AsthmaEarly Phase 1NCT03926741
GSNOR Phenotyping/GSNO Challenge in Severe Asthma
A Early Phase 1 study testing GSNO Challenge in people with Asthma, run by James Reynolds at 2 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 50 yearsHealthy volunteers can take part
- Conditions the study is for
- Asthma
- What is being tested?
- GSNO Challenge
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 48 participants
- Where
- 2 sitesUnited States
- Study dates
- 30 Apr 2019to 29 Feb 2024
- Phase
- Early Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 50 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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
Show all 11Show fewer
- 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
Who cannot join
- -> 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
Show all 25Show fewer
- 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.
Trial locations and contacts
2 sites in 1 country.
United States2 sites
University Hospitals Cleveland Medical Center
Cleveland, Ohio, 44106
Indiana University School of Medicine
Indianapolis, Indiana, 46202
About this study
Official title: Methods to Identify and Treat Severe Asthma Patients Project 1: GSNOR Phenotyping and GSNO Challenge
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).
Read more
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.
Read the 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.
- Conditions
- Asthma
- Being tested
- GSNO Challenge
- Medical subject headings
- Asthma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
GSNO ChallengeDrug
Subjects will use a nebulizer to inhale (breathe in) a solution of GSNO followed by repeated measurements of airway function (breathing tests)
| Study group | Role | What they receive |
|---|---|---|
| GSNO Challenge - Healthy | Active comparator | Subjects determined to have normal lung function and no chronic disease condition Receives: Drug: GSNO Challenge |
| GSNO Challenge - Asthma | Experimental | Subjects determined to have Stable Asthma defined by GINA criteria Receives: Drug: GSNO Challenge |
What is being measured
The primary outcome is the main question the study is designed to answer.
FeNO
The Fractional expired Nitric Oxide, FeNO, is measured by exhaling into a tube connected to the monitoring device. Nitric oxide is one of the breakdown products of GSNO so measuring it in the breath indicates how fast GSNO is metabolized by the lung
Measured: Approximately 70-80 minutes with measurements taken before and at 10 min intervals up to 1 h after GSNO inhalation
Change in FeV1
The Forced expiratory Volume 1, is the volume of air expired (exhaled) in one second. It is recorded before and after GSNO administration. Subjects breathe through a tube to inhale and then blast exhale. The FeV1 is a standard measure of lung function.
Measured: Approximately 1-2 minutes for each test with testing conducted before and after GSNO administration
Secondary outcomes (1)
Expression of GSNO Metabolic Enzymes in Human Airways
Endobronchial biopsies from subjects who received GSNO were analyzed by Visium HD spatial transcriptomics. Batch analyses were conducted at the the end of the study. The measuments focused on 3 specific enzymes, AKR1A1, ADH5 and CBR1, involved in the breakdown of GSNO. This assessment was hampered by a low number of usable specimens.
Measured: Lung biopsies were obtained during bronchoscopy
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Apr 2019
- Study start30 Apr 2019
- Primary completion29 Feb 2024
- Study completion29 Feb 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (82)Papers the sponsor has linked to this study.
- Other trials for AsthmaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Early Phase 1
- Primary purpose
- Diagnosis
- Allocation
- Non-randomised
- Intervention model
- Factorial
- Masking
- None (open label)
- Enrolment
- 48 participants (actual)
Sponsor and investigators
- Lead sponsor
- James Reynolds
- Sponsor type
- University, hospital or other
- Collaborators
- University Hospitals Cleveland Medical Center, Case Western Reserve University, National Heart, Lung, and Blood Institute (NHLBI)
- Responsible party
- Sponsor-investigator, James Reynolds, Case Western Reserve University
- Investigators
- Kristie Ross, MD, Principal investigator, University Hospitals Cleveland Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03926741
- Sponsor's protocol ID
- 12-17-11
- Other IDs
- 5P01HL158507
- Status last verified
- May 2026
- First submitted
- 19 Mar 2019
- Last updated
- 20 May 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: All of the individual participant data collected during the trial, after deidentification and analysis will be shared.
Publications
Irie T, Sips PY, Kai S, Kida K, Ikeda K, Hirai S, Moazzami K, Jiramongkolchai P, Bloch DB, Doulias PT, Armoundas AA, Kaneki M, Ischiropoulos H, Kranias E, Bloch KD, Stamler JS, Ichinose F. S-Nitrosylation of Calcium-Handling Proteins in Cardiac Adrenergic Signaling and Hypertrophy. Circ Res. 2015 Oct 9;117(9):793-803. doi: 10.1161/CIRCRESAHA.115.307157. Epub 2015 Aug 10.
PubMed 26259881Dweik RA, Comhair SA, Gaston B, Thunnissen FB, Farver C, Thomassen MJ, Kavuru M, Hammel J, Abu-Soud HM, Erzurum SC. NO chemical events in the human airway during the immediate and late antigen-induced asthmatic response. Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2622-7. doi: 10.1073/pnas.051629498. Epub 2001 Feb 20.
PubMed 11226289Moore WC, Evans MD, Bleecker ER, Busse WW, Calhoun WJ, Castro M, Chung KF, Erzurum SC, Curran-Everett D, Dweik RA, Gaston B, Hew M, Israel E, Mayse ML, Pascual RM, Peters SP, Silveira L, Wenzel SE, Jarjour NN; National Heart, Lung, and Blood Institute's Severe Asthma Research Group. Safety of investigative bronchoscopy in the Severe Asthma Research Program. J Allergy Clin Immunol. 2011 Aug;128(2):328-336.e3. doi: 10.1016/j.jaci.2011.02.042. Epub 2011 Apr 15.
PubMed 21496892Auten RL, Mason SN, Whorton MH, Lampe WR, Foster WM, Goldberg RN, Li B, Stamler JS, Auten KM. Inhaled ethyl nitrite prevents hyperoxia-impaired postnatal alveolar development in newborn rats. Am J Respir Crit Care Med. 2007 Aug 1;176(3):291-9. doi: 10.1164/rccm.200605-662OC. Epub 2007 May 3.
PubMed 17478622Colagiovanni DB, Borkhataria D, Looker D, Schuler D, Bachmann C, Sagelsdorff P, Honarvar N, Rosenthal GJ. Preclinical 28-day inhalation toxicity assessment of s-nitrosoglutathione in beagle dogs and Wistar rats. Int J Toxicol. 2011 Oct;30(5):466-77. doi: 10.1177/1091581811412084. Epub 2011 Aug 25.
PubMed 21868767Foster MW, Hess DT, Stamler JS. Protein S-nitrosylation in health and disease: a current perspective. Trends Mol Med. 2009 Sep;15(9):391-404. doi: 10.1016/j.molmed.2009.06.007. Epub 2009 Aug 31.
PubMed 19726230Haldar SM, Stamler JS. S-nitrosylation: integrator of cardiovascular performance and oxygen delivery. J Clin Invest. 2013 Jan;123(1):101-10. doi: 10.1172/JCI62854. Epub 2013 Jan 2.
PubMed 23281416Marshall HE, Hess DT, Stamler JS. S-nitrosylation: physiological regulation of NF-kappaB. Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):8841-2. doi: 10.1073/pnas.0403034101. Epub 2004 Jun 8. No abstract available.
PubMed 15187230Savidge TC, Urvil P, Oezguen N, Ali K, Choudhury A, Acharya V, Pinchuk I, Torres AG, English RD, Wiktorowicz JE, Loeffelholz M, Kumar R, Shi L, Nie W, Braun W, Herman B, Hausladen A, Feng H, Stamler JS, Pothoulakis C. Host S-nitrosylation inhibits clostridial small molecule-activated glucosylating toxins. Nat Med. 2011 Aug 21;17(9):1136-41. doi: 10.1038/nm.2405.
PubMed 21857653Prasad R, Giri S, Nath N, Singh I, Singh AK. GSNO attenuates EAE disease by S-nitrosylation-mediated modulation of endothelial-monocyte interactions. Glia. 2007 Jan 1;55(1):65-77. doi: 10.1002/glia.20436.
PubMed 17019693Savidge TC, Newman P, Pothoulakis C, Ruhl A, Neunlist M, Bourreille A, Hurst R, Sofroniew MV. Enteric glia regulate intestinal barrier function and inflammation via release of S-nitrosoglutathione. Gastroenterology. 2007 Apr;132(4):1344-58. doi: 10.1053/j.gastro.2007.01.051. Epub 2007 Feb 1.
PubMed 17408650Marshall HE, Potts EN, Kelleher ZT, Stamler JS, Foster WM, Auten RL. Protection from lipopolysaccharide-induced lung injury by augmentation of airway S-nitrosothiols. Am J Respir Crit Care Med. 2009 Jul 1;180(1):11-8. doi: 10.1164/rccm.200807-1186OC. Epub 2009 Mar 26.
PubMed 19324975Que LG, Liu L, Yan Y, Whitehead GS, Gavett SH, Schwartz DA, Stamler JS. Protection from experimental asthma by an endogenous bronchodilator. Science. 2005 Jun 10;308(5728):1618-21. doi: 10.1126/science.1108228. Epub 2005 May 26.
PubMed 15919956Snyder AH, McPherson ME, Hunt JF, Johnson M, Stamler JS, Gaston B. Acute effects of aerosolized S-nitrosoglutathione in cystic fibrosis. Am J Respir Crit Care Med. 2002 Apr 1;165(7):922-6. doi: 10.1164/ajrccm.165.7.2105032.
PubMed 11934715Jenkins KT. Nitrogen compounds. Hamilton & hardy's industrial toxicology. John Wiley & Sons, Inc.; 2015:363-370.
Study at a glance
From the registry record, last updated by the sponsor on 20 May 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Methods to Identify and Treat Severe Asthma Patients Project 1: GSNOR Phenotyping and GSNO Challenge
- ClinicalTrials.gov ID
- NCT03926741
- Acronym / sponsor ID
- 12-17-11
- Conditions
- Asthma
- Phase
- Early Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 48 participants (actual)
- Lead sponsor
- James ReynoldsUniversity, hospital or other
- Collaborators
- University Hospitals Cleveland Medical Center, Case Western Reserve University, National Heart, Lung, and Blood Institute (NHLBI)
- Study start
- 30 Apr 2019 (actual)
- Primary completion
- 29 Feb 2024 (actual)
- Study completion
- 29 Feb 2024 (actual)
- First posted
- 24 Apr 2019 (actual)
- Results
- Posted 20 May 2026
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Diagnosis
- Allocation
- Non-randomised
- Intervention model
- Factorial
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| GSNO Challenge - Healthy | Active comparator | Drug: GSNO ChallengeSubjects determined to have normal lung function and no chronic disease condition |
| GSNO Challenge - Asthma | Experimental | Drug: GSNO ChallengeSubjects determined to have Stable Asthma defined by GINA criteria |
Who may qualify
- Ages
- 18 to 50 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (11 listed)
- 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)
Key exclusion criteria (25 listed)
- -> 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| GSNO ChallengeSubjects will use a nebulizer to inhale (breathe in) a solution of GSNO followed by repeated measurements of airway function (breathing tests) | Drug | GSNO Challenge - Asthma, GSNO Challenge - Healthy |
Primary outcome
FeNO
Time frame: Approximately 70-80 minutes with measurements taken before and at 10 min intervals up to 1 h after GSNO inhalation
The Fractional expired Nitric Oxide, FeNO, is measured by exhaling into a tube connected to the monitoring device. Nitric oxide is one of the breakdown products of GSNO so measuring it in the breath indicates how fast GSNO is metabolized by the lung
Change in FeV1
Time frame: Approximately 1-2 minutes for each test with testing conducted before and after GSNO administration
The Forced expiratory Volume 1, is the volume of air expired (exhaled) in one second. It is recorded before and after GSNO administration. Subjects breathe through a tube to inhale and then blast exhale. The FeV1 is a standard measure of lung function.
1 secondary outcome
Expression of GSNO Metabolic Enzymes in Human Airways
Time frame: Lung biopsies were obtained during bronchoscopy
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 May 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 26259881Irie T, Sips PY, Kai S, Kida K, Ikeda K, Hirai S, Moazzami K, Jiramongkolchai P, Bloch DB, Doulias PT, Armoundas AA, Kaneki M, Ischiropoulos H, Kranias E, Bloch KD, Stamler JS, Ichinose F. S-Nitrosylation of Calcium-Handling Proteins in Cardiac Adrenergic Signaling and Hypertrophy. Circ Res. 2015 Oct 9;117(9):793-803. doi: 10.1161/CIRCRESAHA.115.307157. Epub 2015 Aug 10.
- Background: PubMed 11226289Dweik RA, Comhair SA, Gaston B, Thunnissen FB, Farver C, Thomassen MJ, Kavuru M, Hammel J, Abu-Soud HM, Erzurum SC. NO chemical events in the human airway during the immediate and late antigen-induced asthmatic response. Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2622-7. doi: 10.1073/pnas.051629498. Epub 2001 Feb 20.
- Background: PubMed 21496892Moore WC, Evans MD, Bleecker ER, Busse WW, Calhoun WJ, Castro M, Chung KF, Erzurum SC, Curran-Everett D, Dweik RA, Gaston B, Hew M, Israel E, Mayse ML, Pascual RM, Peters SP, Silveira L, Wenzel SE, Jarjour NN; National Heart, Lung, and Blood Institute's Severe Asthma Research Group. Safety of investigative bronchoscopy in the Severe Asthma Research Program. J Allergy Clin Immunol. 2011 Aug;128(2):328-336.e3. doi: 10.1016/j.jaci.2011.02.042. Epub 2011 Apr 15.
- Background: PubMed 17478622Auten RL, Mason SN, Whorton MH, Lampe WR, Foster WM, Goldberg RN, Li B, Stamler JS, Auten KM. Inhaled ethyl nitrite prevents hyperoxia-impaired postnatal alveolar development in newborn rats. Am J Respir Crit Care Med. 2007 Aug 1;176(3):291-9. doi: 10.1164/rccm.200605-662OC. Epub 2007 May 3.
- Background: PubMed 21868767Colagiovanni DB, Borkhataria D, Looker D, Schuler D, Bachmann C, Sagelsdorff P, Honarvar N, Rosenthal GJ. Preclinical 28-day inhalation toxicity assessment of s-nitrosoglutathione in beagle dogs and Wistar rats. Int J Toxicol. 2011 Oct;30(5):466-77. doi: 10.1177/1091581811412084. Epub 2011 Aug 25.
- Background: PubMed 19726230Foster MW, Hess DT, Stamler JS. Protein S-nitrosylation in health and disease: a current perspective. Trends Mol Med. 2009 Sep;15(9):391-404. doi: 10.1016/j.molmed.2009.06.007. Epub 2009 Aug 31.
- Background: PubMed 23281416Haldar SM, Stamler JS. S-nitrosylation: integrator of cardiovascular performance and oxygen delivery. J Clin Invest. 2013 Jan;123(1):101-10. doi: 10.1172/JCI62854. Epub 2013 Jan 2.
- Background: PubMed 15187230Marshall HE, Hess DT, Stamler JS. S-nitrosylation: physiological regulation of NF-kappaB. Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):8841-2. doi: 10.1073/pnas.0403034101. Epub 2004 Jun 8. No abstract available.
- Background: PubMed 21857653Savidge TC, Urvil P, Oezguen N, Ali K, Choudhury A, Acharya V, Pinchuk I, Torres AG, English RD, Wiktorowicz JE, Loeffelholz M, Kumar R, Shi L, Nie W, Braun W, Herman B, Hausladen A, Feng H, Stamler JS, Pothoulakis C. Host S-nitrosylation inhibits clostridial small molecule-activated glucosylating toxins. Nat Med. 2011 Aug 21;17(9):1136-41. doi: 10.1038/nm.2405.
- Background: PubMed 17019693Prasad R, Giri S, Nath N, Singh I, Singh AK. GSNO attenuates EAE disease by S-nitrosylation-mediated modulation of endothelial-monocyte interactions. Glia. 2007 Jan 1;55(1):65-77. doi: 10.1002/glia.20436.
- Background: PubMed 17408650Savidge TC, Newman P, Pothoulakis C, Ruhl A, Neunlist M, Bourreille A, Hurst R, Sofroniew MV. Enteric glia regulate intestinal barrier function and inflammation via release of S-nitrosoglutathione. Gastroenterology. 2007 Apr;132(4):1344-58. doi: 10.1053/j.gastro.2007.01.051. Epub 2007 Feb 1.
- Background: PubMed 19324975Marshall HE, Potts EN, Kelleher ZT, Stamler JS, Foster WM, Auten RL. Protection from lipopolysaccharide-induced lung injury by augmentation of airway S-nitrosothiols. Am J Respir Crit Care Med. 2009 Jul 1;180(1):11-8. doi: 10.1164/rccm.200807-1186OC. Epub 2009 Mar 26.
- Individual participant dataSharing planned: Yes. All of the individual participant data collected during the trial, after deidentification and analysis will be shared.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Kristie Ross, MD principal investigator
University Hospitals Cleveland Medical Center
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Early Phase 1 study testing GSNO Challenge in people with Asthma, run by James Reynolds at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 20 May 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 20 May 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
FeNO (time frame: Approximately 70-80 minutes with measurements taken before and at 10 min intervals up to 1 h after GSNO inhalation). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03926741, which also lists 82 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 May 2026.