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The Effect of Physical Exercise in a Cold Air Environment on Normal Volunteers and Asthmatic Patients (ALASCAIR1)

Primary Purpose

Asthma, Exercise-Induced

Status
Completed
Phase
Not Applicable
Locations
Belgium
Study Type
Interventional
Intervention
Cold air exercise test
Sponsored by
KU Leuven
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Asthma, Exercise-Induced focused on measuring Asthma, Exercise, Cold air exposure

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesAccepts Healthy Volunteers

INCLUSION CRITERIA - healthy volunteers

  • age between 18 and 60 years at time of signing informed consent
  • BMI between 18-28 kg/m2
  • able to comply with study protocol, in the investigator's judgement
  • non-smoking or ex-smokers for at least 12 months with less than 10 pack years
  • no immunoglobulin E (IgE) mediated hypersensitivity
  • normal spirometry & normal ECG at screening
  • negative histamine provocation (defined as His- if PC20 >/= 8 mg/ml and His+ healthy controls if PC20 > 4 mg/ml and < 8 mg/ml)

INCLUSION CRITERIA - asthmatic patients

  • age between 18 and 60 years at time of signing informed consent
  • BMI between 18-28 kg/m2
  • able to comply with study protocol, in the investigator's judgement
  • non-smoking or ex-smokers for at least 12 months with less than 10 pack years
  • physician-diagnosed asthma for more than 6 months
  • post bronchodilator FEV1 of ≥ 80% at screening
  • documented airway reversibility either by means of post bronchodilator reversibility of > 12% and > 200 ml or in the previous 6 months or by means of documented airway hyperresponsiveness (histamine PC20 <8 mg/ml) at screening
  • Asthma Control Questionnaire (ACQ) < 1,5
  • regular treatment with inhaled corticosteroids (ICS) with or without long-acting beta-agonists (LABA) (unchanged dose for at least 1 month)
  • normal ECG at screening

EXCLUSION CRITERIA - healthy volunteers

  • physician-diagnosed asthma or history of (post)infectious bronchial hyperreactivity
  • major pulmonary or cardiovascular disease
  • treatment with β-blockers
  • pregnancy

EXCLUSION CRITERIA - asthmatics patients

  • unable to produce sputum with sputum induction
  • previous history of intubation or admission to the intensive care unit due to asthma
  • severe asthma exacerbation within one year prior to screening visit
  • treatment with oral or systemic steroids within one year prior to screening visit
  • previous treatment with biologics for asthma
  • treatment with β-blockers
  • other major concurrent pulmonary (such as chronic obstructive pulmonary disease, cystic fibrosis, sarcoidosis, interstitial lung disease, Churg-Strauss syndrome, allergic bronchopulmonary aspergillosis, bronchiectasis) or cardiovascular disease
  • pregnancy

Sites / Locations

  • UZ Leuven Gasthuisberg

Arms of the Study

Arm 1

Arm 2

Arm Type

Other

Other

Arm Label

Healthy volunteers

Asthmatic subjects

Arm Description

Healthy volunteers will perform the same protocol as foreseen for asthmatic patients. Both will perform the cold air exercise test with pre -and post-exposure evaluation of on FEV1, respiratory symptoms, functional airway integrity, local and systemic inflammation and on the airway microbiome.

Asthmatic patients will perform the same protocol as foreseen for healthy volunteers. They will perform the cold air exercise test with pre -and post-exposure evaluation of on FEV1, respiratory symptoms, functional airway integrity, local and systemic inflammation and on the airway microbiome.

Outcomes

Primary Outcome Measures

Change in Forced Expiratory Volume in 1 seconds (FEV1)
Change in FEV1, calculated as a time-weighted average over the 35 minutes after the cold air exercise test and 24 hours and 1 week post-exposure. A maximal fall of 10% will be considered as positive response

Secondary Outcome Measures

Changes in asthma control
Asthma control will be determined using the Asthma Control Questionnaire (ACQ-6), including 6 questions. Each question will be scored from 0-6 and added together. This final score will be divided by the number of questions. If ACQ-6 < 0.75 = controlled asthma, ACQ-6 from 0.75-1.5 = partly controlled asthma and ACQ-6 > 1.5 = uncontrolled asthma.
Changes in respiratory symptom score
The degree of dyspnea will be determined using Borg scale. This Borg scale is 0 to 10 rated scale. With 0 no dyspnea and 10 complete dyspnea.
Cough hypersensitivity
Cough hypersensitivity (Capsaicin cough threshold) will be measured using a capsaicin challenge test. The concentrations (µmol/l) which provokes 2 coughs (C2) and 10 coughs (C10) will be recorded and will be compared before and after cold air exposure.
Bronchial hyperreactivity
Bronchial hyperreactivity will be measured using a histamine provocation. Bronchial hyperreactivity will be confirmed when there is a drop of 20% in FEV1 post histamine provocation (PC20).
Nasal hyperreactivity
Nasal hyperreactivity will be measured using a PNIF measurement. Nasal hyperreactivity will be confirmed when there is a drop of 20% in PNIF.
Airway inflammation
Bronchial airway inflammation. Differential cell count will be performed on sputum samples, determining eosinophilic (>3% eosinophils, <61% neutrophils), neutrophilic (<3% eosinophils and >61% neutrophils), pauci-granulocytic (<3% eosinophils and <61% neutrophils) and mixed granulocytic airway inflammation (>3% eosinophils and >61% neutrophils).
Cytokine pattern in the airways
Cytokines concentrations (pg/ml) will also be determined in sputum supernatant using a U-plex assay.
Biomarkers for airway inflammation
FeNO will be used as biomarker for eosinophilic airway inflammation. FeNO < 25 ppb = eosinophilic inflammation less likely, FeNO between 25 and 50 ppm = need further interpretation with additional clinical information, FeNO > 50 ppm = indication of eosinophilic airway inflammation (according to the American Thoracic Society guidelines)
Nasal inflammation
Cytokine concentrations (pg/ml) will be determined in the nasal fluid as biomarkers for nasal inflammation
Systemic inflammation
The degree of system inflammation will be determined via differential blood cell count.
Biomarkers for systemic inflammation
The degree of system inflammation will be determined via C-reactive protein (CRP) levels. Normal values for CRP are considered < 10 mg/ml.
Changes in microbiome in lung and nose
The presence of 22 common respiratory viruses, 5 bacteria and 1 fungi will be determined using qualitative reverse transcription polymerase chain reaction (qRT-PCR) in sputum and nasal fluid. Pre and post-exposure microbiome patterns will be compared.
Evaluation of the heart rate pattern
Cardiovascular health will be evaluated by determining the heart rate pattern using ECG. Deviation from a normal ECG pattern will be recorded.
Determining the exercise capacity
Exercise capacity will be checked. In a single test pre-exposure, the aerobic heart rate zone, anaerobic heart rate zone and maximal oxygen volume uptake (VO2max) heart rate zone will be evaluated to determine the exercise capacity

Full Information

First Posted
January 23, 2019
Last Updated
December 16, 2020
Sponsor
KU Leuven
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1. Study Identification

Unique Protocol Identification Number
NCT03840044
Brief Title
The Effect of Physical Exercise in a Cold Air Environment on Normal Volunteers and Asthmatic Patients
Acronym
ALASCAIR1
Official Title
The Effect of Physical Exercise in a Cold Air Environment on Normal Volunteers and Asthmatic Patients
Study Type
Interventional

2. Study Status

Record Verification Date
December 2020
Overall Recruitment Status
Completed
Study Start Date
June 3, 2019 (Actual)
Primary Completion Date
April 30, 2020 (Actual)
Study Completion Date
May 30, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
KU Leuven

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of the study is to compare airway physiologic reactions to physical exercise in a cold air environment (-5°C, 60% relative humidity) between normal volunteers and subjects with mild/moderate asthma. For this purpose, the investigators intend to evaluate the effect of a cold air exercise test on the Forced Expiratory Volume in 1 second (FEV1), respiratory symptoms, functional airway integrity, local and systemic inflammation and on the airway microbiome. This study also features as an exploratory study for a subsequent interventional study in order to establish the feasibility of the cold air exercise protocol and to determine the extent of the effects in subjects with mild/moderate asthma.
Detailed Description
It is already demonstrated that exercising during cold air exposure and at a high altitude may induce asthmatic symptoms, a variable degree of airway obstruction and increased neutrophilic airway inflammation in asthmatic patients. Therefore, in this project, the investigators want to evaluate the feasibility, of a shorter standardized "cold air exercise test" (a submaximal exercise challenge in a controlled cold air (-5°C, relative humidity 60%) environment) and to compare the respiratory physiologic reactions to physical exercise during cold exposure between healthy volunteers and asthmatic patients. For this purpose, they intend to evaluate the effect of a cold air exercise test on FEV1, respiratory symptoms, functional airway integrity, local and systemic inflammation and on the airway microbiome. This study features as an exploratory study for a subsequent interventional study, that will assess the protective effect of azithromycin versus placebo on the cold air exercise induced changes in patients with mild/moderate asthma (ALASCAIR2 study). The present preparatory study is needed to standardize the cold air exercise test in a controlled environment so that it would be possible to use it as challenge test in an interventional study and to identify the most appropriate design for such a study. The primary objective of this study is to compare the proportional change in FEV1, pre to post a 90 minutes submaximal exercise in a cold air environment between healthy volunteers versus mild/moderate asthmatics, calculated as a time-weighted average over the 30 minutes post-exposure. The primary endpoint is the change in FEV1, calculated as a time-weighted average over the 30 minutes after the cold exercise test. At each time point (pre-exposure, 5' post-exposure, and at 15, 25 and 35 minutes post-exposure), FEV1 (L) will be measured in triplicate. They want to evaluate whether the exercise test in a cold air environment produces respiratory symptoms (such as nasal discharge or obstruction, dyspnea, cough and/or mucus production, etc.), has an impact on airway integrity (nasal patency, airflow obstruction, lung ventilation inhomogeneity & small airway dysfunction, bronchial hyperreactivity, cough reflex hypersensitivity), induces local or systemic inflammatory changes (biomarkers in nasal fluid, sputum and blood) or changes to the airway microbiome (in nasal fluid and sputum) in healthy volunteers and in mild/moderate asthmatics. The study group also want to compare the observed changes induced by the cold air exercise test between the healthy volunteers and the mild/moderate asthmatics. The secondary endpoints of this study include the observed changes in (respiratory) symptom score, Peak Nasal Inspiratory Flow (PNIF), Forced Vital Capacity (FVC), Forced Expiratory Flow (FEF25-75), Fraction of Exhaled Nitric Oxide (FeNO), histamine provocative concentration causing 20% drop in FEV1 (PC20), cough threshold C2 & C5, sputum differential cell count, biomarkers in nasal fluid, sputum and blood, nasal and sputum microbial communities between the healthy volunteers and the mild/moderate asthmatics.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Asthma, Exercise-Induced
Keywords
Asthma, Exercise, Cold air exposure

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
Healthy volunteers will be compared with asthmatic subjects
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
45 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Healthy volunteers
Arm Type
Other
Arm Description
Healthy volunteers will perform the same protocol as foreseen for asthmatic patients. Both will perform the cold air exercise test with pre -and post-exposure evaluation of on FEV1, respiratory symptoms, functional airway integrity, local and systemic inflammation and on the airway microbiome.
Arm Title
Asthmatic subjects
Arm Type
Other
Arm Description
Asthmatic patients will perform the same protocol as foreseen for healthy volunteers. They will perform the cold air exercise test with pre -and post-exposure evaluation of on FEV1, respiratory symptoms, functional airway integrity, local and systemic inflammation and on the airway microbiome.
Intervention Type
Other
Intervention Name(s)
Cold air exercise test
Intervention Description
Subjects will perform a submaximal 90 minutes exercise test in a controlled cold air environment (-5°C, 60% relative humidity) in a climate chamber with evaluation pre§/during*/post§ of heart rate (HR)§* and blood pressure (BP)§*, spirometry§*, PNIF§, FeNO§, electrocardiogram (ECG)§*, body & exhaled air temperature§*, capsaicin cough threshold test§, histamine bronchial challenge test§, and sampling of nasal fluid§, induced sputum§, and venous blood§.
Primary Outcome Measure Information:
Title
Change in Forced Expiratory Volume in 1 seconds (FEV1)
Description
Change in FEV1, calculated as a time-weighted average over the 35 minutes after the cold air exercise test and 24 hours and 1 week post-exposure. A maximal fall of 10% will be considered as positive response
Time Frame
pre-, 5, 15, 25 and 35 minutes, 24 hours and 1 week post-exposure
Secondary Outcome Measure Information:
Title
Changes in asthma control
Description
Asthma control will be determined using the Asthma Control Questionnaire (ACQ-6), including 6 questions. Each question will be scored from 0-6 and added together. This final score will be divided by the number of questions. If ACQ-6 < 0.75 = controlled asthma, ACQ-6 from 0.75-1.5 = partly controlled asthma and ACQ-6 > 1.5 = uncontrolled asthma.
Time Frame
Pre-exposure and immediately, 24 hours and 1 week post-exposure
Title
Changes in respiratory symptom score
Description
The degree of dyspnea will be determined using Borg scale. This Borg scale is 0 to 10 rated scale. With 0 no dyspnea and 10 complete dyspnea.
Time Frame
Pre-exposure and immediately, 24 hours and 1 week post-exposure
Title
Cough hypersensitivity
Description
Cough hypersensitivity (Capsaicin cough threshold) will be measured using a capsaicin challenge test. The concentrations (µmol/l) which provokes 2 coughs (C2) and 10 coughs (C10) will be recorded and will be compared before and after cold air exposure.
Time Frame
Pre-exposure and 24 hours and 1 week post-exposure
Title
Bronchial hyperreactivity
Description
Bronchial hyperreactivity will be measured using a histamine provocation. Bronchial hyperreactivity will be confirmed when there is a drop of 20% in FEV1 post histamine provocation (PC20).
Time Frame
Pre-exposure and 1 week post-exposure
Title
Nasal hyperreactivity
Description
Nasal hyperreactivity will be measured using a PNIF measurement. Nasal hyperreactivity will be confirmed when there is a drop of 20% in PNIF.
Time Frame
Pre-exposure and immediately and 24 hours post-exposure
Title
Airway inflammation
Description
Bronchial airway inflammation. Differential cell count will be performed on sputum samples, determining eosinophilic (>3% eosinophils, <61% neutrophils), neutrophilic (<3% eosinophils and >61% neutrophils), pauci-granulocytic (<3% eosinophils and <61% neutrophils) and mixed granulocytic airway inflammation (>3% eosinophils and >61% neutrophils).
Time Frame
Pre-exposure and 24 hours and 1 week post-exposure
Title
Cytokine pattern in the airways
Description
Cytokines concentrations (pg/ml) will also be determined in sputum supernatant using a U-plex assay.
Time Frame
Pre-exposure and 24 hours and 1 week post-exposure
Title
Biomarkers for airway inflammation
Description
FeNO will be used as biomarker for eosinophilic airway inflammation. FeNO < 25 ppb = eosinophilic inflammation less likely, FeNO between 25 and 50 ppm = need further interpretation with additional clinical information, FeNO > 50 ppm = indication of eosinophilic airway inflammation (according to the American Thoracic Society guidelines)
Time Frame
Pre-exposure and 24 hours and 1 week post-exposure
Title
Nasal inflammation
Description
Cytokine concentrations (pg/ml) will be determined in the nasal fluid as biomarkers for nasal inflammation
Time Frame
Pre-exposure and immediately and 24 hours post-exposure
Title
Systemic inflammation
Description
The degree of system inflammation will be determined via differential blood cell count.
Time Frame
Pre-exposure and immediately, 24 hours and 1 week post-exposure
Title
Biomarkers for systemic inflammation
Description
The degree of system inflammation will be determined via C-reactive protein (CRP) levels. Normal values for CRP are considered < 10 mg/ml.
Time Frame
Pre-exposure and immediately, 24 hours and 1 week post-exposure
Title
Changes in microbiome in lung and nose
Description
The presence of 22 common respiratory viruses, 5 bacteria and 1 fungi will be determined using qualitative reverse transcription polymerase chain reaction (qRT-PCR) in sputum and nasal fluid. Pre and post-exposure microbiome patterns will be compared.
Time Frame
Pre-exposure and 1 week post-exposure
Title
Evaluation of the heart rate pattern
Description
Cardiovascular health will be evaluated by determining the heart rate pattern using ECG. Deviation from a normal ECG pattern will be recorded.
Time Frame
Pre-exposure and during the 90 minutes cold air exposure
Title
Determining the exercise capacity
Description
Exercise capacity will be checked. In a single test pre-exposure, the aerobic heart rate zone, anaerobic heart rate zone and maximal oxygen volume uptake (VO2max) heart rate zone will be evaluated to determine the exercise capacity
Time Frame
Pre-exposure

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
INCLUSION CRITERIA - healthy volunteers age between 18 and 60 years at time of signing informed consent BMI between 18-28 kg/m2 able to comply with study protocol, in the investigator's judgement non-smoking or ex-smokers for at least 12 months with less than 10 pack years no immunoglobulin E (IgE) mediated hypersensitivity normal spirometry & normal ECG at screening negative histamine provocation (defined as His- if PC20 >/= 8 mg/ml and His+ healthy controls if PC20 > 4 mg/ml and < 8 mg/ml) INCLUSION CRITERIA - asthmatic patients age between 18 and 60 years at time of signing informed consent BMI between 18-28 kg/m2 able to comply with study protocol, in the investigator's judgement non-smoking or ex-smokers for at least 12 months with less than 10 pack years physician-diagnosed asthma for more than 6 months post bronchodilator FEV1 of ≥ 80% at screening documented airway reversibility either by means of post bronchodilator reversibility of > 12% and > 200 ml or in the previous 6 months or by means of documented airway hyperresponsiveness (histamine PC20 <8 mg/ml) at screening Asthma Control Questionnaire (ACQ) < 1,5 regular treatment with inhaled corticosteroids (ICS) with or without long-acting beta-agonists (LABA) (unchanged dose for at least 1 month) normal ECG at screening EXCLUSION CRITERIA - healthy volunteers physician-diagnosed asthma or history of (post)infectious bronchial hyperreactivity major pulmonary or cardiovascular disease treatment with β-blockers pregnancy EXCLUSION CRITERIA - asthmatics patients unable to produce sputum with sputum induction previous history of intubation or admission to the intensive care unit due to asthma severe asthma exacerbation within one year prior to screening visit treatment with oral or systemic steroids within one year prior to screening visit previous treatment with biologics for asthma treatment with β-blockers other major concurrent pulmonary (such as chronic obstructive pulmonary disease, cystic fibrosis, sarcoidosis, interstitial lung disease, Churg-Strauss syndrome, allergic bronchopulmonary aspergillosis, bronchiectasis) or cardiovascular disease pregnancy
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Lieven Dupont, Prof. dr
Organizational Affiliation
KU Leuven/ UZ Leuven
Official's Role
Principal Investigator
Facility Information:
Facility Name
UZ Leuven Gasthuisberg
City
Leuven
ZIP/Postal Code
3000
Country
Belgium

12. IPD Sharing Statement

Plan to Share IPD
No

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The Effect of Physical Exercise in a Cold Air Environment on Normal Volunteers and Asthmatic Patients

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