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Oxidative Stress in Asthma

Primary Purpose

Asthma, Obesity

Status

Recruiting

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Hyperpolarized 129XeMRI

About this trial

This is an interventional diagnostic trial for Asthma focused on measuring Asthma, MRI, Obesity

Eligibility Criteria

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

Inclusion Criteria:

Asthma Cohort INCLUSION

Adequate completion of informed consent process with written documentation
Male and female patients, 18 - 65 years old, inclusive
Physician diagnosis of asthma for > 1 year
Able to perform reproducible spirometry according to ATS criteria
Post-bronchodilator FEV1 ≥ 60% of predicted at Visit 0
All racial/ethnic backgrounds may participate
BMI ≥ 30 kg/m2
Regular treatment with ICS or ICS/LABA and/or LAMA combination medication for at least 3 months; on a stable dose for the 4 weeks prior to Visit 0
Smoking history <10 pack years and no smoking in the last 3 months
Late onset asthma: Age of asthma onset (diagnosis) ≥12 years;
FeNO < 25 ppb at Visit 0
Negative allergen skin test
Early onset asthma: Age of asthma onset (diagnosis) <12 years
FeNO ≥ 25 ppb at Visit 0
Positive allergen skin test

Non-Asthma Cohort INCLUSION

No history of asthma or other chronic lung diseases
Male and female patients, 18 - 65 years old, inclusive
Not currently smoking or using other forms of tobacco-related products (including vaping)
Smoking history <10 pack years and no smoking in the past 3 months
FEV1 > 80% of predicted and FEV1/FVC > lower limit of normal.
Ability to sign consent
BMI ≥ 30 kg/m2
Negative allergen skin test

Additional INCLUSION Criteria for MRI

Outpatients of either gender, age > 18
Willing and able to give informed consent and adhere to visit/protocol schedules. (Consent must be given before any study procedures are performed.)
Women of childbearing potential must have a negative urine pregnancy test prior to MRI.

EXCLUSION Criteria

Asthma Cohort EXCLUSION:

Respiratory tract infection within the 4 weeks prior to Visit 0
Oral or systemic corticosteroid burst (for any indication) within the 4 weeks prior to Visit 0. One-time doses, such as intra-articular injections into a shoulder or knee joint, require a 4- week washout prior to Visit 0
Asthma-related ER visit within the previous 4 weeks of Visit 0
History of ICU admission/intubation due to asthma in the past 1 year
Three or more asthma exacerbations requiring treatment with systemic corticosteroids in the past year consistent with severe asthma
Asthma exacerbation requiring systemic corticosteroids within the 4 weeks prior to Visit 0
Significant concomitant medical illness, including (but not limited to) heart disease, cancer, uncontrolled diabetes, other chronic lung diseases
Chronic renal failure (creatinine > 2.0) at Visit 0
Positive urine pregnancy test at Visit 0 or at any time during the study
Untreated sleep apnea
Participation in an intervention study (including, bronchoscopy) or use of investigative drugs within the past 30 days or plans to enroll in such a trial during the study
Unable or unlikely to complete study assessments in the opinion of the Investigator
Study intervention poses undue risk to patient in the opinion of the Investigator
History of bronchial thermoplasty

Non-Asthma Cohort EXCLUSION:

Respiratory tract infection within the 4 weeks prior to Visit 0 Oral or systemic corticosteroid burst (for any indication) within the 4 weeks prior to Visit 0. One-time doses, such as intra-articular injections into a shoulder or knee joint, require a 4-week washout prior to Visit 0
Significant concomitant medical illness, including (but not limited to) heart disease, cancer, uncontrolled diabetes, other chronic lung diseases
Chronic renal failure (creatinine > 2.0) at Visit 0
Positive urine pregnancy test at Visit 0 or at any time during the study
Untreated sleep apnea
Participation in an intervention study (including bronchoscopy) or use of investigative drugs within the past 30 days or plans to enroll in such a trial during the study
Unable or unlikely to complete study assessments in the opinion of the Investigator
Study intervention poses undue risk to patient in the opinion of the Investigator

Additional EXCLUSION Criteria for MRI

Medical or psychological conditions which, in the opinion of the investigator, might create undue risk to the subject or interfere with the subject's ability to comply with the protocol requirements
Conditions that will prohibit MRI scanning (metal in eye, claustrophobia, inability to lie supine, shoulder circumference >140 cm*.) *This measurement is not an absolute as it can vary based on weight distribution.

Sites / Locations

Duke Asthma Allergy and Airway CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Obese Asthmatics

Obese Non-Asthmatics

Arm Description

Obese patients that come to Duke that have been diagnosed with Asthma will be approached.

The obese non-asthmatics will be collected from an IRB pre-approved Healthy Volunteer Data Repository.

Outcomes

Primary Outcome Measures

Percent trichrome or elastic or fiber staining between fixed and reversible airway segments in obese asthma groups (early onset, late onset) and non-asthma controls will be determined.

Percent neutrophils in peripheral blood in obese and lean asthmatics will be determined.

Percent eosinophils in peripheral blood in obese and lean asthmatics will be determined.

Percent change in 3-Nitrotyrosine production by airway epithelial cells harvested from obese and lean asthmatics and non-asthmatic obese controls will be determined.

Percent change in H202 production by airway epithelial cells harvested from obese and lean asthmatics and non-asthmatic obese controls will be determined.

Leptin stimulated human airway fibroblast invasiveness will be determined by counting mean numbers of invading fibroblasts in obese and lean asthmatics and non-asthmatic obese controls.

Percent change in intracellular ROS production by airway fibroblasts will be assessed using flow cytometry.

Secondary Outcome Measures

Full Information

NCT ID

NCT04512547

First Posted

July 20, 2020

Last Updated

January 4, 2023

Sponsor

Bastiaan Driehuys

Collaborators

National Institutes of Health (NIH)

1. Study Identification

Unique Protocol Identification Number

NCT04512547

Brief Title

Oxidative Stress in Asthma

Official Title

Oxidative Stress and Regional Airway Remodeling and Fibrosis in Obese Asthma

Study Type

Interventional

2. Study Status

Record Verification Date

January 2023

Overall Recruitment Status

Recruiting

Study Start Date

April 1, 2021 (Actual)

Primary Completion Date

January 1, 2025 (Anticipated)

Study Completion Date

January 1, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Bastiaan Driehuys

Collaborators

National Institutes of Health (NIH)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

40% of all asthma patients in the US are obese. Obese asthmatics have more severe disease than lean asthmatics and do not respond as well to conventional anti-inflammatory therapies. This proposal will utilize 3D functional imaging with 129XeMRI and single cell RNA sequencing to study mechanisms driving regional airway remodeling and fibrosis in obese asthma subjects and in preclinical models of obese asthma.

Detailed Description

ABSTRACT Obesity, a major comorbidity and a potential modulator of asthma, affects nearly 40% of asthmatics in the U.S., and increases its severity. Obese asthmatics do not respond as well to conventional anti-inflammatory therapies and new biologics targeting asthma are less effective in obese asthmatics compared to lean. Very little research has been conducted in obese animals or obese asthmatics, resulting in a major knowledge deficit. A key feature of asthma is airway remodeling and fibrosis, broadly defined as a change in distribution, thickness, composition, mass or volume of structural components of the airway wall of patients relative to healthy patients. Airway remodeling is difficult to diagnose in obese patients as mechanical changes in chest wall compliance can contribute to the physiological changes seen. Classically, evidence of airway remodeling and fibrosis are revealed as fixed airway obstruction on spirometry. However, spirometry is not only insensitive to the peripheral airways, where airway remodeling occurs, but is fundamentally incapable of localizing the sites of remodeling and fibrosis. Thus, a critical research limitation in the study of airway remodeling and fibrosis in asthma is defining regions of disease activity to explore disease-specific mechanisms. To understand the nature of airway remodeling and fibrosis in obese asthma and to rapidly screen for novel therapies requires translation between preclinical models and patients, while using advanced imaging. Recent work in asthma using 3D functional imaging with 129Xe MRI has revealed the location of both reversible and fixed ventilation defects (defined based on bronchodilator responsivity). Several studies suggest that fixed defects represent sites of airway remodeling and fibrosis, but to date, this has been inferred indirectly from sputum analyses and CT scans. The central hypothesis is that sites of abnormal ventilation on 129XeMRI represent areas of airway remodeling and fibrosis and are enriched with fibroblasts that are invasive, proliferative and fibrogenic. It is further hypothesized that regional alterations in oxidant stress driving the production of transforming growth factor-beta (TGF-β) direct pro-remodeling fibroblast functions. Lastly, it is hypothesized that 129XeMRI will be a sensitive and specific biomarker of airway remodeling and fibrosis in obese asthmatics and rat models of obese asthma. By leveraging our excellence in clinical asthma, bronchoscopy, and translational expertise in cell function/signaling and 3D MR imaging in both patients and animal models, both ex vivo cell-specific mechanistic studies and in vivo animal model studies will be conducted to uncover the mechanisms of molecular and cellular function through the following Specific Aims: Aim 1) Identify the pathology, structural cell profile (airway fibroblast and epithelial cell) and redox status corresponding to regional areas of fixed and reversible post-bronchodilator defects (BD) in obese asthmatics; 2) Define the cellular requirement for redox-mediated TGF-β signaling between airway epithelial cells and fibroblasts driving regional remodeling in obese asthma; 3) Develop non-invasive 3D imaging techniques to assess airway regional remodeling in experimental rodent models of obese asthma.

6. Conditions and Keywords

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

Asthma, Obesity

Keywords

Asthma, MRI, Obesity

7. Study Design

Primary Purpose

Diagnostic

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

Participant

Allocation

Non-Randomized

Enrollment

40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Obese Asthmatics

Arm Type

Experimental

Arm Description

Obese patients that come to Duke that have been diagnosed with Asthma will be approached.

Arm Title

Obese Non-Asthmatics

Arm Type

Active Comparator

Arm Description

The obese non-asthmatics will be collected from an IRB pre-approved Healthy Volunteer Data Repository.

Intervention Type

Drug

Intervention Name(s)

Hyperpolarized 129XeMRI

Intervention Description

Images obtained using 129XeMRI will be obtained on both obese asthmatic and non-asthmatics

Primary Outcome Measure Information:

Title

Percent trichrome or elastic or fiber staining between fixed and reversible airway segments in obese asthma groups (early onset, late onset) and non-asthma controls will be determined.

Time Frame

Up to 6 weeks

Title

Percent neutrophils in peripheral blood in obese and lean asthmatics will be determined.

Time Frame

Up to 6 weeks

Title

Percent eosinophils in peripheral blood in obese and lean asthmatics will be determined.

Time Frame

Up to 6 weeks

Title

Percent change in 3-Nitrotyrosine production by airway epithelial cells harvested from obese and lean asthmatics and non-asthmatic obese controls will be determined.

Time Frame

Baseline, visit 1 (one week +/- 7 day), visit 2 (one week +/- 7 day), visit 3 (one week +/- 7 day)

Title

Percent change in H202 production by airway epithelial cells harvested from obese and lean asthmatics and non-asthmatic obese controls will be determined.

Time Frame

Baseline, visit 1 (one week +/- 7 day), visit 2 (one week +/- 7 day), visit 3 (one week +/- 7 day)

Title

Leptin stimulated human airway fibroblast invasiveness will be determined by counting mean numbers of invading fibroblasts in obese and lean asthmatics and non-asthmatic obese controls.

Time Frame

Up to 6 weeks

Title

Percent change in intracellular ROS production by airway fibroblasts will be assessed using flow cytometry.

Time Frame

Baseline, visit 1 (one week +/- 7 day), visit 2 (one week +/- 7 day), visit 3 (one week +/- 7 day)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Asthma Cohort INCLUSION Adequate completion of informed consent process with written documentation Male and female patients, 18 - 65 years old, inclusive Physician diagnosis of asthma for > 1 year Able to perform reproducible spirometry according to ATS criteria Post-bronchodilator FEV1 ≥ 60% of predicted at Visit 0 All racial/ethnic backgrounds may participate BMI ≥ 30 kg/m2 Regular treatment with ICS or ICS/LABA and/or LAMA combination medication for at least 3 months; on a stable dose for the 4 weeks prior to Visit 0 Smoking history <10 pack years and no smoking in the last 3 months Late onset asthma: Age of asthma onset (diagnosis) ≥12 years; FeNO < 25 ppb at Visit 0 Negative allergen skin test Early onset asthma: Age of asthma onset (diagnosis) <12 years FeNO ≥ 25 ppb at Visit 0 Positive allergen skin test Non-Asthma Cohort INCLUSION No history of asthma or other chronic lung diseases Male and female patients, 18 - 65 years old, inclusive Not currently smoking or using other forms of tobacco-related products (including vaping) Smoking history <10 pack years and no smoking in the past 3 months FEV1 > 80% of predicted and FEV1/FVC > lower limit of normal. Ability to sign consent BMI ≥ 30 kg/m2 Negative allergen skin test Additional INCLUSION Criteria for MRI Outpatients of either gender, age > 18 Willing and able to give informed consent and adhere to visit/protocol schedules. (Consent must be given before any study procedures are performed.) Women of childbearing potential must have a negative urine pregnancy test prior to MRI. EXCLUSION Criteria Asthma Cohort EXCLUSION: Respiratory tract infection within the 4 weeks prior to Visit 0 Oral or systemic corticosteroid burst (for any indication) within the 4 weeks prior to Visit 0. One-time doses, such as intra-articular injections into a shoulder or knee joint, require a 4- week washout prior to Visit 0 Asthma-related ER visit within the previous 4 weeks of Visit 0 History of ICU admission/intubation due to asthma in the past 1 year Three or more asthma exacerbations requiring treatment with systemic corticosteroids in the past year consistent with severe asthma Asthma exacerbation requiring systemic corticosteroids within the 4 weeks prior to Visit 0 Significant concomitant medical illness, including (but not limited to) heart disease, cancer, uncontrolled diabetes, other chronic lung diseases Chronic renal failure (creatinine > 2.0) at Visit 0 Positive urine pregnancy test at Visit 0 or at any time during the study Untreated sleep apnea Participation in an intervention study (including, bronchoscopy) or use of investigative drugs within the past 30 days or plans to enroll in such a trial during the study Unable or unlikely to complete study assessments in the opinion of the Investigator Study intervention poses undue risk to patient in the opinion of the Investigator History of bronchial thermoplasty Non-Asthma Cohort EXCLUSION: Respiratory tract infection within the 4 weeks prior to Visit 0 Oral or systemic corticosteroid burst (for any indication) within the 4 weeks prior to Visit 0. One-time doses, such as intra-articular injections into a shoulder or knee joint, require a 4-week washout prior to Visit 0 Significant concomitant medical illness, including (but not limited to) heart disease, cancer, uncontrolled diabetes, other chronic lung diseases Chronic renal failure (creatinine > 2.0) at Visit 0 Positive urine pregnancy test at Visit 0 or at any time during the study Untreated sleep apnea Participation in an intervention study (including bronchoscopy) or use of investigative drugs within the past 30 days or plans to enroll in such a trial during the study Unable or unlikely to complete study assessments in the opinion of the Investigator Study intervention poses undue risk to patient in the opinion of the Investigator Additional EXCLUSION Criteria for MRI Medical or psychological conditions which, in the opinion of the investigator, might create undue risk to the subject or interfere with the subject's ability to comply with the protocol requirements Conditions that will prohibit MRI scanning (metal in eye, claustrophobia, inability to lie supine, shoulder circumference >140 cm*.) *This measurement is not an absolute as it can vary based on weight distribution.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Shelby Martindale, AS, CRTT

Phone

919-668-6532

shelby.martindale@duke.edu

First Name & Middle Initial & Last Name or Official Title & Degree

Catherine M Foss, BS, RRT

Phone

919-613-7627

catherine.foss@duke.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Loretta Que, MD

Organizational Affiliation

Duke

Official's Role

Principal Investigator

Facility Information:

Facility Name

Duke Asthma Allergy and Airway Center

City

Durham

State/Province

North Carolina

ZIP/Postal Code

27705

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Antoinette Santoro, MS, BSRT

12. IPD Sharing Statement

Plan to Share IPD

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Oxidative Stress in Asthma

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