Trial Outcomes & Findings for Functional Magnetic Resonance Imaging of ATP Cough in Chronic Cough Patients (NCT NCT03722849)

Results Overview

fMRI will be used to determine the location and magnitude of neural responses in the brainstem during Capsaicin inhalation: in particular, the nucleus of the solitary tract and the paratrigeminal nucleus. fMRI non-invasively measures Blood Oxygen Level Dependent (BOLD) signals in the brain which can be used to identify regions of the brain that increase activity associated with the inhaled stimuli. BOLD signals detected are to be reported as % BOLD signal change in response to Capsaicin greater than control saline.

Recruitment status

COMPLETED

Study phase

NA

Target enrollment

58 participants

Primary outcome timeframe

fMRI was performed in a single session on the day of the cough challenge testing session and not more than seven days after.

Results posted on

2024-08-22

Participant Flow

All participants were initially screened via telephone interviews for inclusion and exclusion criteria and gave written, informed consent prior to study enrolment. Refractory and unexplained chronic cough were diagnosed by a respiratory or laryngology specialist or general practitioner and inclusion required cough of at least 6 months duration with no abnormalities on chest X-ray or CT scan.

Participant milestones

Participant milestones
Measure	Chronic Cough Participant Twenty-nine (29) Idiopathic chronic cough patients, defined as refractory to disease modifying therapies (eg anti-asthma medications), were recruited. Participants attended two sessions. In the first they inhaled in a single breath nebulized solutions of increasing doses of Adenosine Triphosphate (ATP; 0.2-300 microM) and capsaicin (0.5-125 microM) to determine their individual cough and urge-to-cough thresholds. In the second session, participants underwent functional brain imaging (fMRI) for 1 hour while inhaling over 24 seconds randomly administered nebulized solutions of saline, or threshold doses of ATP or capsaicin.	Healthy Control Participant Twenty-nine (29) appropriately age and sex matched healthy non-smoking individuals were recruited as the comparison group. Participants attended two sessions. In the first they inhaled in a single breath nebulized solutions of increasing doses of Adenosine Triphosphate (ATP; 0.2-300 microM) and capsaicin (0.5-125 microM) to determine their individual cough and urge-to-cough thresholds. In the second session, participants underwent functional brain imaging (fMRI) for 1 hour while inhaling over 24 seconds randomly administered nebulized solutions of saline, or threshold doses of ATP or capsaicin.
Overall Study STARTED	29	29
Overall Study COMPLETED	28	28
Overall Study NOT COMPLETED	1	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Chronic Cough Participant Twenty-nine (29) Idiopathic chronic cough patients, defined as refractory to disease modifying therapies (eg anti-asthma medications), were recruited. Participants attended two sessions. In the first they inhaled in a single breath nebulized solutions of increasing doses of Adenosine Triphosphate (ATP; 0.2-300 microM) and capsaicin (0.5-125 microM) to determine their individual cough and urge-to-cough thresholds. In the second session, participants underwent functional brain imaging (fMRI) for 1 hour while inhaling over 24 seconds randomly administered nebulized solutions of saline, or threshold doses of ATP or capsaicin.	Healthy Control Participant Twenty-nine (29) appropriately age and sex matched healthy non-smoking individuals were recruited as the comparison group. Participants attended two sessions. In the first they inhaled in a single breath nebulized solutions of increasing doses of Adenosine Triphosphate (ATP; 0.2-300 microM) and capsaicin (0.5-125 microM) to determine their individual cough and urge-to-cough thresholds. In the second session, participants underwent functional brain imaging (fMRI) for 1 hour while inhaling over 24 seconds randomly administered nebulized solutions of saline, or threshold doses of ATP or capsaicin.
Overall Study Withdrawal by Subject	1	1

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Chronic Cough Participant n=29 Participants Twenty-nine (29) Idiopathic chronic cough patients, defined as refractory to disease modifying therapies (eg anti-asthma medications), were recruited. Participants attended two sessions. In the first they inhaled in a single breath nebulized solutions of increasing doses of Adenosine Triphosphate (ATP; 0.2-300 microM) and capsaicin (0.5-125 microM) to determine their individual cough and urge-to-cough thresholds. In the second session, participants underwent functional brain imaging (fMRI) for 1 hour while inhaling over 24 seconds randomly administered nebulized solutions of saline, or threshold doses of ATP or capsaicin.	Healthy Control Participant n=29 Participants Twenty-nine (29) appropriately age and sex matched healthy non-smoking individuals were recruited as the comparison group. Participants attended two sessions. In the first they inhaled in a single breath nebulized solutions of increasing doses of Adenosine Triphosphate (ATP; 0.2-300 microM) and capsaicin (0.5-125 microM) to determine their individual cough and urge-to-cough thresholds. In the second session, participants underwent functional brain imaging (fMRI) for 1 hour while inhaling over 24 seconds randomly administered nebulized solutions of saline, or threshold doses of ATP or capsaicin.	Total n=58 Participants Total of all reporting groups
Age, Continuous	60.6 years STANDARD_DEVIATION 12.2 • n=29 Participants	59.7 years STANDARD_DEVIATION 12.0 • n=29 Participants	60.1 years STANDARD_DEVIATION 12 • n=58 Participants
Sex: Female, Male Female	19 Participants n=29 Participants	19 Participants n=29 Participants	38 Participants n=58 Participants
Sex: Female, Male Male	10 Participants n=29 Participants	10 Participants n=29 Participants	20 Participants n=58 Participants
Race and Ethnicity Not Collected	—	—	0 Participants Race and Ethnicity were not collected from any participant.
Region of Enrollment Australia	29 participants n=29 Participants	29 participants n=29 Participants	58 participants n=58 Participants
Hull Cough Hypersensitivity Questionnaire (HARQ) score	33.1 units on a scale STANDARD_DEVIATION 13.1 • n=29 Participants	2.3 units on a scale STANDARD_DEVIATION 2.8 • n=29 Participants	17.5 units on a scale STANDARD_DEVIATION 18.1 • n=58 Participants
Newcastle Laryngeal Hypersensitivity Questionnaire (LHQ) score	14.8 units on a scale STANDARD_DEVIATION 3.0 • n=29 Participants	20.1 units on a scale STANDARD_DEVIATION 1.1 • n=29 Participants	17.5 units on a scale STANDARD_DEVIATION 3.5 • n=58 Participants
Leicester Cough Questionnaire (LCQ) score	13.9 units on a scale STANDARD_DEVIATION 3.6 • n=29 Participants	20.8 units on a scale STANDARD_DEVIATION 0.3 • n=29 Participants	17.3 units on a scale STANDARD_DEVIATION 4.5 • n=58 Participants

PRIMARY outcome

Timeframe: fMRI was performed in a single session on the day of the cough challenge testing session and not more than seven days after.

Population: Cough participants displayed characteristic signs and symptoms of refractory chronic cough. 1 participant from each group withdrew prior to completion of the primary endpoint investigation.

fMRI will be used to determine the location and magnitude of neural responses in the brainstem during Capsaicin inhalation: in particular, the nucleus of the solitary tract and the paratrigeminal nucleus. fMRI non-invasively measures Blood Oxygen Level Dependent (BOLD) signals in the brain which can be used to identify regions of the brain that increase activity associated with the inhaled stimuli. BOLD signals detected are to be reported as % BOLD signal change in response to Capsaicin greater than control saline.

Outcome measures

Outcome measures
Measure	Chronic Cough Participant n=28 Participants Twenty-nine (29) refractory chronic cough patients, defined as refractory to disease modifying therapies (eg anti-asthma medications), were recruited. Participants attended two sessions. In the first they inhaled in a single breath nebulized solutions of increasing doses of Adenosine Triphosphate (ATP; 0.2-300 microM) and capsaicin (0.5-125 microM) to determine their individual cough and urge-to-cough thresholds. In the second session, participants underwent functional brain imaging (fMRI) for 1 hour while inhaling over 24 seconds randomly administered nebulized solutions of saline, or threshold doses of ATP or capsaicin.	Healthy Control Participant n=28 Participants Twenty-nine (29) appropriately age and sex matched healthy non-smoking individuals were recruited as the comparison group. Participants attended two sessions. In the first they inhaled in a single breath nebulized solutions of increasing doses of Adenosine Triphosphate (ATP; 0.2-300 microM) and capsaicin (0.5-125 microM) to determine their individual cough and urge-to-cough thresholds. In the second session, participants underwent functional brain imaging (fMRI) for 1 hour while inhaling over 24 seconds randomly administered nebulized solutions of saline, or threshold doses of ATP or capsaicin.
Brainstem Neural Activations to Capsaicin %BOLD signal Change: Nucleus of the Solitary Tract	0.09 Percentage change in BOLD signal Standard Deviation 0.60	0.39 Percentage change in BOLD signal Standard Deviation 0.47
Brainstem Neural Activations to Capsaicin %BOLD signal Change: Paratrigeminal Nucleus	-0.14 Percentage change in BOLD signal Standard Deviation 0.69	0.44 Percentage change in BOLD signal Standard Deviation 1.06

PRIMARY outcome

Timeframe: fMRI was performed in a single session on the day of the cough challenge testing session and not more than seven days after.

Population: Cough participants displayed characteristic signs and symptoms of refractory chronic cough. 1 participant from each group withdrew prior to completion of the primary endpoint investigation.

fMRI will be used to determine the location and magnitude of neural responses in the brainstem during ATP inhalation: in particular, the nucleus of the solitary tract and the paratrigeminal nucleus. fMRI non-invasively measures Blood Oxygen Level Dependent (BOLD) signals in the brain which can be used to identify regions of the brain that increase activity associated with the inhaled stimuli. BOLD signals detected are to be reported as % BOLD signal change in response to ATP greater than control saline.

Outcome measures

Outcome measures
Measure	Chronic Cough Participant n=28 Participants Twenty-nine (29) refractory chronic cough patients, defined as refractory to disease modifying therapies (eg anti-asthma medications), were recruited. Participants attended two sessions. In the first they inhaled in a single breath nebulized solutions of increasing doses of Adenosine Triphosphate (ATP; 0.2-300 microM) and capsaicin (0.5-125 microM) to determine their individual cough and urge-to-cough thresholds. In the second session, participants underwent functional brain imaging (fMRI) for 1 hour while inhaling over 24 seconds randomly administered nebulized solutions of saline, or threshold doses of ATP or capsaicin.	Healthy Control Participant n=28 Participants Twenty-nine (29) appropriately age and sex matched healthy non-smoking individuals were recruited as the comparison group. Participants attended two sessions. In the first they inhaled in a single breath nebulized solutions of increasing doses of Adenosine Triphosphate (ATP; 0.2-300 microM) and capsaicin (0.5-125 microM) to determine their individual cough and urge-to-cough thresholds. In the second session, participants underwent functional brain imaging (fMRI) for 1 hour while inhaling over 24 seconds randomly administered nebulized solutions of saline, or threshold doses of ATP or capsaicin.
Brainstem Neural Activations to ATP %BOLD signal Change: Nucleus of the Solitary Tract	0.04 Percent change in BOLD signal Standard Deviation 0.47	0.28 Percent change in BOLD signal Standard Deviation 0.58
Brainstem Neural Activations to ATP %BOLD signal Change: Paratrigeminal Nucleus	0.01 Percent change in BOLD signal Standard Deviation 0.65	0.58 Percent change in BOLD signal Standard Deviation 0.71

SECONDARY outcome

Timeframe: Thresholds for cough sensitivity were measured during a 1 hr session prior to fMRI scanning

Population: Cough participants displayed characteristic signs and symptoms of refractory chronic cough.

Participant responses (cough and the urge-to-cough) evoked by Capsaicin will be measured by counting audible coughs to doubling doses of Capsaicin and by asking participants to rate their perception of urge-to-cough using visual analogue scales (VAS) to each dose. Thresholds for cough sensitivity are to be reported as microM. Cu is the threshold dose required to elicit a non-zero urge-to-cough rating. C2 is the threshold dose required to elicit two audible coughs. Smax is the largest dose that could be inhaled for 24s without eliciting an audible cough. fMRI dose was the dose used during fMRI scanning.

Outcome measures

Outcome measures
Measure	Chronic Cough Participant n=29 Participants Twenty-nine (29) refractory chronic cough patients, defined as refractory to disease modifying therapies (eg anti-asthma medications), were recruited. Participants attended two sessions. In the first they inhaled in a single breath nebulized solutions of increasing doses of Adenosine Triphosphate (ATP; 0.2-300 microM) and capsaicin (0.5-125 microM) to determine their individual cough and urge-to-cough thresholds. In the second session, participants underwent functional brain imaging (fMRI) for 1 hour while inhaling over 24 seconds randomly administered nebulized solutions of saline, or threshold doses of ATP or capsaicin.	Healthy Control Participant n=29 Participants Twenty-nine (29) appropriately age and sex matched healthy non-smoking individuals were recruited as the comparison group. Participants attended two sessions. In the first they inhaled in a single breath nebulized solutions of increasing doses of Adenosine Triphosphate (ATP; 0.2-300 microM) and capsaicin (0.5-125 microM) to determine their individual cough and urge-to-cough thresholds. In the second session, participants underwent functional brain imaging (fMRI) for 1 hour while inhaling over 24 seconds randomly administered nebulized solutions of saline, or threshold doses of ATP or capsaicin.
Behavioral Responses During Cough Challenge Testing: Cough Sensitivity to Capsaicin Capsaicin Urge to Cough threshold Cu	0.91 microM Standard Error 5.25	2.00 microM Standard Error 2.75
Behavioral Responses During Cough Challenge Testing: Cough Sensitivity to Capsaicin Capsaicin Cough threshold C2	3.80 microM Standard Error 4.90	12.89 microM Standard Error 2.75
Behavioral Responses During Cough Challenge Testing: Cough Sensitivity to Capsaicin Capsaicin maximum tolerable dose Smax	0.91 microM Standard Error 4.27	3.02 microM Standard Error 3.47
Behavioral Responses During Cough Challenge Testing: Cough Sensitivity to Capsaicin Capsaicin fMRI dose	0.79 microM Standard Error 4.17	1.66 microM Standard Error 3.39

SECONDARY outcome

Timeframe: Thresholds for cough sensitivity were measured during a 1 hr session prior to fMRI scanning

Population: Cough participants displayed characteristic signs and symptoms of refractory chronic cough.

Participant responses (cough and the urge-to-cough) evoked by ATP will be measured by counting audible coughs to doubling doses of ATP and by asking participants to rate their perception of urge-to-cough using visual analogue scales (VAS) to each dose. Thresholds for cough sensitivity are to be reported as milliM. Cu is the threshold dose required to elicit a non-zero urge-to-cough rating. C2 is the threshold dose required to elicit two audible coughs. Smax is the largest dose that could be inhaled for 24s without eliciting an audible cough. fMRI dose was the dose used during fMRI scanning.

Outcome measures

Outcome measures
Measure	Chronic Cough Participant n=29 Participants Twenty-nine (29) refractory chronic cough patients, defined as refractory to disease modifying therapies (eg anti-asthma medications), were recruited. Participants attended two sessions. In the first they inhaled in a single breath nebulized solutions of increasing doses of Adenosine Triphosphate (ATP; 0.2-300 microM) and capsaicin (0.5-125 microM) to determine their individual cough and urge-to-cough thresholds. In the second session, participants underwent functional brain imaging (fMRI) for 1 hour while inhaling over 24 seconds randomly administered nebulized solutions of saline, or threshold doses of ATP or capsaicin.	Healthy Control Participant n=29 Participants Twenty-nine (29) appropriately age and sex matched healthy non-smoking individuals were recruited as the comparison group. Participants attended two sessions. In the first they inhaled in a single breath nebulized solutions of increasing doses of Adenosine Triphosphate (ATP; 0.2-300 microM) and capsaicin (0.5-125 microM) to determine their individual cough and urge-to-cough thresholds. In the second session, participants underwent functional brain imaging (fMRI) for 1 hour while inhaling over 24 seconds randomly administered nebulized solutions of saline, or threshold doses of ATP or capsaicin.
Behavioral Responses During Cough Challenge Testing: Cough Sensitivity to ATP ATP Urge to Cough threshold Cu	1.29 milliM Standard Error 4.27	2.75 milliM Standard Error 3.63
Behavioral Responses During Cough Challenge Testing: Cough Sensitivity to ATP ATP Cough threshold C2	5.75 milliM Standard Error 7.08	57.54 milliM Standard Error 4.79
Behavioral Responses During Cough Challenge Testing: Cough Sensitivity to ATP ATP maximum tolerable dose Smax	2.82 milliM Standard Error 5.75	19.95 milliM Standard Error 5.89
Behavioral Responses During Cough Challenge Testing: Cough Sensitivity to ATP ATP fMRI dose	2.82 milliM Standard Error 5.50	12.02 milliM Standard Error 4.47

SECONDARY outcome

Timeframe: Urge-to-cough ratings were reported during the 1 hour cough challenge testing session and during the subsequent fMRI scanning session

Population: Cough participants displayed characteristic signs and symptoms of refractory chronic cough.

Participant responses (cough and the urge-to-cough) evoked by ATP will be measured by counting audible coughs to doubling doses of ATP and by asking participants to rate their perception of urge-to-cough using visual analogue scales (VAS) to each dose.Urge-to-cough score is reported by the participant using a Bog scale ranging from 0 (no urge) to 10 (most intense urge imaginable) where the higher score, the worse the outcome. Cu is the threshold dose required to elicit a non-zero urge-to-cough rating. C2 is the threshold dose required to elicit two audible coughs. Smax is the largest dose that could be inhaled for 24s without eliciting an audible cough. fMRI dose was the dose used during fMRI scanning.

Outcome measures

Outcome measures
Measure	Chronic Cough Participant n=29 Participants Twenty-nine (29) refractory chronic cough patients, defined as refractory to disease modifying therapies (eg anti-asthma medications), were recruited. Participants attended two sessions. In the first they inhaled in a single breath nebulized solutions of increasing doses of Adenosine Triphosphate (ATP; 0.2-300 microM) and capsaicin (0.5-125 microM) to determine their individual cough and urge-to-cough thresholds. In the second session, participants underwent functional brain imaging (fMRI) for 1 hour while inhaling over 24 seconds randomly administered nebulized solutions of saline, or threshold doses of ATP or capsaicin.	Healthy Control Participant n=29 Participants Twenty-nine (29) appropriately age and sex matched healthy non-smoking individuals were recruited as the comparison group. Participants attended two sessions. In the first they inhaled in a single breath nebulized solutions of increasing doses of Adenosine Triphosphate (ATP; 0.2-300 microM) and capsaicin (0.5-125 microM) to determine their individual cough and urge-to-cough thresholds. In the second session, participants underwent functional brain imaging (fMRI) for 1 hour while inhaling over 24 seconds randomly administered nebulized solutions of saline, or threshold doses of ATP or capsaicin.
Behavioral Responses to Cough Challenge Testing: Urge to Cough Ratings to Capsaicin and ATP Capsaicin Urge to Cough rating at C2	4.48 Score on a scale Standard Error 2.32	6.80 Score on a scale Standard Error 2.29
Behavioral Responses to Cough Challenge Testing: Urge to Cough Ratings to Capsaicin and ATP Capsaicin Urge to Cough rating at Cu	2.07 Score on a scale Standard Error 2.03	1.61 Score on a scale Standard Error 1.47
Behavioral Responses to Cough Challenge Testing: Urge to Cough Ratings to Capsaicin and ATP ATP Urge to Cough rating at Cu	2.31 Score on a scale Standard Error 2.12	1.80 Score on a scale Standard Error 1.65
Behavioral Responses to Cough Challenge Testing: Urge to Cough Ratings to Capsaicin and ATP ATP Urge to Cough rating at C2	5.03 Score on a scale Standard Error 2.57	6.43 Score on a scale Standard Error 2.26
Behavioral Responses to Cough Challenge Testing: Urge to Cough Ratings to Capsaicin and ATP Capsaicin fMRI urge to cough rating	3.65 Score on a scale Standard Error 2.06	3.89 Score on a scale Standard Error 1.97
Behavioral Responses to Cough Challenge Testing: Urge to Cough Ratings to Capsaicin and ATP ATP fMRI urge to cough rating	2.90 Score on a scale Standard Error 1.41	3.93 Score on a scale Standard Error 2.10
Behavioral Responses to Cough Challenge Testing: Urge to Cough Ratings to Capsaicin and ATP Saline fMRI urge to cough rating	0.86 Score on a scale Standard Error 1.20	0.44 Score on a scale Standard Error 0.71

Adverse Events

Chronic Cough Participant

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Healthy Control Participant

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Adverse event data not reported

Additional Information

Dr Stuart Mazzone

The University of Melbourne

Phone: +61383446457

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place