A randomized clinical trial of lipid metabolism modulation with fenofibrate for acute coronavirus disease 2019.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cytotoxicity may involve inhibition of peroxisome proliferator-activated receptor alpha. Fenofibrate activates peroxisome proliferator-activated receptor alpha and inhibits SARS-CoV-2 replication in vitro. Whether fenofibrate can be used to treat coronavirus disease 2019 (COVID-19) infection in humans remains unknown. Here, we randomly assigned inpatients and outpatients with COVID-19 within 14 d of symptom onset to 145 mg of oral fenofibrate nanocrystal formulation versus placebo for 10 d, in a double-blinded fashion. The primary endpoint was a severity score whereby participants were ranked across hierarchical tiers incorporating time to death, mechanical ventilation duration, oxygenation, hospitalization and symptom severity and duration. In total, 701 participants were randomized to fenofibrate (n = 351) or placebo (n = 350). The mean age of participants was 49 ± 16 years, 330 (47%) were female, mean body mass index was 28 ± 6 kg/m2 and 102 (15%) had diabetes. Death occurred in 41 participants. Compared with placebo, fenofibrate had no effect on the primary endpoint. The median (interquartile range) rank in the placebo arm was 347 (172, 453) versus 345 (175, 453) in the fenofibrate arm (P = 0.819). There was no difference in secondary and exploratory endpoints, including all-cause death, across arms. There were 61 (17%) adverse events in the placebo arm compared with 46 (13%) in the fenofibrate arm, with slightly higher incidence of gastrointestinal side effects in the fenofibrate group. Overall, among patients with COVID-19, fenofibrate has no significant effect on various clinically relevant outcomes ( NCT04517396 ).

A Randomized Trial of Lipid Metabolism Modulation with Fenofibrate for Acute Coronavirus Disease 2019.

Background Abnormal cellular lipid metabolism appears to underlie SARS-CoV-2 cytotoxicity and may involve inhibition of peroxisome proliferator activated receptor alpha (PPARα). Fenofibrate, a PPAR-α activator, modulates cellular lipid metabolism. Fenofibric acid has also been shown to affect the dimerization of angiotensin-converting enzyme 2, the cellular receptor for SARS-CoV-2. Fenofibrate and fenofibric acid have been shown to inhibit SARS-CoV-2 replication in cell culture systems in vitro . Methods We randomly assigned 701 participants with COVID-19 within 14 days of symptom onset to 145 mg of fenofibrate (nanocrystal formulation with dose adjustment for renal function or dose-equivalent preparations of micronized fenofibrate or fenofibric acid) vs. placebo for 10 days, in a double-blinded fashion. The primary endpoint was a ranked severity score in which participants were ranked across hierarchical tiers incorporating time to death, duration of mechanical ventilation, oxygenation parameters, subsequent hospitalizations and symptom severity and duration. ClinicalTrials.gov registration: NCT04517396. Findings: Mean age of participants was 49 ± 16 years, 330 (47%) were female, mean BMI was 28 ± 6 kg/m 2 , and 102 (15%) had diabetes mellitus. A total of 41 deaths occurred. Compared with placebo, fenofibrate administration had no effect on the primary endpoint. The median (interquartile range [IQR]) rank in the placebo arm was 347 (172, 453) vs. 345 (175, 453) in the fenofibrate arm (P = 0.819). There was no difference in various secondary and exploratory endpoints, including all-cause death, across randomization arms. These results were highly consistent across pre-specified sensitivity and subgroup analyses. Conclusion Among patients with COVID-19, fenofibrate has no significant effect on various clinically relevant outcomes.

Continuation versus discontinuation of renin-angiotensin system inhibitors in patients admitted to hospital with COVID-19: a prospective, randomised, open-label trial.

BACKGROUND: Biological considerations suggest that renin-angiotensin system inhibitors might influence the severity of COVID-19. We aimed to evaluate whether continuing versus discontinuing renin-angiotensin system inhibitors (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) affects outcomes in patients admitted to hospital with COVID-19. METHODS: The REPLACE COVID trial was a prospective, randomised, open-label trial done at 20 large referral hospitals in seven countries worldwide. Eligible participants were aged 18 years and older who were admitted to hospital with COVID-19 and were receiving a renin-angiotensin system inhibitor before admission. Individuals with contraindications to continuation or discontinuation of renin-angiotensin system inhibitor therapy were excluded. Participants were randomly assigned (1:1) to continuation or discontinuation of their renin-angiotensin system inhibitor using permuted block randomisation, with allocation concealed using a secure web-based randomisation system. The primary outcome was a global rank score in which participants were ranked across four hierarchical tiers incorporating time to death, duration of mechanical ventilation, time on renal replacement or vasopressor therapy, and multiorgan dysfunction during the hospitalisation. Primary analyses were done in the intention-to-treat population. The REPLACE COVID trial is registered with ClinicalTrials.gov, NCT04338009. FINDINGS: Between March 31 and Aug 20, 2020, 152 participants were enrolled and randomly assigned to either continue or discontinue renin-angiotensin system inhibitor therapy (continuation group n=75; discontinuation group n=77). Mean age of participants was 62 years (SD 12), 68 (45%) were female, mean body-mass index was 33 kg/m2 (SD 8), and 79 (52%) had diabetes. Compared with discontinuation of renin-angiotensin system inhibitors, continuation had no effect on the global rank score (median rank 73 [IQR 40-110] for continuation vs 81 [38-117] for discontinuation; ß-coefficient 8 [95% CI -13 to 29]). There were 16 (21%) of 75 participants in the continuation arm versus 14 (18%) of 77 in the discontinuation arm who required intensive care unit admission or invasive mechanical ventilation, and 11 (15%) of 75 participants in the continuation group versus ten (13%) of 77 in the discontinuation group died. 29 (39%) participants in the continuation group and 28 (36%) participants in the discontinuation group had at least one adverse event (χ2 test of adverse events between treatment groups p=0·77). There was no difference in blood pressure, serum potassium, or creatinine during follow-up across the two groups. INTERPRETATION: Consistent with international society recommendations, renin-angiotensin system inhibitors can be safely continued in patients admitted to hospital with COVID-19. FUNDING: REPLACE COVID Investigators, REPLACE COVID Trial Social Fundraising Campaign, and FastGrants.

Randomized elimination and prolongation of ACE inhibitors and ARBs in coronavirus 2019 (REPLACE COVID) Trial Protocol.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), is associated with high incidence of multiorgan dysfunction and death. Angiotensin-converting enzyme 2 (ACE2), which facilitates SARS-CoV-2 host cell entry, may be impacted by angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), two commonly used antihypertensive classes. In a multicenter, international randomized controlled trial that began enrollment on March 31, 2020, participants are randomized to continuation vs withdrawal of their long-term outpatient ACEI or ARB upon hospitalization with COVID-19. The primary outcome is a hierarchical global rank score incorporating time to death, duration of mechanical ventilation, duration of renal replacement or vasopressor therapy, and multiorgan dysfunction severity. Approval for the study has been obtained from the Institutional Review Board of each participating institution, and all participants will provide informed consent. A data safety monitoring board has been assembled to provide independent oversight of the project.

Estudio comparativo de marcadores bioquímicos de salud, en dos grupos etarios de docentes universitarios, 2017 / Comparative study of biochemical health markers, in two groups of university professors of the same age group, 2017

Objetivo: Comparar los valores de los marcadores bioquímicos sanguíneos: ácido úrico, creatinina, glucosa, colesterol y triglicéridos, entre dos grupos de docentes universitarios aparentemente sanos. Métodos: El primer grupo, formado por 58 docentes de 60 a 64 años y, el segundo por 35 docentes de 75 a 81 años; para evaluar si hay diferencia estadística significativa entre ambos grupos. Resultados: Los valores de ácido úrico en el grupo I estuvieron entre 2,50 mg/dL. y 8,20 mg/dL, y en el grupo II entre 2,50 mg/dL y 8,63 mg/dL, con diferencia significativa (p=0.035). Los valores de creatinina en el grupo I estuvieron entre 0,64 mg/dL y 1,56 mg/dL, y en el grupo II entre 0,80 mg/dL y 1,61 mg/dL., con diferencia significativa (p=0.004). Los valores de glucosa en el grupo I estuvieron entre 63 mg/dL y 188 mg/dL, y en el grupo II entre 60 mg/dL y 297 mg/dL, sin encontrar diferencia significativa (p=0.671). Los valores de colesterol en el grupo I estuvieron entre 125 mg/dL y 265 mg/ dL, y en el grupo II entre 107 mg/dL y 244 mg/dL, sin encontrar diferencia significativa (p=0.053). Los valores de triglicéridos en el grupo I estuvieron entre 58 mg/dL y 507 mg/dL, y en el grupo II entre 68 mg/dL y 314 mg/ dL, sin encontrar diferencia significativa (p=0.104). Conclusión: En los marcadores bioquímicos de ácido úrico y creatinina hay diferencia significativa entre ambos grupos etarios. En cambio, en los marcadores de glucosa, colesterol y triglicéridos, no se demuestra diferencia significativa entre ambos grupos etarios.

Objective: Compare the values of the blood biomakers: uric acid, creatinine, glucose, cholesterol and triglycerides, in two groups of university professors apparently healthy. Methods: The first group, formed by 58 professors aged 60 to 64, and the second formed by 35 professors aged 75 to 81, in order to evaluate if there is a significant statistic difference in both groups. Results: The values of uric acid in group I were between 2,50 mg/dL. and 8,20 mg/dL; in groups II were between 2,50 mg/dL and 8,63 mg/dL, showing a significant difference (p=0.035). The values of creatinine in group I were between 0,64 mg/dL and 1,56 mg/dL; and in group II were between 0,80 mg/ dL and 1,61 mg/dL., showing a significant difference (p=0.004). The values of glucose in group I were between 63 mg/dL and 188 mg/dL; and in group II were between 60 mg/dL y 297 mg/dL, not showing significant difference (p=0.671). The values of cholesterol in group I were between 125 mg/dL and 265 mg/dL; and in group II were between 107 mg/dL and 244 mg/dL; not showing significant difference (p=0.053). The values of triglycerides in group I were between 58 mg/dL and 507 mg/dL; and in group II were between 68 mg/dL and 314 mg/dL; not showing significant difference (p=0.104). Conclusion: There is a significant difference in the biomarkers of uric acid and creatinine between the age groups; however, there was not found significant difference in the biomarkers of glucose, cholesterol and triglycerides between the age groups.