Background Sulodexide has pleiotropic properties within the vascular endothelium that can prove beneficial for the treatment of patients with COVID-19. We aimed to evaluate the effect of sulodexide when used in the early clinical stages of COVID-19. Methods In an outpatient setting, we conducted a randomized controlled trial with a parallel-group design. Including patients within three days of clinical onset, who were at a high risk of severe clinical progression due to chronic comorbidities. Participants were randomly assigned to receive an oral dose of sulodexide (500 LRU twice a day) or placebo for 21 days. Primary outcomes were need-length of hospitalization and need-length of oxygen support. Results Between June 5 and August 30, 2020, 243 patients were included in the per-protocol analysis. 124 of them received sulodexide, while 119 received placeboes. At 21 days follow-up, 17.7% patients required hospitalization in the sulodexide group compared to 29.4% in the placebo group, p=0.03. 29.8% required oxygen support in the sulodexide group vs 42% in the placebo group, p=0.05 and for fewer days [9 (7.2 SD) in the sulodexide group vs. 11.5 (9.6 SD) in the placebo group; p=0.02]. There was no between-group difference concerning the length of hospital stay. Interpretation Early intervention in COVID-19 patients with sulodexide reduced hospital admissions and oxygen support requirements. This has beneficial implications in the patient's well-being, making sulodexide a favorable medication until an effective vaccine or an antiviral becomes available. Funding Researcher independently initiated, partially funded by Alfasigma, Mexico. ISRCTN registry listed under ID ISRCTN59048638.

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BackgroundTargeting endothelial cells has been suggested for the treatment of patients with COVID-19 and sulodexide has pleiotropic properties within the vascular endothelium that can prove beneficial to the same. We aimed to evaluate the effect of sulodexide when used in the early clinical stages of COVID-19.MethodsWe conducted a single-centre, outpatient setting, randomised controlled trial with a parallel-group design in Mexico. Including patients within three days of clinical symptom onset, who were at a high risk of severe clinical progression due to chronic comorbidities. Participants were randomly allocated to receive an oral dose of sulodexide (500 LRU twice a day) or the placebo for 21 days. Primary outcomes were need and length of hospitalisation, need and length of oxygen support.ResultsBetween June 5 and August 30, 2020, 243 patients were included in the “per-protocol” analysis. One hundred twenty-four of them received sulodexide, while 119 received placeboes. At 21 days follow-up, 22 of 124 patients required hospitalisation in the sulodexide group compared to 35 of 119 in the placebo group [relative risk (RR), 0·6; 95% confidence interval (CI), 0·37-0·96; p=0·03]. Fewer patients required oxygen support in the sulodexide group [37 of 124 vs. 50 of 119; RR, 0·71; 95% CI, 0·5 to 1; p=0·05], and for fewer days (9±7·2 in the sulodexide group vs. 11·5±9·6 in the placebo group; p=0·02). There was no between-group difference concerning the length of hospital stay.InterpretationEarly intervention in COVID-19 patients with sulodexide reduced hospital admissions and oxygen support requirements, although with no significant effect on mortality. This has beneficial implications in the patient well-being, making sulodexide a favourable medication until an effective vaccine or an antiviral becomes available.FundingResearcher independently initiated, partially funded by Alfasigma, Mexico.Listed in the ISRCTN registry under ID ISRCTN59048638.

Background: Patients with novel coronavirus disease-2019 , present a systemic inflammatory response with vascular endothelial damage and an increased risk of thromboembolic complications. Sulodexide can help restore venous and arterial endothelial glycocalyx integrity lost in certain chronic diseases, which can downregulate or limit the response to inflammatory molecules. It has an antithrombotic effect that could help reduce the incidence of thromboembolic complications which can be beneficial in these patients. We hypothesize that sulodexide, instituted in the early symptomatic stages of COVID-19, would improve the clinical outcomes with decreased hospital admission, decrease morbidity, and mortality.Methods: Prospectively, patients were recruited with early clinical symptoms of COVID-19 (shortness of breath, fever, headache, cough, etc), and screened for inclusion criteria, age 40 to 80 years, male or female, and risk of developing a severe presentation of the disease >50% given by the IMSS (Mexican Social Security Institute) COVID-19 health risk calculator. Exclusion criteria were negative COVID-19 test result, chronic use of steroid medication or anticoagulation. Patients were randomized for allocation into control group to received placebo + standard of care, or study group to receive an oral dose of 500 lipase releasing units sulodexide two times per day. The treatment lasted 21 days. A follow-up visit was scheduled via electronic media at 7 days intervals or as needed. Primary end points variables to measure were, days of hospital care, the need for supplemental oxygen, D-dimer, and C-reactive protein serum levels, and mortality rate.Results: A total of 243 patients were randomly assigned to the sulodexide group (n ¼ 124) or the placebo group (n ¼ 119). The demographics and clinical characteristics of the patients were similar in both groups. The symptoms that presented a significant improvement in the sulodexide group were body aches at week 2 (P ¼ .002), malaise/fatigue at week 3 (P ¼ .003), and shortness of breath at week 2 (P ¼ .001) and week3 (P ¼ .031). A total of 37 patients (29%) developed respiratory symptoms that warrant the need for in-home oxygen support in the sulodexide group versus 50 (42%) in the control group (P ¼ .047). A total of 56 patients (24%) required hospital admission, 22 (17.7%) in the sulodexide group and 35 (29.4%) in the placebo group (P ¼ .032), with an average length of stay of 6.4 days in the sulodexide group versus 7.8 control group (P ¼ .211). A total of 3 patients (2.4%) died in the sulodexide group versus 7 (5.8%) in the placebo group (P ¼ .121).Conclusions: Our findings supported the effectiveness of sulodexide in the prevention of a severe clinical progression of COVID-19 when used in the early symptomatic stages compare to the standard of care, reducing the need for hospital care of these patients.

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Background: SARS-CoV-2 can induce several vascular endothelial-dependent systemic complications and treatment targeting endothelial cells has been suggested. Sulodexide is a heparin and glycosaminoglycan compound that has pleiotropic properties within the vascular endothelium that can prove beneficial in COVID-19 patients. Aims: We aimed to evaluate the effect of sulodexide when used in the early clinical stages of COVID-19. Methods: In an outpatient setting, we conducted a randomized placebo-controlled trial. Key inclusion criteria were patients within three days of COVID-19 clinical onset and being deemed at high risk (> 50%) of severe clinical disease progression. The risk was assessed using the COVID-19 Health Complication (C19HC) calculator, which clusters the importance of various chronic comorbidities into a percentage value. After inclusion, patients were randomly assigned to receive an oral dose of sulodexide (500 LRU twice a day) or a placebo for 21 days. We performed follow-ups to assess the study endpoints via remote communication with participants or household members every seven days or as deemed necessary. Participants continued the standard of care under the supervision of their healthcare provider's primary physician. The need for hospital care was the primary outcome. Also evaluated, were the need for supplemental oxygen support, D-dimer and C reactive protein (CRP) serum levels, thromboembolic events, and mortality. Physicians responsible to determine the need for hospital care or supplemental oxygen at home were blinded to group allocation. This trial was conducted throughout the regional lockdown caused by the first wave of COVID-19 which caused some unforeseen limitations during the trial. Differences in means were calculated using the Student's t-test, while differences in percentages were assessed using the χ 2 test. Before and after serum levels in the same patients were analyzed using two paired t-tests. If the data were not normally distributed, a Wilcoxon test was used. A Kaplan-Meier curve was used to graphically compare time-to-endpoint for hospital admission and mortality. Results: 312 patients were included in the intent to treat analysis. At 21 days follow-up, 23 of 155 patients required hospitalization in the sulodexide group compared to 38 of 157 in the placebo group [relative risk (RR), 0.6; 95% confidence interval (CI), 0.38-0.97; p=0.037]. The benefit persisted with a per-protocol analysis (RR 0.6, p=0.031). Fewer patients required oxygen support in the sulodexide group [39 of 155 vs. 56 of 157; RR, 0.61; 95% CI, 0.38 to 0.9; p=0.04], and for fewer days (9 ± 7.2 in the sulodexide group vs. 11.5 ± 9.6 in the placebo group; p=0.02). Mean D-dimer levels at week 2 were significantly higher in the placebo group than in the sulodexide group (p < 0.01). 28 of the 155 patients (18%) in the sulodexide group showed a D-dimer value > 500 ng/dl, compared to 59 out of 157 (37.5%) in the placebo group (RR of 0.48; 95% CI of 0.31 to 0.67; p > 0.01). Mean C-reactive protein levels at week 2 were lower in the sulodexide group than in the placebo group (p < 0.01). There was no between-group difference concerning, hospital length of stay, thromboembolic events, major bleeding, or mortality. Conclusions: Early intervention on COVID-19 patients with sulodexide resulted in a reduced need for supplemental oxygen and hospital care. The synergistic activity of sulodexide's antithrombotic and non-antithrombotic effects on different biological targets may play an essential role in limiting disease progression. Added a low risk of bleeding or significant side effects, sulodexide might be an alternative to other oral anticoagulants which makes it a valuable medication in the outpatient treatment of COVID-19. Disclosures Gonzalez-Ochoa: Alfasigma: Consultancy, Research Funding; servier: Consultancy.