A Pilot Study of Cough Reflex Desensitization for the Treatment of Cough Hypersensitivity Syndrome
Phase: EARLY_PHASE1
Conditions: Cough
Sponsor: University of Montana

 
 
 
STUDY TITLE: Cough Desensitization Therapy for Cough 
Hypersensitivity Syndrome 
 
Clinicaltrials.gov identifier: NCT04256733 
 
Document Date: 2/22/22 
      
 

 
STUDY TITLE: Cough Desensitization Therapy for Cough Hypersensitivity Syndrome 
 
Clinicaltrials.gov identifier: NCT04256733 
 
 
Protocol: 
 
Purpose: 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 epithelium5-9, which contributes 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)10-12 and behavioral cough 
suppression therapy (BCST)13-16, 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 suppression13,17,18. 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 therapy is called cough desensitization therapy (CDT). The advantage of using 
capsaicin as a cough stimulant in the therapy is that it can be diluted to any concentration, which 
allows us to control the strength of the cough stimulant. Current research suggests BCST works by 
reducing cough sensitivity via neuroplasticity, as a result of suppressing cough when an urge-to-cough 
exists.  The theoretical basis for CDT is exactly the same except that aerosolized capsaicin affords 
control over the cough stimulant, so that an urge-to-cough, that is strong enough to be felt but weak 
enough to suppress, can easily be produced. We hypothesize  this treatment will result in a reduction 
in cough-reflex sensitivity, improvement in cough-related quality of life, and reduction in cough 
frequency.  
 
Study design: Single-blind, sham-controlled randomized control trial 
Study population: Non-smoking males or females at least 18 years of age currently suffering from a 
non-productive cough that started at least 8 weeks ago, who meet the following inclusion/exclusion 
criteria:  
1. have seen at least one physician for the cough;  
2. have received medical treatment without success (i.e., refractory chronic cough);  
3. have normal chest x-ray, pulmonary function testing, and laryngoscopy;  
4. not diagnosed with a respiratory or pulmonary condition (e.g., asthma, COPD, 
emphysema, lung cancer, bronchitis);  
5. not currently a smoker; 
6. not taking any of the following medications within one month of enrollment: 
lisinopril/Prinivil/Zestril, captopril/Capoten, enalapril/Epaned/Asotec, ramipril/Altace, 
benazepril/Lotensin, fosinopril/Monopril, moexipril/Univasc, perindopril/Aceon, 
quinapril/Accupril, trandolapril/Mavik; and 
7. willing to sign an informed consent form; 

8. not pregnant and willing to take a pregnancy test before enrollment (if applicable). 
9. Women who are of childbearing age, and have any potential of becoming pregnant, must 
agree to use contraception during the study. 
 
Study duration: Six weeks per participant. 18 months to complete data collection. 
Number participants planned: 20 (10 per group) 
Study procedures: three phases 
 
Phase I: Baseline Outcome Testing 
Pulmonary function testing: Pulmonary function testing (PFT) will be completed using 
standard procedures. A minimum of two trials will be given to ensure reliability. Cough sensory 
testing will only proceed if PFT is normal.  
Cough sensory testing: Standardized procedures that have been established and previously 
approved by the FDA (IND #69642 and #076866) will be used to determine participants' cough 
sensory threshold. All participants will complete spirometry testing before and after cough sensory 
testing. The following diluted capsaicin concentrations: .49, .98, 1.95, 3.9, 7.8, 15.6, 31.2, 62.5, 125, 
250, 500, and 1000 μM will be made prior to testing under the direct supervision of Dr. Sarjubhai 
Patel. Participants will inhale single breaths of capsaicin aerosol through the DeVilbiss 646 nebulizer 
that is connected to a dosimeter (KoKo Digidoser). The single-dose method will be used during 
inhalation trials, with a delivery time of .6 second, which yields .002mL/inhalation. Table 1 shows the 
amounts of capsaicin per concentration that will be given per inhalation.. The initial concentration will 
be .49 μM followed by subsequent doubling doses. We will determine the capsaicin concentration that 
causes two coughs (C2) and five coughs (C5) within 15 seconds of capsaicin inhalation. Capsaicin 
trials will be discontinued once the C5 level is determined, or the 1000 μM dose is given, whichever 
comes first. We will also measure perceived urge-to-cough (UTC) following each inhalation of 
capsaicin on a scale from 0 (no UTC) to 10 (maximum UTC). This testing session will take 
approximately 30 minutes.  
 
Table 1: Amount of capsaicin ingested per inhalation at each concentration.  
Capsaicin 19 
 
g Capsaicin 
Nebulized per 
inhalation 
0.49 
 
2.980e-10 
(.000298 µg) 
0.98 
 
5.970e-10 
1.95 
 
1.193e-9 
3.9 
 
2.386e-9 
7.8 
 
4.772e-9 
15.6 
 
9.544e-9 
31.2 
 
1.908e-8 
62.5 
 
3.817e-8 
125 
 
7.635e-8 
250 
 
1.527e-7 
500 
 
3.054e-7 
625 
 
3.817e-7 

750 
 
4.581e-7 
1000 
 
6.108e-7 
 
Cough frequency testing: Participants will be asked to wear a small digital mp3 audio 
recording device for 24 consecutive hours20. The participant will simply clip the audio recorder to 
his/her belt or place the recorder in a pocket or fanny pack. A small microphone will be attached to the 
participant’s shirt. The recordings will be analyzed by a software program to determine the exact 
frequency of coughs during the 24-hour period. The audio recordings will be deleted after they have 
been analyzed.  The analysis is fully confidential and the recordings are deleted following analysis. 
Dr. Surrinder Birring, who conceptualized the assessment and created the computer program to 
analyze the recordings, named this method the Leicester Cough Monitor. The exact mp3 recorder 
(Sony ICD PX333 digital recorder) and microphone recommended by Dr. Surrinder Birring have 
been purchased for this use. 
Cough-related quality of life (QOL) testing: The Leicester Cough Questionnaire (LCQ)21 will 
be used to measure cough-related QOL. 
 
Phase II: Treatment phase 
Participants will attend treatment sessions 2 times per week for up to three weeks, with at least 3 days 
between each session. Each session will begin with PFT. Treatment will only proceed if PFT is 
normal. During treatment sessions participants will be exposed to aerosolized capsaicin in progressive 
doses while implementing cough suppression strategies. The first capsaicin dose will be one dose 
below each participant’s C2 cough threshold dose. At least one minute will lapse between each 
capsaicin exposure and a sip of water will be allowed between each trial. The capsaicin concentration 
will increase when the participant is able to receive two exposures of the same dose without coughing. 
Each increase of capsaicin will be a doubling dose up to 500 μM. Two concentrations between 500 
and 1000 μM (i.e., 625 and 750 μM) will be used to minimize the large increase between 500 and 
1000 μM. No more than 6 inhalations of capsaicin will be given in any single session and no more 
than 3 inhalations above 500 μM will be given in a single session. Each session will last 35-45 
minutes (depending on scheduling constraints). We will measure the participant's number of coughs, 
urge-to-cough, and discomfort level (0-10) following each capsaicin inhalation.  
 
Phase III: Post-Treatment Outcome Testing  
Cough-sensory, cough-frequency, and cough-related QOL testing, as outlined in Phase I, will be 
completed at one week and three-weeks following the final treatment session. During cough-sensory 
and cough-frequency testing, participants will be instructed to NOT attempt to suppress their cough.  
 
 
Statistical Analysis Plan: 
 
The data will be analyzed with linear or generalized linear mixed models with a random subject effect 
to account for three repeated measurements (baseline, PT1, and PT2) on each participant, with fixed 
effects for the three time points and group (treatment, placebo) and their interaction, incorporated.