Managing Endothelial Dysfunction in COVID-19: A Pilot, Double-Blind, Placebo-Controlled, Randomized Clinical Trial at the Lebanese American University Medical Center - Rizk Hospital (MEDIC-LAUMCRH)

Background Coronavirus disease 2019 (Covid-19) is associated with endothelial dysfunction. Pharmacologically targeting the different mechanisms of endothelial dysfunction may improve clinical outcomes and lead to reduced morbidity and mortality Methods In this pilot, double-blind, placebo-controlled, randomized clinical trial we assigned patients who were admitted to the hospital with mild, moderate, or severe COVID-19 infection to receive, on top of optimal medical therapy, either an endothelial protocol consisting of (Nicorandil, L-arginine, Folate, Nebivolol, and Atorvastatin) or placebo for up to 14 days. The primary outcome was time to recovery, measured by an 8 category ordinal scale and defined by the time to being discharged from the hospital or hospitalized for infection-control or other nonmedical reasons. Secondary outcomes included the composite outcome of ICU admission or the need for mechanical ventilation, all-cause mortality, and the occurrence of side effects Results Of 42 randomized patients, 37 were included in the primary analysis. The mean age of the patients was 57 years; the mean BMI of study participants was 29.14. History of hypertension was present in 27% of the patients, obesity in 45 % , and Diabetes Mellitus in 21.6%. The median(Interquartile range) time to recovery was not significantly different between the endothelial protocol group (6 [4-12] days) and the placebo group (6 [5-8]days)(p-value = 0.854). Furthermore, there were no statistically significant differences in the need for mechanical ventilation or ICU admission, all-cause mortality, and the occurrence of side effects between the endothelial protocol group and the placebo group. Conclusion Among patients hospitalized with mild, moderate, or severe COVID-19 infection, targeting endothelial dysfunction by administering Nicorandil, L-arginine, Folate, Nebivolol, and Atorvastatin on top of optimal medical therapy did not decrease time to recovery. However, this treatment protocol was associated with an excellent safety profile. Adequately sized prospective randomized controlled trials are needed for the evaluation of the role of treating endothelial dysfunction in COVID-19 infection. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT04631536 ### Funding Statement Trial Medications were provided by the Lebanese American University Medical Center Rizk Hospital ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: institutional review board at the Lebanese American University I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data relevant to the study are included in the article and are available on reasonable request from the last author GG