Analysis of the costs of teleconsultation for the treatment of diabetes mellitus in the SUS.

OBJECTIVE: To present the results of a cost analysis of remote consultations (teleconsultations) compared to in-person consultations for patients with type 2 diabetes, in the Brazilian public healthcare system (SUS) in the city of Joinville, Santa Catarina (SC). In addition to the costs from the local manager's perspective, the article also presents estimates from the patient's perspective, based on the transportation costs associated with each type of consultation. METHOD: Data were collected from 246 consultations, both remote and in-person, between 2021 and 2023, in the context of a randomized clinical trial on the impact of teleconsultation carried out in the city of Joinville, SC. Teleconsultations were carried out at Primary Health Units (PHU) and in-person consultations at the Specialized Health Center. The consultation costs were calculate by the method time and activity-based costing (TDABC), and for the estimate of transportation costs data was collected directly from the research participants . The mean costs and time required to carry out each type of consultation in different scenarios and perspectives were analyzed and compared descriptively. RESULTS: Considering only the local SUS manager's perspective, the costs for carrying out a teleconsultation were 4.5% higher than for an in-person consultation. However, when considering the transportation costs associated with each patient, the estimated value of the in-person consultation becomes 7.7% higher and, in the case of consultations in other municipalities, 15% higher than the teleconsultation. CONCLUSION: The results demonstrate that the incorporation of teleconsultation within the SUS can bring economic advantages depending on the perspective and scenario considered, in addition to being a strategy with the potential to increase access to specialized care in the public network.

Application of ventilator-associated events (VAE) in ventilator-associated pneumonia (VAP) notified in Brazil (IMPACTO MR-PAV): a protocol for a cohort study.

INTRODUCTION: Certain criteria for ventilator-associated events (VAE) definition might influence the type of an event, its detection rate and consequently the resource expenditure in intensive care unit. The Impact of Infections by Antimicrobial-Resistant Microorganisms - Ventilator-Associated Pneumonia (IMPACTO MR-PAV) aims to evaluate the incidence and diagnostic accuracy of ventilator-associated pneumonia (VAP) using the current criteria for VAP surveillance in Brazil versus the VAE criteria defined by the US National Healthcare Safety Network-Center for Diseases Control and Prevention (CDC) criteria. METHODS AND ANALYSIS: The study will be conducted in around 15 centres across Brazil from October 2022 to December 2023. Trained healthcare professionals will collect data and compare the incidence of VAP using both the current criteria for VAP surveillance in Brazil and the VAE criteria defined by the CDC. The accuracy of the two criteria for identifying VAP will also be analysed. It will also characterise other events associated with mechanical ventilation (ventilator-associated condition, infection-related ventilator-associated complication) and adjudicate VAP reported to the Brazilian Health Regulatory Agency (ANVISA) using current epidemiological diagnostic criteria. ETHICS AND DISSEMINATION: This study was approved by the Institutional Review Board under the number 52354721.0.1001.0070. The study's primary outcome measure will be the incidence of VAP using the two different surveillance criteria, and the secondary outcome measures will be the accuracy of the two criteria for identifying VAP and the adjudication of VAP reported to ANVISA. The results will contribute to the improvement of VAP surveillance in Brazil and may have implications for other countries that use similar criteria. TRIAL REGISTRATION NUMBER: NCT05589727; Clinicaltrials.gov.

Impact of switching between reference biologics and biosimilars of tumour necrosis factor inhibitors for rheumatoid arthritis: a systematic review and network meta-analysis.

What is the impact of switching between biologics and biosimilars of adalimumab, etanercept, and infliximab on efficacy and safety for rheumatoid arthritis? A systematic review and network meta-analysis were performed to compare switching and non-switching groups of treatments. Pooled Risk Relative (RR) or standardised mean differences (SMD) with 95% credible intervals (95% CrIs) were obtained. Seventeen randomized trials with a switching phase involving 6,562 patients were included. Results showed that a single switch from biologics to biosimilars compared to continuing biologics had comparable effects for primary and co-primary outcomes, the American College of Rheumatology criteria with 20% response (ACR20) (7 trials, 1,926 patients, RR 0.98, 95% CrIs 0.93 to 1.03) and the Health Assessment Questionnaire-Disability Index (HAQ-DI) (5 trials, 1,609 patients, SMD - 0.07, 95% CrIs - 0.23 to 0.1), and within the equivalence margins: ACR20 [RR 0.94, 1.06] and HAQ-DI [SMD - 0.22, 0.22]. The risk of treatment-emergent adverse events, discontinuation, and positive anti-drug antibodies were comparable after switching. Safety results were imprecise, and the follow-up period might not be sufficient to evaluate long-term effects, especially malignancies. Overall, the practice of single switching between approved biologics and biosimilars of Tumour Necrosis Factor inhibitors is efficacious and safe for rheumatoid arthritis.

Mapping the characteristics, concepts and methodologies of matching-adjusted indirect comparison studies assessing pharmacological therapies in oncology: a scoping review protocol.

INTRODUCTION: Matching-adjusted indirect comparison (MAIC) studies are a subtype of indirect comparison, which uses propensity score weighting to enhance comparability. This method adjusts aggregated data based on covariables from individual patient data from studies to produce population-adjusted indirect comparisons. Some national Health Technology Assessment agencies have recently received submissions containing MAIC models. However, there can be a lack of confidence in its estimates when they are poorly reported and inconsistent with other techniques. The objective of this study is to map the characteristics, concepts and methodology of MAIC studies used for pharmacological therapies in the field of oncology. METHODS AND ANALYSIS: A scoping review methodology will be applied following the Joanna Briggs Institute framework and the results will be reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses Extension for Scoping Reviews. Studies that used MAIC to compare treatments in oncology conditions will be considered eligible. A systematic search will be conducted in PubMed, Embase and the Cochrane Library. No restriction of location or language will be applied. Study screening will be documented and presented in a Preferred Reporting Items for Systematic reviews and Meta-Analyses flow diagram. Data will be extracted and recorded on a predefined data form and will be presented in a tabular form accompanied by a descriptive summary. ETHICS AND DISSEMINATION: No ethical approval is required for this study. The results of this scoping review will be disseminated through peer-reviewed publications.

Therapeutic Equivalence of Biosimilar and Reference Biologic Drugs in Rheumatoid Arthritis: A Systematic Review and Meta-analysis.

Importance: Biosimilar drugs are potentially lower-cost versions of biologics that may improve access to therapy. However, there is a lack of adequate systematic reviews demonstrating equivalence between these drugs for the treatment of rheumatoid arthritis (RA). Objectives: To assess the efficacy, safety, and immunogenicity associated with biosimilars of adalimumab, etanercept, and infliximab compared with their reference biologics in patients with RA. Data Sources: MEDLINE via PubMed, Embase, Cochrane Central Register of Controlled Trials, and LILACS databases were searched from inception to September 2021. Study Selection: Head-to-head randomized clinical trials (RCTs) of biosimilars of adalimumab, etanercept, and infliximab and their biologic reference drugs for RA were assessed. Data Extraction and Synthesis: Two authors independently abstracted all data. Meta-analysis was conducted with bayesian random effects using relative risks (RRs) for binary outcomes and standardized mean differences (SMDs) for continuous outcomes, with 95% credible intervals (CrIs) and trial sequential analysis. Specific domains were assessed for the risk of bias in equivalence and noninferiority trials. This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline. Main Outcomes and Measures: Equivalence was tested using prespecified margins for the American College of Rheumatology criteria, with at least 20% improvement in the core set measures (ACR20) (ie, RR, 0.94 to 1.06), and for the Health Assessment Questionnaire-Disability Index (HAQ-DI) (ie, SMD, -0.22 to 0.22). Secondary outcomes included 14 items measuring safety and immunogenicity. Results: A total of 25 head-to-head trials provided data on 10 642 randomized patients with moderate to severe RA. Biosimilars met equivalence with reference biologics in terms of ACR20 response (24 RCTs with 10 259 patients; RR, 1.01; 95% CrI, 0.98 to 1.04; τ2 = 0.000) and change of HAQ-DI scores (14 RCTs with 5579 patients; SMD, -0.04; 95% CrI, -0.11 to 0.02; τ2 = 0.002) considering prespecified margins of equivalence. Trial sequential analysis found evidence for equivalence for ACR20 since 2017 and HAQ-DI since 2016. Overall, biosimilars were associated with similar safety and immunogenicity profiles compared with reference biologics. Conclusion and Relevance: In this systematic review and meta-analysis, biosimilars of adalimumab, infliximab, and etanercept were associated with clinically equivalent treatment effects compared with their reference biologics for the treatment of RA.

Clinical Equivalence between Generic Versus Branded Antibiotics: Systematic Review and Meta-Analysis.

Regulatory authorities authorize the clinical use of generic drugs (GD) based on bioequivalence studies, which consist of the evaluation of pharmacokinetics after a single dose in vitro or in healthy individuals. There are few data on clinical equivalence between generic and branded antibiotics. Our aim was to synthesize and analyze the available evidence on the clinical efficacy and safety of generic antibiotics compared to their original formulations. A systematic review was performed on Medline (PubMed) and Embase and validated through Epistemonikos and Google Scholar. The last search was conducted on 30 June 2022. Meta-analyses of clinical cure and mortality outcomes were performed. One randomized clinical trial (RCT) and 10 non-randomized intervention studies were included. No differences in clinical cure were observed between groups in the meta-analysis (OR = 0.89, 95% CI [0.61-1.28]; I2 = 70%, p = 0.005). No difference was observed between groups when considering the use of carbapenems for overall mortality (OR = 0.99, 95% CI [0.63-1.55]; I2 = 78%) or death associated with infections (OR = 0.79, 95% CI [0.48-1.29], I2 = 67%). Most of the studies were observational, and the duration of follow-up, the characteristics of the participants, and the sites of infections were heterogeneous. Due to the uncertainty of the evidence, it is not possible to contraindicate the use of generics, which is an important strategy to expand access.

Rivaroxaban to prevent major clinical outcomes in non-hospitalised patients with COVID-19: the CARE - COALITION VIII randomised clinical trial.

Background: COVID-19 progression is associated with an increased risk of arterial and venous thrombosis. Randomised trials have demonstrated that anticoagulants reduce the risk of thromboembolism in hospitalised patients with COVID-19, but a benefit of routine anticoagulation has not been demonstrated in the outpatient setting. Methods: We conducted a randomised, open-label, controlled, multicentre study, evaluating the use of rivaroxaban in mild or moderate COVID-19 patients. Adults ≥18 years old, with probable or confirmed SARS-CoV-2 infection, presenting within ≤7 days from symptom onset with no clear indication for hospitalization, plus at least 2 risk factors for complication, were randomised 1:1 either to rivaroxaban 10 mg OD for 14 days or to routine care. The primary efficacy endpoint was the composite of venous thromboembolic events, need of mechanical ventilation, acute myocardial infarction, stroke, acute limb ischemia, or death due to COVID-19 during the first 30 days. ClinicalTrials.gov: NCT04757857. Findings: Enrollment was prematurely stopped due to sustained reduction in new COVID-19 cases. From September 29th, 2020, through May 23rd, 2022, 660 patients were randomised (median age 61 [Q1-Q3 47-69], 55.7% women). There was no significant difference between rivaroxaban and control in the primary efficacy endpoint (4.3% [14/327] vs 5.8% [19/330], RR 0.74; 95% CI: 0.38-1.46). There was no major bleeding in the control group and 1 in the rivaroxaban group. Interpretation: On light of these findings no decision can be made about the utility of rivaroxaban to improve outcomes in outpatients with COVID-19. Metanalyses data provide no evidence of a benefit of anticoagulant prophylaxis in outpatients with COVID-19. These findings were the result of an underpowered study, therefore should be interpreted with caution. Funding: COALITION COVID-19 Brazil and Bayer S.A.

Hydroxychloroquine for Non-Hospitalized COVID-19 Patients: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. / Hidroxicloroquina para Pacientes com COVID-19 não Hospitalizados: Uma Revisão Sistemática e Metanálise de Ensaios Clínicos Randomizados.

BACKGROUND: Previous systematic reviews have identified no benefit of hydroxychloroquine and chloroquine in non-hospitalized COVID-19 patients. After publication of these reviews, the results of COPE, the largest randomized trial conducted to date, became available. OBJECTIVES: To conduct a systematic review and meta-analyses of randomized clinical trials (RCTs) to synthesize the evidence on the efficacy and safety of hydroxychloroquine and chloroquine for non-hospitalized COVID-19 patients compared to placebo or standard of care. METHODS: Searches were conducted in PubMed, Embase, The Cochrane Library, and ClinicalTrials.gov complemented by manual search. Pairwise meta-analyses, risk of bias, and evidence certainty assessments were conducted, including optimal information size analysis (OIS). A level of significance of 0.05 was adopted in the meta-analysis. PROSPERO: CRD42021265427. RESULTS: Eight RCTs with 3,219 participants were included. COVID-19 hospitalization and any adverse events rates were not significantly different between hydroxychloroquine (5.6% and 35.1%) and control (7.4% and 20.4%) (risk ratio, RR, 0.77, 95% confidence interval, CI, 0.57-1.04, I2: 0%; RR 1.78, 95%-CI 0.90; 3.52, I2: 93%, respectively). The OIS (7,880) was not reached for COVID-19 hospitalization, independently of the simulation for anticipated event rate and RR reduction estimate. CONCLUSION: Evidence of very low certainty showed lack of benefit with hydroxychloroquine in preventing COVID-19 hospitalizations. Despite being the systematic review with the largest number of participants included, the OIS, considering pre-vaccination response to infection, has not yet been reached.

FUNDAMENTO: Revisões sistemáticas anteriores não identificaram benefício do uso da hidroxicloroquina ou da cloroquina em pacientes com COVID-19 não hospitalizados. Após a publicação dessas revisões, os resultados do COPE, o maior ensaio clínico randomizado até hoje, tornaram-se disponíveis. OBJETIVOS: Conduzir uma revisão sistemática e metanálise de ensaios clínicos randomizados (ECRs) para sintetizar as evidências sobre a eficácia e a segurança da hidroxicloroquina e da cloroquina em pacientes com COVID-19 não hospitalizados em comparação a controle ou tratamento padrão. MÉTODOS: As buscas foram conduzidas nos bancos de dados PubMed, Embase, The Cochrane Library e ClinicalTrials.gov, e complementadas por busca manual. Foram realizadas metanálises diretas e avaliações de risco de viés e certeza da evidência, incluindo análise do tamanho ótimo da informação (OIS, optimal information size). Um nível de significância de 0,05 foi adotado na metanálise. PROSPERO: CRD42021265427. RESULTADOS: Oito ECRs com 3219 participantes foram incluídos. As taxas de internação por COVID-19 e de eventos adversos não foram significativamente diferentes entre hidroxicloroquina (5,6% e 5,1%) e controle (7,4% e 20,4%) [risco relativo (RR) 0,77, intervalo de confiança 95% (IC95%), 0,57-1,04, I2: 0%; RR 1,78, IC95% 0,90; 3,52, I2: 93%, respectivamente)]. O OIS (7880) não foi alcançado para hospitalização por COVID-19, independentemente da simulação para a taxa de evento e redução do RR estimados. CONCLUSÃO: A evidência de muito baixa qualidade indicou falta de benefício com hidroxicloroquina em prevenir internações por COVID-19. Apesar de ser a revisão sistemática com o maior número de participantes incluídos, o OIS, considerando a resposta à infecção anterior à vacinação, não foi atingido.

Hidroxicloroquina para Pacientes com COVID-19 não Hospitalizados: Uma Revisão Sistemática e Metanálise de Ensaios Clínicos Randomizados / Hydroxychloroquine for Non-Hospitalized COVID-19 Patients: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

Resumo Fundamento: Revisões sistemáticas anteriores não identificaram benefício do uso da hidroxicloroquina ou da cloroquina em pacientes com COVID-19 não hospitalizados. Após a publicação dessas revisões, os resultados do COPE, o maior ensaio clínico randomizado até hoje, tornaram-se disponíveis. Objetivos: Conduzir uma revisão sistemática e metanálise de ensaios clínicos randomizados (ECRs) para sintetizar as evidências sobre a eficácia e a segurança da hidroxicloroquina e da cloroquina em pacientes com COVID-19 não hospitalizados em comparação a controle ou tratamento padrão. Métodos: As buscas foram conduzidas nos bancos de dados PubMed, Embase, The Cochrane Library e ClinicalTrials.gov, e complementadas por busca manual. Foram realizadas metanálises diretas e avaliações de risco de viés e certeza da evidência, incluindo análise do tamanho ótimo da informação (OIS, optimal information size). Um nível de significância de 0,05 foi adotado na metanálise. PROSPERO: CRD42021265427. Resultados: Oito ECRs com 3219 participantes foram incluídos. As taxas de internação por COVID-19 e de eventos adversos não foram significativamente diferentes entre hidroxicloroquina (5,6% e 5,1%) e controle (7,4% e 20,4%) [risco relativo (RR) 0,77, intervalo de confiança 95% (IC95%), 0,57-1,04, I2: 0%; RR 1,78, IC95% 0,90; 3,52, I2: 93%, respectivamente)]. O OIS (7880) não foi alcançado para hospitalização por COVID-19, independentemente da simulação para a taxa de evento e redução do RR estimados. Conclusão: A evidência de muito baixa qualidade indicou falta de benefício com hidroxicloroquina em prevenir internações por COVID-19. Apesar de ser a revisão sistemática com o maior número de participantes incluídos, o OIS, considerando a resposta à infecção anterior à vacinação, não foi atingido.

Abstract Background: Previous systematic reviews have identified no benefit of hydroxychloroquine and chloroquine in non-hospitalized COVID-19 patients. After publication of these reviews, the results of COPE, the largest randomized trial conducted to date, became available. Objectives: To conduct a systematic review and meta-analyses of randomized clinical trials (RCTs) to synthesize the evidence on the efficacy and safety of hydroxychloroquine and chloroquine for non-hospitalized COVID-19 patients compared to placebo or standard of care. Methods: Searches were conducted in PubMed, Embase, The Cochrane Library, and ClinicalTrials.gov complemented by manual search. Pairwise meta-analyses, risk of bias, and evidence certainty assessments were conducted, including optimal information size analysis (OIS). A level of significance of 0.05 was adopted in the meta-analysis. PROSPERO: CRD42021265427. Results: Eight RCTs with 3,219 participants were included. COVID-19 hospitalization and any adverse events rates were not significantly different between hydroxychloroquine (5.6% and 35.1%) and control (7.4% and 20.4%) (risk ratio, RR, 0.77, 95% confidence interval, CI, 0.57-1.04, I2: 0%; RR 1.78, 95%-CI 0.90; 3.52, I2: 93%, respectively). The OIS (7,880) was not reached for COVID-19 hospitalization, independently of the simulation for anticipated event rate and RR reduction estimate. Conclusion: Evidence of very low certainty showed lack of benefit with hydroxychloroquine in preventing COVID-19 hospitalizations. Despite being the systematic review with the largest number of participants included, the OIS, considering pre-vaccination response to infection, has not yet been reached.

IMPACTO-MR: um estudo brasileiro de plataforma nacional para avaliar infecções e multirresistência em unidades de terapia intensiva / IMPACTO-MR: a Brazilian nationwide platform study to assess infections and multidrug resistance in intensive care units

RESUMO Objetivo: Descrever o IMPACTO-MR, um estudo brasileiro de plataforma nacional em unidades de terapia intensiva focado no impacto das infecções por bactérias multirresistentes relacionadas à assistência à saúde. Métodos: Descrevemos a plataforma IMPACTO-MR, seu desenvolvimento, critérios para seleção das unidades de terapia intensiva, caracterização da coleta de dados, objetivos e projetos de pesquisa futuros a serem realizados na plataforma. Resultados: Os dados principais foram coletados por meio do Epimed Monitor System® e consistiram em dados demográficos, dados de comorbidades, estado funcional, escores clínicos, diagnóstico de internação e diagnósticos secundários, dados laboratoriais, clínicos e microbiológicos e suporte de órgãos durante a internação na unidade de terapia intensiva, entre outros. De outubro de 2019 a dezembro de 2020, 33.983 pacientes de 51 unidades de terapia intensiva foram incluídos no banco de dados principal. Conclusão: A plataforma IMPACTO-MR é um banco de dados clínico brasileiro de unidades de terapia intensiva focado na pesquisa do impacto das infecções por bactérias multirresistentes relacionadas à assistência à saúde. Essa plataforma fornece dados para o desenvolvimento e pesquisa de unidades de terapia intensiva individuais e ensaios clínicos observacionais e prospectivos multicêntricos.

ABSTRACT Objective: To describe the IMPACTO-MR, a Brazilian nationwide intensive care unit platform study focused on the impact of health care-associated infections due to multidrug-resistant bacteria. Methods: We described the IMPACTO-MR platform, its development, criteria for intensive care unit selection, characterization of core data collection, objectives, and future research projects to be held within the platform. Results: The core data were collected using the Epimed Monitor System® and consisted of demographic data, comorbidity data, functional status, clinical scores, admission diagnosis and secondary diagnoses, laboratory, clinical, and microbiological data, and organ support during intensive care unit stay, among others. From October 2019 to December 2020, 33,983 patients from 51 intensive care units were included in the core database. Conclusion: The IMPACTO-MR platform is a nationwide Brazilian intensive care unit clinical database focused on researching the impact of health care-associated infections due to multidrug-resistant bacteria. This platform provides data for individual intensive care unit development and research and multicenter observational and prospective trials.

Forecasting models for leprosy cases: a scoping review protocol.

INTRODUCTION: Leprosy is a neglected tropical disease caused by Mycobacterium leprae that mainly affects the skin, the peripheral nerves, the mucosa of the upper respiratory tract and the eyes. Mathematical models and statistical methodologies could play an important role in decision-making and help maintain the gains in elimination programmes. Various models for predicting leprosy cases have been reported in the literature, but they have different settings and distinct approaches to predicting the cases. This study describes the protocol for a scoping review to identify and synthesise information from studies using models to forecast leprosy cases. METHODS AND ANALYSIS: A scoping review methodology will be applied following the Joanna Briggs Institute methodology for scoping reviews and will be reported according to Preferred Reporting Items for Systematic Reviews and Meta-analysis Extension for Scoping Reviews. We will perform a systematic search from when each database started until April 2022 and we will include the following electronic databases: MEDLINE via PubMed, Embase, Cochrane Library and Latin American and Caribbean Health Science Literature Database. Data will be extracted and recorded on a calibrated predefined data form and will be presented in a tabular form accompanied by a descriptive summary. The Prediction Model Study Risk of Bias Assessment Tool (PROBAST) will be used. ETHICS AND DISSEMINATION: No ethical approval is required for this study. This scoping review will identify and map the methodological and other characteristics of modelling studies predicting leprosy cases. We hope that the review will contribute to scientific knowledge in this area and act as a basis for researchers designing and conducting leprosy models. This information can also be used to enhance national surveillance systems and to target specific policies. The protocol and consequent publications of this scoping review will be disseminated through peer-reviewed publications and policy briefs. SYSTEMATIC REVIEW REGISTRATION: This scoping review was registered in the Open Science Framework (https://doi.org/10.17605/OSF.IO/W9375).

Rationale and Design of the COVID-19 Outpatient Prevention Evaluation (COPE - Coalition V) Randomized Clinical Trial: Hydroxychloroquine vs. Placebo in Non-Hospitalized Patients. / Justificativa e Desenho do Ensaio Clínico Randomizado COVID-19 Outpatient Prevention Evaluation (COPE - Coalition V): Hidroxicloroquina vs. Placebo em Pacientes Não Hospitalizados.

BACKGROUND: Despite the need for targeting specific therapeutic options for coronavirus disease 2019 (COVID-19), there has been no evidence of effectiveness of any specific treatment for the outpatient clinical setting. There are few randomized studies evaluating hydroxychloroquine (HCQ) in non-hospitalized patients. These studies indicate no benefit from the use of HCQ, but they assessed different primary outcomes and presented important biases for outcome evaluation. OBJECTIVE: To evaluate if HCQ may prevent hospitalization due to COVID-19 compared to a matching placebo. METHODS: The COVID-19 Outpatient Prevention Evaluation (COPE) study is a pragmatic, randomized, double-blind, placebo-controlled clinical trial evaluating the use of HCQ (800 mg on day 1 and 400 mg from day 2 to day 7) or matching placebo for the prevention of hospitalization due to COVID-19 in early non-hospitalized confirmed or suspected cases. Inclusion criteria are adults (≥ 18 years) seeking medical care with mild symptoms of COVID-19, with randomization ≤ 7 days after symptom onset, without indication of hospitalization at study screening, and with at least one risk factor for complication (> 65 years; hypertension; diabetes mellitus; asthma; chronic obstructive pulmonary disease or other chronic lung diseases; smoking; immunosuppression; or obesity). All hypothesis tests will be two-sided. A p-value < 0.05 will be considered statistically significant in all analyses. Clinicaltrials.gov: NCT04466540. RESULTS: Clinical outcomes will be centrally adjudicated by an independent clinical event committee blinded to the assigned treatment groups. The primary efficacy endpoint will be assessed following the intention-to-treat principle. CONCLUSION: This study has the potential to reliably answer the scientific question of HCQ use in outpatients with COVID-19. To our knowledge, this is the largest trial evaluating HCQ in non-hospitalized individuals with COVID-19.

FUNDAMENTO: Apesar da necessidade de opções terapêuticas específicas para a doença do coronavírus 2019 (covid-19), ainda não há evidências da eficácia de tratamentos específicos no contexto ambulatorial. Há poucos estudos randomizados que avaliam a hidroxicloroquina (HCQ) em pacientes não hospitalizados. Esses estudos não indicaram benefício com o uso da HCQ; no entanto, avaliaram desfechos primários diferentes e apresentaram vieses importantes na avaliação dos desfechos. OBJETIVO: Investigar se a HCQ possui o potencial de prevenir hospitalizações por covid-19 quando comparada ao placebo correspondente. MÉTODOS: O estudo COVID-19 Outpatient Prevention Evaluation (COPE) é um ensaio clínico randomizado, pragmático, duplo-cego, multicêntrico e controlado por placebo que avalia o uso da HCQ (800 mg no dia 1 e 400 mg do dia 2 ao dia 7) ou placebo correspondente na prevenção de hospitalizações por covid-19 em casos precoces confirmados ou suspeitos de pacientes não hospitalizados. Os critérios de inclusão são adultos (≥ 18 anos) que procuraram atendimento médico com sintomas leves de covid-19, com randomização ≤ 7 dias após o início dos sintomas, sem indicação de hospitalização na triagem do estudo e com pelo menos um fator de risco para complicações (> 65 anos, hipertensão, diabetes melito, asma, doença pulmonar obstrutiva crônica ou outras doenças pulmonares crônicas, tabagismo, imunossupressão ou obesidade). Todos os testes de hipótese serão bilaterais. Um valor de p < 0,05 será considerado estatisticamente significativo em todas as análises. Clinicaltrials.gov: NCT04466540. RESULTADOS: Os desfechos clínicos serão avaliados centralmente por um comitê de eventos clínicos independente cegado para a alocação dos grupos de tratamento. O desfecho primário de eficácia será avaliado de acordo com o princípio da intenção de tratar. CONCLUSÃO: Este estudo apresenta o potencial de responder de forma confiável a questão científica do uso da HCQ em pacientes ambulatoriais com covid-19. Do nosso conhecimento, este é o maior estudo avaliando o uso de HCQ em indivíduos com covid-19 não hospitalizados.

Justificativa e Desenho do Ensaio Clínico Randomizado COVID-19 Outpatient Prevention Evaluation (COPE - Coalition V): Hidroxicloroquina vs. Placebo em Pacientes Não Hospitalizados / Rationale and Design of the COVID-19 Outpatient Prevention Evaluation (COPE - Coalition V) Randomized Clinical Trial: Hydroxychloroquine vs. Placebo in Non-Hospitalized Patients

Resumo Fundamento Apesar da necessidade de opções terapêuticas específicas para a doença do coronavírus 2019 (covid-19), ainda não há evidências da eficácia de tratamentos específicos no contexto ambulatorial. Há poucos estudos randomizados que avaliam a hidroxicloroquina (HCQ) em pacientes não hospitalizados. Esses estudos não indicaram benefício com o uso da HCQ; no entanto, avaliaram desfechos primários diferentes e apresentaram vieses importantes na avaliação dos desfechos. Objetivo Investigar se a HCQ possui o potencial de prevenir hospitalizações por covid-19 quando comparada ao placebo correspondente. Métodos O estudo COVID-19 Outpatient Prevention Evaluation (COPE) é um ensaio clínico randomizado, pragmático, duplo-cego, multicêntrico e controlado por placebo que avalia o uso da HCQ (800 mg no dia 1 e 400 mg do dia 2 ao dia 7) ou placebo correspondente na prevenção de hospitalizações por covid-19 em casos precoces confirmados ou suspeitos de pacientes não hospitalizados. Os critérios de inclusão são adultos (≥ 18 anos) que procuraram atendimento médico com sintomas leves de covid-19, com randomização ≤ 7 dias após o início dos sintomas, sem indicação de hospitalização na triagem do estudo e com pelo menos um fator de risco para complicações (> 65 anos, hipertensão, diabetes melito, asma, doença pulmonar obstrutiva crônica ou outras doenças pulmonares crônicas, tabagismo, imunossupressão ou obesidade). Todos os testes de hipótese serão bilaterais. Um valor de p < 0,05 será considerado estatisticamente significativo em todas as análises. Clinicaltrials.gov: NCT04466540. Resultados Os desfechos clínicos serão avaliados centralmente por um comitê de eventos clínicos independente cegado para a alocação dos grupos de tratamento. O desfecho primário de eficácia será avaliado de acordo com o princípio da intenção de tratar. Conclusão Este estudo apresenta o potencial de responder de forma confiável a questão científica do uso da HCQ em pacientes ambulatoriais com covid-19. Do nosso conhecimento, este é o maior estudo avaliando o uso de HCQ em indivíduos com covid-19 não hospitalizados.

Abstract Background Despite the need for targeting specific therapeutic options for coronavirus disease 2019 (COVID-19), there has been no evidence of effectiveness of any specific treatment for the outpatient clinical setting. There are few randomized studies evaluating hydroxychloroquine (HCQ) in non-hospitalized patients. These studies indicate no benefit from the use of HCQ, but they assessed different primary outcomes and presented important biases for outcome evaluation. Objective To evaluate if HCQ may prevent hospitalization due to COVID-19 compared to a matching placebo. Methods The COVID-19 Outpatient Prevention Evaluation (COPE) study is a pragmatic, randomized, double-blind, placebo-controlled clinical trial evaluating the use of HCQ (800 mg on day 1 and 400 mg from day 2 to day 7) or matching placebo for the prevention of hospitalization due to COVID-19 in early non-hospitalized confirmed or suspected cases. Inclusion criteria are adults (≥ 18 years) seeking medical care with mild symptoms of COVID-19, with randomization ≤ 7 days after symptom onset, without indication of hospitalization at study screening, and with at least one risk factor for complication (> 65 years; hypertension; diabetes mellitus; asthma; chronic obstructive pulmonary disease or other chronic lung diseases; smoking; immunosuppression; or obesity). All hypothesis tests will be two-sided. A p-value < 0.05 will be considered statistically significant in all analyses. Clinicaltrials.gov: NCT04466540. Results Clinical outcomes will be centrally adjudicated by an independent clinical event committee blinded to the assigned treatment groups. The primary efficacy endpoint will be assessed following the intention-to-treat principle. Conclusion This study has the potential to reliably answer the scientific question of HCQ use in outpatients with COVID-19. To our knowledge, this is the largest trial evaluating HCQ in non-hospitalized individuals with COVID-19.

Equivalence and switching between biosimilars and reference molecules in rheumatoid arthritis: protocol for a systematic review and meta-analysis.

BACKGROUND: Biologic drugs such as adalimumab, etanercept, and infliximab represent major first-line and second-line treatments for rheumatoid arthritis (RA) patients. However, their high cost poses a massive burden on healthcare systems worldwide. The expiration of patents for these biologics has driven the production of biosimilar drugs, which are potentially less costly and remarkably similar, albeit not identical to the reference molecules. This paper aims to outline the protocol of a systematic review that will investigate the efficacy and safety profile of biosimilars compared to biologics (objective 1) and the impact of switching between biosimilar drugs and reference biologics on the management of RA patients (objective 2). METHODS: We will investigate the effects of any biosimilars of adalimumab, etanercept, and infliximab on RA patients. We will include randomized controlled trials (RCTs) or quasi-RCTs to assess efficacy and safety outcomes and RCTs with two- or multiple-part designs to evaluate the consequences of switching from reference biologics to biosimilar drugs (and vice-versa). Electronic searches will be performed through MEDLINE (via PubMed), EMBASE, LILACS, and CENTRAL (from inception to April 2021). Two independent reviewers will screen studies, extract data, and evaluate the risk of bias. The latter will be carried out considering specific domains from equivalence trials and switching studies. Random-effects models will be fitted to obtain summary estimates using either relative risk or standardized mean difference as a metric. The primary outcome will be the rate of treatment success according to the American College of Rheumatology 20 (ACR20), and the co-primary outcome will be the Health Assessment Questionnaire-Disability Index (HAQ-DI). Conclusions will be based on equivalence hypothesis testing using predefined margins of equivalence elicited from a group of experienced rheumatologists and prior studies. The overall certainty of the evidence will be assessed based on the GRADE system. DISCUSSION: The present investigation proposes a comprehensive, clinician-oriented approach to assess the equivalence and the impact of switching between biosimilars and biologics on the management of patients with RA. Our results will elucidate the efficacy, safety, immunogenicity of biosimilars, and the clinical consequences of substituting biologics with biosimilars in the management of RA. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019137152 and CRD42019137155.

Opportunities to improve reporting of rapid response in health technology assessment.

INTRODUCTION: Mini health technology assessment (HTA) reports have been used to support policy makers and health systems by providing a timely summary of scientific evidence. The objective of this meta-epidemiologic study was to evaluate the quality of reporting of mini-HTA reports published in Brazil. METHODS: An electronic search for all mini-HTA reports published between 2014 and March 2019 was conducted in the SISREBRATS and CONITEC databases. The study selection and data extraction were performed by two independent assessors. The following data were extracted: bibliographic data; research question; characteristics of the population, health technologies and outcomes assessed; eligibility criteria; information about searches and study selection; risk of bias assessment; quality of evidence assessment; synthesis of results; and recommendation about the technology evaluated. A descriptive analysis was used to summarize the information retrieved from all the included mini-HTA reports. RESULTS: We included 103 mini-HTA reports, the great majority of which (92.3 percent) focused on the coverage of the technologies in the healthcare system, with more than 60 percent being about drugs. Only five mini-HTA reports (4.8 percent) gave reasons for the choice of outcomes, and fifteen (14.5 percent) discriminated between primary and secondary outcomes. All mini-HTAs reported the databases searched and 99 percent of them reported using Medline. Sixty percent of the mini-HTA reported assessing the risk of bias, and 52 percent reported assessing the quality of evidence. CONCLUSION: The quality of reporting of the mini-HTA reports performed in Brazil is insufficient and needs to be improved to guarantee transparency and replicability.

FIRST LINE OF SUBCUTANEOUS ANTI-TNF THERAPY FOR RHEUMATOID ARTHRITIS: A PROSPECTIVE COHORT STUDY.

Objectives: This study aims to evaluate and compare the use of subcutaneous anti-TNF for RA in a Brazilian real-life setting. Methods: A prospective cohort of biological disease-modifying antirheumatic drug (bDMARD)-naïve patients treated with adalimumab, etanercept, golimumab, and certolizumab was developed. Medication persistence, disease activity by the Clinical Disease Activity Index (CDAI), functionality by the Health Assessment Questionnaire (HAQ), quality of life by the European Quality of Life 5 Dimensions (EQ-5D), and safety were evaluated at 6 and 12 months. Results: In a total of 327 individuals, 211 (64.5%) were persistent at 12 months. Patients improved after the use of anti-TNF, with a reduction in the mean of CDAI and HAQ, in addition to an increase in the mean of EQ-5D (p < 0.05). The number of patients who achieved the clinical response was 114 (34.86%) by CDAI, 212 (64.83%) by HAQ, and 215 (65.75%) by EQ-5D at 12 months. There were no statistically significant differences among the drugs (p > 0.05). The anti-TNF was well tolerated. Conclusion: Anti-TNF reduced disease activity, in addition to improving patients' functionality and quality of life. Additional pharmacotherapeutic monitoring can be essential to achieve better results.

Guidelines for the pharmacological treatment of COVID-19. The task-force/consensus guideline of the Brazilian Association of Intensive Care Medicine, the Brazilian Society of Infectious Diseases and the Brazilian Society of Pulmonology and Tisiology. / Diretrizes para o tratamento farmacológico da COVID-19. Consenso da Associação de Medicina Intensiva Brasileira, da Sociedade Brasileira de Infectologia e da Sociedade Brasileira de Pneumologia e Tisiologia.

INTRODUCTION: Different therapies are currently used, considered, or proposed for the treatment of COVID-19; for many of those therapies, no appropriate assessment of effectiveness and safety was performed. This document aims to provide scientifically available evidence-based information in a transparent interpretation, to subsidize decisions related to the pharmacological therapy of COVID-19 in Brazil. METHODS: A group of 27 experts and methodologists integrated a task-force formed by professionals from the Brazilian Association of Intensive Care Medicine (Associação de Medicina Intensiva Brasileira - AMIB), the Brazilian Society of Infectious Diseases (Sociedad Brasileira de Infectologia - SBI) and the Brazilian Society of Pulmonology and Tisiology (Sociedade Brasileira de Pneumologia e Tisiologia - SBPT). Rapid systematic reviews, updated on April 28, 2020, were conducted. The assessment of the quality of evidence and the development of recommendations followed the GRADE system. The recommendations were written on May 5, 8, and 13, 2020. RESULTS: Eleven recommendations were issued based on low or very-low level evidence. We do not recommend the routine use of hydroxychloroquine, chloroquine, azithromycin, lopinavir/ritonavir, corticosteroids, or tocilizumab for the treatment of COVID-19. Prophylactic heparin should be used in hospitalized patients, however, no anticoagulation should be provided for patients without a specific clinical indication. Antibiotics and oseltamivir should only be considered for patients with suspected bacterial or influenza coinfection, respectively. CONCLUSION: So far no pharmacological intervention was proven effective and safe to warrant its use in the routine treatment of COVID-19 patients; therefore such patients should ideally be treated in the context of clinical trials. The recommendations herein provided will be revised continuously aiming to capture newly generated evidence.

Impact of biologic DMARDs on quality of life: 12-month results of a rheumatic diseases cohort using the Brazilian EQ-5D tariff.

OBJECTIVES: To evaluate the association between biological Disease-Modifying Anti-Rheumatic Drugs (bDMARDs) use and quality of life (QoL) in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). PATIENTS AND METHODS: We evaluated adult patients prescribed biological DMARDs whose quality of life was evaluated at six and 12 months. The EuroQol 5 dimensions (EQ-5D) was used with the Brazilian tariff. RESULTS: Patients receiving bDMARDs had significant improvements in quality of life after 6 and 12 months (p < 0.001), regardless of the rheumatic condition and the therapeutic regimen (bDMARDs vs bDMARDs plus synthetic DMARDs) (ANCOVA; p > 0.05). At the end of one year, 62.6% of the participants presented significant clinical improvement in QoL. According to a sensitivity analysis, QoL results in the complete case analysis and in the multiple imputation model yielded similar conclusions. Patients with two or more comorbidities and worse QoL and disability status on baseline presented worse QoL at 12 months when compared to those with better disability status on baseline. Baseline clinical disease measured by activity indexes (BASDAI and CDAI) did not influence QoL after 12 months of bDMARD treatment. Pain and malaise were the EQ-5D domain that most influenced quality of life. CONCLUSION: Patients with rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis displayed significantly better QoL levels following treatment with DMARDs.

Guidelines for the pharmacological treatment of COVID-19. The task-force/consensus guideline of the Brazilian Association of Intensive Care Medicine, the Brazilian Society of Infectious Diseases and the Brazilian Society of Pulmonology and Tisiology

Different therapies are currently used, considered, or proposed for the treatment of COVID-19; for many of those therapies, no appropriate assessment of effectiveness and safety was performed. This document aims to provide scientifically available evidence-based information in a transparent interpretation, to subsidize decisions related to the pharmacological therapy of COVID-19 in Brazil. A group of 27 experts and methodologists integrated a task-force formed by professionals from the Brazilian Association of Intensive Care Medicine (Associação de Medicina Intensiva Brasileira - AMIB), the Brazilian Society of Infectious Diseases (Sociedad Brasileira de Infectologia - SBI) and the Brazilian Society of Pulmonology and Tisiology (Sociedade Brasileira de Pneumologia e Tisiologia - SBPT). Rapid systematic reviews, updated on April 28, 2020, were conducted. The assessment of the quality of evidence and the development of recommendations followed the GRADE system. The recommendations were written on May 5, 8, and 13, 2020. Eleven recommendations were issued based on low or very-low level evidence. We do not recommend the routine use of hydroxychloroquine, chloroquine, azithromycin, lopinavir/ritonavir, corticosteroids, or tocilizumab for the treatment of COVID-19. Prophylactic heparin should be used in hospitalized patients, however, no anticoagulation should be provided for patients without a specific clinical indication. Antibiotics and oseltamivir should only be considered for patients with suspected bacterial or influenza coinfection, respectively. So far no pharmacological intervention was proven effective and safe to warrant its use in the routine treatment of COVID-19 patients; therefore such patients should ideally be treated in the context of clinical trials. The recommendations herein provided will be revised continuously aiming to capture newly generated evidence.

Há diversas terapias sendo utilizadas, consideradas ou propostas para o tratamento da COVID-19, muitas carecendo de apropriada avaliação de efetividade e segurança. O propósito deste documento é fornecer recomendações baseadas nas evidências científicas disponíveis e em sua interpretação transparente, para subsidiar decisões sobre o tratamento farmacológico da COVID-19 no Brasil. Um grupo de 27 especialistas e metodologistas integraram a força-tarefa formada pela Associação de Medicina Intensiva Brasileira (AMIB), pela Sociedade Brasileira de Infectologia (SBI) e pela Sociedade Brasileira de Pneumologia e Tisiologia (SBPT). Foram realizadas revisões sistemáticas rápidas, atualizadas até 28 de abril de 2020. A qualidade das evidências e a elaboração das recomendações seguiram o sistema GRADE. As recomendações foram elaboradas nos dias 5, 8 e 13 de maio de 2020. Foram geradas 11 recomendações, embasadas em evidência de nível baixo ou muito baixo. Não há indicação para uso de rotina de hidroxicloroquina, cloroquina, azitromicina, lopinavir/ritonavir, corticosteroides ou tocilizumabe no tratamento da COVID-19. Heparina deve ser utilizada em doses profiláticas no paciente hospitalizado, mas não deve ser realizada anticoagulação na ausência de indicação clínica específica. Antibacterianos e oseltamivir devem ser considerados somente nos pacientes em suspeita de coinfecção bacteriana ou por influenza, respectivamente. Até o momento, não há intervenções farmacológicas com efetividade e segurança comprovada que justifiquem seu uso de rotina no tratamento da COVID-19, devendo os pacientes serem tratados preferencialmente no contexto de pesquisa clínica. As recomendações serão revisadas continuamente, de forma a capturar a geração de novas evidências

Diretrizes para o tratamento farmacológico da COVID-19. Consenso da Associação de Medicina Intensiva Brasileira, da Sociedade Brasileira de Infectologia e da Sociedade Brasileira de Pneumologia e Tisiologia / Guidelines for the pharmacological treatment of COVID-19. The task-force/consensus guideline of the Brazilian Association of Intensive Care Medicine, the Brazilian Society of Infectious Diseases and the Brazilian Society of Pulmonology and Tisiology

RESUMO Introdução: Há diversas terapias sendo utilizadas, consideradas ou propostas para o tratamento da COVID-19, muitas carecendo de apropriada avaliação de efetividade e segurança. O propósito deste documento é fornecer recomendações baseadas nas evidências científicas disponíveis e em sua interpretação transparente, para subsidiar decisões sobre o tratamento farmacológico da COVID-19 no Brasil. Métodos: Um grupo de 27 especialistas e metodologistas integraram a força-tarefa formada pela Associação de Medicina Intensiva Brasileira (AMIB), pela Sociedade Brasileira de Infectologia (SBI) e pela Sociedade Brasileira de Pneumologia e Tisiologia (SBPT). Foram realizadas revisões sistemáticas rápidas, atualizadas até 28 de abril de 2020. A qualidade das evidências e a elaboração das recomendações seguiram o sistema GRADE. As recomendações foram elaboradas nos dias 5, 8 e 13 de maio de 2020. Resultados: Foram geradas 11 recomendações, embasadas em evidência de nível baixo ou muito baixo. Não há indicação para uso de rotina de hidroxicloroquina, cloroquina, azitromicina, lopinavir/ritonavir, corticosteroides ou tocilizumabe no tratamento da COVID-19. Heparina deve ser utilizada em doses profiláticas no paciente hospitalizado, mas não deve ser realizada anticoagulação na ausência de indicação clínica específica. Antibacterianos e oseltamivir devem ser considerados somente nos pacientes em suspeita de coinfecção bacteriana ou por influenza, respectivamente. Conclusão: Até o momento, não há intervenções farmacológicas com efetividade e segurança comprovada que justifiquem seu uso de rotina no tratamento da COVID-19, devendo os pacientes serem tratados preferencialmente no contexto de pesquisa clínica. As recomendações serão revisadas continuamente, de forma a capturar a geração de novas evidências.

ABSTRACT Introduction: Different therapies are currently used, considered, or proposed for the treatment of COVID-19; for many of those therapies, no appropriate assessment of effectiveness and safety was performed. This document aims to provide scientifically available evidence-based information in a transparent interpretation, to subsidize decisions related to the pharmacological therapy of COVID-19 in Brazil. Methods: A group of 27 experts and methodologists integrated a task-force formed by professionals from the Brazilian Association of Intensive Care Medicine (Associação de Medicina Intensiva Brasileira - AMIB), the Brazilian Society of Infectious Diseases (Sociedad Brasileira de Infectologia - SBI) and the Brazilian Society of Pulmonology and Tisiology (Sociedade Brasileira de Pneumologia e Tisiologia - SBPT). Rapid systematic reviews, updated on April 28, 2020, were conducted. The assessment of the quality of evidence and the development of recommendations followed the GRADE system. The recommendations were written on May 5, 8, and 13, 2020. Results: Eleven recommendations were issued based on low or very-low level evidence. We do not recommend the routine use of hydroxychloroquine, chloroquine, azithromycin, lopinavir/ritonavir, corticosteroids, or tocilizumab for the treatment of COVID-19. Prophylactic heparin should be used in hospitalized patients, however, no anticoagulation should be provided for patients without a specific clinical indication. Antibiotics and oseltamivir should only be considered for patients with suspected bacterial or influenza coinfection, respectively. Conclusion: So far no pharmacological intervention was proven effective and safe to warrant its use in the routine treatment of COVID-19 patients; therefore such patients should ideally be treated in the context of clinical trials. The recommendations herein provided will be revised continuously aiming to capture newly generated evidence.