Methemoglobin Concentration in High Dose Inhaled Nitric Oxide

Healthy Subjects Clinical Trial

Official title:

Kinetics of Methemoglobin Concentration in Healthy Subjects Exposed to High Dose Inhaled Nitric Oxide

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05612074
• Other study ID #: 2022P002884
• Status: Active, not recruiting
• Phase: Early Phase 1
• Start date: October 16, 2023
• Est. completion date: December 2025

Study information

• Verified date: June 2024
• Source: Massachusetts General Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The goal of this clinical trial is to learn about the kinetic of methemoglobin in healthy subjects breathing high dose inhaled nitric oxide.

The main questions it aims to answer are:

• What are the kinetics of methemoglobin formation at a maximum of 300 parts per million of nitric oxide and oxygen

• What are the kinetics of methemoglobin reduction after nitric oxide discontinuation

Participants will be exposed to intermittent high dose inhaled nitric oxide at a maximum of 300 parts per million while being continuously monitored.

Description:

The current proposed physiologic study is a single center, open-label clinical trial in healthy subjects. The primary aim is to describe kinetics of methemoglobin (MetHb) formation and reduction during exposure to high dose inhaled nitric oxide (iNO) at a maximum of 300 parts per million in healthy volunteers. The investigators will also assess the contribution of increased cardiac output in relation to MetHb formation/reduction and of different inspired oxygen concentrations on the production of nitrogen dioxide (NO2).

The study protocol consists of breathing iNO at a maximum of 300 parts per million (ppm) and two different FiO2 levels (i.e. 21% and 80%). The combination of iNO and FiO2 levels identifies 2 study cohorts; five different subjects will be enrolled for each cohort. The maximum number of volunteers enrolled in this clinical trial is 10 spontaneously breathing, awake, healthy subjects, divided in two groups (5 volunteers/group, 2 groups). The first 5 subjects will be exposed to iNO in a mixture of gas at 21% of FiO2, the second group of 5 patients will receive iNO a mixture of gas at 80% of FiO2. Each volunteer will be exposed to a maximum of 300 ppm of iNO at 3 times/day for 5 consecutive days. Thus, a maximum of 150 total iNO treatments will be administered (10 enrolled volunteers, 5 days, 3 treatments/day). On the fifth day of the study, the iNO administration will be performed during physical exercise that will increase the respiratory rate of the subject, in order to study the influence of the respiratory rate on the rate of MetHb formation. During each treatment period, a threshold of MetHb = 10% and/or inspiratory NO2 = 5 ppm (as defined by the OSHA, https://www.osha.gov/chemicaldata/21, last accessed on Oct 31, 2022) will be used as stopping criteria for gas inhalation. Also, iNO administration will be stopped at any time, regardless of the MetHb and NO2 levels, at the discretion of the subject.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 10
• Est. completion date: December 2025
• Est. primary completion date: June 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 64 Years

Eligibility

Inclusion Criteria:

• 18 - 64 years-old volunteers.

• Body Mass Index (BMI) 18 - 30 kg/m2.

• Absence of current systemic and/or respiratory diseases.

• Capacity to consent to the study.

Exclusion Criteria:

• Evidence of any physical, mental, and/or medical conditions that would make the proposed studies relatively more hazardous.

• Systemic and/or respiratory disease with or without any functional limitation.

• Left ventricle ejection fraction < 30%.

• Baseline MetHb = 3%

• Other conditions of increased risk for MetHb formation: genetic diseases (e.g., glucose-6-phosphate dehydrogenase deficiency, cytochrome b5 reductase deficiency, sickle cell disease), significant anemia or baseline elevation in MetHb.

• History of transient ischemic attack or stroke.

• Active smoking and tobacco chewers. Volunteers may be enrolled if they quit smoking for more than 1 year and less than 10 pack years total.

• Any vaping/e-cigarettes use

• Excess alcohol use: more than ½ L/day of wine consumption or equivalent

• Current use of any recreational drugs (including the use of medical marijuana) or use of recreational drugs over the past year.

• Pregnancy determined by blood pregnancy test detecting presence of human chorionic gonadotropin (hCG).

• Less than six weeks postpartum.

• Any current medication uses except oral contraceptives.

• Lower respiratory infection within the last 30 days.

• Claustrophobia (inability to wear a facemask) or other active psychiatric conditions or unwillingness to cooperate with the investigators and other medical teams.

• Currently enrolled in another research study.

• Facial abnormalities that would preclude proper use of a face mask.

Related Conditions & MeSH terms

• Healthy Subjects

Intervention

Drug:
• Inhaled Nitric Oxide
Inhaled nitric oxide (Medical grade, in NO/N2 tanks) will be delivered in a oxygen-air-nitrogen mixture for 30 minutes three times per day

Locations

Country	Name	City	State
United States	Massachusetts General Hospital	Boston	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Massachusetts General Hospital

Country where clinical trial is conducted

United States, 

References & Publications (10)

Bartley BL, Gardner KJ, Spina S, Hurley BP, Campeau D, Berra L, Yonker LM, Carroll RW. High-Dose Inhaled Nitric Oxide as Adjunct Therapy in Cystic Fibrosis Targeting Burkholderia multivorans. Case Rep Pediatr. 2020 Jun 24;2020:1536714. doi: 10.1155/2020/1536714. eCollection 2020. — View Citation

Di Fenza R, Yu B, Carroll RW, Berra L. Chemiluminescence-based Assays for Detection of Nitric Oxide and its Derivatives from Autoxidation and Nitrosated Compounds. J Vis Exp. 2022 Feb 16;(180). doi: 10.3791/63107. — View Citation

Gianni S, Fenza RD, Morais CCA, Fakhr BS, Mueller AL, Yu B, Carroll RW, Ichinose F, Zapol WM, Berra L. High-Dose Nitric Oxide From Pressurized Cylinders and Nitric Oxide Produced by an Electric Generator From Air. Respir Care. 2022 Feb;67(2):201-208. doi: 10.4187/respcare.09308. Epub 2021 Aug 19. — View Citation

Miller C, Miller M, McMullin B, Regev G, Serghides L, Kain K, Road J, Av-Gay Y. A phase I clinical study of inhaled nitric oxide in healthy adults. J Cyst Fibros. 2012 Jul;11(4):324-31. doi: 10.1016/j.jcf.2012.01.003. Epub 2012 Apr 18. — View Citation

Pinciroli R, Traeger L, Fischbach A, Gianni S, Morais CCA, Fakhr BS, Di Fenza R, Robinson D, Carroll R, Zapol WM, Berra L. A Novel Inhalation Mask System to Deliver High Concentrations of Nitric Oxide Gas in Spontaneously Breathing Subjects. J Vis Exp. 2021 May 4;(171). doi: 10.3791/61769. — View Citation

Safaee Fakhr B, Di Fenza R, Gianni S, Wiegand SB, Miyazaki Y, Araujo Morais CC, Gibson LE, Chang MG, Mueller AL, Rodriguez-Lopez JM, Ackman JB, Arora P, Scott LK, Bloch DB, Zapol WM, Carroll RW, Ichinose F, Berra L; Nitric Oxide Study Investigators. Inhaled high dose nitric oxide is a safe and effective respiratory treatment in spontaneous breathing hospitalized patients with COVID-19 pneumonia. Nitric Oxide. 2021 Nov 1;116:7-13. doi: 10.1016/j.niox.2021.08.003. Epub 2021 Aug 13. — View Citation

Safaee Fakhr B, Wiegand SB, Pinciroli R, Gianni S, Morais CCA, Ikeda T, Miyazaki Y, Marutani E, Di Fenza R, Larson GM, Parcha V, Gibson LE, Chang MG, Arora P, Carroll RW, Kacmarek RM, Ichinose F, Barth WH Jr, Kaimal A, Hohmann EL, Zapol WM, Berra L. High Concentrations of Nitric Oxide Inhalation Therapy in Pregnant Patients With Severe Coronavirus Disease 2019 (COVID-19). Obstet Gynecol. 2020 Dec;136(6):1109-1113. doi: 10.1097/AOG.0000000000004128. — View Citation

Valsecchi C, Winterton D, Safaee Fakhr B, Collier AY, Nozari A, Ortoleva J, Mukerji S, Gibson LE, Carroll RW, Shaefi S, Pinciroli R, La Vita C, Ackman JB, Hohmann E, Arora P, Barth WH Jr, Kaimal A, Ichinose F, Berra L; DELiverly oF iNO (DELFiNO) Network Collaborators. High-Dose Inhaled Nitric Oxide for the Treatment of Spontaneously Breathing Pregnant Patients With Severe Coronavirus Disease 2019 (COVID-19) Pneumonia. Obstet Gynecol. 2022 Aug 1;140(2):195-203. doi: 10.1097/AOG.0000000000004847. Epub 2022 Jul 6. — View Citation

Wiegand SB, Safaee Fakhr B, Carroll RW, Zapol WM, Kacmarek RM, Berra L. Rescue Treatment With High-Dose Gaseous Nitric Oxide in Spontaneously Breathing Patients With Severe Coronavirus Disease 2019. Crit Care Explor. 2020 Nov 16;2(11):e0277. doi: 10.1097/CCE.0000000000000277. eCollection 2020 Nov. — View Citation

Wiegand SB, Traeger L, Nguyen HK, Rouillard KR, Fischbach A, Zadek F, Ichinose F, Schoenfisch MH, Carroll RW, Bloch DB, Zapol WM. Antimicrobial effects of nitric oxide in murine models of Klebsiella pneumonia. Redox Biol. 2021 Feb;39:101826. doi: 10.1016/j.redox.2020.101826. Epub 2020 Dec 11. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Methemoglobin kinetics	Levels of methemoglobin formation and reduction during and after exposure to high dose inhaled nitric oxide	7 days
Secondary	Nitric Oxide Metabolites	Measurement of Nitric Oxide metabolites (urinary and plasma) in subjects exposed to high dose iNO.	7 days
Secondary	Nitrogen Dioxide	Inspiratory NO2 concentrations at different inspiratory concentrations of NO and O2	5 days