An Investigation Into the Mechanism of Inhalation Cough Challenge

NCT02039999 | Completed DMC

• 1 other identifier: ACADMED240913
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

Despite its commonplace use in respiratory medicine the mechanism whereby inhalation challenge with a variety of mild acid aerosols produces a dose related and predictable cough is unknown. In this proposal the investigators wish to use established cough challenge methodology to explore the mechanism of action of agents provoking cough both in health and disease. The hypotheses to be tested include:

• Intracellular changes in pH, rather than extracellular changes, are key in the activation of TRP receptors, the main sensor for provoking cough.
• ATP acting through P2X channels is the mechanism of increased nerve excitability underlying cough hypersensitivity.

Conditions

Cough

Keywords

chronic; cough; challenge; ATP; hypersensitivity; TRPA1

Outcome Measures

Primary Outcomes (1)

• Difference in mean C5 (concentration of inhaled substance required to elicit 5 coughs) (ATP) and total cough (citric acid) between the chronic cough arm and the normal volunteer arm.

  Following inhalation of challenge substance, subject will be monitored for 30 seconds and number of coughs recorded. Concentration of challenge substance will increase until subject coughs at least 5 times following challenge. This will be recorded as the C5 value for each subject. The mean C5 value will be compared between the chronic cough arm and the normal volunteer arm. This will be reported as whether or not there is a statistical difference between the mean C5 for the chronic cough group and the normal volunteer group.

  Coughs will be measured in a 30 second period following the inhalation of each challenge substance.

Study Arms (2)

Chronic cough

EXPERIMENTAL

Cough challenges to be administered include: Nebulised citric acid in serial dilutions Nebulised ATP solution in serial dilutions Nebulised TRPA1 agonist solution in serial dilutions

Other: Nebulised citric acid in serial dilutions; Other: Nebulised ATP solution in serial dilutions; Other: Nebulised TRPA1 agonist solution in serial dilutions

Normal volunteer

ACTIVE COMPARATOR

Cough challenges to be administered include: Nebulised citric acid in serial dilutions Nebulised ATP solution in serial dilutions Nebulised TRPA1 agonist solution in serial dilutions

Other: Nebulised citric acid in serial dilutions; Other: Nebulised ATP solution in serial dilutions; Other: Nebulised TRPA1 agonist solution in serial dilutions

Interventions

Nebulised citric acid in serial dilutions OTHER

Citric acid will be delivered in serial dilutions as per the clinical trials unit standard operating procedure for cough challenge using KoKo Digidoser, based on ERS guidelines. Challenge will be repeated until C5 (5 coughs in 30 seconds following challenge) is elicited.

Chronic cough; Normal volunteer

Nebulised ATP solution in serial dilutions OTHER

ATP solution will be delivered in serial dilutions as per the clinical trials unit standard operating procedure for cough challenge using KoKo Digidoser, based on ERS guidelines. Challenge will be repeated until C5 (5 coughs in 30 seconds following challenge) is elicited.

Chronic cough; Normal volunteer

Nebulised TRPA1 agonist solution in serial dilutions OTHER

TRPA1 agonist will be delivered in serial dilutions as per the clinical trials unit standard operating procedure for cough challenge using KoKo Digidoser, based on ERS guidelines. Challenge will be repeated until C5 (5 coughs in 30 seconds following challenge) is elicited.

Chronic cough; Normal volunteer

Eligibility Criteria

• Age: 16 Years - 85 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients will be required to demonstrate significant cough symptoms by a score greater than 20/70 on the Hull Airways Reflux Questionnaire.
• All patients must be current non-smokers.
• Patients must be on stable medication for at least one month.
• Patients must be able to attend the trials unit on at least 3 occasions.
• Patients must have normal lung function patients must be able to give informed consent

You may not qualify if:

• Subjects who are pregnant, or have pacemakers in situ are excluded from this study.
• Those with a serious comorbid conditions such as cancer, severe COPD, or heart failure will be excluded.
• Those who are non-English speakers and special groups (i.e. mentally ill, children under 16 years of age, and those suffering from dementia) will be excluded.
• No test will be performed on any subject during an acute worsening of asthma or upper airway infection. If the subject has had an upper airway infection in the last three weeks they will be offered another appointment.
• If the subject has taken any over the counter (OTC) cough mixture within the last twelve hours: If the subject is willing to come back another time for challenge testing, another appointment should be made.
• If the subject has had any food or drink products containing caffeine or menthol within the last hour. If the subject is unwilling to wait for 1 hour before starting the test, the subject should return another time. If the subject is unwilling to return another time, testing should proceed and the medication used recorded.
• If the participant is currently involved in research, or within 3 months of participation in any type of research, they will be excluded from this study.

Sponsors & Collaborators

• Hull University Teaching Hospitals NHS Trust: lead

Study Sites (1)

Hull Clinical Trials Unit, Respiratory academic department

Cottingham, East Yorkshire, HU16 5JQ, United Kingdom

Location

Related Publications (1)

• Fowles HE, Rowland T, Wright C, Morice A. Tussive challenge with ATP and AMP: does it reveal cough hypersensitivity? Eur Respir J. 2017 Feb 8;49(2):1601452. doi: 10.1183/13993003.01452-2016. Print 2017 Feb.

  PMID: 28179439 BACKGROUND

Related Links

• Publication Link

MeSH Terms

Conditions

Cough; Bronchiolitis Obliterans Syndrome; Hypersensitivity

Condition Hierarchy (Ancestors)

Respiration Disorders; Respiratory Tract Diseases; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Organizing Pneumonia; Bronchiolitis Obliterans; Bronchiolitis; Bronchitis; Bronchial Diseases; Lung Diseases, Obstructive; Lung Diseases; Graft vs Host Disease; Immune System Diseases

Study Officials

• Alyn H Morice, MD, FRCP

  National Health Service, United Kingdom

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 16, 2013
• First Posted: January 20, 2014
• Study Start: February 1, 2015
• Primary Completion: July 1, 2015
• Study Completion: August 1, 2016
• Last Updated: July 15, 2019

Record last verified: 2019-07

Locations

GB (1)