The Severe Asthma Research Program III-Boston Clinical Site

NCT01761630 | Completed DMC

• 1 other identifier: 2012P001528
• Study Type: observational
• Target: 126
• Locations: 1 country
• Sites: 2

Brief Summary

Asthma is a disease characterized by inflammation in the airways. The body naturally makes compounds that reduce inflammation. Unfortunately, for patients with severe asthma, the pathway these compounds use to reduce inflammation seems to be perturbed. Investigators have chosen to focus on the anti-inflammatory compounds called lipoxins and how they work through the "ALX Axis", a name given to the ALX receptor pathway and its ligands. Work from the Brigham and Women's Hospital has suggested that in patients with severe asthma, the ALX axis may not work properly and therefore may not shut off inflammation as expected. Also, there is information to suggest that in some cases, steroids (prednisone and similar drugs), which are commonly used to treat asthma, may affect the ALX axis in a negative way, paradoxically making the inflammation worse instead of better. As part of the NIH Severe Asthma Research Program the Asthma Research Center's goal is to identify what causes the problems in the ALX axis in severe asthma. To do so, participants with severe asthma will be compared to participants with milder forms of asthma. Investigators will use samples taken directly from the lungs of people with asthma, as well as blood, urine and CT scans of the lungs to better understand how the ALX axis changes both before and after corticosteroid treatment and throughout a three year span. Participants will come into the Asthma Research Center to have the procedures done. Investigators expect participants will perform breathing tests and complete questionnaires and diaries. To better understand if corticosteroids negatively affect the ALX axis in severe asthma, researchers will take samples before and after a one time steroid injection equivalent to a prednisone treatment for asthma. Participants will perform two bronchoscopy procedures, before and after corticosteroid treatment, where biopsies and cells will be obtained from the participant's lungs. Investigators will use these samples to observe any changes that the corticosteroid may have on the ALX axis. At the end of the study, researchers at the Brigham and Women's Hospital expect to understand the ALX axis in such a way that will allow them to formulate new therapies and drug targets to treat people with asthma, especially severe asthma, more effectively. In Boston, this study will be run together by the Asthma Research Center at the Brigham and Women's Hospital (adults) and Boston Children's Hospital (children).

Conditions

Asthma

Keywords

Asthma; Severe Asthma; SARP

Outcome Measures

Primary Outcomes (5)

• Longitudinal change in maximum bronchodilator (BD) FEV1 response.

  Evaluated at Visits 1, 3, 4, 5, 6 (Months 0, 1, 12, 24, 36)

• Changes in values of ALX axis ligands and ALX/FPR2 receptor expression before and after corticosteroid treatment in severe asthmatics and non-severe asthmatics.

  Sputum, blood, and bronchoscopic specimens will be obtained before and after parenteral triamcinolone to directly assess the ALX axis in the airway. Particular attention will be paid to the change in LXA4, 15-epi-LXA4, SAA, and ANXA1 ligands.

  Evaluated at Visit 2, 2b, 3, 3b (Days 7, 9, 23,25)

• Change in CT measures of airway wall thickness (WA%) over 3 years

  Data will only be collected from adult participants.

  Evaluated at Visits 2, 6 (Months 0, 36)

• Number of severe asthma exacerbations per subject

  Evaluated at Visits 1, 2, 3, 3a, 4, 4a, 5, 5a, 6 (Months 0, 1, 2, 6, 12, 18, 24, 30, 36)

• Plasma LXA4/CysLT levels and their ability to predict increases or decreases in FEV1, exacerbations, and WA% over time.

  Evaluated at Visits 2, 3, 4, 5, 6 (Months 0, 1, 12, 24, 36)

Study Arms (3)

Severe Asthma

We will classify subjects as having severe asthma using the following stages: Stage 1: Subjects must have asthma which requires treatment with high-dose inhaled corticosteroids plus a 2nd controller, or systemic corticosteroids with or without a 2nd controller to prevent it from becoming uncontrolled or which remains uncontrolled despite this therapy Stage 2: Assess for uncontrolled asthma by any one of the following criteria: 1. Poor symptom control evidenced by an Asthma Control Questionnaire score consistently \> 1.5 or an Asthma Control Test Score \< 20 or not well controlled by NAEPP or GINA asthma treatment guidelines 2. Frequent severe exacerbations as reflected by ≥ 2 bursts of systemic corticosteroids (\> 3 days each) in the previous 12 months 3. Serious exacerbations reflected by at least one hospitalization, ICU stay or mechanical ventilation in the previous 12 months 4. Presence of airflow limitation evidenced by FEV1 \< 80% predicted (in the face of reduced FEV1/FVC)

Non-severe Asthma

Those with mild-to-moderate persistent asthma as defined by the NAEPP EPR-3 guidelines.

Healthy Control

The purpose of the SARP Control Sub-study is to generate reference data for outcomes measured in biospecimens collected from asthmatic subjects enrolled in the SARP Longitudinal Protocol. Seven healthy subjects between the ages of 18-65 will be enrolled.

Eligibility Criteria

• Age: 6 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)
• Sampling Method: Probability Sample

Study Population

The target recruitment goal for our center is 75% adults (age 18 to 60) and 25% children age 6-17 years. Within the pediatric age group, an attempt will be made to enroll equal numbers of children 6-11 and 12-17 years of age. Similarly, an attempt will be made to enroll at least 50% females and 30% minorities. Given the mission of SARP, a diverse sample of subjects with asthma is needed to gain better understanding of asthma and its endotypes. Because there are a number of respiratory disorders that may be confused with asthma or confound asthma assessment, SARP enrollees must meet the all of the eligibility criteria described.

You may qualify if:

• Ages 6-60
• FEV1 bronchodilator reversibility ≥12% or methacholine PC20 ≤16 mg/mL
• Ability to provide informed consent
• Ability to perform pulmonary function tests

You may not qualify if:

• Pregnancy (if undergoing methacholine challenge or bronchoscopy)
• Current smoking
• 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)
• 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
• Participants who cannot undergo bronchoscopy due to: 1) hospitalization for asthma within the 6 weeks prior to bronchoscopy, 2) \> 12 asthma exacerbations within the 6 months prior to bronchoscopy, 3) intubation for asthma within the 6 months prior to bronchoscopy, 4) older than 60 years of age, 5) increased corticosteroid use in the 14 days prior to bronchoscopy. (Increased corticosteroid use recognized as a dose which is both numerically at least twice that of baseline, and which is at least 20 mg/day greater than the baseline dose.)
• History of premature birth before 35 weeks gestation
• Planning to relocate from the clinical center area before study completion
• Currently participating in an investigational drug trial
• Unwillingness to receive an intramuscular triamcinolone acetonide injection.

Sponsors & Collaborators

• Elliot Israel, MD: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (2)

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

Location

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

Related Publications (3)

• Huang BK, Elicker BM, Henry TS, Kallianos KG, Hahn LD, Tang M, Heng F, McCulloch CE, Bhakta NR, Majumdar S, Choi J, Denlinger LC, Fain SB, Hastie AT, Hoffman EA, Israel E, Jarjour NN, Levy BD, Mauger DT, Sumino K, Wenzel SE, Castro M, Woodruff PG, Fahy JV, Sarp FTNSARP. Persistent mucus plugs in proximal airways are consequential for airflow limitation in asthma. JCI Insight. 2024 Feb 8;9(3):e174124. doi: 10.1172/jci.insight.174124.

  PMID: 38127464 DERIVED

• Ash SY, Sanchez-Ferrero GV, Schiebler ML, Rahaghi FN, Rai A, Come CE, Ross JC, Colon AG, Cardet JC, Bleecker ER, Castro M, Fahy JV, Fain SB, Gaston BM, Hoffman EA, Jarjour NN, Lempel JK, Mauger DT, Tattersall MC, Wenzel SE, Levy BD, Washko GR, Israel E, San Jose Estepar R; SARP Investigators. Estimated Ventricular Size, Asthma Severity, and Exacerbations: The Severe Asthma Research Program III Cohort. Chest. 2020 Feb;157(2):258-267. doi: 10.1016/j.chest.2019.08.2185. Epub 2019 Sep 12.

  PMID: 31521672 DERIVED

• 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.

  PMID: 29400693 DERIVED

Related Links

• Severe Asthma Research Program Main Clinicaltrials.gov Webpage

Biospecimen

Retention: SAMPLES WITH DNA

CBC/Diff, Total IgE, Serum, Plasma, DNA, RNA Urine EBC Sputum: Supernatant, Cell Pellet Bronch: BAl, Bronchial Brushings, Bronchial Biopsy

MeSH Terms

Conditions

Asthma

Condition Hierarchy (Ancestors)

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

Study Officials

• Elliot Israel, M.D.

  Brigham and Women's Hospital/Harvard Medical School

  PRINCIPAL INVESTIGATOR

• Bruce Levy, M.D.

  Brigham and Women's Hospital/Harvard Medical School

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor of Medicine

Study Record Dates

• First Submitted: January 3, 2013
• First Posted: January 7, 2013
• Study Start: December 1, 2012
• Primary Completion: March 15, 2020
• Study Completion: January 15, 2021
• Last Updated: March 12, 2021

Record last verified: 2021-03

Locations

US (2)