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GSNOR Phenotyping/GSNO Challenge in Severe Asthma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03926741
Recruitment Status : Recruiting
First Posted : April 24, 2019
Last Update Posted : September 18, 2020
Sponsor:
Collaborators:
University Hospitals Cleveland Medical Center
Case Western Reserve University
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
James Reynolds, University Hospitals Cleveland Medical Center

Tracking Information
First Submitted Date  ICMJE March 19, 2019
First Posted Date  ICMJE April 24, 2019
Last Update Posted Date September 18, 2020
Actual Study Start Date  ICMJE April 30, 2019
Estimated Primary Completion Date March 2, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 23, 2019)
  • Airway GSNOR comparison [ Time Frame: Baseline ]
    Airway GSNOR will be compared among the two different groups (Asthma and Healthy Volunteers).
  • Airway GSNOR comparison [ Time Frame: 3 months ]
    Airway GSNOR will be compared among the two different groups (Asthma and Healthy Volunteers).
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 23, 2019)
  • Fractional Exhaled Nitric Oxide (FeNO) levels changes [ Time Frame: Baseline ]
    FeNO measurements will be compared among the two different groups (Asthma and Healthy Volunteers).
  • Fractional Exhaled Nitric Oxide (FeNO) levels changes [ Time Frame: 3 months ]
    FeNO measurements will be compared among the two different groups (Asthma and Healthy Volunteers).
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE GSNOR Phenotyping/GSNO Challenge in Severe Asthma
Official Title  ICMJE Methods to Identify and Treat Severe Asthma Patients Project 1: GSNOR Phenotyping and GSNO Challenge
Brief Summary

Asthma is caused by or worsened by different things in different people. It is because of these differences that not all people with asthma respond the same to all treatments and medicines. If the investigators can better identify the changes in the airways or breathing pipes in patients with asthma, the investigators may be able to help patients make better choices about the medicines or treatments that are most likely to work best for each patient.

This research study is about one specific factor that is known to affect asthma in some patients. It involves an increase in the activity of an enzyme that is in people's airways. An enzyme is something that helps a chemical reaction to occur. The enzyme the investigators are studying in this research study is called GSNOR (S-nitrosoglutathione reductase) , and when the activity of this enzyme is increased, the result is that there is less GSNO (S-nitrosoglutathione) . GSNO is a chemical that protects people's airways. The initials stand for S-nitrosoglutathione, (pronounced s-nahy-troh-soh-gloo-tuh-thahy-ohn), and it is naturally produced by the body. It has an important role in regulating respiratory function (breathing) and preventing inflammation (swelling) in the respiratory tract (throat, airways, and lungs).

The amount of GSNO found in the body is controlled by the enzyme GSNOR (S-nitrosoglutathione reductase). GSNOR breaks down GSNO. Too much GSNOR leads to low levels of GSNO, and that can cause inflammation (swelling) and loss of airway function in some asthma patients.

The only way to measure GSNOR levels currently is with a bronchoscopy procedure where a scope is inserted into the patient's airways, often under sedation. This research study is being done to test the accuracy of another type of test that can be done in the doctor's office, rather than in a procedure area. This non-invasive diagnostic test, called a GSNO Challenge test, may be able to identify which asthma patients have increased activity of the airway enzyme GSNOR. The investigators are also studying the phenotypes (observable traits) in asthma patients with increased levels of GSNOR. If this research study is successful, in the future (after this research study is done). The investigators may be able to offer a cost-effective and non-invasive way to identify patients who have higher GSNOR activity levels and offer personalized treatments.

The GSNO Challenge test includes giving an investigational drug to breathe in (inhale). The investigational drug is GSNO. "Investigational" means the drug is not approved by any regulatory agencies including the Food and Drug Administration (FDA), and is still being tested for safety and effectiveness. The research is registered with the FDA, but again the GSNO treatment in this study (administered during the GSNO challenge testing) is not an approved treatment or diagnostic test for asthma.

Detailed Description

S-nitrosylation signaling is relevant to a broad range of diseases, including severe asthma. Work in the Severe Asthma Research Program (SARP) and other research networks has established that asthma is remarkably heterogeneous. The response to standard asthmatic therapies is sub-optimal in many patients. Targeting expected responders, or personalizing approach to treatment, would lead to improved outcomes and decreased treatment costs. Furthermore, since patients with asthma that is not responsive to standard therapies are highly symptomatic despite standard therapy, this subset may derive particular benefit from a personalized approach that includes clinical phenotyping, directed diagnostic testing to confirm underlying pathophysiology, and treatment directed specifically towards those findings.

The classical conceptualization of asthma as a disease of allergic inflammation is based on findings that many patients with asthma have a "Th2 high" phenotype characterized by high circulating levels of IgE, eosinophils and periostin. Patients with these features are particularly amenable to exciting, new antibody-based therapies. However, many patients are not in this phenotype, and, within the generalized phenotype, there is a Gaussian distribution of response. Further, these antibody treatments tend to be expensive and require parenteral administration. A myriad of alternative potential targets has been identified in patients with asthma who do not respond to standard asthma therapies, ranging from high levels of airway chitinase to low levels of vitamin D.

Early work documenting the presence of S-nitrosothiols (SNOs) in human airways and characterizing the potent bronchodilator activity of S-nitrosoglutathione (GSNO) led us to consider that in some patients asthma may represent a disorder in pulmonary SNO homeostasis. The focus of this study is on the subset of patients with asthma who have increased airway S-nitrosoglutathione reductase (GSNOR) activity. Increased activity of GSNOR results in a reduction in the available GSNO, resulting in increased smooth muscle constriction, and increased inflammation. This is a highly targetable process for which specific therapeutic agents are now becoming available. This approach can provide a paradigm for other personalized strategies. Identifying alternative approaches for patients with asthma do not respond to standard asthma therapies has important public health implications. The investigators conservatively estimate that formulation of personalized asthma therapies, including the current study, could halve the morbidity and societal costs of asthma. This in turn would result in fewer disease-related deaths and billions of dollars in economic savings per year in the US - the current annual costs of asthma to the American economy are estimated at $56 billion.

Preliminary work from the Severe Asthma Research Program suggests that patients with increased GSNOR activity and increased catabolism of the endogenous bronchodilator GSNO17 have characteristic phenotypic features (younger age, earlier onset of asthma, higher IgE), but this work needs to be expanded through a combination of mechanistic assessments and clinical testing. The investigators have shown in preliminary work that GSNOR activity in bronchoalveolar lavage (BAL) fluid and in cell lysates from BAL fluid is higher on average in subjects with asthma compared with healthy volunteers. The investigators have further shown the relevance of this finding to asthma in that there is a relationship between GSNOR activity and airway hyper-responsiveness, a hallmark of asthma. The significant linear association between GSNOR activity and the concentration of methacholine that provokes a 20% fall in FEV1 (Forced Expiratory Volume in 1 Second) in subjects with asthma but not in healthy volunteers. While the investigators have shown that GSNOR activity is higher on average in subjects with asthma compared with healthy volunteers, activity levels are quite variable across the spectrum of asthma severity. Accurately identifying patients with asthma who have elevated GSNOR activity levels for targeted therapies is an essential next step.

In the preliminary data, GSNOR activity was measured directly using bronchoscopic techniques to collect BAL fluid and directly measure activity levels. While our experience in the Severe Asthma Research Program shows that bronchoscopies can be done safely in subjects with asthma, it will be important to develop non-invasive methodology to identify patients with asthma and elevated GSNOR activity in order to make if more practical and feasible to test and use targeted treatments. The purpose of this protocol is to confirm previous work demonstrating that subjects with asthma have higher GSNOR activity levels than healthy volunteers, expand our ability to predict who will have elevated GSNOR activity levels based on clinical phenotype, and to develop non-invasive and point of care testing that can accurately identify those with elevated GSNOR levels.

Study Type  ICMJE Interventional
Study Phase  ICMJE Early Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Condition  ICMJE
  • Asthma
  • Healthy Volunteers
Intervention  ICMJE Drug: GSNO
patient will use a nebulizer to inhale (breathe in) a solution of GSNO followed by repeated measurements of airway function (breathing tests)
Study Arms  ICMJE Experimental: GSNOR Challenge testing
patient will use a nebulizer to inhale (breathe in) a solution of GSNO followed by repeated measurements of airway function (breathing tests)
Intervention: Drug: GSNO
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 23, 2019)
60
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 30, 2023
Estimated Primary Completion Date March 2, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

For subjects with Asthma

  • Adult males or females age ≥ 18 and ≤ 50 years at the time of enrollment
  • Physician diagnosis of asthma for at least one year
  • FEV1 bronchodilator reversibility > 12% or methacholine PC20 )provocative concentration causing a 20% fall) < 16 mg/ml (historical methacholine data from previous NIH trials including SARP and AsthmaNet will be allowed)
  • Baseline post maximal bronchodilator FEV1 >55% predicted

Healthy Volunteers

  • Adult males or females age ≥ 18 and ≤ 50 years at time of enrollment
  • Non-smokers
  • No history of asthma, chronic obstructive pulmonary disease (COPD), or other chronic lung disease
  • No history of severe allergic/atopic disease requiring immunotherapy or immunomodulators

Exclusion Criteria: General (applying to all participants)

  • > 5 pack year smoking history
  • Body mass index (BMI) > 45
  • Unable to perform repeatable consistent efforts in pulmonary function testing
  • Individuals with prior diagnosis of vocal cord dysfunction or an anatomic anomaly that would increase the risks associated with the bronchoscopy procedure
  • Prior diagnosis of cystic fibrosis, COPD, or other additional lung disease that in the investigator's opinion would make subject unsuitable for study participation
  • History of premature birth before 35 weeks gestation
  • Planning to relocate away from the clinical center (Cleveland, Ohio) area before study completion
  • Lack of reliable communications channel (hard-wire phone, cell phone, email for follow-up contacts after bronchoscopy)
  • Allergic to anesthetic medication(s) that would prevent participation in the study's bronchoscopy
  • Blood pressure parameters outside the normal range of 90-180 mm Hg systolic and 50-100 mm Hg diastolic at time of screening
  • Individuals with diabetes mellitus (type 1 or type 2)
  • Individuals with renal failure or creatinine > 1.8 mg/dl at time of screening
  • Individuals who are pregnant, breastfeeding, or are unwilling to use a medically acceptable method of birth control (as indicated on the Birth Control Methods Reference Card) from the time of consent until the end of the study to avoid pregnancy
  • Individuals who report additional chronic diseases requiring medication of the heart, lungs, kidney, liver, brain, etc., or afflicted with any acute or chronic pathology that in the opinion of the screening physician makes them unsuitable for study such as coronary artery disease
  • Asthma exacerbation requiring oral corticosteroids within the previous 30 days (can be rescreened)
  • More than 3 exacerbations within the past 6 months
  • Intubated for asthma within the past 12 months
  • Respiratory or other infection requiring systemic antibiotics within the previous 14 days (can be rescreened)
  • Current use of a vitamin K antagonist (warfarin) or other anticoagulant (e.g., heparin, clopidogrel, enoxaparin or dalteparin)
  • Current use of beta-adrenergic blockers, tricyclic antidepressants, meperidine (or related central nervous system (CNS) agents), or nitrates
  • Inherited or acquired blood coagulation disorder, congenital methemoglobinemia, or a familial hemoglobinopathy that impacts oxygen delivery (e.g., sickle cell)
  • Any illness, condition or recent surgeries that may increase the risks associated with the study
  • Participation in any investigational drug study other than the Airway pH ( potential hydrogen) Study within the 4 week period prior to screening.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 50 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Laurie Logan 216-286-6566 PACTStudy@UHhospitals.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03926741
Other Study ID Numbers  ICMJE 12-17-11
5P01HL128192 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: All of the individual participant data collected during the trial, after deidentification and analysis will be shared.
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Clinical Study Report (CSR)
Time Frame: Available Immediately following publication. No end date
Access Criteria: Investigators whose proposed use of the data has been approved by an independent review committee ("learned intermediary") identified for this purpose.
Responsible Party James Reynolds, University Hospitals Cleveland Medical Center
Study Sponsor  ICMJE James Reynolds
Collaborators  ICMJE
  • University Hospitals Cleveland Medical Center
  • Case Western Reserve University
  • National Heart, Lung, and Blood Institute (NHLBI)
Investigators  ICMJE
Principal Investigator: Kristie Ross, MD University Hospitals Cleveland Medical Center
PRS Account University Hospitals Cleveland Medical Center
Verification Date September 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP