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NO Prevention of COVID-19 for Healthcare Providers (NOpreventCOVID)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04312243
Recruitment Status : Recruiting
First Posted : March 18, 2020
Last Update Posted : June 16, 2020
Sponsor:
Information provided by (Responsible Party):
Lorenzo Berra, MD, Massachusetts General Hospital

Tracking Information
First Submitted Date  ICMJE March 15, 2020
First Posted Date  ICMJE March 18, 2020
Last Update Posted Date June 16, 2020
Actual Study Start Date  ICMJE April 7, 2020
Estimated Primary Completion Date April 7, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 1, 2020)
COVID-19 diagnosis [ Time Frame: 14 days ]
Percentage of subjects with COVID-19 diagnosis in the two groups
Original Primary Outcome Measures  ICMJE
 (submitted: March 16, 2020)
COVID-19 diagnosis [ Time Frame: 28 days ]
Percentage of subjects with COVID-19 diagnosis
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 1, 2020)
Positive SARS-CoV-2 rt-PCR test [ Time Frame: 14 days ]
Percentage of subjects with a positive test in the two groups
Original Secondary Outcome Measures  ICMJE
 (submitted: March 16, 2020)
Positive SARS-CoV-2 rt-PCR test [ Time Frame: 28 days ]
Percentage of subjects with a positive test in the two groups
Current Other Pre-specified Outcome Measures
 (submitted: April 1, 2020)
  • Total number of quarantine days [ Time Frame: 14 days ]
    Mean/ Median in the two groups
  • Proportion of healthcare providers requiring quarantine [ Time Frame: 14 days ]
    Percentage in the two groups
Original Other Pre-specified Outcome Measures
 (submitted: March 16, 2020)
  • Total number of quarantine days [ Time Frame: 28 days ]
    Mean/ Median in the two groups
  • Proportion of healthcare providers requiring quarantine [ Time Frame: 28 days ]
    Percentage in the two groups
 
Descriptive Information
Brief Title  ICMJE NO Prevention of COVID-19 for Healthcare Providers
Official Title  ICMJE Nitric Oxide Gas Inhalation for Prevention of COVID-19 in Healthcare Providers
Brief Summary

Thousands of healthcare workers have been infected with SARS-CoV-2 and contracted COVID-19 despite their best efforts to prevent contamination. No proven vaccine is available to protect healthcare workers against SARS-CoV-2.

This study will enroll 470 healthcare professionals dedicated to care for patients with proven SARS-CoV-2 infection. Subjects will be randomized either in the observational (control) group or in the inhaled nitric oxide group. All personnel will observe measures on strict precaution in accordance with WHO and the CDC regulations.

Detailed Description

In their efforts to provide care for patients with novel coronavirus (SARS-CoV-2) disease (COVID-19) infection, many healthcare workers around the globe exposed to SARS-CoV-2 got infected and died over the past two months. Quarantined nurses and physicians have become the norm in regions with COVID-19 patients, putting at risk the overall functionality of the regional healthcare system. Other than strict contact-precautions, no proven vaccination or targeted therapy is available to prevent COVID-19 in healthcare workers. Inhaled nitric oxide gas (NO) has shown in a small clinical study to have antiviral activity against a Coronavirus during the 2003 SARS outbreak. We have designed this study to assess whether intermittent inhaled NO in healthcare workers might prevent their infection with SARS-CoV-2.

Background: After almost two months of fight against COVID-19 infection, on February 24, more than 3,000 physicians and nurses were reported as contracting COVID-19 disease in Wuhan (China). Fatalities among those healthcare workers were reported to be related to SARS-CoV-2 infection. Implementation of strict contact protections for all healthcare personnel is essential to decrease and contain the risks of exposure. However, despite best efforts, dozens of thousands of healthcare providers have been quarantined for at least 14 consecutive days in Wuhan alone. Similarly data have been reported in Italy, several healthcare providers have been quarantined, developed pneumonia and died. Most recent information from Italy reported that 12% of healthcare workers are infected.

The shortage of hospital personnel, especially in the critical care and anesthesiology domains, led many hospitals to postpone indefinitely scheduled surgical procedures, including cardiac surgery or oncological procedures. Only urgent and emergent cases are performed in patients without symptoms (i.e., absence of fever, cough or dyspnea), no signs (i.e., negative chest CT for consolidations, normal complete blood count) and a negative test on SARS-CoV-2 reverse transcriptase (rt)-PCR. If time does not allow for thorough screening (i.e., after traumatic injury), such patients are considered to be infected and medical staff in the OR are fully protected with third degree protections (i.e., N95 masks, goggles, protective garments and a gown and double gloving).

Rationale. In 2004 in a collaborative study between the virology laboratory at the University of Leuven (Belgium), the Clinical Physiology Laboratory of Uppsala University (Sweden) and the General Airforce Hospital of China (Beijing, China), nitric oxide (NO) donors (e.g. S-nitroso-N-acetylpenicillamine) greatly increased the survival rate of infected eukaryotic cells with the coronavirus responsible for SARS (SARS-CoV-1), suggesting direct antiviral effects of NO. These authors suggest that oxidation is the antiviral mechanism of nitric oxide. A later work by Akerstrom and colleagues showed that NO or its derivatives reduce palmitoylation SARS-CoV spike (S) protein affecting its fusion with angiotensin converting enzyme 2. Furthermore, NO or its derivatives reduce viral RNA synthesis in the infected cells. Future in-vitro studies should confirm that NO donors are equally effective against SARS-CoV-2, as the current virus shares 88% of its genome with the SARS-CoV [3]. However, at present it is reasonable to assess that a high dose of inhaled NO might be anti-viral against SARS-CoV-2 in the lung. The virus is transmitted by human-to-human contact and occurs primarily via respiratory droplets from coughs and sneezes within a range of about 1.5 meters. The incubation period ranges from 1 to 14 days with an estimated median incubation period of 5 to 6 days according to the World Health Organization [1]. COVID-19 disease is mainly a respiratory system disease, but in the most severe forms can progress to impair also other organ function (i.e., kidneys, liver, heart). Nitric oxide gas inhalation has been successfully and safely used for decades (since 1990) in thousands of newborns and adults to decrease pulmonary artery pressure and improve systemic oxygenation.

Recently at the Massachusetts General Hospital, a high dose of inhaled NO (160 ppm) for 30 - 60 minutes was delivered twice a day to an adolescent with cystic fibrosis and pulmonary infection due to multi-resistant Burkholderia cepacia. There were no adverse events to this patient, blood methemoglobin remained below 5% and lung function and overall well-being improved.

Clinical Gap. Thousands of healthcare workers have been infected with SARS-CoV-2 and contracted COVID-19 despite their best efforts to prevent contamination. No proven vaccine is available to protect healthcare workers against SARS-CoV-2.

Hypothesis. Due to genetic similarities with the Coronavirus responsible for SARS, it is expected that inhaled NO gas retains potent antiviral activity against the SARS-CoV-2 responsible for COVID-19.

Aim. To assess whether intermittent delivery of inhaled NO gas in air at a high dose may protect healthcare workers from SARS-CoV-2 infection.

Observational group: daily symptoms and body temperature monitoring. SARS-CoV-2 RT-PCR test will be performed if fever or COVID-19 symptoms.

Treatment group: the subjects will breathe NO at 160 parts per million (ppm) for two cycles of 15 minutes each at the beginning of each shift and before leaving the hospital. Daily symptoms and body temperature monitoring. SARS-CoV-2 RT-PCR test will be performed if fever or COVID-19 symptoms. Safety: Oxygenation and methemoglobin levels will be monitored via a non-invasive CO-oximeter. If methemoglobin levels rise above 5% at any point of the gas delivery, inhaled NO will be stopped. NO2 gas will be monitored and maintained below 5 ppm.

Blinding. The treatment is not masked.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE
  • Coronavirus Infections
  • Healthcare Associated Infection
Intervention  ICMJE Drug: Inhaled nitric oxide gas
Control group: a SARS-CoV2 rt-PCR will be performed if symptoms arise. Treatment group: the subjects will breathe NO at the beginning of the shift and before leaving the hospital. Inspired NO will be delivered at 160 parts per million (ppm) for 15 minutes in each cycle. A SARS-CoV-2 rt-PCR will be performed if symptoms arise. Safety: Oxygenation and methemoglobin levels will be monitored via a non-invasive CO-oximeter. If methemoglobin levels rise above 5% at any point of the gas delivery, inhaled NO will be halvened. NO2 gas will be monitored and maintained below 5 ppm.
Study Arms  ICMJE
  • Experimental: Treatment Group
    Inhaled NO (160 ppm) before and after the work shift. Daily monitoring of body temperature and symptoms. SARS-CoV-2 RT-PCR test if fever or COVID-19 symptoms.
    Intervention: Drug: Inhaled nitric oxide gas
  • No Intervention: Control Group
    Daily monitoring of body temperature and symptoms. SARS-CoV-2 RT-PCR test if fever or COVID-19 symptoms.
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 1, 2020)
470
Original Estimated Enrollment  ICMJE
 (submitted: March 16, 2020)
460
Estimated Study Completion Date  ICMJE April 7, 2022
Estimated Primary Completion Date April 7, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Age ≥18 years
  2. Scheduled to work with SARS-CoV-2 infected patients for at least 3 days in a week.

Exclusion Criteria:

  1. Previous documented SARS-CoV-2 infections and subsequent negative SARS-CoV-2 rt-PCR test.
  2. Pregnancy
  3. Known hemoglobinopathies.
  4. Known anemia
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 99 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: Lorenzo Berra, MD +16176437733 lberra@mgh.harvard.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04312243
Other Study ID Numbers  ICMJE NOpreCOVID-19
Has Data Monitoring Committee Yes
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  ICMJE
Plan to Share IPD: No
Responsible Party Lorenzo Berra, MD, Massachusetts General Hospital
Study Sponsor  ICMJE Massachusetts General Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Massachusetts General Hospital
Verification Date June 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP