Nitric Oxide Gas Inhalation Therapy in Spontaneous Breathing Patients With Mild/Moderate COVID-19: a Randomized Clinical Trial
Phase: PHASE2
Conditions: Coronavirus Infections, Pneumonia, Viral, Acute Respiratory Distress Syndrome
Sponsor: Massachusetts General Hospital

 
 
 
 
 
 
 
 
 
 
 
 
Cover Page for ClinicalTrials.gov  
Document:  
Study Protocol and Statistical Analysis Plan 
Official Study Title:  
Nitric Oxide Gas Inhalation Therapy in Spontaneous Breathing Patients with 
Mild/Moderate COVID-19: A Randomized Clinical Trial 
Document Date:  
March 13, 2020 
ClinicalTrials.gov ID: 
NCT04305457 
 

Protocol for a randomized controlled trial 
testing inhaled nitric oxide therapy in 
spontaneously breathing patients with 
COVID-19 
 
Chong Lei1, Binxiao Su1,2, Hailong Dong1, Bijan Safaee Fakhr3, Luigi Giuseppe Grassi3, 
Raffaele Di Fenza3, Stefano Gianni3, Riccardo Pinciroli3, Emanuele Vassena3, Caio Cesar Araujo 
Morais3, Andrea Bellavia4, Stefano Spina3, Robert Kacmarek3, Lorenzo Berra3.   
 
1. Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, the 
Fourth Military Medical University. Xi’an, Shaanxi, China. 
2. Intensive Care Unit, Department of Anesthesiology and Perioperative Medicine, 
Xijing Hospital, the Fourth Military Medical University. Xi’an, Shaanxi, China. 
3. Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General 
Hospital, Boston, Massachusetts, USA. 
4. Department of Environmental Health, Harvard T.H. Chan School of Public Health, 
Boston, Massachusetts, USA 
 
Correspondence to Dr. Chong LEI, crystalleichong@126.com and Dr. Lorenzo Berra, 
lberra@ mgh.harvard.edu 
 
 
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Abstract 
Introduction: the current worldwide outbreak of Coronavirus disease 2019 (COVID-19) 
due to a novel coronavirus (SARS-CoV-2) is seriously threatening the public health. The 
number of infected patients is continuously increasing and the need for Intensive Care 
Unit admission ranges from 5 to 26%. The mortality is reported to be around 3.4% with 
higher values for the elderly and in patients with comorbidities. Moreover, this condition 
is challenging the healthcare system where the outbreak reached its highest value. To 
date there is still no available treatment for SARS-CoV-2. Clinical and preclinical 
evidence suggests that nitric oxide (NO) has a beneficial effect on the coronavirus-
mediated acute respiratory syndrome, and this can be related to its viricidal effect. The 
time from the symptoms’ onset to the development of severe respiratory distress is 
relatively long. We hypothesize that high concentrations of inhaled NO administered 
during early phases of COVID-19 infection can prevent the progression of the disease.  
Methods and analysis: This is a multicenter randomized controlled trial. Spontaneous 
breathing patients admitted to the hospital for symptomatic COVID-19 infection will be 
eligible to enter the study. Patients in the treatment group will receive inhaled NO at 
high doses (140-180 parts per million) for 30 minutes, 2 sessions every day for 14 days 
in addition to the hospital care. Patient in the control group will receive only hospital 
care. The primary outcome is the percentage of patients requiring endotracheal 
intubation due to the progression of the disease in the first 28 days from enrollment in 
the study. Secondary outcomes include mortality at 28 days, proportion of negative test 
for SARS-CoV-2 at 7 days and time to clinical recovery. 
 
Ethics and dissemination: The trial protocol has been approved at the Investigation 
Review Boards of Xijing Hospital (Xi’an, China) and The Partners Human Research 
Committee of Massachusetts General Hospital (Boston, USA) is pending. Recruitment 
is expected to start in March 2020. Results of this study will be published in scientific 
journals, presented at scientific meetings, and on related website or media in fighting 
this widespread contagious disease. 
 
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Trial registration. Clinicaltrials.gov. NCT submitted 
 
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Introduction 
The novel Coronavirus 2019 (SARS-CoV-2) has been first identified in China in 
December 2019 [1]. As of today, more than 110,000 cases have been reported (with 
more than 4,000 deaths) and, while the majority of them is still concentrated in China, 
the infection has spread across the country’s border to many Asian countries, as well as 
to Europe and to the USA [2]. 
SARS-CoV-2 is a positive single-stranded RNA virus belonging to the family 
Coronaviridae. The current outbreak would result from the acquired ability of the virus to 
undergo human to human transmission [3], after the jump from the original animal 
reservoir (most likely a bat).  
In the human host, SARS-CoV-2 causes a respiratory syndrome (named COVID-19) 
which can range from a mild involvement of the upper airways to a severe pneumonia 
with Acute Respiratory Syndrome (ARS) and the need of mechanical ventilation in an 
intensive care unit (ICU). In early case series, the risk of critical care admission ranges 
between 5 and 26%, with higher values for the elderly and in patients with comorbidities 
or chronic diseases [4,5]. The time from symptoms onset to development of severe 
respiratory distress is relatively long, with a median time of 8 days in which the patient 
remains in a state of mild disease characterized by dry cough, fever and mild hypoxia 
requiring oxygen supplementation. Once severe disease with the necessity of ICU 
develops, the outcome worsens decisively, with mortality raising from 3.4% to 61% 
[4,6]. Moreover, ICU staying poses a serious strain on resource-limited hospitals. Thus, 
preventing disease progression during the mild phase would be highly desirable both in 
terms of morbidity and mortality improvement and healthcare resource-sparing. At the 
present time, there are no proven etiological treatments for COVID-19 but some 
ongoing clinical trials are testing the effects of anti-viral drugs (NCT04252664 on 
ClinicalTrials.gov).  
In 2004, a pilot study showed that low dose inhaled Nitric Oxide (NO) was able to 
shorten the time of ventilatory support during the SARS epidemic, sustained by another 
coronavirus, SARS-CoV [7]. In an in vitro study, the NO donor compound S-nitroso-N-
acteylpenicillamine increased the survival rate in an in vitro model of SARS-CoV 
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infected Monkey’s epithelial cells [8], suggesting a possible viricidal effect of the gas. 
Inhaled NO at high doses can be administered safely and is known for potential 
microbicidal effects [9–12]. While further in-vitro testing for this specific virus is 
recommended, we propose a randomized clinical trial to test the effectiveness of 
inhaled NO in preventing progression of COVID-19 disease, when administered at an 
early stage.  
 
Methods and analysis  
Study design  
Multicenter randomized clinical trial.   
Study setting  
The coordinating center for China of this study is Xijing Hospital, the Fourth Military 
Medical University in Xi’an, Shaanxi, China.  
The coordinating center for other centers is the Massachusetts General Hospital in 
Boston, Massachusetts, USA. This study is open to other centers willing to participate. 
For more information see section “Contacts”. 
Eligibility criteria 
Adults in-hospital patients (>18 years old) will be recruited within 72 hours after 
confirmation of COVID-19 by real-time Reverse Transcriptase Polymerase Chain 
Reaction (RT-PCR) on oropharyngeal or nasopharyngeal swabs or stool samples. 
Diagnosis can also be obtained by detection of COVID-19 IgM/IgG antibodies in serum, 
plasma or whole blood sample.   
Symptoms of COVID-19 must include presence of fever of at least 36.6 °C from the 
axillary site or 37.2 °C from the oral site or 37.6 °C from the rectal / tympanic site.  
In addition, patient must be spontaneously breathing with a respiratory rate of at least 
24 breaths per minute and/or an objective persistent cough consistent with COVID-19 
symptoms. 
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The patients with or without hypoxia will be included. Gas exchange and ventilation may 
be assisted by means of any continuous positive airway pressure (CPAP) system, or 
any system of non-invasive ventilation (NIV) with positive end-expiratory pressure 
(PEEP) ≤ 10 cmH2O.  
Criteria of exclusion are pregnancy (all women in fertile age should be tested for 
pregnancy before being enrolled); presence of an open tracheostomy; therapy with 
high-flow nasal cannula; clinical contraindication to NO gas delivery, as judged by the 
attending physician; hospitalized and confirmed diagnosis of COVID-19 for more than 
72 hours. 
Table 1 summarize inclusion and exclusion criteria.   
Interventions  
This is a randomized (1:1) controlled, parallel arm clinical trial to verify that brief periods 
of inhaled NO at high doses can improve clinical course reducing the number of patients 
who undergo endotracheal intubation for COVID-19 in the first 28 days after enrollment 
in the study (primary endpoint). 
Once admitted to the hospital with a confirmed diagnosis of COVID-19 (obtained by RT-
PCR for SARS-COVID-2 virus, or positive in COVID-19 IgM/IgG antibodies) the patients 
will be screened. Eligible patients randomized to the treatment group will receive iNO to 
target an average inspiratory concentration between 140 to 180 ppm. The 
administration of iNO will be performed through a non-invasive ventilation circuit with a 
range between 2 and 10 cmH2O of positive end expiratory pressure (PEEP) or a non-
rebreathing mask without positive end expiratory pressure depending on the clinical 
needs of the patient and availability of respiratory equipment. The patients will undergo 
2 sessions per day with the duration between 20 and 30 minutes. A representation of 
the administration setting in shown in Figure 1.  
The NO gas therapy will continue for 14 days or until the primary outcome event is 
reached (i.e., clinical deterioration with indication for intubation and mechanical 
ventilation). Other criteria for the interruption of the therapy are: negative result on RT-
PCR for the presence of the coronavirus (SARS-CoV-2, endpoint 3); hospital discharge 
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or recovery from the symptoms, defined as normalization of fever, respiratory rate, and 
alleviation of cough, sustained for at least 72 hours (endpoint 4). A flowchart of the 
study is presented in Figure 2. 
The evaluation of the patients will continue for 28 day after the enrollment. 
Since treatment with inhaled NO can lead to increase in plasmatic methemoglobin, the 
blood levels of methemoglobin will be monitored via non-invasive CO-oximeter or 
methemoglobin levels in blood. If methemoglobin levels rise above 5% at any point of 
the study, inhaled NO concentration will be immediately stopped until the subsequent 
dose. For safety reason we will also evaluate NO2 level in order to keep it below 5 ppm. 
If we observe an increase above this value, we will immediately interrupt the 
administration of NO until the subsequent dose. 
Patients assigned to the control group will not receive any gas therapy.  
 
 
Outcomes  
The primary outcome will be the proportion of patients who progress to a severe form of 
the disease, defined as the indication given by the attending physician to intubation and 
mechanical ventilation in the first 28 days after enrollment in the study. Patients in 
severe respiratory failure and/or ventilatory distress with indication to intubation but 
concomitant DNI (Do Not Intubate) will meet criteria for primary endpoint. The 
proportion of intubation will be calculated at 28 days from study enrollment.  
Secondary outcomes include:  
-Mortality from any cause at 28 days (endpoint 2) 
-Proportion of negative conversion of SARS-CoV-2 from upper respiratory tract 
specimens at 7 days (endpoint 3) 
-Time to clinical recovery, defined as: normalization of fever (≤ 36.6 C from the axillary 
site; or ≤ 37.2 C from the oral site; or ≤ 37.8 C from the rectal/tympanic site) plus 
normalization of respiratory rate < 24 breaths/min and alleviation of cough (defined as 
mild or absent in a patient-reported scale of severe>>moderate>>mild>>absent) or 
discharge home (endpoint 4).  
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Data collection  
Clinical information including medical history and laboratory exams will be obtained from 
the medical charts and prospectively recorded until discharge or death. Collection of 
study variables will be managed by the outcome assessors by using a dedicated 
patient’s file on Studytrax. The 28 days follow up, if the patient is discharged from the 
hospital, will be performed by a phone call.  
Outcome assessors, treatment providers and the principal investigator will obtain unique 
usernames and password to transfer all data to a Studytrax page dedicated to the 
study. Data access is restricted only to authorized member of the team which will be 
responsible for strict confidentiality all times. The signed informed consent will be kept in 
a secure place for at least 5 years after study completion.  
 
Sample size calculation  
Based on previously published data on COVID 19 [4], we predict an incidence of 
intubation and mechanical ventilation of 12.3%. However, because of the novel nature 
of this study, we do not have enough data to predict the effect of inhaled NO on the 
primary outcome. The dynamic trend of this ongoing outbreak also prevents us to 
determine the rate of enrollment that we can achieve. As such, in Table 2 we are 
displaying the sample size calculation for our primary outcome, for an alpha level of 
0.05 and a power level of 0.8, under different scenario. We will perform a first analysis 
based on 240 patients, evaluating the actual incidence of the primary outcome, effect of 
the treatment and the actual rate of enrollment. The PI will decide, together with the 
DSMB, whether to continue enrollment to 340 patients, if a sufficient rate of enrollment 
and power had not been achieved with the original sample size. Based on results 
reported in Table 2, the same step could then be repeated increasing sample size from 
340 to 500 patients, from 500 patients to 760 and from 760 patients to 1260.  
 
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Statistical analysis 
Data will be analyzed following the intention to treat analysis principle. Demographic 
and clinical data will be presented as proportions for categorical outcomes and mean 
plus standard deviation or median plus interquartile range for continuous outcomes. 
Comparison between groups will be made with the X2 test or the Fisher exact test for 
categorical variables and with the t-test or Wilcoxon rank-sum test for continuous 
variables. For the t-test the normality distribution will be evaluated.  
Time to event outcomes will be analyzed by estimating survival curves over treated and 
non-treated using the Kaplan-Meier method.  
A subgroup analysis will be performed with multiple linear regression, as well as logistic 
and cox regression models to adjust for age, pulmonary comorbidities and co-
administration of other experimental treatment. 
 
Data monitoring  
Data will be monitored by the principal investigator (PI) in collaboration with an 
independent Data and Safety Monitoring Board (DSMB). PI, and DSMB will monitor 
adverse events and quality of the data and provide recommendations. The PI will 
monitor compliance to safety rules every 20 patients. Every violation will be reported to 
the DSMB. Peripheral centers will be provided with a data sheet providing safety rules 
and will be instructed to report every violation to the coordinating hospital. Before the 
beginning of the study, the DSMB will meet to decide safety rules and stopping 
guidelines.  
We will not perform any interim analysis, but the DSMB will be granted the authority to 
stop the trial at any point due to safety concerns.  
 
Conclusion 
The aim of this trial is to evaluate whether high dose of NO administered at an early 
stage can safely reduce or prevent the progression of COVID-19 disease. This study is 
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open to every center that wants to participate. If interested in participating in the study, 
please contact the Principal Investigator.  
 
Contacts 
Lorenzo Berra, MD, lberra@mgh.harvard.edu  
Bijan Safaee Fakhr, MD, bsafaeefakhr@mgh.harvard.edu 
Chong LEI, MD and PhD, crystalleichong@126.com 
 
Authors’ contributions 
Authorship for this trial will be given to key personnel involved in trial design, personnel 
training, recruitment, data collection, statistical plan and data analysis. There are no 
publication restrictions. CL, BS, HD, LB, RP were responsible for conceptualizing trial 
design. CL and LB managed patient safety protocol. CL, BS, HD, LB, BSF, RDF are 
responsible for recruitment, enrolment and data collection. AB, BSF, LG are responsible 
for power calculation, statistical plan and data analysis. CL, BS, HD, LB, EV, BSF, RDF, 
SG and CCAM trained personnel for the clinical trial and built systems for nitric oxide 
delivery and monitoring. All authors have critically revised the study protocol and 
approved the final version. All authors agree to be accountable for the accuracy and 
integrity of all aspects of this trial. 
Funding statement:  
Local departmental funds 
Competing interests’ statement:  
LB salaries are partially supported by NIH/NHLBI 1 K23 HL128882-01A1. 
 
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INCLUSION CRITERIA 
• 
Age ≥ 18 years  
• 
confirmed SARS-CoV-2 infection.  
• 
Hospitalized with at least one 
among:  
o 
Fever  
o 
Tachipnea  
o 
Cough 
• 
Spontaneous breathing with or 
without any kind of NIV 
• 
≤ 8 days since illness onset 
EXCLUSION CRITERIA 
• 
Pregnancy  
• 
Tracheostomy 
• 
High Flow Nasal Cannula 
• 
Clinical contraindications  
• 
Hospitalized and 
confirmed diagnosis for > 
72 h 
RANDOMIZATION 1:1 
Outcome data evaluation at  
28 days 
Daily clinical data recording for 28 days or until discharge 
Daily Assigned treatment 
14 days 
Or until: 
• 
symptoms resolution  
• 
or deterioration of the clinical 
course 
• 
Discharge 
• 
Death 
Daily Assigned treatment 
14 days 
Or until: 
• 
symptoms resolution  
• 
or deterioration of the clinical 
course 
• 
Discharge 
• 
Death 
TREATMENT GROUP 
20-30 min, 2/day: 
• 
PEEP 2-10 cmH2O  
• 
Inhaled NO 140-180 ppm 
CONTROL GROUP 
Absence of placebo 
Figure 2. Study Flowchart 
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