effect of gefapixant on cough-related brain activity in patients with chronic cough

Conditions: Chronic Cough

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. 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.

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.

Eligibility criteria:
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).

Keywords: functional brain imaging atp capsaicin refractory chronic cough mechanism of disease