Methemoglobin Concentration in High Dose Inhaled Nitric Oxide

November 24, 2025 updated by: Lorenzo Berra, MD, Massachusetts General Hospital

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

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.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed 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.

Study Type

Interventional

Enrollment (Actual)

10

Phase

  • Early Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Massachusetts
      • Boston, Massachusetts, United States, 02114
        • Massachusetts General Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 64 years (Adult)

Accepts Healthy Volunteers

Yes

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Nitric Oxide
High dose inhaled nitric oxide (targeting 250 ppm and not exceeding 300 ppm) in a nitrogen-oxygen-air mixture, at two different FiO2 levels (0.21 and 0.8) will be delivered intermittently with a dedicated system and a snug-fitting facemask to healthy volunteers three times per day for 5 days. The subjects will be monitored before, during and after the administration
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
Other Names:
  • Nitric Oxide
  • Gaseous Nitric Oxide

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Methemoglobin kinetics
Time Frame: 7 days
Levels of methemoglobin formation and reduction during and after exposure to high dose inhaled nitric oxide
7 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Nitric Oxide Metabolites
Time Frame: 7 days
Measurement of Nitric Oxide metabolites (urinary and plasma) in subjects exposed to high dose iNO.
7 days
Nitrogen Dioxide
Time Frame: 5 days
Inspiratory NO2 concentrations at different inspiratory concentrations of NO and O2
5 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Massachusetts General Hospital

Investigators

  • Principal Investigator: Lorenzo Berra, MD, Massachusetts General Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 16, 2023

Primary Completion (Estimated)

November 1, 2026

Study Completion (Estimated)

December 1, 2027

Study Registration Dates

First Submitted

October 31, 2022

First Submitted That Met QC Criteria

November 4, 2022

First Posted (Actual)

November 10, 2022

Study Record Updates

Last Update Posted (Actual)

December 2, 2025

Last Update Submitted That Met QC Criteria

November 24, 2025

Last Verified

November 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2022P002884

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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