Chronic Refractory Cough
Conditions
Brief summary
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.
Interventions
DIAGNOSTIC_TESTLaryngeal 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.
Sponsors
Royal Brompton & Harefield NHS Foundation Trust
Bispebjerg Hospital
Study design
Observational model
CASE_CONTROL
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximal increase in glottic anterior angle (degrees) after challenge testing | During challenge testing and from immediately after challenge testing until 5 minutes 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 |
| Change in laryngeal relaxation time (seconds) during challenge testing | At baseline and immediately after 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) |
| Change in laryngeal relaxation time (seconds) in recovery | Immediately after challenge testing and at 5 minutes after 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) |
| Maximal decrease in glottic anterior angle (degrees) 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 | The maximal decrease in glottic anterior angle during challenge testing |
| Maximal laryngeal relaxation time (seconds) | At baseline, during challenge testing and from immediately after challenge testing until 5 minutes after challenge testing | Maximum time for glottic angle to normalise (i.e. achieve a value equal to or above the value prior to sensory stimulus) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cough count and frequency | 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 | 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. |
| Cough 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 | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Trans-diaphragmatic pressure (cmH2O) | 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 | 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. |
| Breathing frequency (1/minute) | 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 | 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. |
| 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 | — |
| 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 | — |
| Breathing frequency variability (entropy, unitless) | 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 | 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. |
| Tidal volume (Litres) | 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 | 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. |
| Tidal volume variability (entropy, unitless) | 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 | 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. |
| Diaphragm activation (Root Mean Square of EMG mcV in a rolling 50ms window centered at the measureing point) | 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 | 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. |
| Oesophageal pressure (cmH2O) | 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 | 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. |
| Gastric pressure (cmH2O) | 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 | 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. |
Countries
Denmark
Contacts
Primary ContactEmil Walsted, MD PhD
Outcome results
None listed