Bronchodilating and Bronchoprotective Effects of Deep Inspirations

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Primary Purpose

Status

Completed

Phase

Not Applicable

Locations

Canada

Study Type

Interventional

Intervention

Methacholine(MCh) Challenge Testing

About this trial

This is an interventional basic science trial for Asthma focused on measuring methacholine, deep inspiration, bronchoprotective effect, bronchodilating effect

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

Individuals aged 18-65 years of age with asthma, CVA and individuals with methacholine-induced cough but normal airway sensitivity. The following definitions will be used:
1. asthma: episodic respiratory symptoms occurring in association with variable airflow obstruction (Canadian Asthma Consensus Report definition);
2. 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);
3. 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
1. Severe airflow limitation (FEV1 <50% predicted or <1.0 L);
2. Heart attack or stroke in last 3 months;
3. Uncontrolled hypertension, systolic BP > 200 or diastolic BP > 100;
4. Known aortic aneurysm;
5. Moderate airflow limitation <60% predicted or 1.5) is a relative contraindication;
6. Inability to perform acceptable quality spirometry;
7. Current use of cholinesterase inhibitor medication (for myasthenia gravis); and
8. Pregnant or nursing mothers.
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.

Sites / Locations

Kingston General Hospital at Queen's University

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

Asthma

Cough Variant Asthma

Mch-induced cough w/normal airway sensitivity

Normal

Arm Description

Individuals diagnosed with asthma.

Individuals diagnosed with cough variant asthma.

Individuals with chronic cough normal PC20 MCh(>16 mg/mL) & who cough during Mch challenge testing.

Individuals with no history of asthma or chronic cough

Outcomes

Primary Outcome Measures

Mid expiratory flows

The bronchodilating effect of a DI will be examined using responses to high-dose methacholine challenge testing (Visit 1) 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 PC20 and PC50 with that recorded at baseline.

Secondary Outcome Measures

percent fall in FEV1

The bronchoprotective effect of a deep inspiration will be measured by the difference between the percent fall in FEV1 following administration of methacholine using modified single-dose methacholine challenge tests on Visits 2 and 3 (with or without preceding deep inspirations)

respiratory system reactance (X5)

The bronchoprotective effect of a DI will be also examined by comparing mechanical responses to methacholine using impulse oscillometry (IOS). 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.

peripheral resistance (R5-R20)

The bronchoprotective effect of a DI will be also examined by comparing mechanical responses to methacholine using impulse oscillometry (IOS). 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.

Central airway resistance

The bronchoprotective effect of a DI will be also examined by comparing mechanical responses to methacholine using impulse oscillometry (IOS). 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.

Forced vital capacity (FVC)

As an index of airway closure.

FEV1/FVC

As an index of airway narrowing (obstruction)

Full Information

NCT ID

NCT01659476

First Posted

July 30, 2012

Last Updated

April 4, 2018

Sponsor

Queen's University

1. Study Identification

Unique Protocol Identification Number

NCT01659476

Brief Title

Bronchodilating and Bronchoprotective Effects of Deep Inspirations

Official Title

Bronchodilating and Bronchoprotective Effects of Deep Inspirations in Asthma, Cough Variant Asthma and Chronic Cough With Normal Airway Sensitivity and Sensory-Mechanical Responses to High-Dose Methacholine in Healthy Normal Subjects

Study Type

Interventional

2. Study Status

Record Verification Date

April 2018

Overall Recruitment Status

Completed

Study Start Date

October 2012 (undefined)

Primary Completion Date

August 2017 (Actual)

Study Completion Date

August 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Queen's University

4. Oversight

Data Monitoring Committee

No

5. Study Description

Brief Summary

The objectives of this research are to compare (i) the bronchodilating and (ii) the bronchoprotective effects of deep inspirations (DIs) in individuals with: (a) asthma, (b) CVA, (c) methacholine-induced cough but normal airway sensitivity and . (d) in healthy individuals (without asthma, chronic cough or asymptomatic airway hyperresponsiveness). Hypotheses: i. The bronchodilating effect of a DI will be: (a) absent or impaired in individuals with classic asthma; (b) impaired in individuals with CVA; (c) preserved in individuals with methacholine-induced cough but normal airway sensitivity; and (d) preserved in healthy individuals (without asthma, chronic cough or asymptomatic airway hyperresponsiveness). ii. The bronchoprotective effect of a DI will be: (a) absent in individuals with classic asthma; (b) impaired in individuals with CVA; (c) preserved in those with methacholine-induced cough but normal airway sensitivity; and (d) preserved in healthy individuals (without asthma, chronic cough or asymptomatic airway hyperresponsiveness). iii. Healthy individuals without asthma, chronic cough, or asymptomatic airway hyperresponsiveness, will not cough, or develop significant dyspnea, small airways obstruction or dynamic hyperinflation during high-dose methacholine bronchoprovocation.

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) and may or may not have eosinophilic bronchitis. The purpose of this research is to examine the pathophysiologic differences between three causes of chronic cough: asthma, cough variant asthma and methacholine-induced cough with normal airway sensitivity. The responses in healthy normal subjects are crucial to understand the clinical relevance of methacholine-induced cough with normal airway sensitivity.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Asthma, Cough

Keywords

methacholine, deep inspiration, bronchoprotective effect, bronchodilating effect

7. Study Design

Primary Purpose

Basic Science

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

43 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Asthma

Arm Type

Experimental

Arm Description

Individuals diagnosed with asthma.

Arm Title

Cough Variant Asthma

Arm Type

Experimental

Arm Description

Individuals diagnosed with cough variant asthma.

Arm Title

Mch-induced cough w/normal airway sensitivity

Arm Type

Experimental

Arm Description

Individuals with chronic cough normal PC20 MCh(>16 mg/mL) & who cough during Mch challenge testing.

Arm Title

Normal

Arm Type

Experimental

Arm Description

Individuals with no history of asthma or chronic cough

Intervention Type

Other

Intervention Name(s)

Methacholine(MCh) Challenge Testing

Other Intervention Name(s)

Drug:MCh[inhalation of sequential doubling doses of MCh(0.0625-256 mg/mL)], Other names: Provocholine

Intervention Description

Visit 1: High-dose methacholine challenge test Visit 2 or 3: Will be conducted in random order and subjects will perform one of two modified single-dose methacholine challenge tests at either visit. During these modified challenges, subjects will (a) perform five DIs from functional residual capacity (FRC) to total lung capacity (TLC) back to FRC, or (b) refrain from taking DIs prior to inhaling the previously measured single PC20 dose of methacholine.

Intervention Type

Other

Intervention Name(s)

Methacholine(MCh) Challenge Testing

Other Intervention Name(s)

Drug:MCh[inhalation of sequential doubling doses of MCh(0.0625-256 mg/mL)], Other names: Provocholine

Intervention Description

Visit 1: Baseline tests, and subjects will be randomized to complete either a high-dose methacholine using maximal expiratory flow-volume loop (MEFV), or a high-dose methacholine challenge with impulse oscillometry (IOS) and partial expiratory flow-volume loop (PEFV) and MEFV at each dose step. Visit 2: Subjects will perform the opposite protocol, based on their first visit:

Primary Outcome Measure Information:

Title

Mid expiratory flows

Description

The bronchodilating effect of a DI will be examined using responses to high-dose methacholine challenge testing (Visit 1) 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 PC20 and PC50 with that recorded at baseline.

Time Frame

Time frame of the methacholine challenge varies between individuals. At provocative concentration of methacholine causing a 20% and 50% decline in FEV1 (PC20 and PC50 respectively). On average, these occur about 15-25 minutes into the challenge test.

Secondary Outcome Measure Information:

Title

percent fall in FEV1

Description

The bronchoprotective effect of a deep inspiration will be measured by the difference between the percent fall in FEV1 following administration of methacholine using modified single-dose methacholine challenge tests on Visits 2 and 3 (with or without preceding deep inspirations)

Time Frame