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IMPORTANCEData on the efficacy of hydroxychloroquine or lopinavir-ritonavir for the treatment of high-risk outpatients with COVID-19 in developing countries are needed. OBJECTIVE To determine whether hydroxychloroquine or lopinavir-ritonavir reduces hospitalization among high-risk patients with early symptomatic COVID-19 in an outpatient setting. DESIGN, SETTING, AND PARTICIPANTS This randomized clinical trial was conducted in Brazil.Recently symptomatic adults diagnosed with respiratory symptoms from SARS-CoV-2 infection were enrolled between June 2 and September 30, 2020. The planned sample size was 1476 patients, with interim analyses planned after 500 patients were enrolled. The trial was stopped after the interim analysis for futility with a sample size of 685 patients. Statistical analysis was performed in December 2020.INTERVENTIONS Patients were randomly assigned to hydroxychloroquine (800 mg loading dose, then 400 mg daily for 9 days), lopinavir-ritonavir (loading dose of 800 mg and 200 mg, respectively, every 12 hours followed by 400 mg and 100 mg, respectively, every 12 hours for the next 9 days), or placebo. MAIN OUTCOMES AND MEASURESThe primary outcomes were COVID-19-associated hospitalization and death assessed at 90 days after randomization. COVID-19-associated hospitalization was analyzed with a Cox proportional hazards model. The trial included the following secondary outcomes: all-cause hospitalization, viral clearance, symptom resolution, and adverse events. RESULTSOf 685 participants, 632 (92.3%) self-identified as mixed-race, 377 (55.0%) were women, and the median (range) age was 53 (18-94) years. A total of 214 participants were randomized to hydroxychloroquine; 244, lopinavir-ritonavir; and 227, placebo. At first interim analysis, the data safety monitoring board recommended stopping enrollment of both hydroxychloroquine and lopinavir-ritonavir groups because of futility. The proportion of patients hospitalized for COVID-19 was 3.7% (8 participants) in the hydroxychloroquine group, 5.7% (14 participants) in the lopinavirritonavir group, and 4.8% (11 participants) in the placebo group. We found no significant differences between interventions for COVID-19-associated hospitalization (hydroxychloroquine: hazard ratio [HR], 0.76 [95% CI, 0.30-1.88]; lopinavir-ritonavir: HR, 1.16 [95% CI, 0.53-2.56] as well as for the secondary outcome of viral clearance through day 14 (hydroxychloroquine: odds ratio [OR], 0.91 (continued)

Background Observational studies have postulated a therapeutic role of metformin in treating COVID-19. We conducted an adaptive platform clinical trial to determine whether metformin is an effective treatment for high-risk patients with early COVID-19 in an outpatient setting. Methods The TOGETHER Trial is a placebo-controled, randomized, platform clinical trial conducted in Brazil. Eligible participants were symptomatic adults with a positive antigen test for SARS-CoV-2. We enroled eligible patients over the age of 50 years or with a known risk factor for disease severity. Patients were randomly assigned to receive either placebo or metformin (750 mg twice daily for 10 days or placebo, twice daily for 10 days). The primary outcome was hospitalization defined as either retention in a COVID-19 emergency setting for > 6 h or transfer to tertiary hospital due to COVID-19 at 28 days post randomization. Secondary outcomes included viral clearance at day 7, time to hospitalization, mortality, and adverse drug reactions. We used a Bayesian framework to determine probability of success of the intervention compared to placebo. Findings The TOGETHER Trial was initiated June 2, 2020. We randomized patients to metformin starting January 15, 2021. On April 3, 2021, the Data and Safety Monitoring Committee recommended stopping enrollment into the metformin arm due to futility. We recruited 418 participants, 215 were randomized to the metformin arm and 203 to the placebo arm. More than half of participants (56.0%) were over the age of 50 years and 57.2% were female. Median age was 52 years. The proportion of patients with the primary outcome at 28 days was not different between the metformin and placebo group (relative risk [RR] 1.14[95% Credible Interval 0.73; 1.81]), probability of superiority 0.28. We found no significant differences between the metformin and placebo group on viral clearance through to day 7 (Odds ratio [OR], 0.99, 95% Confidence Intervals 0.88–1.11) or other secondary outcomes. Interpretation In this randomized trial, metformin did not provide any clinical benefit to ambulatory patients with COVID-19 compared to placebo, with respect to reducing the need for retention in an emergency setting or hospitalization due to worsening COVID-19. There were also no differences between metformin and placebo observed for other secondary clinical outcomes.

Previous trials have shown the effects of fluvoxamine alone and inhaled budesonide alone for prevention of disease progression among outpatients with COVID-19. This placebo-controlled, randomized trial, conducted at 12 clinical sites in Brazil, sought to determine whether the combined effect of both drugs would increase treatment effects.

Background: There remains a need for an effective and affordable outpatient treatment for early COVID-19. Multiple repurposed drugs have shown promise in treating COVID-19. We describe a master protocol that will assess the efficacy of different repurposed drugs as treatments for early COVID-19 among outpatients at a high risk for severe complications. Methods: The TOGETHER Trial is a multi-center platform adaptive randomized, placebo-controlled, clinical trial. Patients are included if they are at least 18 years of age, have a positive antigen test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and have an indication for high risk of disease severity, including co-morbidities, older age, or high body mass index. Eligible patients are randomized with equal chance to an investigational product (IP) or to placebo.The primary endpoint is hospitalization defined as either retention in a COVID-19 emergency setting for greater than 6 hours or transfer to tertiary hospital due to COVID-19. Secondary outcomes include mortality, adverse events, adherence, and viral clearance. Scheduled interim analyses are conducted and reviewed by the Data and Safety Monitoring Committee (DSMC), who make recommendations on continuing or stopping each IP. The platform adaptive design go-no-go decision rules are extended to dynamically incorporate external evidence on COVID-19 interventions from ongoing independent randomized clinical trials. Discussion: Results from this trial will assist in the identification of therapeutics for the treatment of early diagnosed COVID-19. The novel methodological extension of the platform adaptive design to dynamically incorporate external evidence is one of the first of its kind and may provide highly valuable information for all COVID-19 trials going forward. Clinicaltrials.gov registration: NCT04727424 (27/01/2021)

BackgroundRecent evidence indicates a potential therapeutic role of fluvoxamine for COVID-19. In the TOGETHER randomized platform clinical trial for acutely symptomatic patients with COVID-19, we assessed the efficacy of fluvoxamine vs. placebo in preventing either extended emergency room observation or hospitalization due to COVID-19. Herein, we report the preliminary findings.MethodsThis placebo-controlled, randomized, adaptive, platform trial conducted among symptomatic Brazilian adults confirmed positive for SARS-CoV-2 included eligible patients with a known risk factor for progression to severe disease. Patients were randomly assigned to either fluvoxamine (100 mg twice daily for 10 days) or placebo. The primary endpoint was a composite outcome of emergency room observation for >6 hours or hospitalization from COVID-19 up to 28 days post randomization. Secondary outcomes included viral clearance at day 7, time to hospitalization, mortality, and adverse drug reactions. We used a Bayesian analytic framework to determine effects along with probability of success of intervention compared to placebo. The trial is registered at clinicaltrials.gov (NCT04727424) and is ongoing.ResultsThe study team screened 9020 potential participants for this trial. The trial was initiated on June 2, 2020, with the current protocol reporting randomization from January 15, 2021 to August 6th 2021, when the trial arms were stopped for superiority. A total of 3238 patients were allocated to fluvoxamine (n=739), placebo (n=733) and other treatments (n=1766). Herein, we report the effectiveness of fluvoxamine vs. a concurrent placebo control. The average age of participants was 50 years (range 18-102 years); 57% were female. The proportion of patients observed in an emergency room for >6 hours or admitted to hospital due to COVID-19 was lower for the fluvoxamine group compared to placebo (77/739 vs 108/733; Relative Risk [RR]: 0.71; 95% Bayesian Credible Interval [95% BCI]: 0.54 - 0.93), with a probability of superiority of 99.4% surpassing the prespecified superiority threshold of 97.6% (risk difference 4.3%). Of the composite primary outcome events, 88% were hospitalizations. We found no significant relative effects between the fluvoxamine and placebo groups on viral clearance at day 7 (Odds ratio [OR]: 0.75; 95% Confidence Intervals [95% CI]: 0.53 - 1.07), mortality (OR: 0.70; 95% CI: 0.36 - 1.30), time to death (Hazard ratio [HR]: 0.79; 95% CI: 0.58 - 1.08), days hospitalized (Mean Difference (MD) 1.22 days; 95% CI: 0.98 - 1.53), number of days ventilated (MD 1.10; 95% CI: 0.70 - 1.73) or other secondary outcomes. Data capturing all 28 days of follow-up will be reported after August 26th, 2021.ConclusionsTreatment with fluvoxamine (100 mg twice daily for 10 days) among high-risk outpatients with early diagnosed COVID-19, reduced the need for extended emergency room observation or hospitalization.FundingThe trial was supported by FastGrants and The Rainwater Foundation.

We declare no confl ict of interest. ABSTRACTVaccinia virus is responsible for a zoonosis that usually affects cattle and human beings in Brazil. The initial clinical signs of the infection are focal red skin areas, fever, and general symptoms similar to those of a cold. Then, pustules and ulcerated lesions surrounded by edema and erythema follow, as well as local lymphadenopathy that can last for weeks. Cure and healing of the lesions occur over several weeks, leaving a typical scar in the skin of people and animals affected. The infection defi nitive diagnosis is made through morphological characterization of the virus by use of electron microscopy, followed by PCR for specifi c viral genes. Since 1963, circulating orthopoxviruses in infectious outbreaks in several regions of Brazil have been reported. Later, the etiological agent of those infections was characterized as samples of Vaccinia virus. In addition, the widespread use of those viruses in research laboratories and mass vaccination of militaries have contributed to increase the cases of those infections worldwide. Thus, several epidemiological and clinical studies are required, as well as studies of viral immunology, public health, and economic impact, because little is known about those Vaccinia virus outbreaks in Brazil.

Este artigo apresenta resultados de um rastreamento de funcionários de um supermercado de Belo Horizonte, a fim de identificar indivíduos com níveis glicêmicos e pressóricos alterados. A atividade foi realizada em dois momentos e participaram 46 funcionários. No primeiro momento, foi aplicado um questionário, mensurados dados antropométricos e realizada aferição pressão arterial e glicemia capilar; no segundo, houve apresentação dos resultados aos funcionários e os mesmos foram orientados quanto a hábitos de vida saudáveis. Observaram-se casos de obesidade, hipertensão arterial e diabetes mellitus tipo 2 nessa população. A educação em saúde é fundamental para que as pessoas se conscientizem da importância da manutenção de hábitos de vida saudáveis, já que as doenças crônicas analisadas possuem grande relação com o estilo de vida adotado.Palavras-chave: Doenças crônicas. Prevenção. Promoção da saúde. Hábitos de vida saudáveis.