Matched vs Nonmatched Placebos in a Randomized Trial of COVID-19 Treatments.

Importance: Matched placebo interventions are complex and resource intensive. Recent evidence suggests matched placebos may not always be necessary. Previous studies have predominantly evaluated potential bias of nonmatched placebos (ie, differing on dose, frequency of administration, or formulation) in pain and mental health, but to date no systematic examination has been conducted in infectious disease. Objective: To test for differences between nonmatched and matched placebo arms with respect to clinical outcome measures across multiple therapeutics for COVID-19. Design, Setting, and Participants: In a comparative effectiveness research study, a post hoc analysis was conducted of data on individual patients enrolled in a large, multiarm, platform randomized clinical trial in symptomatic adult outpatients with COVID-19 between January 15, 2021, to September 28, 2023, in which the outcomes of both matched and nonmatched placebo groups were reported. Bayesian and frequentist covariate-adjusted techniques were compared with 7 intervention-placebo pairs. Exposures: Seven matched and nonmatched placebo pairs (for a total of 7 comparisons) were evaluated throughout the primary platform trial. Comparisons were made between treatment and its associated matched (concurrent) placebo, as well as with nonmatched placebo (alone and in combination) assessed at a similar time point. Main Outcomes and Measures: Outcomes assessed included hospitalizations, EuroQol 5-Dimension 5-level scores, and PROMIS Global-10 scores. Results: A total of 7 intervention-control pairs (N = 2684) were assessed, including 1620 (60.4%) women, with mean (SD) age, 47 (15.2) years; the most common comorbidities were obesity (41.9%) and hypertension (37.9%). In a meta-analysis with decoupled SEs, accounting for overlapping placebo patients, the overall odds ratio (OR) of nonmatched compared with matched placebo was 1.01 (95% credible interval, 0.77-1.32), with posterior probability of equivalence, defined as 0.8 ≤ OR ≤ 1.2 (a deviation from perfect equivalence ie, OR = 1, by no more than 0.2) of 85.4%, implying no significant difference. Unadjusted analysis of the event rate difference between all nonmatched and matched placebo groups did not identify any notable differences across all 7 treatment-placebo combinations assessed. Similar analysis that was conducted for patient-reported quality of life outcomes did not yield statistically significant differences. Conclusions and Relevance: In this post hoc study of a randomized clinical platform trial, pooling matched and nonmatched placebo patient data did not lead to inconsistencies in treatment effect estimation for any of the investigational drugs. These findings may have significant implications for future platform trials, as the use of nonmatched placebo may improve statistical power, or reduce barriers to placebo implementation.

Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial.

BACKGROUND: Recent evidence indicates a potential therapeutic role of fluvoxamine for COVID-19. In the TOGETHER trial for acutely symptomatic patients with COVID-19, we aimed to assess the efficacy of fluvoxamine versus placebo in preventing hospitalisation defined as either retention in a COVID-19 emergency setting or transfer to a tertiary hospital due to COVID-19. METHODS: This placebo-controlled, randomised, adaptive platform trial done among high-risk symptomatic Brazilian adults confirmed positive for SARS-CoV-2 included eligible patients from 11 clinical sites in Brazil with a known risk factor for progression to severe disease. Patients were randomly assigned (1:1) to either fluvoxamine (100 mg twice daily for 10 days) or placebo (or other treatment groups not reported here). The trial team, site staff, and patients were masked to treatment allocation. Our primary outcome was a composite endpoint of hospitalisation defined as either retention in a COVID-19 emergency setting or transfer to tertiary hospital due to COVID-19 up to 28 days post-random assignment on the basis of intention to treat. Modified intention to treat explored patients receiving at least 24 h of treatment before a primary outcome event and per-protocol analysis explored patients with a high level adherence (>80%). We used a Bayesian analytic framework to establish the effects along with probability of success of intervention compared with placebo. The trial is registered at ClinicalTrials.gov (NCT04727424) and is ongoing. FINDINGS: The study team screened 9803 potential participants for this trial. The trial was initiated on June 2, 2020, with the current protocol reporting randomisation to fluvoxamine from Jan 20 to Aug 5, 2021, when the trial arms were stopped for superiority. 741 patients were allocated to fluvoxamine and 756 to placebo. The average age of participants was 50 years (range 18-102 years); 58% were female. The proportion of patients observed in a COVID-19 emergency setting for more than 6 h or transferred to a teritary hospital due to COVID-19 was lower for the fluvoxamine group compared with placebo (79 [11%] of 741 vs 119 [16%] of 756); relative risk [RR] 0·68; 95% Bayesian credible interval [95% BCI]: 0·52-0·88), with a probability of superiority of 99·8% surpassing the prespecified superiority threshold of 97·6% (risk difference 5·0%). Of the composite primary outcome events, 87% were hospitalisations. Findings for the primary outcome were similar for the modified intention-to-treat analysis (RR 0·69, 95% BCI 0·53-0·90) and larger in the per-protocol analysis (RR 0·34, 95% BCI, 0·21-0·54). There were 17 deaths in the fluvoxamine group and 25 deaths in the placebo group in the primary intention-to-treat analysis (odds ratio [OR] 0·68, 95% CI: 0·36-1·27). There was one death in the fluvoxamine group and 12 in the placebo group for the per-protocol population (OR 0·09; 95% CI 0·01-0·47). We found no significant differences in number of treatment emergent adverse events among patients in the fluvoxamine and placebo groups. INTERPRETATION: Treatment with fluvoxamine (100 mg twice daily for 10 days) among high-risk outpatients with early diagnosed COVID-19 reduced the need for hospitalisation defined as retention in a COVID-19 emergency setting or transfer to a tertiary hospital. FUNDING: FastGrants and The Rainwater Charitable Foundation. TRANSLATION: For the Portuguese translation of the abstract see Supplementary Materials section.

Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19: The TOGETHER Randomized Clinical Trial.

Importance: Data 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 Measures: The 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. Results: Of 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 lopinavir-ritonavir 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 [95% CI, 0.82-1.02]; lopinavir-ritonavir: OR, 1.04 [95% CI, 0.94-1.16]). At the end of the trial, there were 3 fatalities recorded, 1 in the placebo group and 2 in the lopinavir-ritonavir intervention group. Conclusions and Relevance: In this randomized clinical trial, neither hydroxychloroquine nor lopinavir-ritonavir showed any significant benefit for decreasing COVID-19-associated hospitalization or other secondary clinical outcomes. This trial suggests that expedient clinical trials can be implemented in low-income settings even during the COVID-19 pandemic. Trial Registration: ClinicalTrials.gov Identifier: NCT04403100.

Nascer em Belo Horizonte: cesarianas desnecessárias e prematuridade / Birth in Belo Horizonte: unnecessary cesarean sections and prematurity

O Brasil é o líder mundial de cirurgias cesarianas com uma taxa de 56% do total de partos, enquanto o índice recomendado pela Organização Mundial de Saúde é de 15%. Esse alto índice, já considerado uma epidemia no país, traz sérios riscos para a saúde da mulher e do recém-nascido, apresentando relação direta com o aumento da morbi-mortalidade materna e neonatal. Estima-se que no Brasil quase um milhão de mulheres são submetidas a essa cirurgia sem indicação médica e obstétrica adequada, impactando no aumento das taxas de cesáreas desnecessárias e prematuridade. A região sudeste se destaca como a região com maior índice desse tipo de parto. Objetivo: Analisar as cesáreas desnecessárias em Belo Horizonte e a prematuridade relacionada. Método: Trata-se de um estudo de coorte, de base hospitalar, desenvolvido em maternidades públicas e privadas de Belo Horizonte, Minas Gerais, no período de novembro de 2011 a março de 2013. A amostra foi constituída por puérperas hospitalizadas por motivo de parto hospitalar e seus conceptos vivos, independente de peso e idade gestacional ou mortos com peso maior que 500 gramas e idade gestacional maior que 22 semanas. Os dados foram coletados por meio de entrevistas com as puérperas, nos prontuários da mãe e do recém-nascido e no cartão de pré-natal. Para estimativa da idade gestacional usou-se o algoritmo proposto por Pereira et al.,(2014) e a ultrassonografia precoce ( 7 a 20 semanas). As cesáreas desnecessárias foram analisadas utilizando-se a classificação dos 10 grupos de Robson e em relação às seguintes variáveis: tipo de hospital (público ou privado), procedência, idade, raça/cor da pele e classe econômica da puérpera, plano de saúde, acompanhante e justificativa para a realização da cesárea. Os dados foram analisados por técnicas de estatística descritiva e os resultados expressos em tabelas com ênfase nas taxas esperada, observada e desnecessária...

Brazil is the world´s leader in cesarean surgery, with a rate of 56% of total births, while the percentage recommended by the World Health Organization is 15%. This high rate is considered an epidemic in the country and is associated with increased morbidity as well as maternal and newborn mortality. In Brazil, it is estimated that almost a million women undergo this surgery without medical advice and adequate obstetric care, which affects the increase in rates of unnecessary cesarean sections and prematurity. The Southeast region stands out as the region with the highest rate of this type of birth. Objective: It is to analyze the unnecessary cesarean sections in Belo Horizonte and related prematurity. Method: This is a hospital-based study that was conducted in public and private maternity hospitals in Belo Horizonte, Minas Gerais, Brazil, from November 2011 to March 2013. The sample is comprised of hospitalized mothers for birth reasons as well as their living fetuses, regardless of the weight and gestational age, or dead fetuses that weigh more than 500 grams and obtain gestational age greater than 22 weeks. Data were collected through interviews with the mothers, based in their medical records as well as the newborn´s and prenatal card. An algorithm proposed by Pereira was used to estimate the gestational age et al (2014) and early pregnancy ultrasound (7 to 20 weeks). The unnecessary caesarean sections were analyzed through the use of Robson´s 10 groups classification, based on the following variables: Type of hospital (public or private), origin, age, race/skin color and postpartum women´s economic status, health plan, her company and justifications for conducting the caesarian. Data were analyzed by descriptive statistics and the results expressed on tables with emphasis on expected rates and unnecessary cesareans as well as the proportion of unnecessary cesareans. Prematurity was analyzed by different methods of...

Atuação do enfermeiro nos serviços de atendimento pré-hospitalares móveis no Brasil: revisão integrativa / Nurses´roles in mobile prehospital care services in Brazil: integrative review / Actuación del enfermero en los servicios de atención pre-hospitalarios móviles en Brasil: revisión integradora

Objetivo: analisar, na literatura nacional e internacional, a atuação do enfermeiro nos Serviços de Atendimento Pré-Hospitalares móveis no Brasil, os desafios encontrados e suas perspectivas. Método: revisão integrativa que analisou artigos científicos publicados no período de 2009 a 2013 com vistas a responder as questões norteadoras << Como tem sido a atuação do enfermeiro nos Serviços de Atendimento Pré-Hospitalar móvel no Brasil? E quais são os desafios e perspectivas encontrados por estes profissionais? >> Resultados: a ideia de atender a vítima no local da emergência é bem antiga no país, porém, a atuação do enfermeiro no atendimento pré-hospitalar móvel é uma atividade recente. Desde então, este profissional é participante ativo dessas equipes, desenvolvendo várias funções e enfrentando muitos desafios. Conclusão: a enfermagem vem ocupando novas áreas, sendo sua inserção neste serviço uma delas. O estudo evidenciou baixo conhecimento dos enfermeiros recém-formados quanto às questões de urgência e emergência, entretanto, mesmo com os desafios encontrados, realizam com sucesso a prestação do cuidado. Espera-se que este trabalho contribua com maiores reflexões e novos estudos.(AU)

Objective: to analyze, in national and international literature, the nurse's role in mobile Prehospital Care Services in Brazil, the challenges and its prospects. Method: integrative review that examined scientific articles published from 2009 to 2013 with the answer after considering the guiding questions << How has been the nurse's role in mobile Prehospital Care Services in Brazil? And what are the challenges and prospects encountered by these professionals? >> Results: the idea of meeting the victim at the emergency room is very old in the country, but the work of nurses in the mobile pre-hospital care is a recent activity. Since then, the nurse is an active participant of these teams, developing various functions and facing many challenges. Conclusion: the nursing is occupying new areas and their insertion is one of them in this service. The study showed low knowledge of newly graduated nurses about the urgent and emergency issues, however, even with the challenges they successfully carry out the provision of care. It is hoped that this work will contribute to further reflection and further studies.(AU)

Objetivo: analizar, en la literatura nacional e internacional, la actuación del enfermero en los Servicios de Atención Pre-Hospitalarios móviles en Brasil, los desafíos encontrados y sus perspectivas. Método: revisión integradora que analizó artículos científicos publicados en el período de 2009 a 2013 para responder las preguntas guiadoras << ¿Cómo ha sido la actuación del enfermero en los Servicios de Atención Pre-Hospitalario móvil en Brasil? y ¿Cuáles son los desafíos y perspectivas encontrados por estos profesionales? >> Resultados: la idea de atender a la víctima en el local de la emergencia es muy antigua en el país, pero la actuación del enfermero en la atención pre-hospitalario móvil es una actividad reciente. Desde entonces, el enfermero es participante activo de esos equipos, desarrollando varias funciones y enfrentando muchos desafíos. Conclusión: la enfermería viene ocupando nuevas áreas siendo su inserción en este servicio una de ellas. El estudio mostró bajo conocimiento de los enfermeros recién formados sobre los asuntos de urgencia y emergencia, sin embargo, mismo con los desafíos encontrados, ellos realizan con suceso la prestación de cuidado. Se espera que este trabajo contribuya con mayores reflexiones y nuevos estudios. (AU)