Investigating the Role of ATP Production by Airway Epithelium in Patients With Refractory and Unexplained Chronic Cough (RCC/UCC). (APEC)

Chronic cough is a common troublesome symptom which has a global prevalence of approximately 10%, but with wide variations across continents. Patients with refractory and unexplained chronic cough (RCC/UCC) often exhibit dysregulated vagal pathways, necessitating a neuronal biomarker for targeted treatment. ATP, involved in the ATP/P2X3 pathway, may serve as a potential biomarker due to its role in the cough reflex. The study aims to discover if ATP production by the airway epithelium is greater in RCC/UCC patients compared with healthy controls, if the epithelium is a source of ATP, whether gene and protein expression related to ATP production differs between these groups and whether ATP release is triggered by mechanical and chemical stimulation. Additionally, the study seeks to determine if biomarker gene expression signatures can differentiate RCC/UCC patients from healthy controls.

Study Overview

• Status: Recruiting
• Conditions: Chronic Cough (CC)
• Intervention / Treatment: Diagnostic test: Bronchoscopy

• Study Type: Observational
• Enrollment (Estimated): 30

Contacts and Locations

• Study Contact: Name: Imran Satia, MB BChir (cantab) MRCP PhD; Phone Number: 76645 905-521-2100; Email: satiai@mcmaster.ca

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8S 4L8
      • Recruiting
      • Imran Satia
      • Contact: Imran Satia, MD PhD; Email: satiai@mcmaster.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Healthy controls will be recruited through local advertising, existing study databases or participation in previous studies where they have given permission to be contacted. Participants with RCC/UCC will be recruited by the investigators from existing study databases, clinics at either of the following sites:

McMaster University Medical Centre, Department of Respiratory Medicine, 1200 Main St. West, Hamilton, Ontario, Canada, L8N 3Z5

Firestone Institute for Respiratory Health, St Joseph's Healthcare, 50 Charlton Ave E, Hamilton, ON L8N 4A6

Description

Inclusion Criteria for RCC/UCC:

• Patients with a history of RCC/UCC.
• Normal Chest X-ray in the last 5 years.
• No Evidence of Airflow Obstruction (FEV1/FVC ratio above LLN)
• Cough Severity VAS ≥ 40 mm at screening.

Inclusion Criteria for Healthy Controls:

• No history of chronic cough, asthma, COPD, or clinical history of bronchiectasis or interstitial lung disease
• No current smokers or those with >10 pack year history.
• No evidence of airflow obstruction ( FEV1/FVC ratio above LLN).
• Able to understand and give written informed consent.

Exclusion Criteria:

• Participants who are currently established on treatment and their chronic cough is well controlled.
• Unable to perform acceptable and reproducible spirometry.
• Participants with a positive covid-19 test within 2 weeks of screening.
• Current smoker or ex-smoker with ≥20 pack year smoking history and abstinence of ≤6 months
• Symptoms of upper respiratory tract infection in the last 1 month which have not resolved
• Lower respiratory tract infection or pneumonia in the last 1 month
• Asthma exacerbation in the previous month requiring an increase or start of an inhaled corticosteroid (ICS) or oral corticosteroid (OCS)
• Significant other primary pulmonary disorders in particular; pulmonary embolism, pulmonary hypertension, lung cancer, cystic fibrosis, significant radiologically proven emphysema, interstitial lung disease or bronchiectasis.
• History of psychiatric illness, drug or alcohol abuse which may interfere in the participation of the trial.
• Allergy or intolerance to sedation medication including fentanyl and midazolam, or a history of complications during procedural sedation
• Severe coagulopathy, bleeding disorder, or medical need for anti- coagulation that would increase the risk of endobronchial biopsy as determined by the investigator

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Healthy Controls	Diagnostic test: Bronchoscopy; Bronchoscopy will be performed in patients with refractory or unexplained chronic cough and healthy controls.
Refractory or Unexplained Chronic Cough	Diagnostic test: Bronchoscopy; Bronchoscopy will be performed in patients with refractory or unexplained chronic cough and healthy controls.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in expressed genes	Expression of genes involved in intracellular ATP production, transport, extracellular metabolism in the airway epithelium will be compared in both RCC/UCC and healthy controls.	At baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference Immune Cells and Cytokines	Investigate differences in the levels of neuroinflammatory mediators and immune cells from the respiratory airways and distal alveoli.	12 months
Gene Expression	To compare the differences in RCC/UCC and healthy control in gene expression profiling in bronchial biopsies (sub-epithelial dominant).	At baseline
Difference in Nerve Morphology	Investigate differences in nerve length, nerve branch points, nerves expressive P2X3 receptors on airway sensory nerves expressing P2X3 receptor in RCC/UCC compared with healthy controls.	baseline
Difference in ATP release	ATP release from the cultured bronchial epithelial cells (BEC) taken from RCC/UCC and healthy controls after exposure to dynamic mechanical stretch and environmental exposures (cigarette smoke and NO2).	5,15,30 minutes

Collaborators and Investigators

• Sponsor: McMaster University
• Investigators: Principal Investigator: Imran Satia, MB BChir (cantab) MRCP PhD, McMaster University

Study record dates

Study Major Dates

• Study Start (Actual): November 22, 2024
• Primary Completion (Estimated): October 1, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: September 12, 2024
• First Submitted That Met QC Criteria: September 16, 2024
• First Posted (Actual): September 19, 2024

Study Record Updates

• Last Update Posted (Actual): May 8, 2025
• Last Update Submitted That Met QC Criteria: May 5, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: chronic cough; ATP; airway nerves
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Signs and Symptoms, Respiratory; Chronic Cough; Cough
• Other Study ID Numbers: Hireb:17668

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: This is an single visit of 15 patients with RCC/UCC compared with 15 Healthy Controls undergoing bronchoscopy at single centre in Hamilton, Ontario, Canada. Due to the small sample size individual level details will not be shared to protect confidentiality.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes