Mechanisms of Change in Behavioral Cough Suppression Therapy for Refractory Chronic Cough

Summary

This study is testing new ways to help people who have chronic cough that has not improved with typical treatments. One approach is called behavioral cough suppression (BCS) therapy, which teaches people techniques to stop themselves from coughing. Another approach uses a natural substance thought to help reduce the body's sensitivity to cough triggers. In this study, we will test two treatments and include one no-treatment control group. The control group will undergo baseline testing, cough monitoring, and an fMRI brain scan and will be offered BCS at end of study participation. The two treatments include: * BCS therapy with active inhaled treatment (BCS+active), * BCS therapy with inactive inhaled treatment (BCS+inactive), The investigators will enroll 135 adults with refractory chronic cough (RCC). 100 participants who qualify and are willing and able to complete 14 study visits in the clinic and two online study visits will be randomly assigned to one of the two treatments. The no-treatment control group (n=35) will be recruited from adults with RCC who are willing to complete baseline testing and fMRI but are not able or willing to attend 14 study clinic visits. These participants will not be randomized. The investigators want to find out how these treatments affect: * How sensitive someone is to things that make them cough, * How well they can hold back a cough when they try, * How their brain responds to things that cause an urge-to-cough, * And how much their coughing affects their quality of life. The investigators believe both treatments will reduce sensitivity to cough stimulants, reduce cough severity, and improve quality of life, but BCS+active inhaled treatment will work better than BCS+inactive inhaled treatment.

Detailed Description

Refractory chronic cough (RCC) is a persistent and costly condition that is difficult to treat, often persisting despite appropriate treatment of underlying causes. While behavioral cough suppression (BCS) therapy has shown effectiveness in reducing cough frequency and improving quality of life in controlled studies, it remains underutilized, and the mechanisms by which it works are not well understood. This multi-site randomized controlled trial will investigate the effects and mechanisms of BCS therapy with and without the addition of an inhaled substance designed to enhance the effect of BCS treatment. The active inhaled substance used in the study has demonstrated desensitization effects on sensory pathways in conditions such as chronic rhinitis and pain syndromes, suggesting potential utility in modulating cough-related neural pathways. Inhalation of this substance has been shown to be safe across multiple studies. The investigators will recruit 135 participants diagnosed with RCC. 100 participants will be randomized into one of two treatment arms -- BCS combined with an active inhaled substance, and BCS combined with an inactive inhalant. A non-randomized no-treatment control group (n=35) will be included to provide a control comparison to fMRI. Participants in the treatment arms will undergo 12 treatment sessions over several weeks. The study will evaluate both behavioral and neural markers of treatment response. Primary outcome measures will include: * Cough sensory threshold (C5): the lowest concentration of citric acid causing five or more coughs, * Cough suppression ability (CS Thresh Diff): the ability to suppress cough when instructed, quantified by the difference between the dose of capsaicin causing five or more coughs when trying to suppress cough (CS5) and C5, * Urge-to-cough (UTC) sensory-motor threshold difference (UTC S-M Thresh Diff): a measure of how perception of the need to cough relates to actual coughing behavior, * Blood oxygen level dependent (BOLD) neural responses using whole-brain functional MRI (fMRI) during UTC stimulation. The following patient-report outcome measures (PROMS) will be included as secondary outcomes: * Leicester Cough Questionnaire (LCQ): Assesses patient-reported cough-related quality of life, relevant for assessing the broader impact of treatment. * PROMIS-Global Health: Assesses patient-reported generalized quality of life, relevant for assessing the broader impact of treatment. * Voice Handicap Index-10 (VHI-10): Assesses patient-reported impact of voice problems and is relevant for assessing the broader impact of treatment. * Newcastle Laryngeal Hypersensitivity Questionnaire (NLHQ): Assesses patient-reported laryngeal sensory symptoms and is relevant for assessing the broader impact of treatment * Multidimensional Assessment of Interoceptive Awareness (MAIA-2): Assesses patient-reported awareness and regulation of bodily sensations and is relevant for assessing the broader impact of treatment * Patient Global Impression of Severity (PGI-S): Assesses patient-reported overall perception of cough severity and is relevant for assessing the broader impact of treatment * Patient Global of Impression of Change (PGI-C): Assesses patient-reported impression of change related to treatment and is relevant for assessing the broader impact of treatment * PROMIS-Sleep: Assesses patient-reported sleep quality and is relevant for assessing the broader impact of treatment Ambulatory cough frequency monitoring will also be included as a secondary outcome. This data will be collected with the CoughMonitor smartwatch by Hyfe, Inc. The investigators hypothesize that both treatments will lead to desensitization of cough sensitivity (i.e., increase in C5). We further hypothesize that the combination of BCS+active inhaled treatment will provide the greatest therapeutic benefit on all outcome measures due to simultaneous peripheral desensitization and central sensory-motor modulation. Regarding fMRI, we hypothesize that both treatments will result in increased activity in areas responsible for motor inhibition (e.g., prefrontal cortex).

Eligibility Criteria

Interventions