Chronic Cough (CC), Refractory Chronic Cough, Unexplained Chronic Cough
Conditions
Keywords
cough hypersensitivity syndrome, randomized control trial, neurogenic cough, refractory chronic cough, unexplained chronic cough, chronic cough, behavioral cough suppression therapy
Brief 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).
Interventions
BEHAVIORALBCS+inactive
Behavioral cough suppression therapy plus inactive inhaled drug. Treatment given twice per week for 12 sessions.
COMBINATION_PRODUCTBCS+active
Behavioral cough suppression therapy combined with inhaled natural substance known to desensitize sensory nerves. Treatment given twice per week for 12 sessions.
Sponsors
University of Montana
University of Colorado, Denver
Emory University
University of Melbourne
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
To be eligible to participate, participants must meet the following criteria: * 18 - 99 years of age * Diagnosis of refractory or unexplained chronic cough * Normal chest imaging (x-ray or CT scan) within past 2 years, without change in cough symptoms * If you a potential participant has asthma, the following criteria must be met: * Asthma diagnosed by a pulmonary provider * Documentation from a pulmonary provider that asthma is well-controlled * Agree to carry prescribed rescue inhaler to each study visit * Can tolerate, and agree to, avoid rescue inhaler use for 4 hours prior to each study visit. If rescue inhaler use is unavoidable within 4 hours of a study visit, agree to inform researchers in advance so that the session can be rescheduled. * Normal pulmonary function testing with spirometry (FEV1/FVC of at least 70% if diagnosed with asthma) within 2 years (6 months for those with a diagnosis of asthma), without change in symptoms since (NOTE: spirometry is included as part of cough threshold testing and can serve as this criteria if the participant has not had spirometry within the designated time.) * Laryngoscopy or stroboscopy within 2 years without evidence of structural pathology and no change in vocal quality since exam * Proficient reader/speaker of English * Willing to take a pregnancy test before enrollment (if applicable) * Willing to use contraception during the study (if applicable) * Access to reliable internet, working email address (for surveys) and a smart phone (for use with CoughMonitor Watch) * Demonstrates understanding in study procedures and risks in order to consent * Available, and willing, to comply to all study procedures and clinic visits.
Exclusion criteria
Any of the following will be grounds for exclusion from the study: * Currently a smoker of any substance or has a positive history of smoking any substance within the last 6 months * Currently suffering from any signs of an upper respiratory infection (other than cough) * Hemoptysis (coughing up blood) within the last 6 months * Pulmonary diagnosis other than asthma * Asthma criteria - participant is deemed ineligible if screened for one or more of the following: * Use of rescue inhaler in response to active asthma symptoms ≥ 2 times per week * Respiratory related emergency department visit within the past 4 weeks * Respiratory related ICU admission within the past 12 months * Asthma exacerbation requiring systemic corticosteroid use within the past 4 weeks * Pregnant or trying to become pregnant * Any complaints or clinical symptoms of dysphagia * Live with someone with chronic cough or work with someone with chronic cough who is in close proximity (e.g., within 25 feet) on a daily or nearly daily basis * Known allergy to peppers * Currently receiving or has received BCS therapy for management of refractory chronic cough * Excluded concomitant medications: * Inhaled pulmonary medications (inhaled corticosteroids, short-acting beta agonists, long-acting beta-agonist, short-acting muscarinic antagonists), unless prescribed for asthma by pulmonary provider: 30 days prior to Visit 1 through completion of study participation * ACE inhibitor (benazepril, captopril, enalapril, fosiniopril, lisinopril, perindopril, quinapril, ramipril, trandolapril): 30 days prior to Visit 1 through completion of study participation. * Narcotic antitussive (hydrocodone, oxycodone, morphine, codeine, tramadol): 7 days prior to Visit 1 through completion of study participation * Non-narcotic antitussive (benzonatate/Tessalon, dextromethorphan/Delsym, carbetapentane/Solotuss): 7 days prior to Visit 1 through completion of study * P2X3 receptor antagonist (gefapixant/Lyfnua): 14 days prior to Visit 1 through completion of study * Any off-label prescription medication prescribed for cough (pregabalin/Lyrica, gabapentin/Neurontin, amitriptyline/Elavil): 14 days prior to Visit 1 through completion of study \*if a neuromodulator is prescribed for something other than cough, participant must be on a stable dose for a minimum of 7 days The following additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cough suppression threshold difference (CS Thresh Diff) | From enrollment to 4 weeks following enrollment | Measure of cough suppression ability. The participant first completes cough suppression threshold testing which involves inhalation of progressive doses of citric acid while actively trying to suppress cough. The dose causing 5 or more coughs when trying to not cough (CS5) is the endpoint. CS Thresh Diff is the difference between CS5 and C5. |
| Urge-to-Cough Sensory Motor Threshold Difference (UTC S-M Thresh Diff) | From enrollment to 4 weeks following enrollment | A measure of the relationship between sensation of UTC and motor action of coughing. The measure is determined by calculating the difference between first UTC felt during cough threshold testing (Cu) and UTC at the dose of citric acid that causes 2 or more coughs (C2) (i.e., UTC at C2 - UTC at Cu). |
| Blood oxygen level dependent neural responses (BOLD) | 4 weeks following enrollment BCS+CAP and BCS+Sham participants; enrollment to 1 week post-enrollment for the fMRI control group | Whole-brain fMRI performed during inhalation of capsaicin to trigger urge-to-cough. (NOTE: this measure is only required for those enrolling at Univ. of Colorado) |
| Cough threshold sensory testing (CTT) | From enrollment to 4 weeks following enrollment | Measure of cough sensitivity using progressive doses of inhaled vaporized citric acid. The dose causing 5 or more coughs (C5) is the endpoint. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cough frequency | From enrollment to 11 weeks following enrollment | Ambulatory cough frequency monitoring with a specialized smartwatch, which is worn for 5 days before treatment and 5 days following treatment |
| Newcastle Laryngeal Hypersensitivity Questionnaire (NLHQ) | From enrollment to 19 weeks following enrollment | The NLHQ consists of 14 questions assessing laryngeal paresthesia (i.e., abnormal sensory symptoms) commonly seen in RCC. A lower score indicates greater paresthesia. |
| Voice Handicap Index - 10 (VHI-10) | From enrollment to 19 weeks following enrollment | The VHI-10 assesses the functional impact of dysphonia on life, which is often seen in patients with RCC. The higher the score, the greater the impact of dysphonia on life. |
| Multidimensional Assessment of Interoceptive Awareness (MAIA-2) | From enrollment to 8 weeks following enrollment | The MAIA-2 has 14 questions and is collected via an electronic survey at the Baseline Visit (Visit 1) and Visit 14 (PT1). The primary purpose of MAIA-2 is to assess participants general interoceptive awareness (i.e., awareness of internal bodily sensations). The key domains are noticing, not-distracting, emotional awareness, self-regulation, body listening, and trusting. |
| PROMIS - Global Health | From enrollment to 11 weeks following enrollment | The PROMIS - Global Health assesses general, health-related quality of life. This instrument has 10 questions in the key domains of physical health, mental health, social health, pain, and fatigue. |
| PROMIS - Sleep | From enrollment to 8 weeks following enrollment | The PROMIS - Sleep questionnaire assesses quality of life relating to sleep. It has 10 questions. |
| Patient Global Impression of Severity (PGI-S) | From enrollment to 19 weeks following enrollment | PGI-S is a single, global severity construct that assesses participants overall perception of cough severity. Using the single question of "How would you rate the overall severity of your cough?", participants will rate their perception of cough severity between 0-4 (0 representing "no cough" and 4 representing "very severe". |
| Patient Global Impression of Change (PGI-C) | From enrollment to 19 weeks following enrollment | PGI-C is a single, global change construct used to assess participants overall perception of change following a treatment. It will be asked specifically in regard to treatment for chronic cough using the single question of "Since beginning treatment, how would you describe the overall change in your chronic cough?". Participants will rate their perception of change between 1-7 (1 representing "very much improved", 4 representing "no change", and 7 representing "very much worse". |
| Study Specific Questions (3; 3-SSQ) | From enrollment to 19 weeks following enrollment | There are three, study specific questions that will be collected as a PROM at Baseline Visit (Visit 1), Visit 8, Visit 14/PT1, PT2, and PT3 to assess frequency of daily uncontrollable coughing, frequency of daily urinary incontinence, and frequency of daily urge-to-cough. |
| Leicester Cough Questionnaire (LCQ) | From enrollment to 19 weeks following enrollment | 19-item patient-report outcome measure related to the impact of cough on quality of life |
Countries
United States
Contacts
CONTACTLaurie J Slovarp, PhD
CONTACTMarie Jetté, PhD
PRINCIPAL_INVESTIGATORLaurie J Slovarp, PhD
University of Montana
PRINCIPAL_INVESTIGATORMarie Jetté, PhD
University of Colorado, Denver
PRINCIPAL_INVESTIGATORAmanda Gillespie, PhD
Emory University
Outcome results
None listed