Therapeutic Relevance of Abnormal Airway Morphology in Asthma

Phase 4

Not yet recruiting

• Conditions: Asthma
• Interventions: Drug: Inhaled corticosteroid (ICS); Drug: Oral Corticosteroid (OCS)

• Registration Number: NCT06970080
• Lead Sponsor: McMaster University

Brief Summary

Most individuals with asthma can effectively manage their symptoms and maintain normal lung function using inhaled medications, unfortunately, there is a subset of asthma sufferers whose symptoms, lung function, and risk of asthma attacks remain unimproved despite conventional inhaled medications. There could be several reasons for this. One possibility is that inhaled medications fail to reach the intended areas within the lungs, due to structural abnormalities within the airways themselves. Much like road conditions or closures can impede the speed and efficiency of vehicle travel, factors such as airway narrowing or mucus blockages, which are common in asthma, can obstruct the passage of inhaled medications through the airways. Our team has now optimized advanced medical imaging techniques, including magnetic resonance imaging (MRI) and computed tomography (CT), required to investigate this. This study will use these imaging methods to visually assess and measure individual patients' airways and determine whether abnormal airway structures impact how well they respond to inhaled and orally delivered medications. We anticipate finding that abnormal airway structures make inhaled medications less effective, but that they do not affect the response to oral medications.

Detailed Description

The cornerstone of asthma management lies in inhaled medications, including corticosteroids (ICS) and long-acting beta2-agonists (LABA). Unfortunately, individual responses to these first-line inhalers vary, and are ineffective in some people with asthma.

In asthma, the airways are the central site of disease pathology. Chronic airway inflammation, bronchial hyperresponsiveness, mucus plugging, and/or airway remodelling lead to luminal obstruction and airflow limitation that drive asthma symptoms. These factors can impact airflow, and the passage of inhaled drugs through the airways in asthma. Because optimal therapeutic effect likely depends, in part, on the dose topically deposited to the site of pathology, we propose that abnormal airway morphology may limit inhaled drug delivery to diseased airways and be a major factor contributing to poor response to inhaled drugs. Systemic (e.g., oral) drug delivery may achieve therapeutic targeting to diseased airways inaccessible by inhalation. This has not been investigated, and it constitutes the primary focus of the AirPATH study.

AirPATH is a two-phase open-label clinical study in adult patients with uncontrolled eosinophilic asthma to determine whether differences in their response to inhaled (ICS) and oral corticosteroid (OCS) treatments are predicted based on imaging-derived metrics of airway morphology and function.

Phase I Procedures Study Phase I is a 12-week clinical study of people with uncontrolled eosinophilic asthma. Patients will be screened for airway eosinophilia (sputum eosinophils ≥3% and/or FeNO ≥35ppb), uncontrolled asthma (ACQ-5 score ≥1.5), adequate inhaler technique and compliance. On clinical grounds, patients who meet these criteria require a "step-up" in their anti-inflammatory treatment. They will continue whatever ICS/LABA that they are on at screening and receive additional same dose of extra-fine particle ICS (i.e., their ICS would be doubled) for 12-weeks. Additional ICS will be delivered as equivalent of hydrofloroalkaline-beclomethasone dipropionate (Qvar) through a metered dose inhaler using an AeroChamber spacer. Patients will continue all their pre-study medication throughout the study.

Visit procedures: At screening (visit 1, week -1), demographics (age, biological sex, self-identified gender, BMI and race/ethnicity) and asthma characteristics will be collected (ICS dose, asthma duration), pre and post-bronchodilator pulmonary function tests (PFT) will be performed, sputum induction will be performed to quantify airway eosinophils, and the ACQ-5 will be completed to document asthma control. Eligible patients will proceed to a baseline visit (visit 2, week 0), and undergo inspiratory and expiratory chest CT, 129Xe and 1H MRI, PFTs, sputum induction, FeNO, blood draw, and complete questionnaires (ACQ-5, ACT, AQLQ), before their ICS dose is doubled. To determine the biological, physiological, and clinical response to additional ICS, patients will be followed-up at 12-weeks (visit 3) for outcome assessment, at which time all baseline (visit 2) procedures will be repeated.

Phase II Procedures Participants with persistent uncontrolled eosinophilic asthma (sputum eosinophils ≥3% and/or FeNO ≥35ppb and ACQ-5 score ≥1.5) after study Phase I will enter Phase II. Study phase II is a 1-week, clinical study in which all participants, regardless of their inhaled corticosteroid dose, will receive add-on oral prednisone (30mg/day) for one-week. Visit 3/week 12 will serve as the Phase II baseline, such that patients would have undergone inspiratory and expiratory chest CT, 129Xe and 1H MRI, PFTs, sputum induction, FeNO, blood draw, and completed the ACQ-5, before receiving add-on OCS. All other asthma medication would be continued. To document the biological, physiological, and clinical response to add-on OCS, participants will be followed-up at one-week (visit 4, week 13) for outcome assessment, at which time all baseline procedures except CT will be repeated.

Analysis Plan Multivariable linear regression models will be generated to determine if specific baseline imaging-metrics are independent predictors of biological response (∆ in sputum eosinophil percentage and FeNO), physiological response (∆ in 129Xe MRI VDP, FEV1, etc.), and/or clinical response (∆ in ACQ-5 score, etc.) to ICS (Phase I) and OCS (Phase II).

Study Timeline

• Study First Submitted: 2025-04-17
• Status Verified: 2025-05
• Study First Submitted QC: 2025-05-05
• Last Update Submitted: 2025-05-05
• Study First Posted: 2025-05-14
• Last Update Posted: 2025-05-14
• Study Start: 2025-06
• Primary Completion: 2028-06
• Study Completion: 2028-06

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 242

Inclusion Criteria

• Able and willing to provide written informed consent.
• Able and willing to comply with the study protocol.
• Males and females ≥ 18 years of age.
• Asthma diagnosed by a respiratory physician.
• Airway hyperresponsiveness (defined as methacholine PC20 ≤8mg/mL) and/or bronchodilator reversibility (defined as post-bronchodilator FEV1 improvement ≥200mL and 12%) in the last 6 months
• ACQ ≥1.5 during the screening period.
• Sputum eosinophils ≥3% and/or FeNO ≥35ppb during the screening period.

Exclusion Criteria

• Current smoker, defined as someone having smoked ≥1 cigarette/day (or vape/pipe/cigar/marijuana) for ≥30 days within 12 months prior to screening.
• Pregnant or breastfeeding
• Non-English speaking
• Oral corticosteroids in past 1-month
• Biologic therapy in past 6-months
• Unable to perform proper MDI technique during the screening period
• Other pulmonary diseases (e.g., chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, cystic fibrosis, pulmonary arterial hypertension, tuberculosis) requiring treatment within 12 months prior to screening.
• Unable to undergo MRI. Patient has an implanted mechanically, electrically, or magnetically activated device or any metal in their body which cannot be removed, including but not limited to pacemakers, neurostimulators, biostimulators, implanted insulin pumps, aneurysm clips, bioprosthesis, artificial limb, metallic fragment or foreign body, shunt, surgical staples (including clips or metallic sutures and/or ear implants) (at the discretion of the MRI Technologist). Suffers from any physical, psychological, or other condition(s) that might prevent performance of the MRI, such as severe claustrophobia.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Uncontrolled eosinophilic asthma	Inhaled corticosteroid (ICS)	In Phase I, participants will receive a doubling of their current ICS dose. If their asthma remains uncontrolled, they will receive an OCS burst in phase II.
Uncontrolled eosinophilic asthma	Oral Corticosteroid (OCS)	In Phase I, participants will receive a doubling of their current ICS dose. If their asthma remains uncontrolled, they will receive an OCS burst in phase II.

Primary Outcome Measures

Name	Time	Method
Biological response to additional ICS	12 weeks	Biological response to additional ICS evaluated as change from baseline in sputum eosinophil percent and FeNO at 12 weeks.
Biological response to add-on OCS	1 week	Biological response to add-on OCS evaluated as change from Phase II baseline (Visit 3/Week 12) in sputum eosinophil percent and FeNO at one-week (Visit 4/Week 13).

Secondary Outcome Measures

Name	Time	Method
Respiratory system resistance (Rrs) at 19Hz response to add-on OCS	1 week	Physiological response to add-on OCS evaluated as change from Phase II baseline (Visit 3/Week 12) in Rrs19Hz at one-week (Visit 4/Week 13).
Frequency dependence of Rrs (Rrs5-19Hz) response to add-on OCS	1 week	Physiological response to add-on OCS evaluated as change from Phase II baseline (Visit 3/Week 12) in Rrs5-19Hz at one-week (Visit 4/Week 13).
Integrated area of low frequency reactance (AX) response to add-on OCS	1 week	Physiological response to add-on OCS evaluated as change from Phase II baseline (Visit 3/Week 12) in AX at one-week (Visit 4/Week 13).
ACQ-5 response to add-on OCS	1 week	Clinical response to add-on OCS evaluated as change from Phase II baseline (Visit 3/Week 12) in the Asthma Control Questionnaire-5 (ACQ-5) score at one-week (Visit 4/Week 13).
AQLQ response to add-on OCS	1 week	Clinical response to add-on OCS evaluated as change from Phase II baseline (Visit 3/Week 12) in the Asthma Quality of Life Questionnaire (AQLQ) score at one-week (Visit 4/Week 13).
ACT response to add-on OCS	1 week	Clinical response to add-on OCS evaluated as change from Phase II baseline (Visit 3/Week 12) in the Asthma Control Test (ACT) score at one-week (Visit 4/Week 13).
Respiratory system reactance (Xrs) at 5Hz response to add-on OCS	1 week	Physiological response to add-on OCS evaluated as change from Phase II baseline (Visit 3/Week 12) in Xrs5Hz at one-week (Visit 4/Week 13).
129Xe MRI ventilation defect percent (VDP) response to additional ICS	12 weeks	Change in 129Xe MRI VDP between baseline (week 0) and week 12.
FEV1 response to additional ICS	12 weeks	Physiological response to additional ICS evaluated as change from baseline in FEV1 at 12 weeks.
Respiratory system resistance (Rrs) at 5Hz response to additional ICS	12 weeks	Change in Rrs5Hz between baseline (week 0) and week 12.
Respiratory system reactance (Xrs) at 5Hz response to additional ICS	12 weeks	Physiological response to additional ICS evaluated as change from baseline in Xrs5Hz at 12 weeks.
Respiratory system resistance (Rrs) at 19Hz response to additional ICS	12 weeks	Physiological response to additional ICS evaluated as change from baseline in Rrs19Hz at 12 weeks.
Frequency dependence of Rrs (Rrs5-19Hz) response to additional ICS	12 weeks	Physiological response to additional ICS evaluated as change from baseline in Rrs5-19Hz at 12 weeks.
Integrated area of low frequency reactance (AX) response to additional ICS	12 weeks	Physiological response to additional ICS evaluated as change from baseline in AX at 12 weeks.
ACQ-5 response to additional ICS	12 weeks	Clinical response to additional ICS evaluated as change from baseline in Asthma Control Questionnaire-5 (ACQ-5) score at 12 weeks.
AQLQ response to additional ICS	12 weeks	Clinical response to additional ICS evaluated as change from baseline in Asthma Quality of Life Questionnaire (AQLQ) score at 12 weeks.
ACT response to additional ICS	12 weeks	Clinical response to additional ICS evaluated as change from baseline in Asthma Control Test (ACT) score at 12 weeks.
129Xe MRI ventilation defect percent (VDP) response to add-on OCS	1 weeks	Physiological response to add-on OCS evaluated as change from Phase II baseline (Visit 3/Week 12) in 129Xe MRI VDP at one-week (Visit 4/Week 13).
FEV1 response to add-on OCS	1 week	Physiological response to add-on OCS evaluated as change from Phase II baseline (Visit 3/Week 12) in FEV1 at one-week (Visit 4/Week 13).
Respiratory system resistance (Rrs) at 5Hz response to add-on OCS	1 week	Physiological response to add-on OCS evaluated as change from Phase II baseline (Visit 3/Week 12) in Rrs5Hz at one-week (Visit 4/Week 13).

Trial Locations

Locations (2)

St. Joseph's Healthcare Hamilton; 🇨🇦 Hamilton, Ontario, Canada

Western University; 🇨🇦 London, Ontario, Canada