A Comprehensive Evaluation of the Impact of ATP on Laryngeal Symptoms, Hypersensitivity and Function (MISP COUGH)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Chronic Refractory Cough
• Intervention / Treatment: Diagnostic test: Laryngeal sensitivity testing

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

Contacts and Locations

• Study Contact: Name: Emil Walsted, MD PhD; Phone Number: (+45)30338750; Email: emilwalsted@dadlnet.dk

Study Locations

• Denmark
  • Copenhagen, Denmark, 2400
    • Recruiting
    • Bispebjerg Hospital
    • Contact: Emil Walsted, MD PhD; Email: emil.ingerslev.walsted@regionh.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Adult patients (≥ 18 years) with chronic refractory cough and age-/gender matched healthy controls.

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Chronic Refractory Cough (CRC); Individuals with a diagnosis of chronic refractory cough	Diagnostic test: Laryngeal sensitivity testing; 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.
Healthy controls; Healthy control subjects matched to the CRC group by age and gender	Diagnostic test: Laryngeal sensitivity testing; 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.

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Breathing frequency (1/minute)	This is a descriptive delineation of the ATP/Breathing frequency 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
Breathing frequency variability (entropy, unitless)	This is a descriptive delineation of the ATP/Breathing frequency variability 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
Tidal volume (Litres)	This is a descriptive delineation of the ATP/Tidal volume 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
Tidal volume variability (entropy, unitless)	This is a descriptive delineation of the ATP/Tidal volume variability 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
Diaphragm activation (Root Mean Square of EMG mcV in a rolling 50ms window centered at the measureing point)	This is a descriptive delineation of the ATP/Diaphragm activation 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
Oesophageal pressure (cmH2O)	This is a descriptive delineation of the ATP/Oesophageal pressure 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
Gastric pressure (cmH2O)	This is a descriptive delineation of the ATP/Gastric pressure 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
Trans-diaphragmatic pressure (cmH2O)	This is a descriptive delineation of the ATP/Transdiaphragmatic pressure 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
Single cough episode duration (seconds)		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
Single cough episode intensity VAS (0-100 mm)		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

Collaborators and Investigators

• Sponsor: Bispebjerg Hospital
• Collaborators: Royal Brompton & Harefield NHS Foundation Trust

Study record dates

Study Major Dates

• Study Start (Actual): November 28, 2022
• Primary Completion (Anticipated): July 31, 2023
• Study Completion (Anticipated): December 31, 2023

Study Registration Dates

• First Submitted: September 14, 2022
• First Submitted That Met QC Criteria: October 4, 2022
• First Posted (Actual): October 7, 2022

Study Record Updates

• Last Update Posted (Actual): December 1, 2022
• Last Update Submitted That Met QC Criteria: November 28, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Hypersensitivity
• Other Study ID Numbers: H-21076805

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No