Functional Magnetic Resonance Imaging of ATP Cough in Chronic Cough Patients

NCT03722849 | Completed Results

• 1 other identifier: Study 58136
• Study Type: interventional
• Target: 58
• Locations: 1 country
• Sites: 1

Brief Summary

Persistent cough is a distressing symptom for people with respiratory disorders. Patients also often experience an ongoing urge-to-cough that prompts coughing, and which fails to resolve the sensation. Understanding how the brain controls cough and the urge-to-cough could lead to new cough suppressing therapies. The overall objective of this project is to use functional brain imaging (fMRI) to identify brain regions that are involved in the exaggerated urge-to-cough in humans with chronic cough. Our focus will be on the brainstem where information from the airways first arrives in the central nervous system.

Conditions

Cough

Keywords

functional brain imaging; ATP; Capsaicin; Refractory cough

Outcome Measures

Primary Outcomes (2)

• Brainstem Neural Activations to Capsaicin

  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.

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

• Brainstem Neural Activations to ATP

  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.

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

Secondary Outcomes (3)

• Behavioral Responses During Cough Challenge Testing: Cough Sensitivity to Capsaicin

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

• Behavioral Responses During Cough Challenge Testing: Cough Sensitivity to ATP

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

• Behavioral Responses to Cough Challenge Testing: Urge to Cough Ratings to Capsaicin and ATP

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

Study Arms (2)

Chronic cough participant

EXPERIMENTAL

Twenty-five (25) Idiopathic chronic cough patients, defined as refractory to disease modifying therapies (eg anti-asthma medications), will be recruited. Participants will attend two sessions. In the first they will inhale in a single breath a nebulized solutions of increasing doses of Adenosine Triphosphate (ATP; 0.2-300 milliM) and capsaicin (0.5-125 microM) to determine their individual cough and urge-to-cough thresholds. In the second session, participants will undergo 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.

Drug: Adenosine Triphosphate; Drug: Capsaicin; Other: Functional Brain Imaging

Healthy control participant

EXPERIMENTAL

Twenty-five (25) appropriately age and sex matched healthy non-smoking individuals will be recruited as the comparison group. Participants will attend two sessions. In the first they will inhale in a single breath a nebulized solutions of increasing doses of ATP (0.2-300 milliM) and capsaicin (0.5-125 microM) to determine their individual cough and urge-to-cough thresholds. In the second session, participants will undergo fMRI for 1 hour while inhaling over 24 seconds randomly administered nebulized solutions of saline, or threshold doses of ATP or capsaicin.

Drug: Adenosine Triphosphate; Drug: Capsaicin; Other: Functional Brain Imaging

Interventions

Adenosine Triphosphate DRUG

Participants will inhale escalating concentrations of Adenosine Triphosphate (ATP) to induce cough and the urge-to-cough

Also known as: ATP

Chronic cough participant; Healthy control participant

Capsaicin DRUG

Participants will inhale escalating concentrations of capsaicin to induce cough and the urge-to-cough

Chronic cough participant; Healthy control participant

Functional Brain Imaging OTHER

Participants will have scans of their brain activity using 3 Tesla (3T) brainstem restricted functional brain imaging (fMRI)

Also known as: fMRI

Chronic cough participant; Healthy control participant

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with physician diagnosed chronic refractory cough (cough lasting \>8 weeks).
• \> 18 years of age
• Must be cognitively impaired

You may not qualify if:

• People with contraindications to MRI scanning (i.e. metal implants, claustrophobia).
• History of uncontrolled asthma or chronic respiratory disease (other than refractory cough).
• Evidence of an allergic reaction to capsaicin (chilli).
• Pregnant women.
• Smoking, current or recent history (last 6 months).

Sponsors & Collaborators

• Stuart Mazzone: lead
• Imperial College London: collaborator
• Queen's University, Belfast: collaborator
• Monash University: collaborator

Study Sites (1)

The University of Melbourne

Parkville, Victoria, 3010, Australia

Location

Related Publications (6)

• Chung KF, Pavord ID. Prevalence, pathogenesis, and causes of chronic cough. Lancet. 2008 Apr 19;371(9621):1364-74. doi: 10.1016/S0140-6736(08)60595-4.

  PMID: 18424325 BACKGROUND

• Morice AH, Jakes AD, Faruqi S, Birring SS, McGarvey L, Canning B, Smith JA, Parker SM, Chung KF, Lai K, Pavord ID, van den Berg J, Song WJ, Millqvist E, Farrell MJ, Mazzone SB, Dicpinigaitis P; Chronic Cough Registry. A worldwide survey of chronic cough: a manifestation of enhanced somatosensory response. Eur Respir J. 2014 Nov;44(5):1149-55. doi: 10.1183/09031936.00217813. Epub 2014 Sep 3.

  PMID: 25186267 BACKGROUND

• Chung KF, McGarvey L, Mazzone SB. Chronic cough as a neuropathic disorder. Lancet Respir Med. 2013 Jul;1(5):414-22. doi: 10.1016/S2213-2600(13)70043-2. Epub 2013 May 3.

  PMID: 24429206 BACKGROUND

• Mazzone SB, McLennan L, McGovern AE, Egan GF, Farrell MJ. Representation of capsaicin-evoked urge-to-cough in the human brain using functional magnetic resonance imaging. Am J Respir Crit Care Med. 2007 Aug 15;176(4):327-32. doi: 10.1164/rccm.200612-1856OC. Epub 2007 Jun 15.

  PMID: 17575093 BACKGROUND

• Ando A, Smallwood D, McMahon M, Irving L, Mazzone SB, Farrell MJ. Neural correlates of cough hypersensitivity in humans: evidence for central sensitisation and dysfunctional inhibitory control. Thorax. 2016 Apr;71(4):323-9. doi: 10.1136/thoraxjnl-2015-207425. Epub 2016 Feb 9.

  PMID: 26860344 BACKGROUND

• Abdulqawi R, Dockry R, Holt K, Layton G, McCarthy BG, Ford AP, Smith JA. P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study. Lancet. 2015 Mar 28;385(9974):1198-205. doi: 10.1016/S0140-6736(14)61255-1. Epub 2014 Nov 25.

  PMID: 25467586 BACKGROUND

MeSH Terms

Conditions

Cough

Interventions

Adenosine Triphosphate; Capsaicin; Functional Neuroimaging

Condition Hierarchy (Ancestors)

Respiration Disorders; Respiratory Tract Diseases; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Adenine Nucleotides; Purine Nucleotides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Nucleotides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleotides; Polyunsaturated Alkamides; Amides; Organic Chemicals; Alkenes; Hydrocarbons, Acyclic; Hydrocarbons; Catechols; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Solanaceous Alkaloids; Alkaloids; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Fatty Acids; Lipids; Neuroimaging; Diagnostic Imaging; Diagnostic Techniques and Procedures; Diagnosis; Diagnostic Techniques, Neurological; Investigative Techniques

Results Point of Contact

• Title: Dr Stuart Mazzone
• Organization: The University of Melbourne

stuart.mazzone@unimelb.edu.au

+61383446457

Study Officials

• Stuart Mazzone, PhD

  University of Melbourne

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor of Neuroscience

Model Details: The experiment will consist of two sessions. The first session will involve questionnaires, followed by measures of sensitivity and behavioural responses to tussive (cough evoking) stimulation. The second session will involve functional brain imaging measures of responses to tussive stimulation.

Study Record Dates

• First Submitted: October 24, 2018
• First Posted: October 29, 2018
• Study Start: March 1, 2019
• Primary Completion: May 13, 2022
• Study Completion: May 13, 2022
• Last Updated: August 22, 2024
• Results First Posted: August 22, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share

Locations

AU (1)