University of Wisconsin Severe Asthma Research Program III

• ClinicalTrials.gov Identifier: NCT01760915
• Recruitment Status: Suspended
• First Posted: January 4, 2013
• Last Update Posted: April 3, 2020
• Sponsor: University of Wisconsin, Madison
• Collaborators: National Institutes of Health (NIH); Washington University School of Medicine; National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): University of Wisconsin, Madison

Study Description

Brief Summary:

The overall goal of this proposal is to better understand the basis of structural airway changes in severe asthma and how asthma exacerbations may contribute to their progression over time. The investigators propose to study a well-characterized cohort of adult and pediatric subjects with asthma using a multidisciplinary state-of-the-art approach. We hypothesize that severe asthma exacerbations, in some patients, are associated with incomplete recovery and activation of airway inflammatory cells in a regional distribution. The end result is a more permanent and less reversible airway obstruction that is a prominent feature of severe asthma.

Condition or disease	Intervention/treatment
Asthma	Other: NC100182 Hyperpolarized 3He

Detailed Description:

We have shown that patients with severe asthma have heterogeneous regional ventilation defects and air trapping. Some of these defects are persistent, while others can be provoked with virus-induced exacerbations or bronchial challenge and recur in the same general areas on repeated challenge, suggesting localized airway dysfunction. In preliminary studies, inflammatory parameters tended to be more prominent in segments that showed ventilation defects on imaging. Therefore, we hypothesize that asthma exacerbations, in some patients, are associated with incomplete recovery and activation of airway inflammatory cells in a regional distribution. This leads to enhanced airway injury with airway dysfunction as reflected by ventilation defects and air trapping, and a more generalized increase in disease severity. To evaluate this hypothesis we propose the following specific aims: 1. To refine phenotyping of severe asthma using new variables from multiple domains in a large longitudinal patient cohort; and to determine the contribution of asthma exacerbations to disease progression. 2. To characterize regional obstructive patterns at baseline and their relationship to changes in pulmonary function; and to determine how incremental changes in regional airway dysfunction after asthma exacerbations may contribute to severe asthma. 3. To determine the contribution of established and novel biomarkers (YKL-40, vWF, & P-selectin), in refining the severe asthma phenotypes and the role of inflammatory cells in causing airway injury following virus-induced asthma exacerbations with subsequent development of ventilation defects.

Study Design

• Study Type: Observational
• Estimated Enrollment: 120 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Severe Asthma Research Program (SARP) - University of Wisconsin
• Actual Study Start Date: November 28, 2012
• Estimated Primary Completion Date: February 2021
• Estimated Study Completion Date: February 2021

Groups and Cohorts

Group/Cohort	Intervention/treatment
Severe asthma; Subjects with severe asthma (SARP protocol definition)	Other: NC100182 Hyperpolarized 3He; Magnetic Resonance Imaging (MRI) will take place and include inhalation of hyperpolarized helium to construct an image of the lungs.; Other Name: helium
Well controlled asthma; Subjects with well controlled asthma	Other: NC100182 Hyperpolarized 3He; Magnetic Resonance Imaging (MRI) will take place and include inhalation of hyperpolarized helium to construct an image of the lungs.; Other Name: helium
Normal control; Subjects that are healthy normals	Other: NC100182 Hyperpolarized 3He; Magnetic Resonance Imaging (MRI) will take place and include inhalation of hyperpolarized helium to construct an image of the lungs.; Other Name: helium

Outcome Measures

Primary Outcome Measures :

1. Lung function [ Time Frame: Baseline versus 3 years ]
   Changes in airway function after a severe exacerbation, and longitudinally over 3 years, as measured by lung function.

Secondary Outcome Measures :

1. Plethysmographic lung volumes [ Time Frame: Baseline versus 3 years ]
   Changes in airway function after a severe exacerbation, and longitudinally over 3 years, as measured by Plethysmographic lung volumes.
2. Hyperpolarized gas magnetic resonance imaging [ Time Frame: Baseline versus 3 years ]
   Changes in airway function after a severe exacerbation, and longitudinally over 3 years, as measured by Hyperpolarized gas magnetic resonance imaging.
3. Multidetector computed tomography imaging [ Time Frame: Baseline versus 3 years ]
   Changes in airway function after a severe exacerbation, and longitudinally over 3 years, as measured by Multidetector computed tomography imaging (adults only).
4. Exacerbations [ Time Frame: Baseline versus 3 years ]
   Exacerbation requiring systemic steroids
5. Plasma levels of biomarkers [ Time Frame: Baseline versus 3 years ]
   Changes in airway function after a severe exacerbation, and longitudinally over 3 years, as measured by plasma levels of biomarkers.
6. Induced sputum mediators [ Time Frame: Baseline versus 3 years ]
   Changes in airway function after a severe exacerbation, and longitudinally over 3 years, as measured by induced sputum mediators.
7. Nasal washing samples for virology [ Time Frame: Baseline versus 3 years ]
   Changes in airway function after a severe exacerbation, and longitudinally over 3 years, as measured by nasal washing samples for virology.
8. Bronchoscopy samples for virology, inflammatory cells and mediators [ Time Frame: Baseline versus 3 years ]
   Changes in airway function after a severe exacerbation, and longitudinally over 3 years, as measured by bronchoscopy samples for virology, inflammatory cells and mediators (adults only).

Biospecimen Retention:   Samples With DNA

whole blood, serum, plasma, DNA, RNA, sputum, urine, bronchial tissue, bronchoalveolar lavage, bronchial brushings, exhaled breath condensate

Eligibility Criteria

• Ages Eligible for Study: 6 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes
• Sampling Method: Non-Probability Sample

Study Population

Subjects with asthma (severe asthma, well controlled asthma) and healthy normal controls from Madison, WI region

Criteria

Inclusion Criteria:

1. Physician diagnosis of asthma
2. Age 6 years and older
3. Evidence of historical reversibility, including either:

1. FEV1 bronchodilator reversibility ≥ 12%, or

2. Airway hyperresponsiveness reflected by a methacholine PC20 ≤16 mg/mL.

Exclusion Criteria:

1. No primary medical caregiver,
2. Pregnancy (if undergoing methacholine challenge or bronchoscopy),
3. Current smoking
4. Smoking history > 10 pack years if ≥ 30 years of age or smoking history > 5 pack years if < 30 years of age (Note: If a subject has a smoking history, no smoking within the past year)
5. Other chronic pulmonary disorders associated with asthma-like symptoms,including (but not limited to) cystic fibrosis, chronic obstructive pulmonary disease, chronic bronchitis, vocal cord dysfunction that is the sole cause of asthma symptoms, severe scoliosis or chest wall deformities that affect lung function, or congenital disorders of the lungs or airways,
6. History of premature birth before 35 weeks gestation,
7. Evidence that the participant or family may be unreliable or poorly adherent to their asthma treatment or study procedures,
8. Planning to relocate from the clinical center area before study completion, or
9. Any other criteria that place the subject at unnecessary risk according to the judgment of the Principal Investigator and/or attending physician(s) of record.

Contacts and Locations

Locations

United States, Wisconsin

UW Madison

Madison, Wisconsin, United States, 53792

Sponsors and Collaborators

University of Wisconsin, Madison

National Institutes of Health (NIH)

Washington University School of Medicine

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Nizar N Jarjour, MD; UW Madison

More Information

Additional Information:

SARP Website 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Dunican EM, Elicker BM, Gierada DS, Nagle SK, Schiebler ML, Newell JD, Raymond WW, Lachowicz-Scroggins ME, Di Maio S, Hoffman EA, Castro M, Fain SB, Jarjour NN, Israel E, Levy BD, Erzurum SC, Wenzel SE, Meyers DA, Bleecker ER, Phillips BR, Mauger DT, Gordon ED, Woodruff PG, Peters MC, Fahy JV; National Heart Lung and Blood Institute (NHLBI) Severe Asthma Research Program (SARP). Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction. J Clin Invest. 2018 Mar 1;128(3):997-1009. doi: 10.1172/JCI95693. Epub 2018 Feb 5.

Denlinger LC, Phillips BR, Ramratnam S, Ross K, Bhakta NR, Cardet JC, Castro M, Peters SP, Phipatanakul W, Aujla S, Bacharier LB, Bleecker ER, Comhair SA, Coverstone A, DeBoer M, Erzurum SC, Fain SB, Fajt M, Fitzpatrick AM, Gaffin J, Gaston B, Hastie AT, Hawkins GA, Holguin F, Irani AM, Israel E, Levy BD, Ly N, Meyers DA, Moore WC, Myers R, Opina MT, Peters MC, Schiebler ML, Sorkness RL, Teague WG, Wenzel SE, Woodruff PG, Mauger DT, Fahy JV, Jarjour NN; National Heart, Lung, and Blood Institute’s Severe Asthma Research Program-3 Investigators. Inflammatory and Comorbid Features of Patients with Severe Asthma and Frequent Exacerbations. Am J Respir Crit Care Med. 2017 Feb 1;195(3):302-313. doi: 10.1164/rccm.201602-0419OC. Erratum in: Am J Respir Crit Care Med. 2018 Apr 1;197(7):971.

Witt CA, Sheshadri A, Carlstrom L, Tarsi J, Kozlowski J, Wilson B, Gierada DS, Hoffman E, Fain SB, Cook-Granroth J, Sajol G, Sierra O, Giri T, O'Neill M, Zheng J, Schechtman KB, Bacharier LB, Jarjour N, Busse W, Castro M; NHLBI Severe Asthma Research Program (SARP). Longitudinal changes in airway remodeling and air trapping in severe asthma. Acad Radiol. 2014 Aug;21(8):986-93. doi: 10.1016/j.acra.2014.05.001.

• Responsible Party: University of Wisconsin, Madison
• ClinicalTrials.gov Identifier: NCT01760915
• Other Study ID Numbers: 2012-0571; 4U10HL109168 ( U.S. NIH Grant/Contract ); A534285 ( Other Identifier: UW, Madison ); SMPH/MEDICINE/PULMON MED ( Other Identifier: UW, Madison )
• First Posted: January 4, 2013
• Last Update Posted: April 3, 2020
• Last Verified: April 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

Keywords provided by University of Wisconsin, Madison:

asthma; severe

Additional relevant MeSH terms:

Asthma; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases