Efficacy and safety of CD24Fc in hospitalised patients with COVID-19: a randomised, double-blind, placebo-controlled, phase 3 study.

BACKGROUND: Non-antiviral therapeutic options are required for the treatment of hospitalised patients with COVID-19. CD24Fc is an immunomodulator with potential to reduce the exaggerated inflammatory response to tissue injuries. We aimed to evaluate the safety and efficacy of CD24Fc in hospitalised adults with COVID-19 receiving oxygen support. METHODS: We conducted a randomised, double-blind, placebo-controlled, phase 3 study at nine medical centres in the USA. Hospitalised patients (age ≥18 years) with confirmed SARS-CoV-2 infection who were receiving oxygen support and standard of care were randomly assigned (1:1) by site-stratified block randomisation to receive a single intravenous infusion of CD24Fc 480 mg or placebo. The study funder, investigators, and patients were masked to treatment group assignment. The primary endpoint was time to clinical improvement over 28 days, defined as time that elapsed between a baseline National Institute of Allergy and Infectious Diseases ordinal scale score of 2-4 and reaching a score of 5 or higher or hospital discharge. The prespecified primary interim analysis was done when 146 participants reached the time to clinical improvement endpoint. Efficacy was assessed in the intention-to-treat population. Safety was assessed in the as-treated population. This study is registered with ClinicalTrials.gov, NCT04317040. FINDINGS: Between April 24 and Sept 22, 2020, 243 hospitalised patients were assessed for eligibility and 234 were enrolled and randomly assigned to receive CD24Fc (n=116) or placebo (n=118). The prespecified interim analysis was done when 146 participants reached the time to clinical improvement endpoint among 197 randomised participants. In the interim analysis, the 28-day clinical improvement rate was 82% (81 of 99) for CD24Fc versus 66% (65 of 98) for placebo; median time to clinical improvement was 6·0 days (95% CI 5·0-8·0) in the CD24Fc group versus 10·0 days (7·0-15·0) in the placebo group (hazard ratio [HR] 1·61, 95% CI 1·16-2·23; log-rank p=0·0028, which crossed the prespecified efficacy boundary [α=0·0147]). 37 participants were randomly assigned after the interim analysis data cutoff date; among the 234 randomised participants, median time to clinical improvement was 6·0 days (95% CI 5·0-9·0) in the CD24Fc group versus 10·5 days (7·0-15·0) in the placebo group (HR 1·40, 95% CI 1·02-1·92; log-rank p=0·037). The proportion of participants with disease progression within 28 days was 19% (22 of 116) in the CD24Fc group versus 31% (36 of 118) in the placebo group (HR 0·56, 95% CI 0·33-0·95; unadjusted p=0·031). The incidences of adverse events and serious adverse events were similar in both groups. No treatment-related adverse events were observed. INTERPRETATION: CD24Fc is generally well tolerated and accelerates clinical improvement of hospitalised patients with COVID-19 who are receiving oxygen support. These data suggest that targeting inflammation in response to tissue injuries might provide a therapeutic option for patients hospitalised with COVID-19. FUNDING: Merck & Co, National Cancer Institute, OncoImmune.

Análisis de estudios en metales pesados en zonas agrícolas de Colombia / Analysis of Studies in Heavy Metals in Agricultural Areas of Colombia / Análise de Estudos em Metais Pesados em Zonas Agrícolas ee Colômbia

Resumen El recurso suelo oferta servicios ecosistémicos fundamentales entre las que se resaltan el soporte para la producción de alimentos y su importancia en la mitigación de los efectos del cambio climático debido a la dinámica del carbono. Sin embargo, actividades antrópicas como la densificación urbana, la industrialización y principalmente la agricultura aportan elementos como metales pesados, responsables de la degradación del suelo en algunas regiones del planeta. Naturalmente los suelos en su base geoquímica contienen metales pesados, en la mayoría de las regiones éstas concentraciones no representan riesgo ambiental. En este sentido, el propósito de la presente investigación fue recopilar los estudios de metales pesados desarrollados en sistemas de producción agrícola en Colombia para establecer una línea base, que permita identificar necesidades futuras de investigación en esta temática. Entre los resultados encontrados, se identificó que los metales pesados estudiados en el país son Cd>Pb>Hg>Cr>Ni>Cu=Zn=As>Mn>Fe, destacándose el Cd, Pb, Hg y Cr. Sin embargo en Colombia la producción científica en la que son relacionados los metales pesados en la producción agrícola (suelo, cultivos o insumo) es relativamente baja. Asimismo, estos trabajos se localizan en la región central del país, evidenciando que regiones como la Orinoquia considerada como la frontera y despensa agrícola del país, únicamente se reportan tres estudios que fueron publicados en los últimos años. Finalmente con esto se resalta la importancia de generar investigaciones en valores de referencia para estos elementos en los suelos colombianos, que permitan establecer programas de monitoreo y de evaluación en posibles casos de contaminación.

Abstract The soil resource offers fundamental ecosystem services, among which stand out the support for food production and its importance in mitigating the effects of climate change due to carbon dynamics. However, anthropic activities such as urbandensification, industrialization and mainly agriculture contribute elements such as heavy metals, responsible for soil degradation in some regions of the planet. Naturally the soils in their geochemical base contain heavy metals, in the majority of the regions these concentrations do not represent environmental risk. In this sense, the purpose of the present investigation was to compile the studies of heavy metals developed in agricultural production systems in Colombia to establish a baseline, which allows identifying future research needs in this subject. Among the results found, it was identified that the heavy metals studied in the country are Cd> Pb> Hg> Cr> Ni> Cu = Zn = As> Mn> Fe, highlighting Cd, Pb, Hg and Cr. However in Colombia The scientific production in which heavy metals are related to agricultural production (soil, crops or inputs) is relatively low. Also, these works are located in the central region of the country, evidencing that regions such as the Orinoquia considered as the border and agricultural pantry of the country, only three studies that were published in recent years are reported. Finally, this highlights the importance of generating research on reference values for these elements in Colombian soils, which allow the establishment of monitoring and evaluation programs in possible cases of contamination

Resumo O recurso solo oferece serviços ecossistêmicos fundamentais entre as que se realçam o suporte para a produção de alimentos e sua importância na mitigação dos efeitos da mudança climática devido à dinâmica do carbono. No entanto, atividades antrópicas como a densificação urbana, a industrialização e principalmente a agricultura contribuem elementos como metais pesados, responsáveis pela degradação do solo em algumas regiões do planeta. Naturalmente os solos em sua base geoquímica contêm metais pesados, na maioria das regiões estas concentrações não representam risco ambiental. Neste sentido, o propósito da presente investigação foi recopilar os estudos de metais pesados desenvolvidos em sistemas de produção agrícola em Colômbia para estabelecer uma linha base, que permita identificar necessidades futuras de investigação nesta temática. Entre os resultados encontrados, identificou-se que os metais pesados estudados no país são Cd>Pb>Hg>Cr>Nem>Cu=Zn=As>Mn>Fé, se destacando o Cd, Pb, Hg e Cr. No entanto em Colômbia a produção científica na que são relacionados os metais pesados na produção agrícola (solo, cultivos ou insumo) é relativamente baixa. Assim mesmo, estes trabalhos localizam-se na região central do país, evidenciando que regiões como a Orinoquia considerada como a fronteira e despensa agrícola do país, unicamente reportam-se três estudos que foram publicados nos últimos anos. Finalmente com isto se realça a importância de gerar investigações em valores de referência para estes elementos nos solos colombianos, que permitam estabelecer programas de monitorização e de avaliação em possíveis casos de contaminação.