Nitric Oxide Gas Inhalation Therapy for Mild/Moderate COVID-19 (NoCovid)

• ClinicalTrials.gov Identifier: NCT04305457
• Recruitment Status: Active, not recruiting
• First Posted: March 12, 2020
• Last Update Posted: November 1, 2022
• Sponsor: Massachusetts General Hospital
• Collaborator: University of Alabama at Birmingham
• Information provided by (Responsible Party): Lorenzo Berra, MD, Massachusetts General Hospital

Tracking Information

• First Submitted Date: March 9, 2020
• First Posted Date: March 12, 2020
• Last Update Posted Date: November 1, 2022
• Actual Study Start Date: March 21, 2020
• Estimated Primary Completion Date: April 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 11, 2020)

Reduction in the incidence of patients with mild/moderate COVID-19 requiring intubation and mechanical ventilation [ Time Frame: 28 days ]

The primary outcome will be the reduction in the incidence of patients 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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: March 17, 2020)

• Mortality [ Time Frame: 28 days ]
  Proportion of deaths from all causes
• Time to clinical recovery [ Time Frame: 28 days ]
  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.

Original Secondary Outcome Measures (submitted: March 11, 2020)

• Mortality [ Time Frame: 28 days ]
  Proportion of deaths from all causes
• Negative conversion of COVID-19 RT-PCR from upper respiratory tract [ Time Frame: 7 days ]
  Proportion of patients with a negative conversion of RT-PCR from an oropharyngeal or oropharyngeal swab.
• Time to clinical recovery [ Time Frame: 28 days ]
  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.

Current Other Pre-specified Outcome Measures (submitted: March 17, 2020)

Negative conversion of COVID-19 RT-PCR from upper respiratory tract [ Time Frame: 7 days ]

Proportion of patients with a negative conversion of RT-PCR from an oropharyngeal or oropharyngeal swab.

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Nitric Oxide Gas Inhalation Therapy for Mild/Moderate COVID-19
• Official Title: Nitric Oxide Gas Inhalation Therapy in Spontaneous Breathing Patients With Mild/Moderate COVID-19: a Randomized Clinical Trial
• Brief 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. 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 Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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.

In a third arm, COVID-19 subjects will be enrolled at Providence HealthCare Network, Anchorage (AK). Subjects in this arm will not be randomized and will all receive nitric oxide gas either as an inpatient or outpatient.

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

• Coronavirus Infections
• Pneumonia, Viral
• Acute Respiratory Distress Syndrome

Intervention

Drug: Nitric Oxide

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.

Other Name: Nitric Oxide inhalation

Study Arms

• Experimental: Nitric Oxide inhalation
  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.
  Intervention: Drug: Nitric Oxide
• No Intervention: Control
  Patients assigned to the control group will not receive any gas therapy.
• Experimental: Nitric Oxide Inhalation (Non-Randomized)
  All subjects part of this arm will receive nitric oxide gas either as an inpatient or outpatient. 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. Patients in this arm will not be randomized, so that all patients receive the study medication.
  Intervention: Drug: Nitric Oxide

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: November 15, 2020): 70
• Original Estimated Enrollment (submitted: March 11, 2020): 240
• Estimated Study Completion Date: April 2025
• Estimated Primary Completion Date: April 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Laboratory confirmed COVID19 infection defined with a positive RT-PCR from any specimen and/or detection of SARS-CoV-2 IgM/IgG antibodies.

2. Hospital admission with at least one of the following:

   1. fever ≥ 36.6 °C from axillary site; or ≥ 37.2°C from oral site; or ≥ 37.6°C from tympanic or rectal site.
   2. Respiratory rate ≥ 24 bpm
   3. cough
3. 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.

Exclusion Criteria:

1. Tracheostomy
2. Therapy with high flow nasal cannula
3. Any clinical contraindications, as judged by the attending physician
4. Patients enrolled in another interventional study
5. Hospitalized and confirmed diagnosis of COVID-19 for more than 72 hours
6. Previous intubation for COVID-19
7. Patient not committed to full support (DNR, DNI or CMO)
8. Patient requiring oxygen at home for lung comorbidities
9. Primary cause of hopitalization not due to COVID-19

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04305457
• Other Study ID Numbers: NOgas mildCOVID-19
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• 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

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Lorenzo Berra, MD, Massachusetts General Hospital
• Original Responsible Party: Same as current
• Current Study Sponsor: Massachusetts General Hospital
• Original Study Sponsor: Same as current
• Collaborators: University of Alabama at Birmingham

Investigators

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

• PRS Account: Massachusetts General Hospital
• Verification Date: October 2022