The evaluation of Nitric Oxide generating lozenges on outcome in COVID-19 patient of African American Origin.

IMPACT
This the first and only study to address the health disparities of African Americans with COVID. Furthermore, in this outpatient study, we will capture at-risk patients early on in the disease process and prevent the progression of the disease.  Nitric oxide drug therapy will address all of the underlying risk factors for African Americans with COVID and protect from the long term complications of COVID, including the risk of blood clots, embolism, heart attack, and stroke.

 
INTRODUCTION
Coronavirus disease (COVID-19), is now a worldwide pandemic affecting millions of people around the world.  As of Mid-April, over 2 million people have been infected with over 130,000 deaths.  Early data coming out of China revealed patients with underlying cardiovascular disease were more susceptible to infection, greater disease severity, and a ten times higher mortality. Among the patients studied, the median (range) age was 64 (21-95) years, female (50.7% and the median time to symptom onset was 10 days (interquartile range [IQR]), 1-30). Of this group, 82 (19.7%) had some type of cardiac injury.  It was apparent as the study went on that patients with cardiac injury and COVID-19 fared worse than the patients with COVID-19 but no history of cardiac injury. Patients with cardiac injury with diagnosed COVID-19, compared with patients without cardiac injury, had a higher mortality rate (51.2% vs 4.5%) and risk of death [1]. These observations have been supported by data reported in the U.S., especially those reported for NYC. 
Recent reports from the U.S. database compiled by CDC reports mortality from COVID-19 to have a racial disparity [2].  A disproportionate number of COVID-19 fatalities among African Americans has been observed. While this has been attributed to known disparities in health care, low economic resources, and issues associated with social distancing: occupation, crowded residential spaces, and transportation crowding. Additionally, African Americans have a high incidence of pre-existing and often untreated cardiovascular conditions [3]. However, all these issues are seen in other populations and the higher prevalence of cardiovascular conditions would not explain why African Americans would still be at higher mortal risk than Caucasians with cardiovascular risk factors.  What may be increasing risk for the African American community is some unique physiologic condition(s). Hypertension is highly prevalent in African Americans with an association with diminished nitric oxide (NO) levels [4]. Hypertension often leads to the development of a cardiomyopathy and heart failure [5].  Additionally, there are unique manifestations to the COVID-19 disease that make African Americans with low NO potentially at higher risk.
First coronavirus has a spike protein that affords the virus access to cells by a receptor, the angiotensin-converting enzyme 2(ACE2). In an earlier SARS-CoV-2 virus access to cells was also through the ACE2 receptor. NO was reported to alter the surface protein of SARS-1 (spike protein) preventing attachment to the ACE2 receptor and thus entrance into the cell [6].  It is likely that for the new COVID-19 virus NO may well prevent cellular penetration. 
Nitric oxide is reported to improve oxygenation [7, 8], an action needed as the COVID-19 disease progresses and acute respiratory disease syndrome (ARDS) develops. NO decreases the propensity of blood to clot [9], a problem leading to multi-system damage in patients severely ill with COVID-19 virus. In fact, high D-dimer levels, an indication of enhanced clotting is a strong predictor of death in infected patients.  All these factors; decreased oxygenation, low NO levels in African American patients, decreased oxygenation in severely ill COVID-19 patients, increased clotting, leads one to hypothesize that increasing NO levels in patients with COVID-19 would have a salutatory benefit.  
This current clinical trial aims to test the efficacy of a more potent nitric oxide lozenge (30 mg sodium nitrite) on patients diagnosed with COVID-19 infection to investigate if restoring nitric oxide can prevent the progression of the disease, reduced need for ventilation, and decreased death. 

SELECTION OF STUDY POPULATION 
The target population for this study consists of 840 African American subjects with positive COVID-19 diagnosis (positive by PCR testing).  Each subject will have to fulfill the inclusion criteria listed in Section 4.1. Subjects will not be included in the study if they meet any of the exclusion criteria listed in Section 4.2.

Inclusion Criteria
1.    Male or female of 18-75 years of age
2.    Subjects with recent COVID-19 diagnosis (within 72 hours), that are symptomatic (fever, cough, SOB, weakness, flu-like symptoms).
3.    Agrees to comply with study procedures   
4.    Has given voluntary, written, informed consent to participate in the study
5.    Identifies as African American.
6.    Patients must have at least 1 risk factor (hypertension (BP> 140/99) for at least 1 year by history) CHF history, angina, prior MI, coronary angiography with ASHD finding, or diabetes mellitus. 

Patients will be monitored for 30 days with rate of hospitalization, ventilation, and death a primary endpoint.  Oxygen saturation will be monitored for both safety and efficacy of the lozenge as a secondary endpoint.

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Impact:  
REFERENCES
1.    Shi, S., et al., Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, China. JAMA Cardiol, 2020.
2.    Yancy, C.W., COVID-19 and African Americans. JAMA, 2020.
3.    Carnethon, M.R., et al., Cardiovascular Health in African Americans: A Scientific Statement From the American Heart Association. Circulation, 2017. 136(21): p. e393-e423.
4.    Brothers, R.M., P.J. Fadel, and D.M. Keller, Racial disparities in cardiovascular disease risk: mechanisms of vascular dysfunction. Am J Physiol Heart Circ Physiol, 2019. 317(4): p. H777-H789.
5.    Drazner, M.H., The progression of hypertensive heart disease. Circulation, 2011. 123(3): p. 327-34.
6.    Akerstrom, S., et al., Dual effect of nitric oxide on SARS-CoV replication: viral RNA production and palmitoylation of the S protein are affected. Virology, 2009. 395(1): p. 1-9.
7.    Allen, B.W., J.S. Stamler, and C.A. Piantadosi, Hemoglobin, nitric oxide, and molecular mechanisms of hypoxic vasodilation. Trends Mol Med, 2009. 15(10): p. 452-60.
8.    Zhang, R., et al., Hemoglobin betaCys93 is essential for cardiovascular function and an integrated response to hypoxia. Proc Natl Acad Sci U S A, 2015. 112(20): p. 6425-30.
9.    Radomski, M.W., R.M. Palmer, and S. Moncada, The anti-aggregating properties of vascular endothelium: interactions between prostacyclin and nitric oxide. Br J Pharmacol, 1987. 92(3): p. 639-46.