Cough
Conditions
Keywords
chronic cough, refractory chronic cough, cough hypersensitivity syndrome
Brief summary
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.
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.
Interventions
BIOLOGICALSupra-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.
BIOLOGICALSub-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.
Sponsors
University of Montana
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Masking description
Participants and outcome assessors will be blinded to group assignment (active treatment vs placebo).
Intervention model description
One group will receive the placebo treatment while the second group receives the active treatment.
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Leicester Cough Questionnaire (LCQ) | The LCQ will be measured before treatment and three weeks following treatment | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Urge-to-Cough Testing | Urge-to-cough will be measured before treatment and three weeks following the final treatment session | 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 Testing: Cough Frequency | Baseline and 3 weeks post-treatment | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
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. | 11 |
| 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.
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. | 8 |
| Total | 19 |
Baseline characteristics
| Characteristic | Total | Sub-threshold Capsaicin | Supra-threshold Capsaicin |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 9 Participants | 3 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 5 Participants | 5 Participants |
| Age, Continuous | 63.9 Years STANDARD_DEVIATION 14.5 | 66 Years STANDARD_DEVIATION 13.6 | 62.25 Years STANDARD_DEVIATION 15.9 |
| Leicester Cough Questionnaire (LCQ) | 12.56 units on a scale STANDARD_DEVIATION 2.83 | 12.43 units on a scale STANDARD_DEVIATION 2.69 | 12.65 units on a scale STANDARD_DEVIATION 3.11 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 19 Participants | 8 Participants | 11 Participants |
| Region of Enrollment United States | 19 participants | 8 participants | 11 participants |
| Sex: Female, Male Female | 17 Participants | 6 Participants | 11 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 0 Participants |
| Urge-to-cough (UTC) test: cough frequency sum | 12.36 sum cough frequency STANDARD_DEVIATION 16.64 | 9.67 sum cough frequency STANDARD_DEVIATION 11.76 | 14.38 sum cough frequency STANDARD_DEVIATION 20.12 |
| Urge-to-cough (UTC) test: UTC sum | 16.68 units on a scale STANDARD_DEVIATION 13.65 | 14.67 units on a scale STANDARD_DEVIATION 11.5 | 18.19 units on a scale STANDARD_DEVIATION 15.67 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 8 |
| other Total, other adverse events | 0 / 11 | 0 / 8 |
| serious Total, serious adverse events | 0 / 11 | 0 / 8 |
Outcome results
Primary
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.
Time frame: The LCQ will be measured before treatment and three weeks following treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Supra-threshold Capsaicin | Leicester Cough Questionnaire (LCQ) | 3.2 score on a scale | Standard Deviation 1.78 |
| Sub-threshold Capsaicin | Leicester Cough Questionnaire (LCQ) | 2.06 score on a scale | Standard Deviation 2.48 |
p-value: 0.23Mixed Models Analysis
Secondary
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.
Time frame: Urge-to-cough will be measured before treatment and three weeks following the final treatment session
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Supra-threshold Capsaicin | Urge-to-Cough Testing | -13.75 units on a scale | Standard Deviation 10.45 |
| Sub-threshold Capsaicin | Urge-to-Cough Testing | -8.8 units on a scale | Standard Deviation 10.34 |
p-value: 0.57Mixed Models Analysis
Secondary
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.
Time frame: Baseline and 3 weeks post-treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Supra-threshold Capsaicin | Urge-to-Cough Testing: Cough Frequency | -14.00 coughs | Standard Deviation 20.1 |
| Sub-threshold Capsaicin | Urge-to-Cough Testing: Cough Frequency | -6.33 coughs | Standard Deviation 9.16 |
p-value: <0.0001Mixed Models Analysis