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2.
Trials ; 22(1): 42, 2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33430924

RESUMO

OBJECTIVES: As of December, 1st, 2020, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2, resulted in more than 1 472 917 deaths worldwide and death toll is still increasing exponentially. Many COVID-19 infected people are asymptomatic or experience moderate symptoms and recover without medical intervention. However, older people and those with comorbid hypertension, diabetes, obesity, or heart disease are at higher risk of mortality. Because current therapeutic options for COVID-19 patients are limited specifically for this elderly population at risk, Biophytis is developing BIO101 (20-hydroxyecdysone, a Mas receptor activator) as a new treatment option for managing patients with SARS-CoV-2 infection at the severe stage. The angiotensin converting enzyme 2 (ACE2) serves as a receptor for SARS-CoV-2. Interaction between ACE2 and SARS-CoV2 spike protein seems to alter the function of ACE2, a key player in the renin-angiotensin system (RAS). The clinical picture of COVID-19 includes acute respiratory distress syndrome (ARDS), cardiomyopathy, multiorgan dysfunction and shock, all of which might result from an imbalance of the RAS. We propose that RAS balance could be restored in COVID-19 patients through MasR activation downstream of ACE2 activity, with 20-hydroxyecdysone (BIO101) a non-peptidic Mas receptor (MasR) activator. Indeed, MasR activation by 20-hydroxyecdysone harbours anti-inflammatory, anti-thrombotic, and anti-fibrotic properties. BIO101, a 97% pharmaceutical grade 20-hydroxyecdysone could then offer a new therapeutic option by improving the respiratory function and ultimately promoting survival in COVID-19 patients that develop severe forms of this devastating disease. Therefore, the objective of this COVA study is to evaluate the safety and efficacy of BIO101, whose active principle is 20-hydroxyecdysone, in COVID-19 patients with severe pneumonia. TRIAL DESIGN: Randomized, double-blind, placebo-controlled, multi-centre, group sequential and adaptive which will be conducted in 2 parts. Part 1: Ascertain the safety and tolerability of BIO101 and obtain preliminary indication of the activity of BIO101, in preventing respiratory deterioration in the target population Part 2: Re-assessment of the sample size needed for the confirmatory part 2 and confirmation of the effect of BIO101 observed in part 1 in the target population. The study is designed as group sequential to allow an efficient run-through, from obtaining an early indication of activity to a final confirmation. And adaptive - to allow accumulation of early data and adapt sample size in part 2 in order to inform the final design of the confirmatory part of the trial. PARTICIPANTS: Inclusion criteria 1. Age: 45 and above 2. A confirmed diagnosis of COVID-19 infection, within the last 14 days, prior to randomization, as determined by PCR or other approved commercial or public health assay, in a specimen as specified by the test used. 3. Hospitalized, in observation or planned to be hospitalized due to COVID-19 infection symptoms with anticipated hospitalization duration ≥3 days 4. With evidence of pneumonia based on all of the following: a. Clinical findings on a physical examination b. Respiratory symptoms developed within the past 7 days 5. With evidence of respiratory decompensation that started not more than 4 days before start of study medication and present at screening, meeting one of the following criteria, as assessed by healthcare staff: a. Tachypnea: ≥25 breaths per minute b. Arterial oxygen saturation ≤92% c. A special note should be made if there is suspicion of COVID-19-related myocarditis or pericarditis, as the presence of these is a stratification criterion 6. Without a significant deterioration in liver function tests: a. ALT and AST ≤ 5x upper limit of normal (ULN) b. Gamma-glutamyl transferase (GGT) ≤ 5x ULN c. Total bilirubin ≤ 5×ULN 7. Willing to participate and able to sign an informed consent form (ICF). Or, when relevant, a legally authorized representative (LAR) might sign the ICF on behalf of the study participant 8. Female participants should be: at least 5 years post-menopausal (i.e., persistent amenorrhea 5 years in the absence of an alternative medical cause) or surgically sterile; OR a. Have a negative urine pregnancy test at screening b. Be willing to use a contraceptive method as outlined in inclusion criterion 9 from screening to 30 days after last dose. 9. Male participants who are sexually active with a female partner must agree to the use of an effective method of birth control throughout the study and until 3 months after the last administration of the investigational product. (Note: medically acceptable methods of contraception that may be used by the participant and/or partner include combined oral contraceptive, contraceptive vaginal ring, contraceptive injection, intrauterine device, etonogestrel implant, each supplemented with a condom, as well as sterilization and vasectomy). 10. Female participants who are lactating must agree not to breastfeed during the study and up to 14 days after the intervention. 11. Male participants must agree not to donate sperm for the purpose of reproduction throughout the study and until 3 months after the last administration of the investigational product. 12. For France only: Being affiliated with a European Social Security. Exclusion criteria 1. Not needing or not willing to remain in a healthcare facility during the study 2. Moribund condition (death likely in days) or not expected to survive for >7 days - due to other and non-COVID-19 related conditions 3. Participant on invasive mechanical ventilation via an endotracheal tube, or extracorporeal membrane oxygenation (ECMO), or high-flow Oxygen (delivery of oxygen at a flow of ≥16 L/min.). 4. Participant is not able to take medications by mouth (as capsules or as a powder, mixed in water). 5. Disallowed concomitant medication: Consumption of any herbal products containing 20-hydroxyecdysone and derived from Leuzea carthamoides; Cyanotis vaga or Cyanotis arachnoidea is not allowed (e.g. performance enhancing agents). 6. Any known hypersensitivity to any of the ingredients, or excipients of the study medication, BIO101. 7. Renal disease requiring dialysis, or known renal insufficiency (eGFR≤30 mL/min/1.73 m2, based on Cockcroft & Gault formula). 8. In France only: a. Non-affiliation to compulsory French social security scheme (beneficiary or right-holder). b. Being under tutelage or legal guardianship. Participants will be recruited from approximately 30 clinical centres in Belgium, France, the UK, USA and Brazil. Maximum patients' participation in the study will last 28 days. Follow-up of participants discharged from hospital will be performed through post-intervention phone calls at 14 (± 2) and 60 (± 4) days. INTERVENTION AND COMPARATOR: Two treatment arms will be tested in this study: interventional arm 350 mg b.i.d. of BIO101 (AP 20-hydroxyecdysone) and placebo comparator arm 350 mg b.i.d of placebo. Administration of daily dose is the same throughout the whole treatment period. Participants will receive the study medication while hospitalized for up to 28 days or until a clinical endpoint is reached (i.e., 'negative' or 'positive' event). Participants who are officially discharged from hospital care will no longer receive study medication. MAIN OUTCOMES: Primary study endpoint: The proportion of participants with 'negative' events up to 28 days. 'Negative' events are defined as respiratory deterioration and all-cause mortality. For the purpose of this study, respiratory deterioration will be defined as any of the following: Requiring mechanical ventilation (including cases that will not be intubated due to resource restrictions and triage). Requiring extracorporeal membrane oxygenation (ECMO). Requiring high-flow oxygen defined as delivery of oxygen at a flow of ≥16 L/min. Only if the primary endpoint is significant at the primary final analysis the following Key secondary endpoints will be tested in that order: Proportion of participants with events of respiratory failure at Day 28 Proportion of participants with 'positive' events at Day 28. Proportion of participants with events of all-cause mortality at Day 28 A 'positive' event is defined as the official discharge from hospital care by the department due to improvement in participant condition. Secondary and exploratory endpoints: In addition, a variety of functional measures and biomarkers (including the SpO2 / FiO2 ratio, viral load and markers related to inflammation, muscles, tissue and the RAS / MAS pathways) will also be collected. RANDOMIZATION: Randomization is performed using an IBM clinical development IWRS system during the baseline visit. Block-permuted randomization will be used to assign eligible participants in a 1:1 ratio. In part 1, randomization will be stratified by RAS pathway modulator use (yes/no) and co-morbidities (none vs. 1 and above). In Part 2, randomization will be stratified by centre, gender, RAS pathway modulator use (yes/no), co-morbidities (none vs. 1 and above), receiving Continuous Positive Airway Pressure/Bi-level Positive Airway Pressure (CPAP/BiPAP) at study entry (Yes/No) and suspicion of COVID-19 related myocarditis or pericarditis (present or not). BLINDING (MASKING): Participants, caregivers, and the study team assessing the outcomes are blinded to group assignment. All therapeutic units (TU), BIO101 b.i.d. or placebo b.i.d., cannot be distinguished in compliance with the double-blind process. An independent data-monitoring committee (DMC) will conduct 2 interim analyses. A first one based on the data from part 1 and a second from the data from parts 1 and 2. The first will inform about BIO101 safety, to allow the start of recruitment into part 2 followed by an analysis of the efficacydata, to obtain an indication of activity. The second interim analysis will inform about the sample size that will be required for part 2, in order to achieve adequate statistical power. Numbers to be randomised (sample size) Number of participants randomized: up to 465, in total Part 1: 50 (to obtain the proof of concept in COVID-19 patients). Part 2: 310, potentially increased by 50% (up to 465, based on interim analysis 2) (to confirm the effects of BIO101 observed in part 1). TRIAL STATUS: The current protocol Version is V 10.0, dated on 24.09.2020. The recruitment that started on September 1st 2020 is ongoing and is anticipated to finish for the whole study by March2021. TRIAL REGISTRATION: The trial was registered before trial start in trial registries: EudraCT , No. 2020-001498-63, registered May 18, 2020; and Clinicaltrials.gov, identifier NCT04472728 , registered July 15, 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
/tratamento farmacológico , Ecdisterona/uso terapêutico , Insuficiência Respiratória/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , /fisiopatologia , Progressão da Doença , Método Duplo-Cego , Oxigenação por Membrana Extracorpórea/estatística & dados numéricos , Hospitalização , Humanos , Hipóxia/fisiopatologia , Pessoa de Meia-Idade , Mortalidade , Oxigenoterapia/estatística & dados numéricos , Proteínas Proto-Oncogênicas/metabolismo , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores Acoplados a Proteínas-G/metabolismo , Sistema Renina-Angiotensina , Respiração Artificial/estatística & dados numéricos , Insuficiência Respiratória/fisiopatologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Taquipneia/fisiopatologia , Resultado do Tratamento
3.
Intern Med ; 60(4): 639-643, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33390490

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic has become an urgent global health issue. An older age and underlying conditions, such as diabetes, have been reported as risk factors, but whether or not autoimmune diseases increase the risk remains unknown. An 85-year-old man with Sjögren's syndrome developed a severe COVID-19 infection that required oxygen supplementation. After discussing the goals of care with him and his wife, off-label tocilizumab was given concomitantly, resulting in a rapid improvement in his symptoms and respiratory failure. This patient represents a supplementary case confirming the efficacy and safety of tocilizumab for COVID-19 in elderly patients with autoimmune diseases.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Uso Off-Label , Síndrome de Sjogren/complicações , Corticosteroides/uso terapêutico , Idoso de 80 Anos ou mais , Anti-Inflamatórios/uso terapêutico , Síndrome da Liberação de Citocina , Quimioterapia Combinada , Dispneia/etiologia , Humanos , Masculino , Pandemias , Insuficiência Respiratória/tratamento farmacológico
4.
Trials ; 22(1): 71, 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33472675

RESUMO

BACKGROUND: SARS-CoV-2, the virus that causes COVID-19, enters the cells through a mechanism dependent on its binding to angiotensin-converting enzyme 2 (ACE2), a protein highly expressed in the lungs. The putative viral-induced inhibition of ACE2 could result in the defective degradation of bradykinin, a potent inflammatory substance. We hypothesize that increased bradykinin in the lungs is an important mechanism driving the development of pneumonia and respiratory failure in COVID-19. METHODS: This is a phase II, single-center, three-armed parallel-group, open-label, active control superiority randomized clinical trial. One hundred eighty eligible patients will be randomly assigned in a 1:1:1 ratio to receive either the inhibitor of C1e/kallikrein 20 U/kg intravenously on day 1 and day 4 plus standard care; or icatibant 30 mg subcutaneously, three doses/day for 4 days plus standard care; or standard care alone, as recommended in the clinical trials published to date, which includes supplemental oxygen, non-invasive and invasive ventilation, antibiotic agents, anti-inflammatory agents, prophylactic antithrombotic therapy, vasopressor support, and renal replacement therapy. DISCUSSION: Accumulation of bradykinin in the lungs is a common side effect of ACE inhibitors leading to cough. In animal models, the inactivation of ACE2 leads to severe acute pneumonitis in response to lipopolysaccharide (LPS), and the inhibition of bradykinin almost completely restores the lung structure. We believe that inhibition of bradykinin in severe COVID-19 patients could reduce the lung inflammatory response, impacting positively on the severity of disease and mortality rates. TRIAL REGISTRATION: Brazilian Clinical Trials Registry Universal Trial Number (UTN) U1111-1250-1843. Registered on May/5/2020.


Assuntos
Bradicinina/análogos & derivados , Proteína Inibidora do Complemento C1/administração & dosagem , Insuficiência Respiratória/tratamento farmacológico , Adulto , Bradicinina/administração & dosagem , Bradicinina/efeitos adversos , Bradicinina/antagonistas & inibidores , Bradicinina/imunologia , Bradicinina/metabolismo , Antagonistas de Receptor B2 da Bradicinina/administração & dosagem , Antagonistas de Receptor B2 da Bradicinina/efeitos adversos , Brasil , /imunologia , Ensaios Clínicos Fase II como Assunto , Proteína Inibidora do Complemento C1/efeitos adversos , Esquema de Medicação , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Humanos , Injeções Intravenosas , Injeções Subcutâneas , Calicreínas/antagonistas & inibidores , Calicreínas/metabolismo , Ensaios Clínicos Controlados Aleatórios como Assunto , Insuficiência Respiratória/imunologia , Insuficiência Respiratória/virologia , /patogenicidade , Índice de Gravidade de Doença , Resultado do Tratamento
5.
Diabetes Obes Metab ; 23(4): 886-896, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33319454

RESUMO

AIMS: Coronavirus disease 2019 (COVID-19) is caused by a novel severe acute respiratory syndrome coronavirus 2. It can lead to multiorgan failure, including respiratory and cardiovascular decompensation, and kidney injury, with significant associated morbidity and mortality, particularly in patients with underlying metabolic, cardiovascular, respiratory or kidney disease. Dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, has shown significant cardio- and renoprotective benefits in patients with type 2 diabetes (with and without atherosclerotic cardiovascular disease), heart failure and chronic kidney disease, and may provide similar organ protection in high-risk patients with COVID-19. MATERIALS AND METHODS: DARE-19 (NCT04350593) is an investigator-initiated, collaborative, international, multicentre, randomized, double-blind, placebo-controlled study testing the dual hypotheses that dapagliflozin can reduce the incidence of cardiovascular, kidney and/or respiratory complications or all-cause mortality, or improve clinical recovery, in adult patients hospitalized with COVID-19 but not critically ill on admission. Eligible patients will have ≥1 cardiometabolic risk factor for COVID-19 complications. Patients will be randomized 1:1 to dapagliflozin 10 mg or placebo. Primary efficacy endpoints are time to development of new or worsened organ dysfunction during index hospitalization, or all-cause mortality, and the hierarchical composite endpoint of change in clinical status through day 30 of treatment. Safety of dapagliflozin in individuals with COVID-19 will be assessed. CONCLUSIONS: DARE-19 will evaluate whether dapagliflozin can prevent COVID-19-related complications and all-cause mortality, or improve clinical recovery, and assess the safety profile of dapagliflozin in this patient population. Currently, DARE-19 is the first large randomized controlled trial investigating use of sodium-glucose cotransporter 2 inhibitors in patients with COVID-19.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Glucosídeos/uso terapêutico , Nefropatias/prevenção & controle , Mortalidade , Insuficiência Respiratória/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Aterosclerose/epidemiologia , /epidemiologia , Doenças Cardiovasculares/etiologia , Causas de Morte , Comorbidade , Diabetes Mellitus Tipo 2/epidemiologia , Progressão da Doença , Método Duplo-Cego , Insuficiência Cardíaca/epidemiologia , Humanos , Hipertensão/epidemiologia , Nefropatias/etiologia , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Insuficiência Renal Crônica/epidemiologia , Insuficiência Respiratória/etiologia , Resultado do Tratamento
6.
BMC Infect Dis ; 20(1): 964, 2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33353546

RESUMO

BACKGROUND: Due to the lack of proven therapies, we evaluated the effects of early administration of tocilizumab for COVID-19. By inhibition of the IL-6 receptor, tocilizumab may help to mitigate the hyperinflammatory response associated with progressive respiratory failure from SARS-CoV-2. METHODS: A retrospective, observational study was conducted on hospitalized adults who received intravenous tocilizumab for COVID-19 between March 23, 2020 and April 10, 2020. RESULTS: Most patients were male (66.7%), Hispanic (63.3%) or Black (23.3%), with a median age of 54 years. Tocilizumab was administered at a median of 8 days (range 1-21) after initial symptoms and 2 days (range 0-12) after hospital admission. Within 30 days from receiving tocilizumab, 36 patients (60.0%) demonstrated clinical improvement, 9 (15.0%) died, 33 (55.0%) were discharged alive, and 18 (30.0%) remained hospitalized. Successful extubation occurred in 13 out of 29 patients (44.8%). Infectious complications occurred in 16 patients (26.7%) at a median of 10.5 days. After tocilizumab was administered, there was a slight increase in PaO2/FiO2 and an initial reduction in CRP, but this effect was not sustained beyond day 10. CONCLUSIONS: Majority of patients demonstrated clinical improvement and were successfully discharged alive from the hospital after receiving tocilizumab. We observed a rebound effect with CRP, which may suggest the need for higher or subsequent doses to adequately manage cytokine storm. Based on our findings, we believe that tocilizumab may have a role in the early treatment of COVID-19, however larger randomized controlled studies are needed to confirm this.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Receptores de Interleucina-6/antagonistas & inibidores , Insuficiência Respiratória/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/farmacologia , Estudos de Coortes , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência Respiratória/virologia , Estudos Retrospectivos , Resultado do Tratamento
7.
Pan Afr Med J ; 35(Suppl 2): 130, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33193945

RESUMO

The COVID-19 pandemic has strained health care systems beyond capacity resulting in many people not having access to life-sustaining measures even in well-resourced countries. Palliative and end-of-life care are therefore essential to alleviate suffering and ensure a continuum of care for patients unlikely to survive. This is challenging in sub-Saharan Africa where lack of trained teams on basic palliative care and reduced access to opioids limit implementation of palliative and end-of-life care. At the same time, health care providers have to cope with local cultural conceptions of death and absence of advance care directives.


Assuntos
Betacoronavirus , Infecções por Coronavirus/terapia , Cuidados Paliativos/organização & administração , Pandemias , Pneumonia Viral/terapia , Assistência Terminal/organização & administração , Diretivas Antecipadas , África ao Sul do Saara/epidemiologia , Analgésicos Opioides/provisão & distribução , Analgésicos Opioides/uso terapêutico , Atitude Frente a Morte , Barreiras de Comunicação , Continuidade da Assistência ao Paciente , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/psicologia , Cultura , Acesso aos Serviços de Saúde , Humanos , Cuidados Paliativos/psicologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/psicologia , Relações Profissional-Paciente , Insuficiência Respiratória/tratamento farmacológico , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/mortalidade , Estigma Social , Assistência Terminal/psicologia
8.
Trials ; 21(1): 934, 2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33213529

RESUMO

OBJECTIVES: Zilucoplan (complement C5 inhibitor) has profound effects on inhibiting acute lung injury post COVID-19, and can promote lung repair mechanisms that lead to improvement in lung oxygenation parameters. The purpose of this study is to investigate the efficacy and safety of Zilucoplan in improving oxygenation and short- and long-term outcome of COVID-19 patients with acute hypoxic respiratory failure. TRIAL DESIGN: This is a phase 2 academic, prospective, 2:1 randomized, open-label, multi-center interventional study. PARTICIPANTS: Adult patients (≥18y old) will be recruited at specialized COVID-19 units and ICUs at 9 Belgian hospitals. The main eligibility criteria are as follows: 1) Inclusion criteria: a. Recent (≥6 days and ≤16 days) SARS-CoV-2 infection. b. Chest CT scan showing bilateral infiltrates within the last 2 days prior to randomisation. c. Acute hypoxia (defined as PaO2/FiO2 below 350 mmHg or SpO2 below 93% on minimal 2 L/min supplemental oxygen). d. Signs of cytokine release syndrome characterized by either high serum ferritin, or high D-dimers, or high LDH or deep lymphopenia or a combination of those. 2) Exclusion criteria: e. Mechanical ventilation for more than 24 hours prior to randomisation. f. Active bacterial or fungal infection. g. History of meningococcal disease (due to the known high predisposition to invasive, often recurrent meningococcal infections of individuals deficient in components of the alternative and terminal complement pathways). INTERVENTION AND COMPARATOR: Patients in the experimental arm will receive daily 32,4 mg Zilucoplan subcutaneously and a daily IV infusion of 2g of the antibiotic ceftriaxone for 14 days (or until hospital discharge, whichever comes first) in addition to standard of care. These patients will receive additional prophylactic antibiotics until 14 days after the last Zilucoplan dose: hospitalized patients will receive a daily IV infusion of 2g of ceftriaxone, discharged patients will switch to daily 500 mg of oral ciprofloxacin. The control group will receive standard of care and a daily IV infusion of 2g of ceftriaxone for 1 week (or until hospital discharge, whichever comes first), to control for the effects of antibiotics on the clinical course of COVID-19. MAIN OUTCOMES: The primary endpoint is the improvement of oxygenation as measured by mean and/or median change from pre-treatment (day 1) to post-treatment (day 6 and 15 or at discharge, whichever comes first) in PaO2/FiO2 ratio, P(A-a)O2 gradient and a/A PO2 ratio. (PAO2= Partial alveolar pressure of oxygen, PaO2=partial arterial pressure of oxygen, FiO2=Fraction of inspired oxygen). RANDOMISATION: Patients will be randomized in a 2:1 ratio (Zilucoplan: control). Randomization will be done using an Interactive Web Response System (REDCap). BLINDING (MASKING): In this open-label trial neither participants, caregivers, nor those assessing the outcomes will be blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 81 patients will be enrolled: 54 patients will be randomized to the experimental arm and 27 patients to the control arm. TRIAL STATUS: ZILU-COV protocol Version 4.0 (June 10 2020). Participant recruitment started on June 23 2020 and is ongoing. Given the uncertainty of the pandemic, it is difficult to predict the anticipated end date. TRIAL REGISTRATION: The trial was registered on Clinical Trials.gov on May 11th, 2020 (ClinicalTrials.gov Identifier: NCT04382755 ) and on EudraCT (Identifier: 2020-002130-33 ). 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
Complemento C5/antagonistas & inibidores , Infecções por Coronavirus/complicações , Hipóxia/tratamento farmacológico , Pneumonia Viral/complicações , Insuficiência Respiratória/tratamento farmacológico , Doença Aguda , Adulto , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Bélgica/epidemiologia , Betacoronavirus/isolamento & purificação , Estudos de Casos e Controles , Ceftriaxona/administração & dosagem , Ceftriaxona/uso terapêutico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/tratamento farmacológico , Quimioterapia Combinada , Humanos , Infusões Intravenosas , Injeções Subcutâneas , Oxigênio/sangue , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/fisiopatologia , Pneumonia Viral/virologia , Estudos Prospectivos , Segurança , Resultado do Tratamento
9.
Value Health ; 23(11): 1409-1422, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33127010

RESUMO

OBJECTIVE: To review published economic evaluations of antiviral treatment for pandemics and outbreaks of respiratory illnesses. METHODS: We conducted a systematic review to identify economic evaluations of antiviral treatment for pandemics and outbreaks of respiratory illnesses, including coronavirus disease 2019 (COVID-19). We searched Medline (EBSCOhost), EMBASE (Ovid), EconLit (Ovid), National Health Service Economic Evaluation Database (Ovid), and Health Technology Assessment (Ovid). The search was last rerun on July 5, 2020. Citation tracking and reference checking were used. Only full economic evaluations published as peer-reviewed articles in the last 10 years were included. Studies were quality assessed using the National Institute for Health and Care Excellence economic evaluation checklist. RESULTS: Overall, 782 records were identified, of which 14 studies met the inclusion criteria. The studies were mostly conducted in high-income countries. All were model-based. Seven (50%) were cost-utility analyses, 4 (28.6%) were cost-effectiveness analyses, 2 (14.3%) were cost-consequences analyses, and 1 (7.1%) was a cost-benefit analysis. Strategies including antiviral treatment were found to be either cost-saving or cost-effective, at the study-specific willingness-to-pay thresholds. Empirical treatment was more cost-effective than test-guided treatment for young adults but less so for older adults. CONCLUSIONS: Antiviral treatment for managing pandemics and outbreaks of respiratory illnesses that have very high case fatality rate, similar to COVID-19 pandemic, are likely to be cost-effective either as a standalone intervention or part of a multifaceted strategy. Investing in the development of such curative treatments and promptly evaluating their cost-effectiveness, relative to other strategies in use at the time of their introduction should be the focus going forward to inform resource allocation decisions particularly in low- and middle-income countries.


Assuntos
Antivirais/economia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Análise Custo-Benefício , Surtos de Doenças , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Insuficiência Respiratória/tratamento farmacológico , Insuficiência Respiratória/epidemiologia , Betacoronavirus/efeitos dos fármacos , Humanos , Avaliação da Tecnologia Biomédica
10.
Pediatrics ; 146(4)2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32943536

RESUMO

OBJECTIVES: To evaluate the survival and neurodevelopmental impairment (NDI) in extremely low birth weight (ELBW) infants at 18 to 26 months with early hypoxemic respiratory failure (HRF). We also assessed whether African American infants with early HRF had improved outcomes after exposure to inhaled nitric oxide (iNO). METHODS: ELBW infants ≤1000 g and gestational age ≤26 weeks with maximal oxygen ≥60% on either day 1 or day 3 were labeled as "early HRF" and born between 2007 and 2015 in the Neonatal Research Network were included. Using a propensity score regression model, we analyzed outcomes and effects of exposure to iNO overall and separately by race. RESULTS: Among 7639 ELBW infants born ≤26 weeks, 22.7% had early HRF. Early HRF was associated with a mortality of 51.3%. The incidence of moderate-severe NDI among survivors was 41.2% at 18 to 26 months. Mortality among infants treated with iNO was 59.4%. Female sex (adjusted odds ratio [aOR]: 2.4, 95% confidence interval [CI]: 1.8-3.3), birth weight ≥720 g (aOR: 2.3, 95% CI: 1.7-3.1) and complete course of antenatal steroids (aOR: 1.6, 95% CI: 1.1-2.2) were associated with intact survival. African American infants had a similar incidence of early HRF (21.7% vs 23.3%) but lower exposure to iNO (16.4% vs 21.6%). Among infants with HRF exposed to iNO, intact survival (no death or NDI) was not significantly different between African American and other races (aOR: 1.5, 95% CI: 0.6-3.6). CONCLUSIONS: Early HRF in infants ≤26 weeks' gestation is associated with high mortality and NDI at 18 to 26 months. Use of iNO did not decrease mortality or NDI. Outcomes following iNO exposure were not different in African American infants.


Assuntos
Broncodilatadores/uso terapêutico , Hipóxia/complicações , Lactente Extremamente Prematuro , Transtornos do Neurodesenvolvimento/epidemiologia , Óxido Nítrico Sintase Tipo II/uso terapêutico , Insuficiência Respiratória/mortalidade , Administração por Inalação , Afro-Americanos , Índice de Apgar , Peso ao Nascer , Broncodilatadores/administração & dosagem , Feminino , Ruptura Prematura de Membranas Fetais , Mortalidade Hospitalar , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Incidência , Lactente , Recém-Nascido de Peso Extremamente Baixo ao Nascer , Recém-Nascido , Masculino , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/tratamento farmacológico , Transtornos do Neurodesenvolvimento/etnologia , Óxido Nítrico Sintase Tipo II/administração & dosagem , Alta do Paciente , Gravidez , Pontuação de Propensão , Insuficiência Respiratória/tratamento farmacológico , Insuficiência Respiratória/etnologia , Insuficiência Respiratória/etiologia , Fatores de Risco , Fatores Sexuais , Esteroides/uso terapêutico
11.
J Clin Pharmacol ; 60(11): 1411-1415, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32885463

RESUMO

The pathophysiology of respiratory failure associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains under investigation. One hypothesis is that progressive endothelial damage from the virus leads to microvascular thrombosis. It is uncertain if empiric therapeutic anticoagulation provides benefit over standard deep vein thrombosis (DVT) prophylaxis in critically ill patients with SARS-CoV-2. A retrospective cohort study was performed to evaluate adult patients admitted to the intensive care unit at 3 hospitals with polymerase chain reaction-confirmed SARS-CoV-2-associated respiratory failure requiring invasive mechanical ventilation. A Kaplan-Meier survival analysis was used to compare patients who were initiated on therapeutic anticoagulation prior to the time of intubation and those receiving standard DVT prophylaxis doses. The primary outcome was the difference in the 28-day mortality of patients between the 2 groups. Twenty-eight-day mortality did not differ between groups, occurring in 26.1% of patients who received therapeutic anticoagulation and 29.5% of those who received a prophylactic dose only (hazard ratio, 0.52; P = .055). There was no difference in 28-day mortality between groups in patients who were admitted with a serum D-dimer ≥ 2 µg/mL (hazard ratio, 0.67; P = .41). Empiric therapeutic anticoagulation in patients who require invasive mechanical ventilation for confirmed SARS-CoV-2 infection does not improve 28-day mortality compared with standard DVT prophylaxis, even among those with elevated D-dimer levels.


Assuntos
Anticoagulantes/uso terapêutico , Infecções por Coronavirus/complicações , Infecções por Coronavirus/mortalidade , Estado Terminal/mortalidade , Pneumonia Viral/complicações , Pneumonia Viral/mortalidade , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/mortalidade , Idoso , Anticoagulantes/efeitos adversos , Estudos de Coortes , Infecções por Coronavirus/tratamento farmacológico , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/tratamento farmacológico , Respiração Artificial , Insuficiência Respiratória/tratamento farmacológico , Estudos Retrospectivos , Análise de Sobrevida
12.
JAMA ; 324(13): 1298-1306, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-32876689

RESUMO

Importance: Coronavirus disease 2019 (COVID-19) is associated with severe lung damage. Corticosteroids are a possible therapeutic option. Objective: To determine the effect of hydrocortisone on treatment failure on day 21 in critically ill patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and acute respiratory failure. Design, Setting, and Participants: Multicenter randomized double-blind sequential trial conducted in France, with interim analyses planned every 50 patients. Patients admitted to the intensive care unit (ICU) for COVID-19-related acute respiratory failure were enrolled from March 7 to June 1, 2020, with last follow-up on June 29, 2020. The study intended to enroll 290 patients but was stopped early following the recommendation of the data and safety monitoring board. Interventions: Patients were randomized to receive low-dose hydrocortisone (n = 76) or placebo (n = 73). Main Outcomes and Measures: The primary outcome, treatment failure on day 21, was defined as death or persistent dependency on mechanical ventilation or high-flow oxygen therapy. Prespecified secondary outcomes included the need for tracheal intubation (among patients not intubated at baseline); cumulative incidences (until day 21) of prone position sessions, extracorporeal membrane oxygenation, and inhaled nitric oxide; Pao2:Fio2 ratio measured daily from day 1 to day 7, then on days 14 and 21; and the proportion of patients with secondary infections during their ICU stay. Results: The study was stopped after 149 patients (mean age, 62.2 years; 30.2% women; 81.2% mechanically ventilated) were enrolled. One hundred forty-eight patients (99.3%) completed the study, and there were 69 treatment failure events, including 11 deaths in the hydrocortisone group and 20 deaths in the placebo group. The primary outcome, treatment failure on day 21, occurred in 32 of 76 patients (42.1%) in the hydrocortisone group compared with 37 of 73 (50.7%) in the placebo group (difference of proportions, -8.6% [95.48% CI, -24.9% to 7.7%]; P = .29). Of the 4 prespecified secondary outcomes, none showed a significant difference. No serious adverse events were related to the study treatment. Conclusions and Relevance: In this study of critically ill patients with COVID-19 and acute respiratory failure, low-dose hydrocortisone, compared with placebo, did not significantly reduce treatment failure (defined as death or persistent respiratory support) at day 21. However, the study was stopped early and likely was underpowered to find a statistically and clinically important difference in the primary outcome. Trial Registration: ClinicalTrials.gov Identifier: NCT02517489.


Assuntos
Anti-Inflamatórios/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Hidrocortisona/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Respiração Artificial , Insuficiência Respiratória/terapia , Idoso , Anti-Inflamatórios/administração & dosagem , Betacoronavirus , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/terapia , Estado Terminal , Método Duplo-Cego , Término Precoce de Ensaios Clínicos , Feminino , Humanos , Hidrocortisona/administração & dosagem , Masculino , Pessoa de Meia-Idade , Oxigenoterapia , Pandemias , Pneumonia Viral/mortalidade , Pneumonia Viral/terapia , Respiração Artificial/estatística & dados numéricos , Insuficiência Respiratória/tratamento farmacológico , Insuficiência Respiratória/etiologia , Falha de Tratamento
13.
Adv Biol Regul ; 77: 100735, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32773098

RESUMO

The novel Corona virus infection (Covid-19) first identified in China in December 2019 has rapidly progressed in pandemic leading to significant mortality and unprecedented challenge for healthcare systems. Although the clinical spectrum of Covid-19 is variable, acute respiratory failure and systemic coagulopathy are common in severe Covid-19 patients. Lung is an important target of the SARS-CoV-2 virus causing eventually acute respiratory distress syndrome associated to a thromboinflammatory state. The cytokinic storm, thromboinflammation and pulmonary tropism are the bedrock of tissue lesions responsible for acute respiratory failure and for prolonged infection that may lead to multiple organ failure and death. The thrombogenicity of this infectious disease is illustrated by the high frequency of thromboembolic events observed even in Covid-19 patients treated with anticoagulation. Increased D-Dimers, a biomarker reflecting activation of hemostasis and fibrinolysis, and low platelet count (thrombocytopenia) are associated with higher mortality in Covid-19 patients. In this review, we will summarize our current knowledge on the thromboembolic manifestations, the disturbed hemostatic parameters, and the thromboinflammatory conditions associated to Covid-19 and we will discuss the modalities of anticoagulant treatment or other potential antithrombotic options.


Assuntos
Anticoagulantes/uso terapêutico , Betacoronavirus/patogenicidade , Infecções por Coronavirus/complicações , Síndrome da Liberação de Citocina/complicações , Coagulação Intravascular Disseminada/complicações , Pneumonia Viral/complicações , Embolia Pulmonar/complicações , Insuficiência Respiratória/complicações , Doença Aguda , Biomarcadores/sangue , Plaquetas/efeitos dos fármacos , Plaquetas/patologia , Plaquetas/virologia , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/diagnóstico , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/virologia , Coagulação Intravascular Disseminada/diagnóstico , Coagulação Intravascular Disseminada/tratamento farmacológico , Coagulação Intravascular Disseminada/virologia , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Heparina/uso terapêutico , Interações Hospedeiro-Patógeno , Humanos , Pulmão/irrigação sanguínea , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/tratamento farmacológico , Embolia Pulmonar/virologia , Insuficiência Respiratória/diagnóstico , Insuficiência Respiratória/tratamento farmacológico , Insuficiência Respiratória/virologia , Análise de Sobrevida
14.
Adv Biol Regul ; 77: 100744, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32773104
16.
J Mol Cell Cardiol ; 146: 32-40, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32681845

RESUMO

SARS-CoV-2 causes a phenotype of pneumonia with diverse manifestation, which is termed as coronavirus disease 2019 (COVID-19). An impressive high transmission rate allows COVID-19 conferring enormous challenge for clinicians worldwide, and developing to a pandemic level. Combined with a series of complications, a part of COVID-19 patients progress into severe cases, which critically contributes to the risk of fatality. To date, coagulopathy has been found as a prominent feature of COVID-19 and severe coagulation dysfunction may be associated with poor prognosis. Coagulopathy in COVID-19 may predispose patients to hypercoagulability-related disorders including thrombosis and even fatal vascular events. Inflammatory storm, uncontrolled inflammation-mediated endothelial injury and renin angiotensin system (RAS) dysregulation are the potential mechanisms. Ongoing efforts made to develop promising therapies provide several potential strategies for hypercoagulability in COVID-19. In this review, we introduce the clinical features of coagulation and the increased vascular thrombotic risk conferred by coagulopathy according to present reports about COVID-19. The potential underlying mechanisms and emerging therapeutic avenues are discussed, emphasizing an urgent need for effective interventions.


Assuntos
Anticoagulantes/uso terapêutico , Betacoronavirus/patogenicidade , Infecções por Coronavirus/complicações , Síndrome da Liberação de Citocina/complicações , Coagulação Intravascular Disseminada/complicações , Pneumonia Viral/complicações , Embolia Pulmonar/complicações , Insuficiência Respiratória/complicações , Doença Aguda , Betacoronavirus/imunologia , Biomarcadores/sangue , Plaquetas/efeitos dos fármacos , Plaquetas/patologia , Plaquetas/virologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/mortalidade , Síndrome da Liberação de Citocina/virologia , Coagulação Intravascular Disseminada/tratamento farmacológico , Coagulação Intravascular Disseminada/mortalidade , Coagulação Intravascular Disseminada/virologia , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Heparina/uso terapêutico , Interações Hospedeiro-Patógeno/imunologia , Humanos , Pulmão/irrigação sanguínea , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Pandemias , Tempo de Tromboplastina Parcial , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Embolia Pulmonar/tratamento farmacológico , Embolia Pulmonar/mortalidade , Embolia Pulmonar/virologia , Insuficiência Respiratória/tratamento farmacológico , Insuficiência Respiratória/mortalidade , Insuficiência Respiratória/virologia , Análise de Sobrevida
17.
Infection ; 48(5): 767-771, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32642806
18.
Proc Natl Acad Sci U S A ; 117(32): 18951-18953, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32699149

RESUMO

Around the tenth day after diagnosis, ∼20% of patients with coronavirus disease 2019 (COVID-19)-associated pneumonia evolve toward severe oxygen dependence (stage 2b) and acute respiratory distress syndrome (stage 3) associated with systemic inflammation often termed a "cytokine storm." Because interleukin-1 (IL-1) blocks the production of IL-6 and other proinflammatory cytokines, we treated COVID-19 patients early in the disease with the IL-1 receptor antagonist, anakinra. We retrospectively compared 22 patients from three different centers in France with stages 2b and 3 COVID-19-associated pneumonia presenting with acute severe respiratory failure and systemic inflammation who received either standard-of-care treatment alone (10 patients) or combined with intravenous anakinra (12 patients). Treatment started at 300 mg⋅d-1 for 5 d, then tapered with lower dosing over 3 d. Both populations were comparable for age, comorbidities, clinical stage, and elevated biomarkers of systemic inflammation. All of the patients treated with anakinra improved clinically (P < 0.01), with no deaths, significant decreases in oxygen requirements (P < 0.05), and more days without invasive mechanical ventilation (P < 0.06), compared with the control group. The effect of anakinra was rapid, as judged by significant decrease of fever and C-reactive protein at day 3. A mean total dose of 1,950 mg was infused with no adverse side effects or bacterial infection. We conclude that early blockade of the IL-1 receptor is therapeutic in acute hyperinflammatory respiratory failure in COVID-19 patients.


Assuntos
Anti-Inflamatórios/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Insuficiência Respiratória/tratamento farmacológico , Idoso , Anti-Inflamatórios/administração & dosagem , Estudos de Casos e Controles , Infecções por Coronavirus/complicações , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Injeções Intravenosas , Proteína Antagonista do Receptor de Interleucina 1/administração & dosagem , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/etiologia , Insuficiência Respiratória/etiologia
19.
Clin Drug Investig ; 40(8): 755-764, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32583295

RESUMO

BACKGROUND AND OBJECTIVE: Opioid-induced respiratory depression (OIRD) is a potentially fatal complication associated with conventional opioids. Currently, there is a paucity of validated endpoints available to measure respiratory safety. Oliceridine, an investigational intravenous (IV) opioid, is a G-protein selective µ-agonist with limited activity on ß-arrestin2, a signaling pathway associated with adverse events including OIRD. In controlled phase III trials, oliceridine 0.35 mg and 0.5 mg demand doses demonstrated comparable analgesia to morphine 1 mg with favorable improvements in respiratory safety. In this exploratory analysis, we report dosing interruption (DI) and average cumulative duration of DI (CDDI) for both oliceridine and morphine. METHODS: Patients requiring analgesia after bunionectomy or abdominoplasty were randomized to IV demand doses of placebo, oliceridine (0.1 mg, 0.35 mg, or 0.5 mg), or morphine (1 mg), administered via patient-controlled analgesia (PCA), following a loading dose (oliceridine 1.5 mg, morphine 4 mg, volume-matched placebo) with a 6-min lockout interval. Certified nurse anesthetists monitored each patient and withheld study medication according to the patient's respiratory status. For each patient, the duration of all DIs was summed and reported as CDDI. A zero-inflated gamma mixture model was used to compute the mean CDDI for each treatment. RESULTS: Proportion of patients with DI was lower with oliceridine (0.1 mg: 3.2%, 0.35 mg: 13.9%, 0.5 mg: 15.1%) versus morphine (22%). The CDDI was also lower across all demand doses of oliceridine versus morphine. CONCLUSION: Using DI as a surrogate for OIRD indicates improved respiratory safety with oliceridine versus morphine that merits further investigation.


Assuntos
Dor Aguda/tratamento farmacológico , Analgésicos Opioides/efeitos adversos , Morfina/efeitos adversos , Dor Pós-Operatória/tratamento farmacológico , Insuficiência Respiratória/induzido quimicamente , Compostos de Espiro/efeitos adversos , Tiofenos/efeitos adversos , Adulto , Analgesia Controlada pelo Paciente , Analgésicos Opioides/administração & dosagem , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Morfina/administração & dosagem , Manejo da Dor , Medição da Dor , Insuficiência Respiratória/tratamento farmacológico , Compostos de Espiro/administração & dosagem , Tiofenos/administração & dosagem
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