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.

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 ).

Hidroxicloroquina para manejo de infección por SARS-CoV-2 Una revisión exploratoria / Hydroxychloroquine for treatment of SARS-CoV-2 infection An exploratory review

Resumen Introducción: la hidroxicloroquina se ha venido postulando en estos tiempos de pandemia como posible tratamiento eficaz frente a COVID-19. Esto ya que se ha demostrado por expertos chinos su capacidad para inhibir la replicación viral usando distintos mecanismos. En este momento es de vital importancia tener conocimiento acerca de las últimas investigaciones y ensayos clínicos en lo que respecta a un esquema de tratamiento efectivo que ayude a un mejor manejo de pacientes con infección por SARS-CoV-2. Objetivo: presentar la información disponible sobre el uso de hidroxicloroquina como opción de manejo para pacientes infectados por SARS-CoV-2. Material y métodos: se realizó una revisión siguiendo el marco metodológico sugerido por Arksey y O'Malley. Las bases de datos utilizadas fueron: PubMed, MedLine, Lilacs, Scopus, Clinical Trials, Cochrane y CNKI. Se incluyeron únicamente textos en español e inglés, finalmente se realizó una caracterización y resumen de los estudios pertinentes para esta revisión. Resultados: se incluyeron en la revisión 87 artículos académicos incluyendo estudios experimentales y no experimentales; todos con evidencia sobre el uso de hidroxicloroquina en COVID-19. Conclusiones: A la fecha no hay información científica disponible que sustente y tenga la suficiente evidencia para soportar el uso de la hidroxicloroquina como tratamiento farmacológico en la pandemia actual. Dos ensayos clínicos aleatorizados se contradicen en cuanto a la efectividad de la hidroxicloroquina; sin embargo, ambos comparten errores metodológicos y tamaños de muestra limitados; y un único ensayo no aleatorizado con los mismos errores demuestra efectividad de la hidroxicloroquina. En cuanto al perfil de seguridad se cuenta con información que evidencia una menor tasa de efectos adversos de la hidroxicloroquina frente a la cloroquina por lo que se preferiría su uso en caso de demostrar efectividad frente a COVID-19. Existen varios ensayos clínicos aleatorizados en curso que se espera esclarezcan las dudas que surgen al revisar la literatura.(Acta Med Colomb 2020; 45. DOI:https://doi.org/10.36104/amc.2020.1880).

Abstract Introduction: hydroxychloroquine has been recommended in this pandemic as a possible effective treatment for COVID-19. This is because Chinese experts have demonstrated its ability to inhibit viral replication through various mechanisms. At this juncture, it is vitally important to understand the latest research and clinical trials regarding an effective treatment regimen which would help improve the treatment of patients with SARS-CoV-2 infection. Objective: to present the available information regarding the use of hydroxychloroquine as a treatment option for patients infected with SARS-CoV-2. Material and methods: a review was carried out following the methodological framework proposed by Arksey and O'Malley. The data bases used were: PubMed, MedLine, Lilacs, Scopus, Clinical Trials, Cochrane and CNKI. Only texts in Spanish and English were included. Finally, the pertinent studies for this review were described and summarized. Results: a total of 87 academic articles were included in the review, including experimental and non-experimental studies, all containing evidence regarding the use of hydroxychloroquine in COVID-19. Conclusions: To date, there is no available substantiating scientific data with enough evidence to support the use of hydroxychloroquine as a pharmacological treatment for the current pandemic. Two randomized clinical trials contradict each other regarding the efficacy of hydroxychloroquine. However, they both share methodological errors and have small sample sizes. A single nonrandomized trial with the same errors shows efficacy of hydroxychloroquine. As far as the safety profile, there is data showing a lower rate of adverse effects for hydroxychloroquine compared with chloroquine, so its use would be preferred if it were to be proven effective against COVID-19. There are several randomized clinical trials underway which, it is hoped, will answer the questions raised by the literature review.(Acta Med Colomb 2020; 45. DOI:https://doi.org/10.36104/amc.2020.1880).

Capacidad discriminatoria y concordancia entre el ELISA-F29 y la PCR en individuos con infección por T. cruzi / Capacidade discriminatória e acordo entre o ELISA-F29 e a PCR em indivíduos infectados com T. cruzi / Discriminatory Power and Concordance between ELISA-F29 and PCR in individuals with infection due to T cruzi

El diagnóstico de la infección por Trypanosoma cruzi (T. cruzi) se realiza rutinariamente mediante pruebas serológicas mientras que el empleo de mÚtodos moleculares se encuentra aún en proceso de estandarización. Objetivo: Evaluar la capacidad discriminatoria y concordancia entre una prueba serológica y una molecular para determinar la infección por T. cruzi. MÚtodos: Se realizo Reaccion en Cadena de la Polimerasa (PCR) y la prueba de ELISA-F29 en 95 muestras de participantes de la cohorte ô Cardiovascular health investigation and collaboration countries of America to assess the markers and outcomes of Chagas diseaseõ CHICAMOCHA. Se evaluó la capacidad discriminatoria del ELISA-F29 respecto al resultado de PCR mediante la estimación del área bajo la curva ROC. Se estimó la tasa de falsos positivos al 25% y sensibilidad al 75%. Se determinó la concordancia mediante kappa de Cohen. Resultados: Se realizaron pruebas de PCR en dos momentos diferentes en 95 individuos (edad media: 38 años; 64% hombres), con tasas de positividad entre 1.1% û 2.2% para los primers S35-S36 y entre 18.3% û 34.7% para los primers 121-122, respectivamente. La capacidad discriminatoria del ELISA- F29 respecto a PCR fue 0.62 (IC95%: 0.53; 0.70) y tasa de falsos positivos del 56% (IC95%: 42; 70). El punto de corte óptimo para el cociente de absorbancia fue 2.53 (sensibilidad 59% y especificidad 60%). Para el primer 121-122 los niveles de acuerdo observado y kappas estimados fueron: 52.6% y 0.10 (IC95%: -0.08, 0.28) para la primera medición, 62.4% y 0.09 (IC95%: -0.09, 0.28) para la segunda medición y 57.5% y 0.13 (IC95%: 0.01, 0.26) al evaluar simultáneamente las dos mediciones. Conclusiones: Los resultados demuestran una baja concordancia evidenciada por los valores de kappa determinados en el estudio. Es necesario afinar los estudios para evaluar la utilidad de las pruebas moleculares en el diagnóstico de la Enfermedad de Chagas.

The diagnosis of infection with Trypanosoma cruzi (T. cruzi) is routinely performed by serological tests while the use of molecular methods is still in process of standardization. Objective: To evaluate the discriminatory capacity and agreement between a serological test and a polymerase chain reaction (PCR) to determine T. cruzi infection. Methodology: PCR and ELISA test-F29 were performed to 95 participants of ôCardiovascular health investigation and collaboration countries of America to assess the markers and outcomes of Chagas diseaseõ (CHICAMOCHA). Discriminatory capacity of ELISA ûF29 with respect to PCR results were evaluated by estimating the area of ROC curve. The false positive rate was estimated to 25% and sensitivity to 75%. The agreement was determined using Cohen's kappa. Results: PCR tests were performed at two different times in 95 individuals (mean age: 38; 64% male), with positivity rates between 1.1 to 2.2% for S35-S36 primers and from 18.3% to 34, 7% for primers 121-122, respectively. ELISA-F29 discriminatory capacity regarding PCR was 0.62 (95% CI: 0.53, 0.70). The false positive rate was 56% (95% CI: 42; 70). The optimal cutoff for absorbance ratio of ELISA-F29 was 2.53 (sensitivity 59%, specificity 60%). For the primers 121-122, levels of observed agreement and kappa estimates were 52.6% and 0.10 (95% CI: -0.08, 0.28) for the first measurement, 62.4% and 0.09 (95% CI: -0.09, 0.28) for the second measurement, and 57.5% and 0.13 (95% CI: 0.01, 0.26) for the two measurements simultaneously evaluated. Conclusions: The results show poor agreement evidenced by kappa values determined in the study. It is necessary to refine the studies to evaluate the utility of molecular testing in the diagnosis of Chagas disease.

O diagnostico de infecção por Trypanosoma cruzi (T. cruzi) Ú rotineiramente realizado por sorologia, enquanto o uso de muitodos moleculares ainda estß sendo padronizado. Objetivo: Avaliar a capacidade discriminat¾ria e a concordÔncia entre um teste sorol¾gico e o molecular para determinar a infecþÒo pelo T. cruzi. Metodologia: Foi realizada a ReaþÒo em Cadeia da Polimerase (PCR) e a prova de ELISA-F29 em 95 amostras de participantes da coorte "Investigação em Saúde Cardiovascular e colaboração com os países da América para avaliar os marcadores e resultados de doença de Chagas" CHICAMOCHA. Foi avaliada a capacidade discriminatória do ELISA-F29 com relação aos resultados de PCR por meio da avaliação da área com a curva de ROC. A taxa de falsos positivos é estimada em 25% e a de sensibilidade em 75%. A correlação é determinada por Cohen kappa. Resultados: Foram realizados testes de PCR em dois momentos diferentes, em 95 indivíduos (idade média: 38 anos; 64% do sexo masculino), com taxas de positividade entre 1,1% - 2,2% para os primeiros S35-S36 e entre 18,3% - 34,7% para os primeiros 121-122, respectivamente. O poder discriminatório ELISA-F29 sobre PCR foi 0,62 (IC 95%: 0,53; 0,70) e taxa de falsos positivos de 56% (IC 95%: 42; 70). O ponto de corte otimo para a relação de absorvãncia foi de 2,53 (59% de sensibilidade, especificidade de 60%). Para os primeiros 121-122, de acordo com os níveis observados e kappas estimadas foram 52.6% e 0.10 (IC95%: -0.08, 0.28) para a primeira medição, 62.4% e 0.09 (IC 95%: -0.09, 0 .28) para a segunda medição, 57.5% e 0,13 (IC95%: 0.01, 0.26) ao avaliar simultaneamente as duas medições. Conclussões: Os resultados mostram pouca concordância evidenciada pelos valores de kappa determinados no estudo. É necessário precisar e ajustar os estudos para avaliar a utilidade do teste molecular no diagnóstico da doença de Chagas.