Cough Desensitization Therapy for Cough Hypersensitivity Syndrome

A Pilot Study of Cough Reflex Desensitization for the Treatment of Cough Hypersensitivity Syndrome

The purpose of this study is to investigate a modified behavioral treatment for chronic cough due to cough hypersensitivity syndrome (CHS). This type of CC is a non-productive cough that is due, in part, to over-expression of transient receptor potential vanilliod (TRPV) receptors in the airway epithelium, which contribute to a dry cough elicited by typically non-tussive stimuli (e.g., cold air, smells) or by low doses of tussive stimuli (e.g., smoke). Currently available treatment options are limited to neuromodulator medications (e.g., gabapentin, amytriptiline) and behavioral cough suppression therapy (BCST), neither of which is 100% effective. The primary component of BCST is teaching patients to suppress their cough in the presence of an urge-to-cough. Studies have confirmed a reduction in cough sensitivity (as tested with inhaled capsaicin) following 1-4 weeks of successful cough suppression. However, patients with severe CHS are not able to suppress their cough in the presence of uncontrollable environmental stimuli and, hence, do not respond well to the therapy. The purpose of this study is to determine the potential of treating CHS by implementing BCST while stimulating cough with progressive concentrations of inhaled diluted aerosolized capsaicin. The investigators hypothesize this treatment will result in a reduction in cough-reflex sensitivity, cough-related quality of life, and cough frequency.

Study Overview

• Status: Completed
• Conditions: Cough
• Intervention / Treatment: Biological: Supra-threshold and progressive doses of diluted capsaicin via a Koko Digidoser nebulizer; Biological: Sub-threshold doses of diluted capsiacin via a KoKo Digidoser nebulizer

Detailed Description

The study will be a randomized, placebo-controlled, blinded study. It will take place in three phases, across 7 weeks.

WEEK 1: BASELINE TESTING AND TRAINING (approximate time = 1 hour).

1. Cough sensitivity testing: Standardized procedures that have been established and approved by the FDA will be used to determine cough sensitivity. Participants will inhale capsaicin vapor (a known cough stimulant) through a nebulizer with dosimeter, that delivers a specific dose of capsaicin in a mist form. They will inhale doubling doses of capsaicin mist from .49 micromolar to 1000 micromolar. The testing will be stopped when the investigators find the dose that causes five coughs or after giving the 1000 micromolar dose, whichever comes first. This testing will take approximately 30 minutes.
2. Urge-to-cough (UTC) testing: Participants be asked to report their UTC on a scale from 0 (no UTC) to 10 (maximum UTC) after each mist of capsaicin and after being presented with the following stimulants/tasks that cause some people to cough: perfume, bleach, vinegar, wood chips, laundry soap, cleaning wipe, deep and fast breath through the mouth, sustained voicing, reading a 55 word passage, and yelling a short phrase). This testing will take about 10 minutes.
3. Cough-related quality of life: Participants will complete the Leicester Cough Questionnaire which is a 23-item validated questionnaire designed to measure cough-related quality of life. It will take about 5 minutes.
4. Cough suppression training. Participants will be trained in cough suppression strategies. These strategies include 1) relaxed throat breathing where they inhale quickly through the nose and exhale through tightly pursed lips, and 2) cough suppression swallow, which involves swallowing saliva or a sip of water with as much effort as possible and while pressing hands together tightly. This training will take approximately 15 minutes.
5. Cough frequency testing: Participants will carry a small audio recording device with a small microphone that attaches to the participant's shirt for 24 hours. The recording device will be in a small carrying case (about half the size of a typical cell phone) that can clip to a belt or waistband. Participants will return the recording device to the investigators at or before the first treatment visit (see below). The audio recording will be analyzed by computer software that counts the number of coughs in the 24-hour period. (NOTE: The audio recording will not be listened to by any PERSON and the recording will be deleted after it is analyzed by the computer software.)

(Following baseline testing, participants will be randomly assigned to either the treatment group or placebo group.)

WEEKS 2-4: TREATMENT. Participants will attend treatment sessions twice per week for three weeks. Participants will use the breathing strategies following inhalation of either progressive doses of diluted capsaicin (experimental condition) or repeated exposures to a single sub-threshold concentration of diluted capsaicin (placebo condition). Participants will do this no more than twelve times per session. Each session will take approximately 45 minutes. If a participant misses a treatment session, the investigators will attempt to re-schedule that session. Each participant must complete at least five of treatment sessions to remain in the study.

WEEKS 5 AND 7: POST-TREATMENT TESTING. Outcome measures, as in the baseline phase, will be take at one-week and three-weeks post-treatment. The LCQ will be measured again at three-months post-treatment.

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Montana
    • Missoula, Montana, United States, 59812
      • University of Montana

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 95 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. At least 18 years of age
2. Currently suffering from a cough that started at least 8 weeks ago
3. Have seen at least one physician for the cough and have received medical treatment without success
4. Normal chest x-ray, pulmonary function testing, and laryngoscopy (laryngoscopy completed by your physician or the speech-language pathologist)
5. Have undergone behavioral cough suppression therapy without full resolution of cough
6. Willing to take a pregnancy test before enrollment (if applicable)
7. Willing to use contraception during the study (if applicable)
8. Willing to sign an informed consent form

Exclusion Criteria:

1. Under 18 years of age
2. Currently a smoker of any substance
3. Pregnant or attempting to become pregnant
4. Diagnosed with a respiratory or pulmonary condition (e.g., asthma, COPD, emphysema, lung cancer, bronchitis)
5. Taken any of the following medications within the past month: lisinopril/Prinivil/Zestril, captopril/Capoten, enalapril/Epaned/Asotec, ramipril/Altace, benazepril/Lotensin, fosinopril/Monopril, moexipril/Univasc, perindopril/Aceonm, quinapril/Accupril, trandolapril/Mavik

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Supra-threshold capsaicin; Participants will be exposed to progressively increasing concentrations of aerosolized capsaicin (the ingredient in chili peppers that makes them spicy, and a known cough stimulant) to stimulate an urge-to-cough. Participants will be coached to implement cough suppression strategies following each exposure.	Biological: Supra-threshold and progressive doses of diluted capsaicin via a Koko Digidoser nebulizer; Participants will be exposured to increasing doses of aerosolized capsaicin (a known cough stimulant) through the Koko Digidoser nebulizer, while implementing behavioral cough suppression strategies. The concentration of capsaicin will increase incrementally as tolerated, as long as participants are still able to suppress cough. The concentration will never exceed 1000 micromolar. Participants will attend 6 treatment sessions and be given up to 12 exposures per treatment session. Participants will be encouraged to use cough suppression strategies outside of treatment sessions as much as possible to attempt to suppress cough.
Placebo Comparator: Sub-threshold capsaicin; Participants will be exposed repeatedly to a single sub-threshold dose of aerosolized capsaicin through a nebulizer during treatment. This sub-threshold dose will elicit minimal or no urge-to-cough.	Biological: Sub-threshold doses of diluted capsiacin via a KoKo Digidoser nebulizer; Participants will be repeatedly exposed to a sub-threshold dose of aerosolized capsaicin through the KoKo Digidoser nebulizer during treatment sessions. Participants will attend 6 treatment sessions and be given up to 12 exposures per treatment session. Participants will be encouraged to use cough suppression strategies outside of treatment sessions as much as possible to attempt to suppress cough.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Leicester Cough Questionnaire (LCQ)	The Leicester Cough Questionnaire (LCQ) is a 19-item validated patient-report questionnaire that measures the impact of cough on quality of life. It takes about 5 minutes to complete and results in three domain scores (Social, Psychological, and Physical), and one Total score. Domain scores are averages of the questions that make up each domain. Minimum and maximum domain scores are 1 and 7, respectively. The domain scores are summed to determine the Total score, which can range from 3 to 21. A higher score means less impact on quality of life. The change in LCQ was determined by subtracting the Total LCQ score at baseline from the Total LCQ score at 3 weeks post-treatment. A positive LCQ change score indicates an improvement.	The LCQ will be measured before treatment and three weeks following treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Urge-to-Cough Testing	Urge-to-cough (UTC) testing involves presenting participants to various scents and vocal and breathing tasks (12 tasks in total) and asking them to rate their maximum perceived UTC on a scale from 0 (no UTC) to 10 (maximum UTC). The UTC score for each testing session is the sum of the the UTC scores from each individual task. This results in a possible score range from 0 (no UTC on any tasks) to 120 (score of 10 on every UTC task). UTC change is determined by subtracting the UTC score on each task at baseline from the UTC score for each task at 3 weeks post-treatment and then summing those scores. A negative UTC change score indicates the UTC score was lower post-treatment relative to baseline, which indicates an improvement.	Urge-to-cough will be measured before treatment and three weeks following the final treatment session
Urge-to-Cough Testing: Cough Frequency	During UTC testing, participants are exposed to various scents and vocal and breathing tasks and the number of coughs elicited during and immediately following each task are counted. A cough frequency score for each testing session is the sum of the number of coughs counted during each task. Change in cough frequency is calculated by subtracting the baseline cough frequency from the 3 week post-treatment cough frequency. A negative score indicates cough frequency was less after treatment, which indicates an improvement.	Baseline and 3 weeks post-treatment

Collaborators and Investigators

• Sponsor: University of Montana
• Investigators: Principal Investigator: Laurie J Slovarp, PhD, University of Montana

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2019
• Primary Completion (Actual): November 30, 2020
• Study Completion (Actual): February 13, 2021

Study Registration Dates

• First Submitted: September 24, 2019
• First Submitted That Met QC Criteria: February 4, 2020
• First Posted (Actual): February 5, 2020

Study Record Updates

• Last Update Posted (Estimated): March 4, 2024
• Last Update Submitted That Met QC Criteria: August 3, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: chronic cough; refractory chronic cough; cough hypersensitivity syndrome
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Respiration Disorders; Signs and Symptoms, Respiratory; Hypersensitivity; Cough; Physiological Effects of Drugs; Peripheral Nervous System Agents; Sensory System Agents; Dermatologic Agents; Antipruritics; Capsaicin
• Other Study ID Numbers: 188-88

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No