Therapeutic Relevance of Abnormal Airway Morphology in Asthma

NCT ID: NCT06970080

Last Updated: 2025-09-11

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 242 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-06-02
• Study Completion Date: 2028-06-30

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).

Conditions

Asthma

Study Design

• Allocation Method: NA
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Uncontrolled eosinophilic asthma

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.

Group Type: EXPERIMENTAL

Inhaled corticosteroid (ICS)

Intervention Type: DRUG

In Phase I, participants will receive additional same dose of extra-fine particle ICS (i.e., their ICS would be doubled) for 12-weeks.

Oral Corticosteroid (OCS)

Intervention Type: DRUG

In phase II, participants will receive add-on oral prednisone (30mg/day) for one-week.

Interventions

Inhaled corticosteroid (ICS)

In Phase I, participants will receive additional same dose of extra-fine particle ICS (i.e., their ICS would be doubled) for 12-weeks.

Intervention Type: DRUG

Oral Corticosteroid (OCS)

In phase II, participants will receive add-on oral prednisone (30mg/day) for one-week.

Intervention Type: DRUG

Other Intervention Names

QVAR; hydrofloroalkaline-beclomethasone dipropionate; prednisone

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

McMaster University

OTHER

Sponsor Role: lead

Responsible Party

Sarah Svenningsen

Assistant Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

St. Joseph's Healthcare Hamilton

Hamilton, Ontario, Canada

Site Status: RECRUITING

Western University

London, Ontario, Canada

Site Status: NOT_YET_RECRUITING

Countries

Canada

Central Contacts

Sarah Svenningsen, PhD

Role: CONTACT

svennins@mcmaster.ca

(905) 522-1155 Ext. 32195

Yonni Friedlander, PhD

Role: CONTACT

yfriedla@stjoes.ca

(905) 522-1155 Ext. 32195

Facility Contacts

Sarah Svenningsen, PhD

Role: primary

svennins@mcmaster.ca

905-522-1155 ext. 32195

Grace Parraga, PhD

Role: primary

gparraga@uwo.ca

519-931-5777 ext. 24197

Other Identifiers

Xe012

Identifier Type: -

Identifier Source: org_study_id