Oxidative Stress in Asthma
Primary Purpose
Asthma, Obesity
Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Hyperpolarized 129XeMRI
Sponsored by
About this trial
This is an interventional diagnostic trial for Asthma focused on measuring Asthma, MRI, Obesity
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.
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
No
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
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
Email
shelby.martindale@duke.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Catherine M Foss, BS, RRT
Phone
919-613-7627
Email
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
No
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Oxidative Stress in Asthma
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