GSNOR Phenotyping/GSNO Challenge in Severe Asthma

• ClinicalTrials.gov Identifier: NCT03926741
• Recruitment Status: Recruiting
• First Posted: April 24, 2019
• Last Update Posted: March 1, 2023
• Sponsor: James Reynolds
• 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

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Asthma; Healthy Volunteers	Drug: GSNO	Early Phase 1

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 60 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• Official Title: Methods to Identify and Treat Severe Asthma Patients Project 1: GSNOR Phenotyping and GSNO Challenge
• Actual Study Start Date: April 30, 2019
• Estimated Primary Completion Date: June 30, 2026
• Estimated Study Completion Date: June 30, 2026

Arms and Interventions

Arm	Intervention/treatment
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)	Drug: GSNO; patient will use a nebulizer to inhale (breathe in) a solution of GSNO followed by repeated measurements of airway function (breathing tests)

Outcome Measures

Primary Outcome Measures :

1. Airway GSNOR comparison [ Time Frame: Baseline ]
   Airway GSNOR will be compared among the two different groups (Asthma and Healthy Volunteers).
2. Airway GSNOR comparison [ Time Frame: 3 months ]
   Airway GSNOR will be compared among the two different groups (Asthma and Healthy Volunteers).

Secondary Outcome Measures :

1. Fractional Exhaled Nitric Oxide (FeNO) levels changes [ Time Frame: Baseline ]
   FeNO measurements will be compared among the two different groups (Asthma and Healthy Volunteers).
2. 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).

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 50 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

For subjects with Asthma

• Adult males or females age ≥ 18 and ≤ 50 years at the time of enrollment
• Non-smoker
• Physician diagnosis of asthma for at least one year
• FEV1 bronchodilator reversibility > 12% or methacholine PC20 < 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-smoker
• 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

-> 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 participant unsuitable for study participation
• History of premature birth before 35 weeks gestation
• Planning to relocate away from the clinical center (Cleveland, Ohio or central Indiana) 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
• Unable or unwilling to withhold medications prior to certain study procedures (skin test, spirometry, methacholine challenge)
• 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 Study within the 4 week period prior to screening.
• Any acute viral illness, including active COVID-19 infection or acute viral respiratory symptoms; can rescreen 4 weeks after positive test result.

Contacts and Locations

Contacts

Contact: Rebecca Gammell; 216-844-6133; PACTStudy@UHhospitals.org

Locations

United States, Indiana

Indiana University School of Medicine; Recruiting

Indianapolis, Indiana, United States, 46202

Contact: Rachel Owensby, BS 317-274-8895 rowensby@iu.edu

Principal Investigator: James F Chmiel, MD, MPH

United States, Ohio

University Hospitals Cleveland Medical Center; Recruiting

Cleveland, Ohio, United States, 44106

Contact: Rebecca Gammell 216-844-6133 PACTStudy@UHhospitals.org

Principal Investigator: Kristie Ross, MD

Sponsors and Collaborators

James Reynolds

University Hospitals Cleveland Medical Center

Case Western Reserve University

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Kristie Ross, MD; University Hospitals Cleveland Medical Center

More Information

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• Responsible Party: James Reynolds, Professor of Anesthesiology & Perioperative Medicine, University Hospitals Cleveland Medical Center
• ClinicalTrials.gov Identifier: NCT03926741
• Other Study ID Numbers: 12-17-11; 5P01HL128192 ( U.S. NIH Grant/Contract )
• First Posted: April 24, 2019
• Last Update Posted: March 1, 2023
• Last Verified: February 2023

Individual Participant Data (IPD) Sharing Statement:

• 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); 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.

• 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

Additional relevant MeSH terms:

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