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

Обзор

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.

Подробное описание

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).

Вмешательства

• Поведенческое BCS+inactive
  Behavioral cough suppression therapy plus inactive inhaled drug. Treatment given twice per week for 12 sessions.
• Комбинированный продукт BCS+active
  Behavioral cough suppression therapy combined with inhaled natural substance known to desensitize sensory nerves. Treatment given twice per week for 12 sessions.

Первичные конечные точки

• Cough threshold sensory testing (CTT) [Срок оценки: From enrollment to 4 weeks following enrollment]
• Cough suppression threshold difference (CS Thresh Diff) [Срок оценки: From enrollment to 4 weeks following enrollment]
• Urge-to-Cough Sensory Motor Threshold Difference (UTC S-M Thresh Diff) [Срок оценки: From enrollment to 4 weeks following enrollment]
• Blood oxygen level dependent neural responses (BOLD) [Срок оценки: 4 weeks following enrollment BCS+CAP and BCS+Sham participants; enrollment to 1 week post-enrollment for the fMRI control group]

Вторичные конечные точки (10)

• Leicester Cough Questionnaire (LCQ) [Срок оценки: From enrollment to 19 weeks following enrollment]
• Cough frequency [Срок оценки: From enrollment to 11 weeks following enrollment]
• Newcastle Laryngeal Hypersensitivity Questionnaire (NLHQ) [Срок оценки: From enrollment to 19 weeks following enrollment]
• Voice Handicap Index - 10 (VHI-10) [Срок оценки: From enrollment to 19 weeks following enrollment]
• Multidimensional Assessment of Interoceptive Awareness (MAIA-2) [Срок оценки: From enrollment to 8 weeks following enrollment]
• PROMIS - Global Health [Срок оценки: From enrollment to 11 weeks following enrollment]
• PROMIS - Sleep [Срок оценки: From enrollment to 8 weeks following enrollment]
• Patient Global Impression of Severity (PGI-S) [Срок оценки: From enrollment to 19 weeks following enrollment]
• Patient Global Impression of Change (PGI-C) [Срок оценки: From enrollment to 19 weeks following enrollment]
• Study Specific Questions (3; 3-SSQ) [Срок оценки: From enrollment to 19 weeks following enrollment]

Критерии участия

Критерии включения

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.

Критерии исключения

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 exclusion criteria will apply to participants who will undergo fMRI:

• Presence of metal implants, devices or fragments (e.g., shrapnel) in the body
• Claustrophobia

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Простое слепое

Основная цель

Лечение

Центры проведения

США · 3 центра

• University of Colorado Anschutz Medical Campus — Aurora
• Emory University — Atlanta
• University of Montana — Missoula

Публикации

• Losche D, Furst W, Falk M, Weickert H. [Preparation of a cytostatic-containing bone cement]. Pharmazie. 1987 Feb;42(2):97-9. German. PMID 3602068
• Moe AAK, Singh N, Dimmock M, Cox K, McGarvey L, Chung KF, McGovern AE, McMahon M, Richards AL, Farrell MJ, Mazzone SB. Brainstem processing of cough sensory inputs in chronic cough hypersensitivity. EBioMedicine. 2024 Feb;100:104976. doi: 10.1016/j.ebiom.2024.104976. Epub 2024 Jan 19. PMID 38244293
• Slovarp LJ, Reynolds JE, Tolbert S, Campbell S, Welby S, Morkrid P. Cough desensitization treatment for patients with refractory chronic cough: results of a second pilot randomized control trial. BMC Pulm Med. 2023 Apr 28;23(1):148. doi: 10.1186/s12890-023-02423-6. PMID 37118696
• Slovarp L, Reynolds JE, Bozarth-Dailey E, Popp S, Campbell S, Morkrid P. Cough desensitization treatment: A randomized, sham-controlled pilot trial for patients with refractory chronic cough. Respir Med. 2022 Mar;193:106739. doi: 10.1016/j.rmed.2022.106739. Epub 2022 Jan 15. PMID 35091204
• Chamberlain SA, Garrod R, Douiri A, Masefield S, Powell P, Bucher C, Pandyan A, Morice AH, Birring SS. The impact of chronic cough: a cross-sectional European survey. Lung. 2015 Jun;193(3):401-8. doi: 10.1007/s00408-015-9701-2. Epub 2015 Mar 19. PMID 25787221

Идентификаторы

NCT: NCT06960759 · 25-0206

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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