A Comprehensive Evaluation of the Impact of ATP on Laryngeal Symptoms, Hypersensitivity and Function

Study Overview
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Brief Summary
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OBJECTIVES To deliver a comprehensive model of laryngeal assessment, evaluating both the sensory and motor components of upper airway control and to relate this to symptom disturbance. Determine if laryngeal control is altered by coughing and the impact of repeated coughing on overall laryngeal control and relaxation to its baseline state. Evaluate if cell damage and tissue inflammation (including exposure to ATP) modulates laryngeal hypersensitivity and function, by using a comprehensive array of test modalities. AIM To utilise state-of-the-art comprehensive assessment tools to evaluate laryngeal hypersensitivity and function in a cohort of individuals with chronic refractory cough and control subjects. The test modalities utilise direct stimulation of the laryngeal adductor reflex, measurement of laryngeal EMG and assessment of functional laryngeal response to an inhalational challenge with laryngoscopic techniques. HYPOTHESIS Physiological markers of laryngeal hypersensitivity and dysfunction are highly prevalent in patients with chronic refractory cough and manifestations are driven by ATP stimulation. OUTCOME MEASURES Measurements of laryngeal symptomatology will be measured over a run-in period and during challenge testing. Laryngeal relaxation will be studied using our novel tracking software capability, combining endoscopic imaging and physiological measurements of diaphragm activation.

Official Title
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A Comprehensive Evaluation of the Impact of ATP on Laryngeal Symptoms, Hypersensitivity and Function - an Observational Controlled Study

Conditions
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Chronic Refractory Cough

Intervention / Treatment
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* Diagnostic Test: Laryngeal sensitivity testing


Participation Criteria
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Eligibility Criteria
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Inclusion criteria (controls) Age ≥ 18 years Healthy - with no history of any medical conditions No history of asthma / allergies Normal spirometric indices Non smoker Inclusion criteria (patients) Age ≥ 18 years Chronic cough as per ATS definition (>8 weeks duration) High symptom burden (i.e. Cough VAS >= 40 mm at the screening visit) Chest radiograph or CT within 3 years of the screening visit with no abnormalities considered to contribute to chronic cough For patients with asthma: a confirmed diagnosis of asthma on the basis of asthma symptoms and reversible airflow obstruction (BDR 200mls + 12% change post bronchodilator and/or positive bronchoprovocation test). Exclusion criteria Current smoker or a smoking history of >10 pack years Asthma that is not well-controlled, as per international asthma guidelines as specified by Global Initiative for Asthma (GINA) Recent exacerbation of cough or asthma within 4 weeks of inclusion Pregnancy or childbearing potential and no contraceptive treatment Respiratory tract infection within 4 weeks of inclusion Currently taking any of the following medications: ACE inhibitors and within 3 months of inclusion Antitussives (opioids, pregabalin, gabapentin, amitriptyline, nortriptyline or over-the-counter medications) within 2 weeks of inclusion Medical treatments for GORD, eosinophilic bronchitis or other cough related conditions, initiated or changed (i.e. not in a stable regimen) for 4 weeks prior to inclusion. Medical history of COPD or chronic bronchitis Medical conditions/history or other circumstances which, in the judgement of the investigator, could increase the risk of adverse events or bias the study results

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Chronic Refractory Cough (CRC)<br>Individuals with a diagnosis of chronic refractory cough | Diagnostic Test: Laryngeal sensitivity testing<br>* Direct stimulation of the laryngeal adductor reflex, measurement of laryngeal EMG and our capability to assess functional laryngeal response to an inhalational challenge with laryngoscopic techniques.<br>|
| Healthy controls<br>Healthy control subjects matched to the CRC group by age and gender | Diagnostic Test: Laryngeal sensitivity testing<br>* Direct stimulation of the laryngeal adductor reflex, measurement of laryngeal EMG and our capability to assess functional laryngeal response to an inhalational challenge with laryngoscopic techniques.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal decrease in glottic anterior angle (degrees) during challenge testing | The maximal decrease in glottic anterior angle during challenge testing | Baseline measurement is taken immediately before beginning the challenge test. Minimal value is taken from continuously measured glottic anterior angle, from immediately after baseline measurement and until immediately after challenge testing | 
| Maximal increase in glottic anterior angle (degrees) after challenge testing | The difference between the minimal glottic anterior angle observed during challenge testing and the maximal glottic anterior angle observed from immediately after challenge testing and until 5 minutes after challenge testing | During challenge testing and from immediately after challenge testing until 5 minutes after challenge testing | 
| Maximal laryngeal relaxation time (seconds) | Maximum time for glottic angle to normalise (i.e. achieve a value equal to or above the value prior to sensory stimulus) | At baseline, during challenge testing and from immediately after challenge testing until 5 minutes after challenge testing | 
| Change in laryngeal relaxation time (seconds) during challenge testing | Change in time for glottic angle to normalise (i.e. achieve a value equal to or above the value prior to sensory stimulus) | At baseline and immediately after challenge testing | 
| Change in laryngeal relaxation time (seconds) in recovery | Change in time for glottic angle to normalise (i.e. achieve a value equal to or above the value prior to sensory stimulus) | Immediately after challenge testing and at 5 minutes after challenge testing | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cough VAS (0-100 mm) | This is a descriptive delineation of the ATP/Cough VAS dose/response relationship. The measure is taken at multiple times (see Time Frame) and visualised graphically. | At baseline, during challenge testing at minutes 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 3:30 and 4:00 (from immediately after an administered dose of ATP and until 15 seconds after an administered dose) and immediately after challenge testing | 
| Cough count and frequency | This is a descriptive delineation of the ATP/Cough count dose/response relationship. The measure is taken at multiple times (see Time Frame) and visualised graphically. | At baseline, during challenge testing at minutes 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 3:30 and 4:00 (from immediately after an administered dose of ATP and until 15 seconds after an administered dose) and immediately after challenge testing |