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3.
Can J Surg ; 63(5): E460-E467, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33107814

RESUMO

BACKGROUND: Enhanced Recovery After Surgery (ERAS) protocols use evidence-based perioperative practices that reduce morbidity and length of stay and improve patient satisfaction. ERAS is considered standard of care; however, utilization remains low and substantial practice variation exists. The aim of this study was to pragmatically characterize variation in colorectal surgery practice and identify predictors of ERAS utilization. METHODS: A survey of general surgeons identified using the Ontario College of Physicians and Surgeons database was conducted. Information on basic demographic characteristics, utilization of ERAS and predictors of ERAS implementation was collected. Nine ERAS behaviours were analyzed. Multivariable analysis was used to determine effects of demographic, hospital and surgeon covariates on ERAS utilization. RESULTS: Seven hundred and ninety-seven general surgeons were invited to participate in the survey, and 235 general surgeons representing 84 Ontario hospitals responded (30% response rate). Surgeons practising in academic settings and in large community hospitals represented 30% and 47% of the respondents, respectively. A total of 20% of the respondents used all 9 ERAS behaviours consistently. Rates of diet advancement on postoperative day 0, intravenous fluid restriction and having catheter and line procedures were significantly higher among respondents who adhered to ERAS protocols than among those who did not (74% v. 54%, p = 0.004; 92% v. 80%, p = 0.01; and 91% v. 41%, p < 0.001, respectively). Respondents from academic settings reported practising nearly 1 more ERAS behaviour than those from small community hospitals (odds ratio [OR] 0.86, 95% confidence interval [CI] 0.42 to 1.31, p < 0.001). Multivariable analysis demonstrated that colorectal fellowship training or exposure to ERAS during training did not significantly affect ERAS behaviour utilization (OR 0.32, 95% CI -0.31 to 0.94, p = 0.16; OR 0.28, 95% CI -0.26 to 0.82, p = 0.16, respectively). CONCLUSION: Substantial practice variation in colorectal surgery still exists. Individual ERAS principles are commonly followed; however, ERAS behaviours are not widely formalized into hospital protocols.


Assuntos
Colo/cirurgia , Procedimentos Cirúrgicos Eletivos/efeitos adversos , Recuperação Pós-Cirúrgica Melhorada/normas , Complicações Pós-Operatórias/prevenção & controle , Padrões de Prática Médica/estatística & dados numéricos , Reto/cirurgia , Centros Médicos Acadêmicos/normas , Centros Médicos Acadêmicos/estatística & dados numéricos , Adulto , Protocolos Clínicos/normas , Feminino , Fidelidade a Diretrizes/normas , Fidelidade a Diretrizes/estatística & dados numéricos , Hospitais Comunitários/normas , Hospitais Comunitários/estatística & dados numéricos , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Ontário , Satisfação do Paciente , Complicações Pós-Operatórias/etiologia , Padrões de Prática Médica/normas , Padrão de Cuidado , Cirurgiões/normas , Inquéritos e Questionários/estatística & dados numéricos
10.
Oncology (Williston Park) ; 34(9): 377-378, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32965670

RESUMO

The telehealth explosion was facilitated by the onset of the coronavirus disease 2019 (COVID-19) pandemic, but what happens when the crisis is over? Will there be lasting changes to the practice of medicine and delivery of care, or will providers and patients alike be eager to go back to the "old way" of doing things? Jeremy Gabrysch, MD, a physician and CEO of Remedy, an on-demand urgent care service that delivers doctors right to your front door, discusses what the future of telehealth may hold.


Assuntos
Assistência à Saúde , Mecanismo de Reembolso , Padrão de Cuidado , Telemedicina/tendências , Betacoronavirus , Infecções por Coronavirus/epidemiologia , Humanos , Pandemias , Pneumonia Viral/epidemiologia , Telemedicina/economia , Telemedicina/métodos , Telemedicina/normas
11.
BMJ Open ; 10(9): e041437, 2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32958495

RESUMO

INTRODUCTION: To find effective and safe treatments for COVID-19, the WHO recommended to systemically evaluate experimental therapeutics in collaborative randomised clinical trials. As COVID-19 was spreading in Europe, the French national institute for Health and Medical Research (Inserm) established a transdisciplinary team to develop a multi-arm randomised controlled trial named DisCoVeRy. The objective of the trial is to evaluate the clinical efficacy and safety of different investigational re-purposed therapeutics relative to Standard of Care (SoC) in patients hospitalised with COVID-19. METHODS AND ANALYSIS: DisCoVeRy is a phase III, open-label, adaptive, controlled, multicentre clinical trial in which hospitalised patients with COVID-19 in need of oxygen therapy are randomised between five arms: (1) a control group managed with SoC and four therapeutic arms with re-purposed antiviral agents: (2) remdesivir + SoC, (3) lopinavir/ritonavir + SoC, (4) lopinavir/ritonavir associated with interferon (IFN)-ß-1a + SoC and (5) hydroxychloroquine + SoC. The primary endpoint is the clinical status at Day 15 on the 7-point ordinal scale of the WHO Master Protocol (V.3.0, 3 March 2020). This trial involves patients hospitalised in conventional departments or intensive care units both from academic or non-academic hospitals throughout Europe. A sample size of 3100 patients (620 patients per arm) is targeted. This trial has begun on 22 March 2020. Since 5 April 2020, DisCoVeRy has been an add-on trial of the Solidarity consortium of trials conducted by the WHO in Europe and worldwide. On 8 June 2020, 754 patients have been included. ETHICS AND DISSEMINATION: Inserm is the sponsor of DisCoVeRy. Ethical approval has been obtained from the institutional review board on 13 March 2020 (20.03.06.51744) and from the French National Agency for Medicines and Health Products (ANSM) on 9 March 2020. Results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04315948 Eudra-CT 2020-000936-23.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/uso terapêutico , Interferon beta-1a/uso terapêutico , Lopinavir/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Ritonavir/uso terapêutico , Monofosfato de Adenosina/uso terapêutico , Adulto , Alanina/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/terapia , Combinação de Medicamentos , Quimioterapia Combinada , Escore de Alerta Precoce , Oxigenação por Membrana Extracorpórea , Mortalidade Hospitalar , Hospitalização , Humanos , Tempo de Internação , Oxigenoterapia , Pandemias , Pneumonia Viral/terapia , Respiração Artificial , Padrão de Cuidado , Resultado do Tratamento
13.
Lancet ; 396(10256): 959-967, 2020 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-32896292

RESUMO

BACKGROUND: The efficacy and safety of azithromycin in the treatment of COVID-19 remain uncertain. We assessed whether adding azithromycin to standard of care, which included hydroxychloroquine, would improve clinical outcomes of patients admitted to the hospital with severe COVID-19. METHODS: We did an open-label, randomised clinical trial at 57 centres in Brazil. We enrolled patients admitted to hospital with suspected or confirmed COVID-19 and at least one additional severity criteria as follows: use of oxygen supplementation of more than 4 L/min flow; use of high-flow nasal cannula; use of non-invasive mechanical ventilation; or use of invasive mechanical ventilation. Patients were randomly assigned (1:1) to azithromycin (500 mg via oral, nasogastric, or intravenous administration once daily for 10 days) plus standard of care or to standard of care without macrolides. All patients received hydroxychloroquine (400 mg twice daily for 10 days) because that was part of standard of care treatment in Brazil for patients with severe COVID-19. The primary outcome, assessed by an independent adjudication committee masked to treatment allocation, was clinical status at day 15 after randomisation, assessed by a six-point ordinal scale, with levels ranging from 1 to 6 and higher scores indicating a worse condition (with odds ratio [OR] greater than 1·00 favouring the control group). The primary outcome was assessed in all patients in the intention-to-treat (ITT) population who had severe acute respiratory syndrome coronavirus 2 infection confirmed by molecular or serological testing before randomisation (ie, modified ITT [mITT] population). Safety was assessed in all patients according to which treatment they received, regardless of original group assignment. This trial was registered at ClinicalTrials.gov, NCT04321278. FINDINGS: 447 patients were enrolled from March 28 to May 19, 2020. COVID-19 was confirmed in 397 patients who constituted the mITT population, of whom 214 were assigned to the azithromycin group and 183 to the control group. In the mITT population, the primary endpoint was not significantly different between the azithromycin and control groups (OR 1·36 [95% CI 0·94-1·97], p=0·11). Rates of adverse events, including clinically relevant ventricular arrhythmias, resuscitated cardiac arrest, acute kidney failure, and corrected QT interval prolongation, were not significantly different between groups. INTERPRETATION: In patients with severe COVID-19, adding azithromycin to standard of care treatment (which included hydroxychloroquine) did not improve clinical outcomes. Our findings do not support the routine use of azithromycin in combination with hydroxychloroquine in patients with severe COVID-19. FUNDING: COALITION COVID-19 Brazil and EMS.


Assuntos
Antivirais/uso terapêutico , Azitromicina/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Idoso , Antivirais/efeitos adversos , Azitromicina/efeitos adversos , Betacoronavirus , Brasil/epidemiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/mortalidade , Quimioterapia Combinada , Feminino , Humanos , Hidroxicloroquina/efeitos adversos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/mortalidade , Terapia Respiratória , Padrão de Cuidado , Resultado do Tratamento
14.
Virol J ; 17(1): 141, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32972430

RESUMO

BACKGROUND: The COVID-19 causing coronavirus is an enveloped RNA virus that utilizes an enzyme RNA dependent RNA polymerase for its replication. Favipiravir (FVP) triphosphate, a purine nucleoside analog, inhibits that enzyme. We have conducted this systematic review and meta-analysis on efficacy and safety of the drug FVP as a treatment for COVID-19. METHODS: Databases like Pubmed, Pubmed Central, Scopus, Embase, Google Scholar, preprint sites, and clinicaltirals.gov were searched. The studies with the standard of care (SOC) and FVP as a treatment drug were considered as the treatment group and the SOC with other antivirals and supportive care as the control group. Quantitative synthesis was done using RevMan 5.4. Clinical improvement, negative conversion of reverse transcription-polymerase chain reaction (RT-PCR), adverse effects, and oxygen requirements were studied. RESULTS: We identified a total of 1798 studies after searching the electronic databases. Nine in the qualitative studies and four studies in the quantitative synthesis met the criteria. There was a significant clinical improvement in the FVP group on the 14th day compared to the control group (RR 1.29, 1.08-1.54). Clinical deterioration rates were less likely in the FVP group though statistically not significant (OR 0.59, 95% CI 0.30-1.14) at the endpoint of study (7-15 days). The meta-analysis showed no significant differences between the two groups on viral clearance (day 14: RR 1.06, 95% CI 0.84-1.33), non-invasive ventilation or oxygen requirement (OR 0.76, 95% CI 0.42-1.39), and adverse effects (OR 0.69, 0.13-3.57). There are 31 randomized controlled trials (RCTs) registered in different parts of the world focusing FVP for COVID-19 treatment. CONCLUSION: There is a significant clinical and radiological improvement following treatment with FVP in comparison to the standard of care with no significant differences on viral clearance, oxygen support requirement and side effect profiles.


Assuntos
Amidas/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Pirazinas/uso terapêutico , Amidas/efeitos adversos , Antivirais/efeitos adversos , Betacoronavirus/enzimologia , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Infecções por Coronavirus/virologia , RNA Polimerases Dirigidas por DNA/antagonistas & inibidores , Bases de Dados Factuais , Inibidores Enzimáticos/uso terapêutico , Humanos , Pandemias , Pneumonia Viral/virologia , Pirazinas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Padrão de Cuidado , Resultado do Tratamento
16.
Trials ; 21(1): 703, 2020 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-32771034

RESUMO

OBJECTIVES: To investigate the potential efficacy of Nigella sativa (NS) oil supplementation on the outcomes of patients with mild Coronavirus Disease 2019 (COVID-19). TRIAL DESIGN: Prospective, two-arm, parallel-group, randomised (1:1 allocation ratio), open-label, controlled, exploratory phase II clinical trial of oral NS oil in patients with mild COVID-19. PARTICIPANTS: Inclusion Criteria: - Patients with mild COVID19 (defined as upper respiratory tract infection symptoms in the absence of clinical or radiological signs of pneumonia). - Adult (18 - 65 years old). - Written informed consent by the patient (or legally authorized representative) prior to initiation of any study procedures. - All patients should understand and agree to comply with planned study procedures. - Polymerase chain reaction (PCR)-confirmed infection with Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) from throat swab. EXCLUSION CRITERIA: - Patients with pneumonia or severe illness requiring admission to intensive care unit. - Severe chronic kidney disease (i.e. estimated glomerular filtration rate [eGFR] < 30 mL / min ) or end stage renal disease requiring dialysis - Severe chronic liver disease (Alanine transaminase [AlT] or Aspartate transaminase [AST] > 5 times the upper limit of normal). - Pregnancy or breast feeding. - Anticipated transfer within 72 hours to another hospital that is not a study site. - Allergy to the study medication The trial is currently conducted on patients recruited from King Abdulaziz University Hospital, Jeddah, Saudi Arabia. INTERVENTION AND COMPARATOR: Intervention group: Nigella sativa oil (MARNYS® Cuminmar) 500 mg softgel capsules, one capsule orally twice daily for 10 days plus standard of care treatment (antipyretic, antitussive). Comparator group: standard of care treatment. MAIN OUTCOMES: Proportion of patients who clinically recovered (defined as 3 days of no symptoms) within 14 days after randomisation. RANDOMISATION: Patients will be randomly assigned to treatment or control groups in a 1:1 ratio using a computer-generated randomization scheme (Random permuted blocks of 10) developed using the web-based program: http://www.randomization.com . BLINDING (MASKING): No blinding. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Up to 200 eligible patients will be randomly assigned to either treatment or control groups. TRIAL STATUS: Protocol version 1, as of July 14, 2020. Recruitment was started on May 21, 2020. The intended completion date is December 31, 2020. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04401202 . Date of trial registration: May 26, 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol.


Assuntos
Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Suplementos Nutricionais , Nigella sativa , Pneumonia Viral/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Adolescente , Adulto , Idoso , Humanos , Pessoa de Meia-Idade , Pandemias , Estudos Prospectivos , Padrão de Cuidado , Adulto Jovem
17.
Trials ; 21(1): 690, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32736592

RESUMO

OBJECTIVES: To determine if a specific intervention reduces the composite of progression of patients with COVID-19-related disease to organ failure or death as measured by time to incidence of any one of the following: death, invasive mechanical ventilation, ECMO, cardiovascular organ support (inotropes or balloon pump), or renal failure (estimated Cockcroft Gault creatinine clearance <15ml/min). TRIAL DESIGN: Randomised, parallel arm, open-label, adaptive platform Phase 2/3 trial of potential disease modifying therapies in patients with late stage 1/stage 2 COVID-19-related disease, with a diagnosis based either on a positive assay or high suspicion of COVID-19 infection by clinical, laboratory and radiological assessment. PARTICIPANTS: Patients aged 18 and over, with a clinical picture strongly suggestive of COVID-19-related disease (with/without a positive COVID-19 test) AND a risk count (as defined below) >3 OR ≥3 if risk count includes "Radiographic severity score >3". A risk count is calculated by the following features on admission (1 point for each): radiographic severity score >3, male gender, non-white ethnicity, diabetes, hypertension, neutrophils >8.0 x109/L, age >40 years and CRP >40 mg/L. Patients should be considered an appropriate subject for intervention with immunomodulatory or other disease modifying agents in the opinion of the investigator and are able to swallow capsules or tablets. The complete inclusion and exclusion criteria as detailed in the Additional file 1 should be fulfilled. Drug specific inclusion and exclusion criteria will also be applied to the active arms. Patients will be enrolled prior to the need for invasive mechanical ventilation, cardiac or renal support. Participants will be recruited across multiple centres in the UK including initially at Cambridge University Hospitals NHS Foundation Trust and St George's University NHS Foundation Trust. Other centres will be approached internationally in view of the evolving pandemic. INTERVENTION AND COMPARATOR: There is increasing evidence of the role of immunomodulation in altering the course of COVID-19. Additionally, various groups have demonstrated the presence of pulmonary shunting in patients with COVID-19 as well as other cardiovascular complications. TACTIC-E will assess the efficacy of the novel immunomodulatory agent EDP1815 versus the approved cardio-pulmonary drugs, Dapagliflozin in combination with Ambrisentan versus the prevailing standard of care. EDP1815 will be given as 2 capsules twice daily (1.6 x 1011 cells) for up to 7 days with the option to extend up to 14 days at the discretion of the principal investigator or their delegate, if the patient is felt to be clinically responding to treatment, is tolerating treatment, and is judged to be likely to benefit from a longer treatment course. Ambrisentan 5mg and Dapagliflozin 10mg will be given in combination once daily orally for up to maximum of 14 days. Patients will be randomised in a 1:1:1 ratio across treatments. Each active arm will be compared with standard of care alone. Additional arms may be added as the trial progresses. No comparisons will be made between active arms in this platform trial. MAIN OUTCOMES: The primary outcome is the incidence (from baseline up to Day 14) to the occurrence of the any one of the following events: death, invasive mechanical ventilation, extra corporeal membrane oxygenation, cardiovascular organ support (inotropes or balloon pump), or renal failure (estimated Cockcroft Gault creatinine clearance <15ml/min). RANDOMISATION: Eligible patients will be randomised using a central web-based randomisation service (Sealed Envelope) in a 1:1:1 ratio, stratified by site to one of the treatment arms or standard of care. BLINDING (MASKING): This is an open-label trial. Data analysis will not be blinded. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): There is no fixed sample size for this study. There will be an early biomarker-based futility analysis performed at a point during the study. If this biomarker futility analysis is not conclusive, then a second futility analysis based on clinical endpoints will be performed after approximately 125 patients have been recruited per arm. Provisionally, further analyses of clinical endpoints will be performed after 229 patients per active arm and later 469 patients per arm have been recruited. Further additional analyses may be triggered by the independent data monitoring committee. TRIAL STATUS: TACTIC-E Protocol version number 1.0 date May 27th, 2020. Recruitment starts on the 3rd of July 2020. The end trial date will be 18 months after the last patient's last visit and cannot be accurately predicted at this time. TRIAL REGISTRATION: Registered on EU Clinical Trials Register EudraCT Number: 2020-002229-27 registered: 9 June 2020. The trial was also registered on ClinicalTrials.gov (NCT04393246) on 19 May 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Assuntos
Compostos Benzidrílicos/administração & dosagem , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Glucosídeos/administração & dosagem , Fatores Imunológicos/uso terapêutico , Fenilpropionatos/administração & dosagem , Pneumonia Viral/tratamento farmacológico , Piridazinas/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Unidades de Terapia Intensiva , Pandemias , Respiração Artificial , Padrão de Cuidado
18.
Trials ; 21(1): 691, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32736596

RESUMO

OBJECTIVES: Stage 1: To evaluate the safety and efficacy of candidate agents as add-on therapies to standard of care (SoC) in patients hospitalised with COVID-19 in a screening stage. Stage 2: To confirm the efficacy of candidate agents selected on the basis of evidence from Stage 1 in patients hospitalised with COVID-19 in an expansion stage. TRIAL DESIGN: ACCORD is a seamless, Phase 2, adaptive, randomised controlled platform study, designed to rapidly test candidate agents in the treatment of COVID-19. Designed as a master protocol with each candidate agent being included via its own sub-protocol, initially randomising equally between each candidate and a single contemporaneous SoC arm (which can adapt into 2:1). Candidate agents currently include bemcentinib, MEDI3506, acalabrutinib, zilucoplan and nebulised heparin. For each candidate a total of 60 patients will be recruited in Stage 1. If Stage 1 provides evidence of efficacy and acceptable safety the candidate will enter Stage 2 where a total of approximately 126 patients will be recruited into each study arm sub-protocol. Enrollees and outcomes will not be shared across the Stages; the endpoint, analysis and sample size for Stage 2 may be adjusted based on evidence from Stage 1. Additional arms may be added as new potential candidate agents are identified via candidate agent specific sub-protocols. PARTICIPANTS: The study will include hospitalised adult patients (≥18 years) with confirmed SARS-CoV-2 infection, the virus that causes COVID-19, that clinically meet Grades 3 (hospitalised - mild disease, no oxygen therapy), Grades 4 (hospitalised, oxygen by mask or nasal prongs) and 5 (hospitalised, non-invasive ventilation or high flow oxygen) of the WHO Working Group on the Clinical Characteristics of COVID-19 9-point category ordinal scale. Participants will be recruited from England, Northern Ireland, Wales and Scotland. INTERVENTION AND COMPARATOR: Comparator is current standard of care (SoC) for the treatment of COVID-19. Current candidate experimental arms include bemcentinib, MEDI3506, acalabrutinib, zilucoplan and nebulised heparin with others to be added over time. Bemcentinib could potentially reduce viral infection and blocks SARS-CoV-2 spike protein; MEDI3506 is a clinic-ready anti-IL-33 monoclonal antibody with the potential to treat respiratory failure caused by COVID; acalabrutinib is a BTK inhibitor which is anti-viral and anti-inflammatory; zilucoplan is a complement C5 inhibitor which may block the severe inflammatory response in COVID-19 and; nebulised heparin has been shown to bind with the spike protein. ACCORD is linked with the UK national COVID therapeutics task force to help prioritise candidate agents. MAIN OUTCOMES: Time to sustained clinical improvement of at least 2 points (from randomisation) on the WHO 9-point category ordinal scale, live discharge from the hospital, or considered fit for discharge (a score of 0, 1, or 2 on the ordinal scale), whichever comes first, by Day 29 (this will also define the "responder" for the response rate analyses). RANDOMISATION: An electronic randomization will be performed by Cenduit using Interactive Response Technology (IRT). Randomisation will be stratified by baseline severity grade. Randomisation will proceed with an equal allocation to each arm and a contemporaneous SoC arm (e.g. 1:1 if control and 1 experimental arm; 1:1:1 if two experimental candidate arms etc) but will be reviewed as the trial progresses and may be changed to 2:1 in favour of the candidate agents. BLINDING (MASKING): The trial is open label and no blinding is currently planned in the study. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): This will be in the order of 60 patients per candidate agent for Stage 1, and 126 patients for Stage 2. However, sample size re-estimation may be considered after Stage 1. It is estimated that up to 1800 patients will participate in the overall study. TRIAL STATUS: Master protocol version ACCORD-2-001 - Master Protocol (Amendment 1) 22nd April 2020, the trial has full regulatory approval and recruitment is ongoing in the bemcentinib (first patient recruited 6/5/2020), MEDI3506 (first patient recruited 19/5/2020), acalabrutinib (first patient recruited 20/5/2020) and zilucoplan (first patient recruited 19/5/2020) candidates (and SoC). The recruitment dates of each arm will vary between candidate agents as they are added or dropped from the trial, but will have recruited and reported within a year. TRIAL REGISTRATION: EudraCT 2020-001736-95 , registered 28th April 2020. FULL PROTOCOL: The full protocol (Master Protocol with each of the candidate sub-protocols) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Antivirais/efeitos adversos , Benzamidas/uso terapêutico , Hospitalização , Humanos , Pandemias , Pirazinas/uso terapêutico , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Padrão de Cuidado
19.
Crit Care ; 24(1): 502, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32795330

RESUMO

BACKGROUND: Calcium release-activated calcium (CRAC) channel inhibitors stabilize the pulmonary endothelium and block proinflammatory cytokine release, potentially mitigating respiratory complications observed in patients with COVID-19. This study aimed to investigate the safety and efficacy of Auxora, a novel, intravenously administered CRAC channel inhibitor, in adults with severe or critical COVID-19 pneumonia. METHODS: A randomized, controlled, open-label study of Auxora was conducted in adults with severe or critical COVID-19 pneumonia. Patients were randomized 2:1 to receive three doses of once-daily Auxora versus standard of care (SOC) alone. The primary objective was to assess the safety and tolerability of Auxora. Following FDA guidance, study enrollment was halted early to allow for transition to a randomized, blinded, placebo-controlled study. RESULTS: In total, 17 patients with severe and three with critical COVID-19 pneumonia were randomized to Auxora and nine with severe and one with critical COVID-19 pneumonia to SOC. Similar proportions of patients receiving Auxora and SOC experienced ≥ 1 adverse event (75% versus 80%, respectively). Fewer patients receiving Auxora experienced serious adverse events versus SOC (30% versus 50%, respectively). Two patients (10%) receiving Auxora and two (20%) receiving SOC died during the 30 days after randomization. Among patients with severe COVID-19 pneumonia, the median time to recovery with Auxora was 5 days versus 12 days with SOC; the recovery rate ratio was 1.87 (95% CI, 0.72, 4.89). Invasive mechanical ventilation was needed in 18% of patients with severe COVID-19 pneumonia receiving Auxora versus 50% receiving SOC (absolute risk reduction = 32%; 95% CI, - 0.07, 0.71). Outcomes measured by an 8-point ordinal scale were significantly improved for patients receiving Auxora, especially for patients with a baseline PaO2/FiO2 = 101-200. CONCLUSIONS: Auxora demonstrated a favorable safety profile in patients with severe or critical COVID-19 pneumonia and improved outcomes in patients with severe COVID-19 pneumonia. These results, however, are limited by the open-label study design and small patient population resulting from the early cessation of enrollment in response to regulatory guidance. The impact of Auxora on respiratory complications in patients with severe COVID-19 pneumonia will be further assessed in a planned randomized, blinded, placebo-controlled study. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04345614 . Submitted on 7 April 2020.


Assuntos
Canais de Cálcio Ativados pela Liberação de Cálcio/antagonistas & inibidores , Infecções por Coronavirus/terapia , Cuidados Críticos/métodos , Pneumonia Viral/terapia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Índice de Gravidade de Doença , Padrão de Cuidado , Resultado do Tratamento
20.
BMJ ; 370: m2980, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32732190

RESUMO

OBJECTIVE: To compare the effects of treatments for coronavirus disease 2019 (covid-19). DESIGN: Living systematic review and network meta-analysis. DATA SOURCES: US Centers for Disease Control and Prevention COVID-19 Research Articles Downloadable Database, which includes 25 electronic databases and six additional Chinese databases to 20 July 2020. STUDY SELECTION: Randomised clinical trials in which people with suspected, probable, or confirmed covid-19 were randomised to drug treatment or to standard care or placebo. Pairs of reviewers independently screened potentially eligible articles. METHODS: After duplicate data abstraction, a bayesian random effects network meta-analysis was conducted. Risk of bias of the included studies was assessed using a modification of the Cochrane risk of bias 2.0 tool, and the certainty of the evidence using the grading of recommendations assessment, development and evaluation (GRADE) approach. For each outcome, interventions were classified in groups from the most to the least beneficial or harmful following GRADE guidance. RESULTS: 23 randomised controlled trials were included in the analysis performed on 26 June 2020. The certainty of the evidence for most comparisons was very low because of risk of bias (lack of blinding) and serious imprecision. Glucocorticoids were the only intervention with evidence for a reduction in death compared with standard care (risk difference 37 fewer per 1000 patients, 95% credible interval 63 fewer to 11 fewer, moderate certainty) and mechanical ventilation (31 fewer per 1000 patients, 47 fewer to 9 fewer, moderate certainty). These estimates are based on direct evidence; network estimates for glucocorticoids compared with standard care were less precise because of network heterogeneity. Three drugs might reduce symptom duration compared with standard care: hydroxychloroquine (mean difference -4.5 days, low certainty), remdesivir (-2.6 days, moderate certainty), and lopinavir-ritonavir (-1.2 days, low certainty). Hydroxychloroquine might increase the risk of adverse events compared with the other interventions, and remdesivir probably does not substantially increase the risk of adverse effects leading to drug discontinuation. No other interventions included enough patients to meaningfully interpret adverse effects leading to drug discontinuation. CONCLUSION: Glucocorticoids probably reduce mortality and mechanical ventilation in patients with covid-19 compared with standard care. The effectiveness of most interventions is uncertain because most of the randomised controlled trials so far have been small and have important study limitations. SYSTEMATIC REVIEW REGISTRATION: This review was not registered. The protocol is included as a supplement. READERS' NOTE: This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/terapia , Pneumonia Viral/terapia , Respiração Artificial/estatística & dados numéricos , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/uso terapêutico , Betacoronavirus/patogenicidade , Centers for Disease Control and Prevention, U.S./estatística & dados numéricos , China/epidemiologia , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Bases de Dados Factuais/estatística & dados numéricos , Combinação de Medicamentos , Medicina Baseada em Evidências/métodos , Medicina Baseada em Evidências/estatística & dados numéricos , Glucocorticoides/uso terapêutico , Humanos , Hidroxicloroquina/uso terapêutico , Lopinavir/uso terapêutico , Metanálise em Rede , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Ritonavir/uso terapêutico , Índice de Gravidade de Doença , Padrão de Cuidado , Resultado do Tratamento , Estados Unidos/epidemiologia
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