 2023.005
- Status last verified
- May 2024
- First submitted
- 20 Mar 2023
- Last updated
- 9 May 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Chung KF, Pavord ID. Prevalence, pathogenesis, and causes of chronic cough. Lancet. 2008 Apr 19;371(9621):1364-74. doi: 10.1016/S0140-6736(08)60595-4.
PubMed 18424325Chung KF, McGarvey L, Mazzone SB. Chronic cough as a neuropathic disorder. Lancet Respir Med. 2013 Jul;1(5):414-22. doi: 10.1016/S2213-2600(13)70043-2. Epub 2013 May 3.
PubMed 24429206Mazzone SB, McLennan L, McGovern AE, Egan GF, Farrell MJ. Representation of capsaicin-evoked urge-to-cough in the human brain using functional magnetic resonance imaging. Am J Respir Crit Care Med. 2007 Aug 15;176(4):327-32. doi: 10.1164/rccm.200612-1856OC. Epub 2007 Jun 15.
PubMed 17575093Ando A, Smallwood D, McMahon M, Irving L, Mazzone SB, Farrell MJ. Neural correlates of cough hypersensitivity in humans: evidence for central sensitisation and dysfunctional inhibitory control. Thorax. 2016 Apr;71(4):323-9. doi: 10.1136/thoraxjnl-2015-207425. Epub 2016 Feb 9.
PubMed 26860344Thomas D, Gibson PG. Gefapixant for chronic cough. Lancet. 2022 Mar 5;399(10328):886-887. doi: 10.1016/S0140-6736(21)02438-7. No abstract available.
PubMed 35248173McGarvey LP, Birring SS, Morice AH, Dicpinigaitis PV, Pavord ID, Schelfhout J, Nguyen AM, Li Q, Tzontcheva A, Iskold B, Green SA, Rosa C, Muccino DR, Smith JA; COUGH-1 and COUGH-2 Investigators. Efficacy and safety of gefapixant, a P2X3 receptor antagonist, in refractory chronic cough and unexplained chronic cough (COUGH-1 and COUGH-2): results from two double-blind, randomised, parallel-group, placebo-controlled, phase 3 trials. Lancet. 2022 Mar 5;399(10328):909-923. doi: 10.1016/S0140-6736(21)02348-5.
PubMed 35248186Smith JA, Kitt MM, Morice AH, Birring SS, McGarvey LP, Sher MR, Li YP, Wu WC, Xu ZJ, Muccino DR, Ford AP; Protocol 012 Investigators. Gefapixant, a P2X3 receptor antagonist, for the treatment of refractory or unexplained chronic cough: a randomised, double-blind, controlled, parallel-group, phase 2b trial. Lancet Respir Med. 2020 Aug;8(8):775-785. doi: 10.1016/S2213-2600(19)30471-0. Epub 2020 Feb 25.
PubMed 32109425Morice AH, Jakes AD, Faruqi S, Birring SS, McGarvey L, Canning B, Smith JA, Parker SM, Chung KF, Lai K, Pavord ID, van den Berg J, Song WJ, Millqvist E, Farrell MJ, Mazzone SB, Dicpinigaitis P; Chronic Cough Registry. A worldwide survey of chronic cough: a manifestation of enhanced somatosensory response. Eur Respir J. 2014 Nov;44(5):1149-55. doi: 10.1183/09031936.00217813. Epub 2014 Sep 3.
PubMed 25186267Morice AH, Kitt MM, Ford AP, Tershakovec AM, Wu WC, Brindle K, Thompson R, Thackray-Nocera S, Wright C. The effect of gefapixant, a P2X3 antagonist, on cough reflex sensitivity: a randomised placebo-controlled study. Eur Respir J. 2019 Jul 4;54(1):1900439. doi: 10.1183/13993003.00439-2019. Print 2019 Jul.
PubMed 31023843Dicpinigaitis PV, Alva RV. Safety of capsaicin cough challenge testing. Chest. 2005 Jul;128(1):196-202. doi: 10.1378/chest.128.1.196.
PubMed 16002935
Study at a glance
From the registry record, last updated by the sponsor on 9 May 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effect of Acute and Prolonged Administration of Gefapixant on Cough-related Brain Activity in Patients With Chronic Cough
- ClinicalTrials.gov ID
- NCT05813223
- Acronym / sponsor ID
- 2023.005
- Conditions
- Chronic Cough
- Keywords
- functional brain imaging, ATP, Capsaicin, Refractory chronic cough, Mechanism of Disease
- Phase
- Early Phase 1
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 31 participants (estimated)
- Lead sponsor
- Stuart MazzoneUniversity, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC, Melbourne Health, Monash University
- Study start
- 1 Jan 2024 (actual)
- Primary completion
- 31 Oct 2025 (estimated)
- Study completion
- 30 Jun 2026 (estimated)
- First posted
- 14 Apr 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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.
Study design
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- Open label, single arm, mechanism of disease study
| Arm | Type | Receives |
|---|---|---|
| Gefapixant treatment | Experimental | Drug: GefapixantParticipants will asked to take an oral tablet containing 45mg Gefapixant twice daily (BID). |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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.
Key exclusion criteria (9 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| GefapixantAlso: Merck (MK)-7264Purinergic (P2X3) Receptor antagonist. Film-coated tablet taken orally. | Drug | Gefapixant treatment |
Primary outcome
Change in cough-related brain activity using brain imaging following Gefapixant administration
Time frame: Gefapixant administration will be for 12 weeks with brain scans to be performed before, 3 days after, and 12 weeks after dosing.
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.
Change in cough-related brain activity using brain imaging following Gefapixant withdrawal
Time frame: Brain imaging will be performed 1 week after Gefapixant withdrawal (Week 13).
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.
21 secondary outcomes
Change in capsaicin and ATP cough challenge test sensitivity following Gefapixant administration
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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.
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: Participant self-report using the CSD will be collected every day from Week 14 until 12 months (relative to start of study).
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 May 2024.
- Background: PubMed 18424325Chung KF, Pavord ID. Prevalence, pathogenesis, and causes of chronic cough. Lancet. 2008 Apr 19;371(9621):1364-74. doi: 10.1016/S0140-6736(08)60595-4.
- Background: PubMed 24429206Chung KF, McGarvey L, Mazzone SB. Chronic cough as a neuropathic disorder. Lancet Respir Med. 2013 Jul;1(5):414-22. doi: 10.1016/S2213-2600(13)70043-2. Epub 2013 May 3.
- Background: PubMed 17575093Mazzone SB, McLennan L, McGovern AE, Egan GF, Farrell MJ. Representation of capsaicin-evoked urge-to-cough in the human brain using functional magnetic resonance imaging. Am J Respir Crit Care Med. 2007 Aug 15;176(4):327-32. doi: 10.1164/rccm.200612-1856OC. Epub 2007 Jun 15.
- Background: PubMed 26860344Ando A, Smallwood D, McMahon M, Irving L, Mazzone SB, Farrell MJ. Neural correlates of cough hypersensitivity in humans: evidence for central sensitisation and dysfunctional inhibitory control. Thorax. 2016 Apr;71(4):323-9. doi: 10.1136/thoraxjnl-2015-207425. Epub 2016 Feb 9.
- Background: PubMed 35248173Thomas D, Gibson PG. Gefapixant for chronic cough. Lancet. 2022 Mar 5;399(10328):886-887. doi: 10.1016/S0140-6736(21)02438-7. No abstract available.
- Background: PubMed 35248186McGarvey LP, Birring SS, Morice AH, Dicpinigaitis PV, Pavord ID, Schelfhout J, Nguyen AM, Li Q, Tzontcheva A, Iskold B, Green SA, Rosa C, Muccino DR, Smith JA; COUGH-1 and COUGH-2 Investigators. Efficacy and safety of gefapixant, a P2X3 receptor antagonist, in refractory chronic cough and unexplained chronic cough (COUGH-1 and COUGH-2): results from two double-blind, randomised, parallel-group, placebo-controlled, phase 3 trials. Lancet. 2022 Mar 5;399(10328):909-923. doi: 10.1016/S0140-6736(21)02348-5.
- Background: PubMed 32109425Smith JA, Kitt MM, Morice AH, Birring SS, McGarvey LP, Sher MR, Li YP, Wu WC, Xu ZJ, Muccino DR, Ford AP; Protocol 012 Investigators. Gefapixant, a P2X3 receptor antagonist, for the treatment of refractory or unexplained chronic cough: a randomised, double-blind, controlled, parallel-group, phase 2b trial. Lancet Respir Med. 2020 Aug;8(8):775-785. doi: 10.1016/S2213-2600(19)30471-0. Epub 2020 Feb 25.
- Background: PubMed 25186267Morice AH, Jakes AD, Faruqi S, Birring SS, McGarvey L, Canning B, Smith JA, Parker SM, Chung KF, Lai K, Pavord ID, van den Berg J, Song WJ, Millqvist E, Farrell MJ, Mazzone SB, Dicpinigaitis P; Chronic Cough Registry. A worldwide survey of chronic cough: a manifestation of enhanced somatosensory response. Eur Respir J. 2014 Nov;44(5):1149-55. doi: 10.1183/09031936.00217813. Epub 2014 Sep 3.
- Background: PubMed 31023843Morice AH, Kitt MM, Ford AP, Tershakovec AM, Wu WC, Brindle K, Thompson R, Thackray-Nocera S, Wright C. The effect of gefapixant, a P2X3 antagonist, on cough reflex sensitivity: a randomised placebo-controlled study. Eur Respir J. 2019 Jul 4;54(1):1900439. doi: 10.1183/13993003.00439-2019. Print 2019 Jul.
- Background: PubMed 16002935Dicpinigaitis PV, Alva RV. Safety of capsaicin cough challenge testing. Chest. 2005 Jul;128(1):196-202. doi: 10.1378/chest.128.1.196.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Stuart B Mazzone, PhD principal investigator
+61383446457
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Early Phase 1 study testing Gefapixant in people with Chronic Cough, run by Stuart Mazzone at 1 site in Australia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 9 May 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Australia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Stuart B Mazzone, PhD (+61383446457, stuart.mazzone@unimelb.edu.au), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in cough-related brain activity using brain imaging following Gefapixant administration (time frame: Gefapixant administration will be for 12 weeks with brain scans to be performed before, 3 days after, and 12 weeks after dosing.). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05813223, which also lists 10 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 May 2024.