Sensory-Mechanical Responses to Eucapneic Voluntary Hyperventilation and Mannitol

Sensory-Mechanical Responses to Eucapneic Voluntary Hyperventilation and Mannitol in Individuals with Cough Variant Asthma and Chronic Cough

The objectives of this study are to determine the sensory-mechanical responses to Eucapneic Voluntary Hyperventilation (EVH) and Mannitol in individuals with cough variant asthma (CVA) and methacholine-induced cough with normal airway sensitivity (COUGH) and compare these responses to a control group of healthy individuals without asthma or chronic cough.

We hypothesize:

1. EVH and Mannitol cause dyspnea, cough, small airway obstruction with resultant dynamic hyperinflation, gas trapping and autoPEEP in individuals with CVA and COUGH, but not healthy controls.
2. The sensory-mechanical responses to both hyperosmolar challenges (EVH and Mannitol) are comparable within groups (CVA, COUGH and healthy controls).

Study Overview

• Status: Recruiting
• Conditions: Cough; Asthma; Cough Variant Asthma
• Intervention / Treatment: Drug: Methacholine (MCh) Challenge Testing; Diagnostic test: Eucapneic Voluntary Hyperventilation (EVH); Drug: Mannitol Inhalation Kit

Detailed Description

Asthma is a chronic respiratory condition characterized by eosinophilic airway inflammation. Individuals with classic asthma experience paroxysmal symptoms including cough, wheeze, shortness of breath and chest tightness. Cough variant asthma (CVA) is asthma in which chronic cough (cough lasting eight weeks or more) is the sole or predominant symptom of asthma. The pathophysiologic mechanisms which differentiate asthma, CVA, and eosinophilic bronchitis without asthma are not fully understood. We have recently identified individuals with chronic cough who cough during methacholine but have normal airway sensitivity (ie. do not have asthma or CVA) (COUGH) and may or may not have eosinophilic bronchitis. The purpose of this research is to further explore the pathophysiologic basis for cough in these conditions using two 'indirect' inhalation challenge tests: eucapneic voluntary hyperventilation (EVH) and Mannitol), which induce osmotic and/or temperature changes in airway. Specifically, this study will collect preliminary data on the sensory-mechanical responses of individuals with CVA, COUGH and healthy controls to EVH and Mannitol Challenges.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: M. Diane Lougheed, MD, MSc; Phone Number: 613-548-2348; Email: diane.lougheed@kingstonhsc.ca
• Study Contact Backup: Name: Taylar Wall, RRT; Phone Number: 2798 613-549-6666; Email: taylar.wall@kingstonhsc.ca

Study Locations

• Canada
  • Ontario
    • Kingston, Ontario, Canada, K7L 2V7
      • Recruiting
      • Kingston Health Sciences Centre
      • Contact: Taylar Wall; Phone Number: 2798 613-549-6666; Email: taylar.wall@kingstonhsc.ca
      • Contact: M Diane Lougheed, MD MSc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Individuals aged 18-65 years of age with CVA and individuals with methacholine-induced cough but normal airway sensitivity. The following definitions will be used:

  1. CVA: chronic cough (≥8 weeks) is the sole or predominant symptom and positive methacholine challenge (PC20 ≤ 16 mg/mL) and history of cough responding to specific asthma treatment (such as inhaled steroid or 1 week trial of bronchodilator);
  2. Methacholine-induced cough but normal airway sensitivity: chronic cough (≥8 weeks) is the sole or predominant symptom and negative methacholine challenges (PC20 > 16 mg/mL).
• Individuals aged 18-65 years of age with no history of asthma or chronic cough.

Exclusion Criteria:

• an exacerbation necessitating a change in medication, emergency department visit or hospitalizations within the previous 4 weeks
• inability to perform acceptable spirometry
• medical contraindications to methacholine challenge testing
• smoking history in excess of 10 pack years Note: Previous treatment with inhaled or systemic corticosteroids is not an exclusion criterion; medication use will be recorded and examined in the analysis.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cough Variant Asthma; Individuals diagnosed with Cough variant asthma	Drug: Methacholine (MCh) Challenge Testing; Visit 1: Informed consent, Baseline screening and pulmonary function tests and Low-dose methacholine challenge testing using partial and full flow-volume loops.; Other Names: Provocholine; MCh[inhalation of sequential doubling doses of MCh(0.0625-16 mg/mL)]; Diagnostic test: Eucapneic Voluntary Hyperventilation (EVH); Visit 2 or 3: Will be conducted in random order and subjects will perform one of the two challenge tests at either visit.; Drug: Mannitol Inhalation Kit; Visit 2 or 3: Will be conducted in random order and subjects will perform one of the two challenge tests at either visit.; Other Names: Mannitol Challenge Test
Experimental: Methacholine-induced cough; Individuals with chronic cough and negative methacholine challenge	Drug: Methacholine (MCh) Challenge Testing; Visit 1: Informed consent, Baseline screening and pulmonary function tests and Low-dose methacholine challenge testing using partial and full flow-volume loops.; Other Names: Provocholine; MCh[inhalation of sequential doubling doses of MCh(0.0625-16 mg/mL)]; Diagnostic test: Eucapneic Voluntary Hyperventilation (EVH); Visit 2 or 3: Will be conducted in random order and subjects will perform one of the two challenge tests at either visit.; Drug: Mannitol Inhalation Kit; Visit 2 or 3: Will be conducted in random order and subjects will perform one of the two challenge tests at either visit.; Other Names: Mannitol Challenge Test
Experimental: Control; Individuals with no history of asthma or chronic cough	Drug: Methacholine (MCh) Challenge Testing; Visit 1: Informed consent, Baseline screening and pulmonary function tests and Low-dose methacholine challenge testing using partial and full flow-volume loops.; Other Names: Provocholine; MCh[inhalation of sequential doubling doses of MCh(0.0625-16 mg/mL)]; Diagnostic test: Eucapneic Voluntary Hyperventilation (EVH); Visit 2 or 3: Will be conducted in random order and subjects will perform one of the two challenge tests at either visit.; Drug: Mannitol Inhalation Kit; Visit 2 or 3: Will be conducted in random order and subjects will perform one of the two challenge tests at either visit.; Other Names: Mannitol Challenge Test

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mid expiratory flows	The bronchodilating effect of a DI will be examined using responses to the challenge testing (Visit 2/3) in these subgroups by comparing the mid-expiratory flow difference between the partial (PEF) and full maximal flow-volume (MEF) loops at 40% above Residual Volume (RV) from the forced vital capacity (FVC) (PEF40 and MEF40 respectively) at provocative dose of 4.5% saline causing a 20% decline in FEV1 (PD20 (HS)) and provocative minute ventilation causing a 20% decline in FEV1 (PC20 (EVH)) with that recorded at baseline.	Time frame of the methacholine challenge varies between individuals. At provocative dose/ventilation causing a 20% decline in FEV1 (PD20 and PC20 respectively). On average, these occur about 15-25 minutes into the challenge test

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Respiratory System Reactance (X5)	Single IOS will measure peripheral airway function using respiratory system reactance (X5) and peripheral resistance (R5-R20) and central resistance (R20) will be used as an index of airway narrowing.	After dose administration; will occur 2-5 minutes after dose
Peripheral Resistance (R5-R20)	Single IOS will measure peripheral airway function using respiratory system reactance (X5) and peripheral resistance (R5-R20) and central resistance (R20) will be used as an index of airway narrowing.	After dose administration; will occur 2-5 minutes after dose
Central Airway Resistance	Single IOS will measure peripheral airway function using respiratory system reactance (X5) and peripheral resistance (R5-R20) and central resistance (R20) will be used as an index of airway narrowing.	After dose administration; will occur 2-5 minutes after dose
Forced Vital Capacity (FVC)	As an index of airway closure.	After dose administration; will occur 2-5 minutes after dose
FEV1/FVC	As an index of airway obstruction.	After dose administration; will occur 2-5 minutes after dose

Collaborators and Investigators

• Sponsor: Dr. Diane Lougheed
• Investigators: Principal Investigator: M. Diane Lougheed, MD, MSc, Department of Medicine, Queen's University

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2022
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): June 30, 2026

Study Registration Dates

• First Submitted: April 4, 2017
• First Submitted That Met QC Criteria: April 4, 2017
• First Posted (Actual): April 10, 2017

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 17, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Asthma; Hypertonic Saline; Cough; Eucapneic Voluntary Hyperventilation
• Additional Relevant MeSH Terms: Immune System Diseases; Respiratory Tract Diseases; Lung Diseases; Respiration Disorders; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Signs and Symptoms, Respiratory; Cough-Variant Asthma; Asthma; Cough; Hyperventilation; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Neurotransmitter Agents; Respiratory System Agents; Diuretics; Natriuretic Agents; Cholinergic Agents; Cholinergic Agonists; Parasympathomimetics; Muscarinic Agonists; Diuretics, Osmotic; Miotics; Bronchoconstrictor Agents; Mannitol; Methacholine Chloride
• Other Study ID Numbers: 2023-17

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
• product manufactured in and exported from the U.S.: No