Coronavirus InfectionsPhase 2NoCovidNCT04305457
Nitric Oxide Gas Inhalation Therapy for Mild/Moderate COVID-19
A Phase 2 study testing Nitric Oxide in people with Coronavirus Infections and Pneumonia, Viral, run by Massachusetts General Hospital at 2 sites in United States.
Trial summary
The scientific community is in search for novel therapies that can help to face the ongoing epidemics of novel Coronavirus (SARS-Cov-2) originated in China in December 2019. At present, there are no proven interventions to prevent progression of the disease. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Coronavirus Infections, Pneumonia, Viral, Acute Respiratory Distress Syndrome
- What is being tested?
- Nitric Oxide
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 62 participants
- Where
- 2 sitesUnited States
- Study dates
- 21 Mar 2020to 23 Aug 2023
- Phase
- Phase 2
- 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 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Laboratory confirmed COVID19 infection defined with a positive RT-PCR from any specimen and/or detection of SARS-CoV-2 IgM/IgG antibodies.
- Hospital admission with at least one of the following:
- fever ≥ 36.6 °C from axillary site; or ≥ 37.2°C from oral site; or ≥ 37.6°C from tympanic or rectal site.
- Respiratory rate ≥ 24 bpm
- cough
- Spontaneous breathing with or without hypoxia of any degree. Gas exchange and ventilation maybe assisted by any continuous continuous airway pressure (CPAP), or any system of Non Invasive Ventilation (NIV), with Positive End-Expiratory Pressure (PEEP) ≤ 10 cmH2O.
Who cannot join
- Tracheostomy
- Therapy with high flow nasal cannula
- Any clinical contraindications, as judged by the attending physician
- Patients enrolled in another interventional study
- Hospitalized and confirmed diagnosis of COVID-19 for more than 72 hours
- Previous intubation for COVID-19
Show all 9Show fewer
- Patient not committed to full support (DNR, DNI or CMO)
- Patient requiring oxygen at home for lung comorbidities
- Primary cause of hopitalization not due to COVID-19
Trial locations and contacts
2 sites in 1 country.
United States2 sites
Massachusetts General Hospital
Boston, Massachusetts, 02114-2621
Louisiana State University Health Shreveport
Shreveport, Louisiana, 71103
About this study
Official title: Nitric Oxide Gas Inhalation Therapy in Spontaneous Breathing Patients With Mild/Moderate COVID-19: a Randomized Clinical Trial
The scientific community is in search for novel therapies that can help to face the ongoing epidemics of novel Coronavirus (SARS-Cov-2) originated in China in December 2019. At present, there are no proven interventions to prevent progression of the disease. Some preliminary data on SARS pneumonia suggest that inhaled Nitric Oxide (NO) could have beneficial effects on SARS-CoV-2 due to the genomic similarities between this two coronaviruses. In this study we will test whether inhaled NO therapy prevents progression in patients with mild to moderate COVID-19 disease.
Read the detailed description
To date, no targeted therapeutic treatments for the ongoing COVID-19 outbreak have been identified. Antiviral combined with adjuvant therapies are currently under investigation. The clinical spectrum of the infection is wide, ranging from mild signs of upper respiratory tract infection to severe pneumonia and death.
In the patients who progress, the time period from symptoms onset to development of dyspnea is reported to be between 5 to 10 days, and that one to severe respiratory distress syndrome from 10 to 14 days. Globally, 15 to 18% of patients deteriorates to the need of mechanical ventilation, despite the use of non-invasive ventilatory support in the earliest phases of the disease. Probability of progression to end stage disease is unpredictable, with the majority of these patients dying from multi-organ failure. Preventing progression in spontaneously breathing patients with mild to moderate disease would translate in improved morbidity and mortality and in a lower use of limited healthcare resources.
In 2004, during the SARS-coronavirus (SARS-CoV) outbreak, a pilot study showed that low dose ( max 30 ppm) inhaled NO for 3 days was able to shorten the time of ventilatory support. At the same time, NO donor compound S-nitroso-N-acetylpenicillamine increased survival rate in an in-vitro model of SARS-CoV infected epithelial cells.Based on the genetic similarities between the two viruses, similar effects of NO on SARS-CoV-2 can be hypothesized. While further in-vitro testing is recommended, we proposed a randomized clinical trial to test the effectiveness of inhaled NO in preventing the progression of SARS-CoV-2 related disease, when administered at an early stage.
- Being tested
- Nitric Oxide
- Keywords
- COVID-19, ARDS, Mechanical Ventilation, Nitric Oxide
- Medical subject headings
- Coronavirus Infections, Pneumonia, Viral, Respiratory Distress Syndrome, COVID-19
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Nitric OxideDrug
Also called Nitric Oxide inhalation
Nitric Oxide (NO) will be delivered together with the standard of care for a period of 20-30 minutes 2 times per day for 14 consecutive days from time of enrollment. Targeted No inhaled concentration will be maintained between 140 and 180 ppm. The gas will be delivered through a CPAP circuit ensuring an end-expiratory pressure between 2 and 10 cmH2O or through a non-rebreathing mask without positive end-expiratory pressure, depending on the clinical needs of the subject.
| Study group | Role | What they receive |
|---|---|---|
| Nitric Oxide inhalation | Experimental | Nitric Oxide will be delivered through a non invasive CPAP system (with minimal pressure support to decrease discomfort due to the facial mask) or through a non-rebreathing mask system. Receives: Drug: Nitric Oxide |
| Control | No intervention | Patients assigned to the control group will not receive any gas therapy. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants With Mild/Moderate COVID-19 Requiring Intubation and Mechanical Ventilation
The primary outcome will be the number of participants requiring intubation and mechanical ventilation, as a marker of deterioration from a mild to a severe form of COVID-19. Patients with indication to intubation and mechanical ventilation but concomitant DNI (Do Not Intubate) or not intubated for any other reason external to the clinical judgment of the attending physician will be considered as meeting the criteria for the primary endpoint.
Measured: 28 days
Secondary outcomes (2)
Mortality
Proportion of deaths from all causes
Measured: 28 days
Time to Clinical Recovery
Time from initiation of the study to discharge or to normalization of fever (defined as <36.6°C from axillary site, or < 37.2°C from oral site or < 37.8°C from rectal or tympanic site), respiratory rate (< 24 bpm while breathing room air), alleviation of cough (defined as mild or absent in a patient reported scale of severe >>moderate>>mild>>absent) and resolution of hypoxia (defined as SpO2 ≥ 93% in room air or P/F ≥ 300 mmHg). All these improvements must be sustained for 72 hours.
Measured: 28 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Mar 2020
- Study start21 Mar 2020
- Primary completion23 Aug 2023
- Study completion23 Aug 2023
Why it stopped: COVID wave passed
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.
- Other trials for Coronavirus InfectionsStudies of the same condition, open and under way.
- More trials run by Massachusetts General HospitalThe sponsor's other registered studies.
- 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
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- This study includes a randomized, parallel arm clinical trial in which subjects will be randomized to receive either inhaled nitric oxide (in addition to the standard of care) or the standard of care alone.
- Masking
- None (open label)
- Enrolment
- 62 participants (actual)
Sponsor and investigators
- Lead sponsor
- Massachusetts General Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- University of Alabama at Birmingham
- Responsible party
- Principal investigator, Lorenzo Berra, MD, Massachusetts General Hospital
- Investigators
- Lorenzo Berra, MD, Principal investigator, Massachusetts General Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04305457
- Sponsor's protocol ID
- NOgas mildCOVID-19
- Acronym
- NoCovid
- Status last verified
- Mar 2026
- First submitted
- 9 Mar 2020
- Last updated
- 23 Mar 2026
- Results posted
- Yes, on ClinicalTrials.gov
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 23 Mar 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Nitric Oxide Gas Inhalation Therapy in Spontaneous Breathing Patients With Mild/Moderate COVID-19: a Randomized Clinical Trial
- ClinicalTrials.gov ID
- NCT04305457
- Acronym / sponsor ID
- NoCovid / NOgas mildCOVID-19
- Keywords
- COVID-19, ARDS, Mechanical Ventilation, Nitric Oxide
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: COVID wave passed
- Enrolment
- 62 participants (actual)
- Lead sponsor
- Massachusetts General HospitalUniversity, hospital or other
- Collaborators
- University of Alabama at Birmingham
- Study start
- 21 Mar 2020 (actual)
- Primary completion
- 23 Aug 2023 (actual)
- Study completion
- 23 Aug 2023 (actual)
- First posted
- 12 Mar 2020 (actual)
- Results
- Posted 23 Mar 2026
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The scientific community is in search for novel therapies that can help to face the ongoing epidemics of novel Coronavirus (SARS-Cov-2) originated in China in December 2019. At present, there are no proven interventions to prevent progression of the disease. Some preliminary data on SARS pneumonia suggest that inhaled Nitric Oxide (NO) could have beneficial effects on SARS-CoV-2 due to the genomic similarities between this two coronaviruses. In this study we will test whether inhaled NO therapy prevents progression in patients with mild to moderate COVID-19 disease.
Detailed description
To date, no targeted therapeutic treatments for the ongoing COVID-19 outbreak have been identified. Antiviral combined with adjuvant therapies are currently under investigation. The clinical spectrum of the infection is wide, ranging from mild signs of upper respiratory tract infection to severe pneumonia and death.
In the patients who progress, the time period from symptoms onset to development of dyspnea is reported to be between 5 to 10 days, and that one to severe respiratory distress syndrome from 10 to 14 days. Globally, 15 to 18% of patients deteriorates to the need of mechanical ventilation, despite the use of non-invasive ventilatory support in the earliest phases of the disease. Probability of progression to end stage disease is unpredictable, with the majority of these patients dying from multi-organ failure. Preventing progression in spontaneously breathing patients with mild to moderate disease would translate in improved morbidity and mortality and in a lower use of limited healthcare resources.
In 2004, during the SARS-coronavirus (SARS-CoV) outbreak, a pilot study showed that low dose ( max 30 ppm) inhaled NO for 3 days was able to shorten the time of ventilatory support. At the same time, NO donor compound S-nitroso-N-acetylpenicillamine increased survival rate in an in-vitro model of SARS-CoV infected epithelial cells.Based on the genetic similarities between the two viruses, similar effects of NO on SARS-CoV-2 can be hypothesized. While further in-vitro testing is recommended, we proposed a randomized clinical trial to test the effectiveness of inhaled NO in preventing the progression of SARS-CoV-2 related disease, when administered at an early stage.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- This study includes a randomized, parallel arm clinical trial in which subjects will be randomized to receive either inhaled nitric oxide (in addition to the standard of care) or the standard of care alone.
| Arm | Type | Receives |
|---|---|---|
| Nitric Oxide inhalation | Experimental | Drug: Nitric OxideNitric Oxide will be delivered through a non invasive CPAP system (with minimal pressure support to decrease discomfort due to the facial mask) or through a non-rebreathing mask system. |
| Control | No intervention | –Patients assigned to the control group will not receive any gas therapy. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Laboratory confirmed COVID19 infection defined with a positive RT-PCR from any specimen and/or detection of SARS-CoV-2 IgM/IgG antibodies.
- Hospital admission with at least one of the following:
- Spontaneous breathing with or without hypoxia of any degree. Gas exchange and ventilation maybe assisted by any continuous continuous airway pressure (CPAP), or any system of Non Invasive Ventilation (NIV), with Positive End-Expiratory Pressure (PEEP) ≤ 10 cmH2O.
Key exclusion criteria (9 listed)
- Tracheostomy
- Therapy with high flow nasal cannula
- Any clinical contraindications, as judged by the attending physician
- Patients enrolled in another interventional study
- Hospitalized and confirmed diagnosis of COVID-19 for more than 72 hours
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 |
|---|---|---|
| Nitric OxideAlso: Nitric Oxide inhalationNitric Oxide (NO) will be delivered together with the standard of care for a period of 20-30 minutes 2 times per day for 14 consecutive days from time of enrollment. Targeted No inhaled concentration will be maintained between 140 and 180 ppm. The gas will be delivered through a CPAP circuit ensuring an end-expiratory pressure between 2 and 10 cmH2O or through a non-rebreathing mask without positive end-expiratory pressure, depending on the clinical needs of the subject. | Drug | Nitric Oxide inhalation |
Primary outcome
Number of Participants With Mild/Moderate COVID-19 Requiring Intubation and Mechanical Ventilation
Time frame: 28 days
The primary outcome will be the number of participants requiring intubation and mechanical ventilation, as a marker of deterioration from a mild to a severe form of COVID-19. Patients with indication to intubation and mechanical ventilation but concomitant DNI (Do Not Intubate) or not intubated for any other reason external to the clinical judgment of the attending physician will be considered as meeting the criteria for the primary endpoint.
2 secondary outcomes
Mortality
Time frame: 28 days
Time to Clinical Recovery
Time frame: 28 days
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Mar 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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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.
Lorenzo Berra, MD principal investigator
Massachusetts General Hospital
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Nitric Oxide in people with Coronavirus Infections and Pneumonia, Viral, run by Massachusetts General Hospital 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 6 inclusion and 9 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: stopped early, as of the sponsor's last update on 23 Mar 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?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
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 23 Mar 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?
Number of Participants With Mild/Moderate COVID-19 Requiring Intubation and Mechanical Ventilation (time frame: 28 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 23 Mar 2026.