Indianapolis, Indiana 46219

  • Airway Disease

Purpose:

Airway pH imbalances cause numerous adverse physiological changes within the airways, including hyperreactivity, cough, bronchoconstriction, ciliopathy, decreased response to bronchodilators, bacterial growth, nitrosative/oxidative stress, neutrophilic/eosinophilic inflammation, and cell death. Airway pH is known to be low (acidic) in chronic and acute pulmonary diseases. The gold standard approach to measuring airway pH is to bronchscopically obtain epithelial cell lining fluid using protected brush sampling. The expense and invasive nature of this approach is a barrier to fully characterizing the role of airway pH in the health and disease. In this study, we will evaluate non-invasive clinical methods that can be done using equipment standard in clinical pulmonary function laboratories for measuring airway pH.


Study summary:

Airway pH imbalances cause numerous adverse physiological changes within the airways, including hyperreactivity, cough, bronchoconstriction, ciliopathy, decreased response to bronchodilators, bacterial growth, nitrosative/oxidative stress, neutrophilic/eosinophilic inflammation, and cell death. Airway pH is known to be low (acidic) in chronic and acute pulmonary diseases. The gold standard approach to measuring airway pH is to bronchscopically obtain epithelial cell lining fluid using protected brush sampling. The expense and invasive nature of this approach is a barrier to fully characterizing the role of airway pH in the health and disease. In this study, we will evaluate non-invasive clinical methods that can be done using equipment standard in clinical pulmonary function laboratories for measuring airway pH. Our group has previously demonstrated that exhaled breath condensate (EBC) pH and changes in fractional exhaled nitric oxide collected at 50mL/sec (FeNO50) after inhalation of an alkaline glycine buffer (AGB) indicate low airway pH. While EBC pH is the most common method and validated method for estimating airway pH, we believe that the change in FeNO50 is the most sensitive test for general airway pH. Specifically, our proposed test makes use of the facts that the pH of nitrite/nitrous acid (NO2-/HNO2) is just under 4. Nitrous acid thus evolves nitric oxide (NO) when pH is less than 6.5, and NO evolution stops when pH is above 7. Because endogenous human airway NO2- levels are normally low μM, (32) NO2 protonation can be used as a noninvasive test for airway pH. Using the Henderson-Hasselbalch equation, we can use these changes in NO to calculate pH. We have now done studies with both inhaled phosphate buffer and AGB, both of which show that specific patients with asthma have a significant fall in FeNO50 following buffer inhalation. While FeNO50 is validated to represent the nitric oxide levels of the middle airways, sampling can be done at several different flowrates and times to evaluate the nitric oxide levels in different compartments of the lung. This can allow for regional airway pH measurement which would be helpful since many airway diseases are heterogeneous and regional. We will further characterize the normal range of airway pH in health and disease compartmentally within the airways and in subsequent studies will evaluate the effects of clinically altering pH when it is abnormal. It has been recently discovered that airway pH is integral to airway cell entry and replication of SARS-CoV-2 virus. Specifically, one of the pathways by which the virus enters cells and replicates is blocked by intracellular alkalinization. We therefore tested to determine whether AGB would cause intracellular alkalinization in cultured primary human airway epithelial cells. It did; and the drug was well-tolerated by the cells in vitro (as it is in vivo). We believe that the next step is to determine whether AGB inhibits viral replication and viral entry in our primary human airway epithelial cultures. To do this, we are partnering with our Indiana University BSL3 virology lab. We have acquired the virus, completed preparations of it, and have infected our human airway epithelial cultures with it. We are awaiting preliminary results of the effects of AGB on viral entry and replication. If in fact AGB inhibits viral cell entry and, thereby, replication, we intend to expand our IND with the FDA, allowing a trial in patients at risk for respiratory distress associated with known COVID-2 respiratory disease. Ultimately, outcomes of this trial would be proposed to include: mortality (primary); as well as ICU length of stay and oxygen saturation index area under the curve (secondary). We have submitted grants to the NIH, the DoD, and several other agencies for this project. The study proposed here will not only provide further insight into the use of AGB in a larger population but also will allow for evaluation of airway pH in those receiving it which could be used to guide therapy.


Criteria:

Inclusion Criteria: - • Study sample will consist of individuals aged 18-60 with a diagnosis of acute or chronic respiratory disorders or normal subjects with no pulmonary disease. Healthy subjects may include: 1. Adult males or females age ≥ 18 and ≤ 60 years at time of enrollment 2. Non-smokers 3. Person with no history of asthma, chronic obstructive pulmonary disease (COPD), or other chronic lung disease 4. Person with no history of severe allergic/atopic disease requiring immunotherapy or immunomodulators Subjects with pulmonary disease may include: 1. Person with well-documented disease with objective diagnostics such a lung function or genetic testing. 2. Person with FEV1 > 55% predicted on the day of study procedures. 3. Person who is clinically stable with no significant changes in health status within 4 weeks. Exclusion Criteria: - • Subjects that are mechanically ventilated. - Subjects that are unable or unwilling to cooperate with specimen collection. - Subjects with diagnosis of any medical condition that in the investigator's opinion would make them unsuitable for study participation. - Subjects who experienced a pulmonary exacerbation within the 4 weeks prior to visit. - Subjects requiring continuous oxygen therapy.


Study is Available At:


Original ID:

2003838272


NCT ID:

NCT04738422


Secondary ID:


Study Acronym:


Brief Title:

Determining Airway pH by Compartmental Exhaled Nitric Oxide Levels During Alkaline Buffer Challenge


Official Title:

Determining Airway pH by Compartmental Exhaled Nitric Oxide Levels During Alkaline Buffer Challenge


Overall Status:

Recruiting


Study Phase:

Phase 2


Genders:

N/A


Minimum Age:

18 Years


Maximum Age:

60 Years


Quick Facts

Healthy Volunteers
Oversight Has DMC
Study Is FDA Regulated
Study Is Section 801
Has Expanded Access

Study Source:

Indiana University


Oversight Authority:

There was an error processing this request


Reasons Why Stopped:


Study Type:

Interventional


Study Design:


Number of Arms:

1


Number of Groups:

0


Total Enrollment:

500


Enrollment Type:

Anticipated


Overall Contact Information

Primary Contact:Kenzie R Mahan
3172748899
krmahan@iu.edu
Backup Contact:Lisa Bendy
3172787152
lbendy@iu.edu

Study Dates

Start Date:September 11, 2020
Completion Date:December 31, 2025
Completion Type:Anticipated
Primary Completion Date:December 31, 2023
Primary Completion Type:Anticipated
Verification Date:February 2021
Last Changed Date:February 1, 2021
First Received Date:February 1, 2021

Study Outcomes

Outcome Type:Primary Outcome
Measure:Exhaled Breath Condensate (EBC) pH
Time Frame:Study is a single visit, lasting less than two hours
Safety Issues:False
Description:Measuring the pH of EBC before and after inhaled alkaline glycine
Outcome Type:Primary Outcome
Measure:Calculated compartmental airway pH
Time Frame:Study is a single visit, lasting less than two hours
Safety Issues:False
Description:Calculating compartmental FeNO before inhaled alkaline glycine and after inhaled alkaline glycine
Outcome Type:Primary Outcome
Measure:Compartmental FeNO
Time Frame:Study is a single visit, lasting less than two hours
Safety Issues:False
Description:Measuring compartmental FeNO before inhaled alkaline glycine and after inhaled alkaline glycine

Study Interventions

Intervention Type:Drug
Name:Alkaline glycine
Description:Subjects will inhale alkaline glycine via nebulizer. Alkaline glycine is an alkaline medication designed for medication.
Arm Name:Alkaline glycine Inhalation
Other Name:Optate

Study Arms

Study Arm Type:Experimental
Arm Name:Alkaline glycine Inhalation
Description:Subjects inhale alkaline glycine

Study Agencies

Agency Class:Other
Agency Type:Lead Sponsor
Agency Name:Indiana University

Sample and Retention Information

There are no available Sample and Retention Information

Study References

There are no available Study References

Data Source: ClinicalTrials.gov

Date Processed: July 25, 2021

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