The Effect of a Cold Air Eucapnic Hyperventilation Test on Lower Respiratory Airways in Healthy Volunteers and Patients With Asthma (CLARINET)

October 23, 2025 updated by: Lieven Dupont, KU Leuven
In this study, we want to evaluate the feasibility and safety of a CAEH test in healthy volunteers and patients with asthma. We want to develop a CAEH test to differentiate patients with different types of asthma and exercise-induced bronchoconstriction from healthy volunteers and to evaluate whether the respiratory phenotype induced by cold air inhalation differs between subjects with asthma and healthy subjects. Furthermore, we want to evaluate whether the CAEH test is more robust over time compared to the EVH test. Previously, our lab has demonstrated that submaximal exercise at subfreezing temperatures in a climate chamber (-5°C) induces an acute respiratory response in patients with asthma and in healthy subjects who have been exposed to high PM10 (unpublished data). Finally, This study will serve as a preliminary study for a subsequent prospective study in which the results and optimized protocol obtained in this study will be used to further evaluate the feasibility of using this CAEH as a diagnostic tool in asthma compared to EIB (CLARINET2). The present study is required to develop a standardized CAEH test in a safe and feasible manner. This study will also help to identify appropriate endpoints (FEV1, multiple breath washout test, biomarkers…) of the subsequent studies.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

In this study, we aim to develop a safe and feasible cold air (-15°C) eucapnic hyperventilation (CAEH) test protocol in which we can compare the lower airway responses between healthy volunteers and subjects with asthma. Consequently, we want to evaluate the effect of cold air inhalation on FEV1, respiratory symptoms, airway integrity, and local and systemic inflammation.

Primary endpoints

The primary endpoint of this study is to compare proportional change in FEV1, (% decrease) after a CAEH test in healthy volunteers and patients with mild to moderate asthma. Post-exposure will be calculated as a time-weighted average over the 30 min after the CAEH test. At each time point (pre-, 5, 10, 15, and 30 minutes post-exposure), FEV1 will be measured in triplicate.

Secondary endpoints

We want to evaluate whether and to what extent the inhalation of cold air during this CAEH test can induce changes in respiratory symptoms (including dyspnea, cough, mucus production, etc.), affects lower airway integrity (airway obstruction (FEV1/FVC), small airway dysfunction (FEF 25/75, lung ventilation inhomogeneity (LCI), bronchial hyperreactivity (PC20 AMP)) and whether it induces (local or systemic) inflammation (different biomarkers in sputum and blood, as defined in section 5.2).

These changes will be compared between healthy volunteers and predisposed subjects with mild to moderate asthma. The abovementioned responses and the proportional change in FEV1 after the CAEH test will be compared to a standard (21°C room air) eucapnic hyperventilation (EVH) test. Furthermore, we will compare the results obtained in this study to the results obtained in the ALASCAIR study of dr. Tatjana Decaesteker. Finally, the effects of the CAEH will be correlated to the amount of air pollution the subject was exposed to, in the days prior to the test (as this may have an effect on the responses to cold air inhalation in healthy volunteers, as found in the Alascair study (unpublished data)), by means of different questionnaires evaluating life style and exposure to air pollution (SF-36, AQLQ, ACQ, SQUASH,…).

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
60

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Belgium
      • Leuven, Belgium, 3000
        • UZ Leuven Gasthuisberg

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  • Age between 18 and 65 years old at time of signing informed consent
  • BMI between 18 and 28 kg/cm2
  • Ability to give informed consent and 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
  • Normal spirometry

Group specific:

Histamine positive healthy controls: histamine bronchial challenge test (< 8 mg/ml) at screening Healthy controls: histamine bronchial challenge test (≥ 8 mg/ml) at screening

Patients with asthma:

  • Physician-diagnosed asthma for at least 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 < 4 mg/ml) at screening
  • Asthma control questionnaire (ACQ) ≤ 1.5
  • Regular treatment with ICS with or without LABA (unchanged dose for at least 30 days) at a low or medium dose of ICS

Exclusion Criteria:

  • Previous history of intubation or admission to ICU due to asthma
  • Severe asthma exacerbation within one month prior to screening visit
  • Treatment with oral or systemic steroids within one month prior to screening visit
  • Previous treatment with biologics for asthma
  • Other major concurrent pulmonary (such as COPD, cystic fibrosis, sarcoidosis, interstitial lung disease, Churg-Strauss syndrome, allergic bronchopulmonary aspergillosis, bronchiectasis) or cardiovascular disease
  • Pregnancy

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Other: Healthy volunteers with negative histamine provocation challenge
Healthy volunteers with negative histamine provocation challenge will perform the same tests as the other 2 arms. The healthy volunteers are assigned in this group after the histamine provocation challenge. All will perform one hyperventilation challenge at room temperature (EVH) and one with cold air (CACh) with pre- and post-exposure evaluation on FEV1, respiratory symptoms and local and systemic inflammation
Device: Cold air challenge
This intervention consists of a standardized cold air eucapnic hyperventilation test using a device that controls temperature, humidity, and ventilation. Airway responses are measured via spirometry and biospecimens (serum and sputum supernatant). It is distinguished from other studies by its prospective design and inclusion of both healthy and asthmatic participants
Other Names:
  • Cold air hyperventilation test
Other: Healthy volunteers with positive histamine provocation challenge
Healthy volunteers with positive histamine provocation challenge will perform the same tests as the other 2 arms. The healthy volunteers are assigned in this group after the histamine provocation challenge. All will perform one hyperventilation challenge at room temperature (EVH) and one with cold air (CACh) with pre- and post-exposure evaluation on FEV1, respiratory symptoms and local and systemic inflammation
Device: Cold air challenge
This intervention consists of a standardized cold air eucapnic hyperventilation test using a device that controls temperature, humidity, and ventilation. Airway responses are measured via spirometry and biospecimens (serum and sputum supernatant). It is distinguished from other studies by its prospective design and inclusion of both healthy and asthmatic participants
Other Names:
  • Cold air hyperventilation test
Other: Patients with asthma
Patients with asthma will perform the same tests as the other 2 arms. The healthy volunteers are assigned in this group after the histamine provocation challenge. All will perform one hyperventilation challenge at room temperature (EVH) and one with cold air (CACh) with pre- and post-exposure evaluation on FEV1, respiratory symptoms and local and systemic inflammation
Device: Cold air challenge
This intervention consists of a standardized cold air eucapnic hyperventilation test using a device that controls temperature, humidity, and ventilation. Airway responses are measured via spirometry and biospecimens (serum and sputum supernatant). It is distinguished from other studies by its prospective design and inclusion of both healthy and asthmatic participants
Other Names:
  • Cold air hyperventilation test

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Proportional change in FEV1 after hyperventilation challenge
Time Frame: After each hyperventilation challenge: pre, immediately, 3, 5, 10, 15 and 30 minutes after the challenge
The proportional change in FEV1 after hyperventilation challenges compared to baseline were measured.
After each hyperventilation challenge: pre, immediately, 3, 5, 10, 15 and 30 minutes after the challenge

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Changes in symptoms
Time Frame: From the first hyperventilation challenge until 1 day after the second
We want to evaluate changes in respiratory symptoms after challenge. The degree of dyspnea and cough will be determined using BORG scale. This is a 0 to 10 scale.
From the first hyperventilation challenge until 1 day after the second
Lung function changes
Time Frame: After each hyperventilation challenge
Changes in lung function (FEV1/FVC, FEF25-75, LCI, PEF...) were measured after hyperventilation challenge
After each hyperventilation challenge
Inflammatory parameters
Time Frame: At baseline and after each hyperventilation challenge

Inflammation was assessed in sputum and blood. Cytokines, allergic response, cellular response, DAMPs and measures of epithelial integrity were assessed.

Differential cell count will be performed on sputum samples, determining eosinophilic (> 3% eosinophils), neutrophilic (> 61% neutrophils), pauci-granulocytic (< 3% eosinophilic, < 61% neutrophils) and mixed granulocytic (> 3% eosinophilic, > 61% neutrophils). Cytokines will be determined in sputum supernatant with a U-plex assay. Airway inflammation is determined with FeNO. < 25 ppm = eosinophilic inflammation less likely, between 25 - 50 ppm = need further interpretation with additional information and > 50 ppm = indication of eosinophilic airway inflammation. Systemic inflammation will be measured in serum using U-plex assay. allergic response is measured with skin prick automated test on 10 allergens and in serum with total IgE.
At baseline and after each hyperventilation challenge

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
KU Leuven

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Universitaire Ziekenhuizen KU Leuven

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Lieven Dupont, KU Leuven/UZ Leuven

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
August 4, 2023

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
November 27, 2024

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
November 27, 2024

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
October 23, 2025

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
October 23, 2025

First Posted (Estimated)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
October 24, 2025

Study Record Updates

Last Update Posted (Estimated)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
October 24, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
October 23, 2025

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
October 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • S66825

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

Yes

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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