Interventions for treatment of COVID-19: Second edition of a living systematic review with meta-analyses and trial sequential analyses (The LIVING Project)
COVID-19 is a rapidly spreading disease that has caused extensive burden to individuals, families, countries, and the world. Effective treatments of COVID-19 are urgently needed. This is the second edition of a living systematic review of randomized clinical trials assessing the effects of all treat...
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| Published in | PloS one Vol. 16; no. 3; p. e0248132 |
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| Main Authors | , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Public Library of Science
11.03.2021
Public Library of Science (PLoS) |
| Subjects | |
| Online Access | Get full text |
| ISSN | 1932-6203 1932-6203 |
| DOI | 10.1371/journal.pone.0248132 |
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| Abstract | COVID-19 is a rapidly spreading disease that has caused extensive burden to individuals, families, countries, and the world. Effective treatments of COVID-19 are urgently needed. This is the second edition of a living systematic review of randomized clinical trials assessing the effects of all treatment interventions for participants in all age groups with COVID-19.
We planned to conduct aggregate data meta-analyses, trial sequential analyses, network meta-analysis, and individual patient data meta-analyses. Our systematic review was based on PRISMA and Cochrane guidelines, and our eight-step procedure for better validation of clinical significance of meta-analysis results. We performed both fixed-effect and random-effects meta-analyses. Primary outcomes were all-cause mortality and serious adverse events. Secondary outcomes were admission to intensive care, mechanical ventilation, renal replacement therapy, quality of life, and non-serious adverse events. According to the number of outcome comparisons, we adjusted our threshold for significance to p = 0.033. We used GRADE to assess the certainty of evidence. We searched relevant databases and websites for published and unpublished trials until November 2, 2020. Two reviewers independently extracted data and assessed trial methodology. We included 82 randomized clinical trials enrolling a total of 40,249 participants. 81 out of 82 trials were at overall high risk of bias. Meta-analyses showed no evidence of a difference between corticosteroids versus control on all-cause mortality (risk ratio [RR] 0.89; 95% confidence interval [CI] 0.79 to 1.00; p = 0.05; I2 = 23.1%; eight trials; very low certainty), on serious adverse events (RR 0.89; 95% CI 0.80 to 0.99; p = 0.04; I2 = 39.1%; eight trials; very low certainty), and on mechanical ventilation (RR 0.86; 95% CI 0.55 to 1.33; p = 0.49; I2 = 55.3%; two trials; very low certainty). The fixed-effect meta-analyses showed indications of beneficial effects. Trial sequential analyses showed that the required information size for all three analyses was not reached. Meta-analysis (RR 0.93; 95% CI 0.82 to 1.07; p = 0.31; I2 = 0%; four trials; moderate certainty) and trial sequential analysis (boundary for futility crossed) showed that we could reject that remdesivir versus control reduced the risk of death by 20%. Meta-analysis (RR 0.82; 95% CI 0.68 to 1.00; p = 0.05; I2 = 38.9%; four trials; very low certainty) and trial sequential analysis (required information size not reached) showed no evidence of difference between remdesivir versus control on serious adverse events. Fixed-effect meta-analysis showed indications of a beneficial effect of remdesivir on serious adverse events. Meta-analysis (RR 0.40; 95% CI 0.19 to 0.87; p = 0.02; I2 = 0%; two trials; very low certainty) showed evidence of a beneficial effect of intravenous immunoglobulin versus control on all-cause mortality, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm or reject realistic intervention effects. Meta-analysis (RR 0.63; 95% CI 0.35 to 1.14; p = 0.12; I2 = 77.4%; five trials; very low certainty) and trial sequential analysis (required information size not reached) showed no evidence of a difference between tocilizumab versus control on serious adverse events. Fixed-effect meta-analysis showed indications of a beneficial effect of tocilizumab on serious adverse events. Meta-analysis (RR 0.70; 95% CI 0.51 to 0.96; p = 0.02; I2 = 0%; three trials; very low certainty) showed evidence of a beneficial effect of tocilizumab versus control on mechanical ventilation, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm of reject realistic intervention effects. Meta-analysis (RR 0.32; 95% CI 0.15 to 0.69; p < 0.00; I2 = 0%; two trials; very low certainty) showed evidence of a beneficial effect of bromhexine versus standard care on non-serious adverse events, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm or reject realistic intervention effects. Meta-analyses and trial sequential analyses (boundary for futility crossed) showed that we could reject that hydroxychloroquine versus control reduced the risk of death and serious adverse events by 20%. Meta-analyses and trial sequential analyses (boundary for futility crossed) showed that we could reject that lopinavir-ritonavir versus control reduced the risk of death, serious adverse events, and mechanical ventilation by 20%. All remaining outcome comparisons showed that we did not have enough information to confirm or reject realistic intervention effects. Nine single trials showed statistically significant results on our outcomes, but were underpowered to confirm or reject realistic intervention effects. Due to lack of data, it was not relevant to perform network meta-analysis or possible to perform individual patient data meta-analyses.
No evidence-based treatment for COVID-19 currently exists. Very low certainty evidence indicates that corticosteroids might reduce the risk of death, serious adverse events, and mechanical ventilation; that remdesivir might reduce the risk of serious adverse events; that intravenous immunoglobin might reduce the risk of death and serious adverse events; that tocilizumab might reduce the risk of serious adverse events and mechanical ventilation; and that bromhexine might reduce the risk of non-serious adverse events. More trials with low risks of bias and random errors are urgently needed. This review will continuously inform best practice in treatment and clinical research of COVID-19.
PROSPERO CRD42020178787. |
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| AbstractList | COVID-19 is a rapidly spreading disease that has caused extensive burden to individuals, families, countries, and the world. Effective treatments of COVID-19 are urgently needed. This is the second edition of a living systematic review of randomized clinical trials assessing the effects of all treatment interventions for participants in all age groups with COVID-19.BACKGROUNDCOVID-19 is a rapidly spreading disease that has caused extensive burden to individuals, families, countries, and the world. Effective treatments of COVID-19 are urgently needed. This is the second edition of a living systematic review of randomized clinical trials assessing the effects of all treatment interventions for participants in all age groups with COVID-19.We planned to conduct aggregate data meta-analyses, trial sequential analyses, network meta-analysis, and individual patient data meta-analyses. Our systematic review was based on PRISMA and Cochrane guidelines, and our eight-step procedure for better validation of clinical significance of meta-analysis results. We performed both fixed-effect and random-effects meta-analyses. Primary outcomes were all-cause mortality and serious adverse events. Secondary outcomes were admission to intensive care, mechanical ventilation, renal replacement therapy, quality of life, and non-serious adverse events. According to the number of outcome comparisons, we adjusted our threshold for significance to p = 0.033. We used GRADE to assess the certainty of evidence. We searched relevant databases and websites for published and unpublished trials until November 2, 2020. Two reviewers independently extracted data and assessed trial methodology. We included 82 randomized clinical trials enrolling a total of 40,249 participants. 81 out of 82 trials were at overall high risk of bias. Meta-analyses showed no evidence of a difference between corticosteroids versus control on all-cause mortality (risk ratio [RR] 0.89; 95% confidence interval [CI] 0.79 to 1.00; p = 0.05; I2 = 23.1%; eight trials; very low certainty), on serious adverse events (RR 0.89; 95% CI 0.80 to 0.99; p = 0.04; I2 = 39.1%; eight trials; very low certainty), and on mechanical ventilation (RR 0.86; 95% CI 0.55 to 1.33; p = 0.49; I2 = 55.3%; two trials; very low certainty). The fixed-effect meta-analyses showed indications of beneficial effects. Trial sequential analyses showed that the required information size for all three analyses was not reached. Meta-analysis (RR 0.93; 95% CI 0.82 to 1.07; p = 0.31; I2 = 0%; four trials; moderate certainty) and trial sequential analysis (boundary for futility crossed) showed that we could reject that remdesivir versus control reduced the risk of death by 20%. Meta-analysis (RR 0.82; 95% CI 0.68 to 1.00; p = 0.05; I2 = 38.9%; four trials; very low certainty) and trial sequential analysis (required information size not reached) showed no evidence of difference between remdesivir versus control on serious adverse events. Fixed-effect meta-analysis showed indications of a beneficial effect of remdesivir on serious adverse events. Meta-analysis (RR 0.40; 95% CI 0.19 to 0.87; p = 0.02; I2 = 0%; two trials; very low certainty) showed evidence of a beneficial effect of intravenous immunoglobulin versus control on all-cause mortality, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm or reject realistic intervention effects. Meta-analysis (RR 0.63; 95% CI 0.35 to 1.14; p = 0.12; I2 = 77.4%; five trials; very low certainty) and trial sequential analysis (required information size not reached) showed no evidence of a difference between tocilizumab versus control on serious adverse events. Fixed-effect meta-analysis showed indications of a beneficial effect of tocilizumab on serious adverse events. Meta-analysis (RR 0.70; 95% CI 0.51 to 0.96; p = 0.02; I2 = 0%; three trials; very low certainty) showed evidence of a beneficial effect of tocilizumab versus control on mechanical ventilation, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm of reject realistic intervention effects. Meta-analysis (RR 0.32; 95% CI 0.15 to 0.69; p < 0.00; I2 = 0%; two trials; very low certainty) showed evidence of a beneficial effect of bromhexine versus standard care on non-serious adverse events, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm or reject realistic intervention effects. Meta-analyses and trial sequential analyses (boundary for futility crossed) showed that we could reject that hydroxychloroquine versus control reduced the risk of death and serious adverse events by 20%. Meta-analyses and trial sequential analyses (boundary for futility crossed) showed that we could reject that lopinavir-ritonavir versus control reduced the risk of death, serious adverse events, and mechanical ventilation by 20%. All remaining outcome comparisons showed that we did not have enough information to confirm or reject realistic intervention effects. Nine single trials showed statistically significant results on our outcomes, but were underpowered to confirm or reject realistic intervention effects. Due to lack of data, it was not relevant to perform network meta-analysis or possible to perform individual patient data meta-analyses.METHODS AND FINDINGSWe planned to conduct aggregate data meta-analyses, trial sequential analyses, network meta-analysis, and individual patient data meta-analyses. Our systematic review was based on PRISMA and Cochrane guidelines, and our eight-step procedure for better validation of clinical significance of meta-analysis results. We performed both fixed-effect and random-effects meta-analyses. Primary outcomes were all-cause mortality and serious adverse events. Secondary outcomes were admission to intensive care, mechanical ventilation, renal replacement therapy, quality of life, and non-serious adverse events. According to the number of outcome comparisons, we adjusted our threshold for significance to p = 0.033. We used GRADE to assess the certainty of evidence. We searched relevant databases and websites for published and unpublished trials until November 2, 2020. Two reviewers independently extracted data and assessed trial methodology. We included 82 randomized clinical trials enrolling a total of 40,249 participants. 81 out of 82 trials were at overall high risk of bias. Meta-analyses showed no evidence of a difference between corticosteroids versus control on all-cause mortality (risk ratio [RR] 0.89; 95% confidence interval [CI] 0.79 to 1.00; p = 0.05; I2 = 23.1%; eight trials; very low certainty), on serious adverse events (RR 0.89; 95% CI 0.80 to 0.99; p = 0.04; I2 = 39.1%; eight trials; very low certainty), and on mechanical ventilation (RR 0.86; 95% CI 0.55 to 1.33; p = 0.49; I2 = 55.3%; two trials; very low certainty). The fixed-effect meta-analyses showed indications of beneficial effects. Trial sequential analyses showed that the required information size for all three analyses was not reached. Meta-analysis (RR 0.93; 95% CI 0.82 to 1.07; p = 0.31; I2 = 0%; four trials; moderate certainty) and trial sequential analysis (boundary for futility crossed) showed that we could reject that remdesivir versus control reduced the risk of death by 20%. Meta-analysis (RR 0.82; 95% CI 0.68 to 1.00; p = 0.05; I2 = 38.9%; four trials; very low certainty) and trial sequential analysis (required information size not reached) showed no evidence of difference between remdesivir versus control on serious adverse events. Fixed-effect meta-analysis showed indications of a beneficial effect of remdesivir on serious adverse events. Meta-analysis (RR 0.40; 95% CI 0.19 to 0.87; p = 0.02; I2 = 0%; two trials; very low certainty) showed evidence of a beneficial effect of intravenous immunoglobulin versus control on all-cause mortality, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm or reject realistic intervention effects. Meta-analysis (RR 0.63; 95% CI 0.35 to 1.14; p = 0.12; I2 = 77.4%; five trials; very low certainty) and trial sequential analysis (required information size not reached) showed no evidence of a difference between tocilizumab versus control on serious adverse events. Fixed-effect meta-analysis showed indications of a beneficial effect of tocilizumab on serious adverse events. Meta-analysis (RR 0.70; 95% CI 0.51 to 0.96; p = 0.02; I2 = 0%; three trials; very low certainty) showed evidence of a beneficial effect of tocilizumab versus control on mechanical ventilation, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm of reject realistic intervention effects. Meta-analysis (RR 0.32; 95% CI 0.15 to 0.69; p < 0.00; I2 = 0%; two trials; very low certainty) showed evidence of a beneficial effect of bromhexine versus standard care on non-serious adverse events, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm or reject realistic intervention effects. Meta-analyses and trial sequential analyses (boundary for futility crossed) showed that we could reject that hydroxychloroquine versus control reduced the risk of death and serious adverse events by 20%. Meta-analyses and trial sequential analyses (boundary for futility crossed) showed that we could reject that lopinavir-ritonavir versus control reduced the risk of death, serious adverse events, and mechanical ventilation by 20%. All remaining outcome comparisons showed that we did not have enough information to confirm or reject realistic intervention effects. Nine single trials showed statistically significant results on our outcomes, but were underpowered to confirm or reject realistic COVID-19 is a rapidly spreading disease that has caused extensive burden to individuals, families, countries, and the world. Effective treatments of COVID-19 are urgently needed. This is the second edition of a living systematic review of randomized clinical trials assessing the effects of all treatment interventions for participants in all age groups with COVID-19. We planned to conduct aggregate data meta-analyses, trial sequential analyses, network meta-analysis, and individual patient data meta-analyses. Our systematic review was based on PRISMA and Cochrane guidelines, and our eight-step procedure for better validation of clinical significance of meta-analysis results. We performed both fixed-effect and random-effects meta-analyses. Primary outcomes were all-cause mortality and serious adverse events. Secondary outcomes were admission to intensive care, mechanical ventilation, renal replacement therapy, quality of life, and non-serious adverse events. According to the number of outcome comparisons, we adjusted our threshold for significance to p = 0.033. We used GRADE to assess the certainty of evidence. We searched relevant databases and websites for published and unpublished trials until November 2, 2020. Two reviewers independently extracted data and assessed trial methodology. We included 82 randomized clinical trials enrolling a total of 40,249 participants. 81 out of 82 trials were at overall high risk of bias. Meta-analyses showed no evidence of a difference between corticosteroids versus control on all-cause mortality (risk ratio [RR] 0.89; 95% confidence interval [CI] 0.79 to 1.00; p = 0.05; I.sup.2 = 23.1%; eight trials; very low certainty), on serious adverse events (RR 0.89; 95% CI 0.80 to 0.99; p = 0.04; I.sup.2 = 39.1%; eight trials; very low certainty), and on mechanical ventilation (RR 0.86; 95% CI 0.55 to 1.33; p = 0.49; I.sup.2 = 55.3%; two trials; very low certainty). The fixed-effect meta-analyses showed indications of beneficial effects. Trial sequential analyses showed that the required information size for all three analyses was not reached. Meta-analysis (RR 0.93; 95% CI 0.82 to 1.07; p = 0.31; I.sup.2 = 0%; four trials; moderate certainty) and trial sequential analysis (boundary for futility crossed) showed that we could reject that remdesivir versus control reduced the risk of death by 20%. Meta-analysis (RR 0.82; 95% CI 0.68 to 1.00; p = 0.05; I.sup.2 = 38.9%; four trials; very low certainty) and trial sequential analysis (required information size not reached) showed no evidence of difference between remdesivir versus control on serious adverse events. Fixed-effect meta-analysis showed indications of a beneficial effect of remdesivir on serious adverse events. Meta-analysis (RR 0.40; 95% CI 0.19 to 0.87; p = 0.02; I.sup.2 = 0%; two trials; very low certainty) showed evidence of a beneficial effect of intravenous immunoglobulin versus control on all-cause mortality, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm or reject realistic intervention effects. Meta-analysis (RR 0.63; 95% CI 0.35 to 1.14; p = 0.12; I.sup.2 = 77.4%; five trials; very low certainty) and trial sequential analysis (required information size not reached) showed no evidence of a difference between tocilizumab versus control on serious adverse events. Fixed-effect meta-analysis showed indications of a beneficial effect of tocilizumab on serious adverse events. Meta-analysis (RR 0.70; 95% CI 0.51 to 0.96; p = 0.02; I.sup.2 = 0%; three trials; very low certainty) showed evidence of a beneficial effect of tocilizumab versus control on mechanical ventilation, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm of reject realistic intervention effects. Meta-analysis (RR 0.32; 95% CI 0.15 to 0.69; p < 0.00; I.sup.2 = 0%; two trials; very low certainty) showed evidence of a beneficial effect of bromhexine versus standard care on non-serious adverse events, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm or reject realistic intervention effects. Meta-analyses and trial sequential analyses (boundary for futility crossed) showed that we could reject that hydroxychloroquine versus control reduced the risk of death and serious adverse events by 20%. Meta-analyses and trial sequential analyses (boundary for futility crossed) showed that we could reject that lopinavir-ritonavir versus control reduced the risk of death, serious adverse events, and mechanical ventilation by 20%. All remaining outcome comparisons showed that we did not have enough information to confirm or reject realistic intervention effects. Nine single trials showed statistically significant results on our outcomes, but were underpowered to confirm or reject realistic intervention effects. Due to lack of data, it was not relevant to perform network meta-analysis or possible to perform individual patient data meta-analyses. No evidence-based treatment for COVID-19 currently exists. Very low certainty evidence indicates that corticosteroids might reduce the risk of death, serious adverse events, and mechanical ventilation; that remdesivir might reduce the risk of serious adverse events; that intravenous immunoglobin might reduce the risk of death and serious adverse events; that tocilizumab might reduce the risk of serious adverse events and mechanical ventilation; and that bromhexine might reduce the risk of non-serious adverse events. More trials with low risks of bias and random errors are urgently needed. This review will continuously inform best practice in treatment and clinical research of COVID-19. PROSPERO CRD42020178787. Background COVID-19 is a rapidly spreading disease that has caused extensive burden to individuals, families, countries, and the world. Effective treatments of COVID-19 are urgently needed. This is the second edition of a living systematic review of randomized clinical trials assessing the effects of all treatment interventions for participants in all age groups with COVID-19. Methods and findings We planned to conduct aggregate data meta-analyses, trial sequential analyses, network meta-analysis, and individual patient data meta-analyses. Our systematic review was based on PRISMA and Cochrane guidelines, and our eight-step procedure for better validation of clinical significance of meta-analysis results. We performed both fixed-effect and random-effects meta-analyses. Primary outcomes were all-cause mortality and serious adverse events. Secondary outcomes were admission to intensive care, mechanical ventilation, renal replacement therapy, quality of life, and non-serious adverse events. According to the number of outcome comparisons, we adjusted our threshold for significance to p = 0.033. We used GRADE to assess the certainty of evidence. We searched relevant databases and websites for published and unpublished trials until November 2, 2020. Two reviewers independently extracted data and assessed trial methodology. We included 82 randomized clinical trials enrolling a total of 40,249 participants. 81 out of 82 trials were at overall high risk of bias. Meta-analyses showed no evidence of a difference between corticosteroids versus tocilizumab might reduce the risk of serious adverse events and mechanical ventilation; and that bromhexine might reduce the risk of non-serious adverse events. More trials with low risks of bias and random errors are urgently needed. This review will continuously inform best practice in treatment and clinical research of COVID-19. control on all-cause mortality (risk ratio [RR] 0.89; 95% confidence interval [CI] 0.79 to 1.00; p = 0.05; I2 = 23.1%; eight trials; very low certainty), onserious adverse events (RR 0.89; 95% CI 0.80 to 0.99; p = 0.04; I2 = 39.1%; eight trials; very low certainty), and on mechanical ventilation (RR 0.86; 95% CI 0.55 to 1.33; p = 0.49; I2 = 55.3%; two trials; very low certainty). The fixed-effect meta-analyses showed indications of beneficial effects. Trial sequential analyses showed that the required information size for all three analyses was not reached. Meta-analysis (RR 0.93; 95% CI 0.82 to 1.07; p = 0.31; I2 = 0%; four trials; moderate certainty) and trial sequential analysis (boundary for futility crossed) showed that we could reject that remdesivir versus control reduced the risk of death by 20%. Meta-analysis (RR 0.82; 95% CI 0.68 to 1.00; p = 0.05; I2 = 38.9%; four trials; very low certainty) and trial sequential analysis (required information size not reached) showed no evidence of difference between remdesivir versus control on serious adverse events. Fixed-effect meta-analysis showed indications of a beneficial effect of remdesivir on serious adverse events. Meta-analysis (RR 0.40; 95% CI 0.19 to 0.87; p = 0.02; I2 = 0%; two trials; very low certainty) showed evidence of a beneficial effect of intravenous immunoglobulin versus control on all-cause mortality, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm or reject realistic intervention effects. Meta-analysis (RR 0.63; 95% CI 0.35 to 1.14; p = 0.12; I2 = 77.4%; five trials; very low certainty) and trial sequential analysis (required information size not reached) showed no evidence of a difference between tocilizumab versus control on serious adverse events. Fixed-effect meta-analysis showed indications of a beneficial effect of tocilizumab on serious adverse events. Meta-analysis (RR 0.70; 95% CI 0.51 to 0.96; p = 0.02; I2 = 0%; three trials; very low certainty) showed evidence of a beneficial effect of tocilizumab versus control on mechanical ventilation, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm of reject realistic intervention effects. Meta-analysis (RR 0.32; 95% CI 0.15 to 0.69; p < 0.00; I2 = 0%; two trials; very low certainty) showed evidence of a beneficial effect of bromhexine versus standard care on non-serious adverse events, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm or reject realistic intervention effects. Meta-analyses and trial sequential analyses (boundary for futility crossed) showed that we could reject that hydroxychloroquine versus control reduced the risk of death and serious adverse events by 20%. Meta-analyses and trial sequential analyses (boundary for futility crossed) showed that we could reject that lopinavir-ritonavir versus control reduced the risk of death, serious adverse events, and mechanical ventilation by 20%. All remaining outcome comparisons showed that we did not have enough information to confirm or reject realistic intervention effects. Nine single trials showed statistically significant results on our outcomes, but were underpowered to confirm or reject realistic intervention effects. Due to lack of data, it was not relevant to perform network meta-analysis or possible to perform individual patient data meta-analyses. Conclusions No evidence-based treatment for COVID-19 currently exists. Very low certainty evidence indicates that corticosteroids might reduce the risk of death, serious adverse events, and mechanical ventilation; that remdesivir might reduce the risk of serious adverse events; that intravenous immunoglobin might reduce the risk of death and serious adverse events; that BackgroundCOVID-19 is a rapidly spreading disease that has caused extensive burden to individuals, families, countries, and the world. Effective treatments of COVID-19 are urgently needed. This is the second edition of a living systematic review of randomized clinical trials assessing the effects of all treatment interventions for participants in all age groups with COVID-19.Methods and findingsWe planned to conduct aggregate data meta-analyses, trial sequential analyses, network meta-analysis, and individual patient data meta-analyses. Our systematic review was based on PRISMA and Cochrane guidelines, and our eight-step procedure for better validation of clinical significance of meta-analysis results. We performed both fixed-effect and random-effects meta-analyses. Primary outcomes were all-cause mortality and serious adverse events. Secondary outcomes were admission to intensive care, mechanical ventilation, renal replacement therapy, quality of life, and non-serious adverse events. According to the number of outcome comparisons, we adjusted our threshold for significance to p = 0.033. We used GRADE to assess the certainty of evidence. We searched relevant databases and websites for published and unpublished trials until November 2, 2020. Two reviewers independently extracted data and assessed trial methodology. We included 82 randomized clinical trials enrolling a total of 40,249 participants. 81 out of 82 trials were at overall high risk of bias. Meta-analyses showed no evidence of a difference between corticosteroids versus control on all-cause mortality (risk ratio [RR] 0.89; 95% confidence interval [CI] 0.79 to 1.00; p = 0.05; I2 = 23.1%; eight trials; very low certainty), on serious adverse events (RR 0.89; 95% CI 0.80 to 0.99; p = 0.04; I2 = 39.1%; eight trials; very low certainty), and on mechanical ventilation (RR 0.86; 95% CI 0.55 to 1.33; p = 0.49; I2 = 55.3%; two trials; very low certainty). The fixed-effect meta-analyses showed indications of beneficial effects. Trial sequential analyses showed that the required information size for all three analyses was not reached. Meta-analysis (RR 0.93; 95% CI 0.82 to 1.07; p = 0.31; I2 = 0%; four trials; moderate certainty) and trial sequential analysis (boundary for futility crossed) showed that we could reject that remdesivir versus control reduced the risk of death by 20%. Meta-analysis (RR 0.82; 95% CI 0.68 to 1.00; p = 0.05; I2 = 38.9%; four trials; very low certainty) and trial sequential analysis (required information size not reached) showed no evidence of difference between remdesivir versus control on serious adverse events. Fixed-effect meta-analysis showed indications of a beneficial effect of remdesivir on serious adverse events. Meta-analysis (RR 0.40; 95% CI 0.19 to 0.87; p = 0.02; I2 = 0%; two trials; very low certainty) showed evidence of a beneficial effect of intravenous immunoglobulin versus control on all-cause mortality, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm or reject realistic intervention effects. Meta-analysis (RR 0.63; 95% CI 0.35 to 1.14; p = 0.12; I2 = 77.4%; five trials; very low certainty) and trial sequential analysis (required information size not reached) showed no evidence of a difference between tocilizumab versus control on serious adverse events. Fixed-effect meta-analysis showed indications of a beneficial effect of tocilizumab on serious adverse events. Meta-analysis (RR 0.70; 95% CI 0.51 to 0.96; p = 0.02; I2 = 0%; three trials; very low certainty) showed evidence of a beneficial effect of tocilizumab versus control on mechanical ventilation, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm of reject realistic intervention effects. Meta-analysis (RR 0.32; 95% CI 0.15 to 0.69; p < 0.00; I2 = 0%; two trials; very low certainty) showed evidence of a beneficial effect of bromhexine versus standard care on non-serious adverse events, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm or reject realistic intervention effects. Meta-analyses and trial sequential analyses (boundary for futility crossed) showed that we could reject that hydroxychloroquine versus control reduced the risk of death and serious adverse events by 20%. Meta-analyses and trial sequential analyses (boundary for futility crossed) showed that we could reject that lopinavir-ritonavir versus control reduced the risk of death, serious adverse events, and mechanical ventilation by 20%. All remaining outcome comparisons showed that we did not have enough information to confirm or reject realistic intervention effects. Nine single trials showed statistically significant results on our outcomes, but were underpowered to confirm or reject realistic intervention effects. Due to lack of data, it was not relevant to perform network meta-analysis or possible to perform individual patient data meta-analyses.ConclusionsNo evidence-based treatment for COVID-19 currently exists. Very low certainty evidence indicates that corticosteroids might reduce the risk of death, serious adverse events, and mechanical ventilation; that remdesivir might reduce the risk of serious adverse events; that intravenous immunoglobin might reduce the risk of death and serious adverse events; that tocilizumab might reduce the risk of serious adverse events and mechanical ventilation; and that bromhexine might reduce the risk of non-serious adverse events. More trials with low risks of bias and random errors are urgently needed. This review will continuously inform best practice in treatment and clinical research of COVID-19.Systematic review registrationPROSPERO CRD42020178787. Background COVID-19 is a rapidly spreading disease that has caused extensive burden to individuals, families, countries, and the world. Effective treatments of COVID-19 are urgently needed. This is the second edition of a living systematic review of randomized clinical trials assessing the effects of all treatment interventions for participants in all age groups with COVID-19. Methods and findings We planned to conduct aggregate data meta-analyses, trial sequential analyses, network meta-analysis, and individual patient data meta-analyses. Our systematic review was based on PRISMA and Cochrane guidelines, and our eight-step procedure for better validation of clinical significance of meta-analysis results. We performed both fixed-effect and random-effects meta-analyses. Primary outcomes were all-cause mortality and serious adverse events. Secondary outcomes were admission to intensive care, mechanical ventilation, renal replacement therapy, quality of life, and non-serious adverse events. According to the number of outcome comparisons, we adjusted our threshold for significance to p = 0.033. We used GRADE to assess the certainty of evidence. We searched relevant databases and websites for published and unpublished trials until November 2, 2020. Two reviewers independently extracted data and assessed trial methodology. We included 82 randomized clinical trials enrolling a total of 40,249 participants. 81 out of 82 trials were at overall high risk of bias. Meta-analyses showed no evidence of a difference between corticosteroids versus control on all-cause mortality (risk ratio [RR] 0.89; 95% confidence interval [CI] 0.79 to 1.00; p = 0.05; I.sup.2 = 23.1%; eight trials; very low certainty), on serious adverse events (RR 0.89; 95% CI 0.80 to 0.99; p = 0.04; I.sup.2 = 39.1%; eight trials; very low certainty), and on mechanical ventilation (RR 0.86; 95% CI 0.55 to 1.33; p = 0.49; I.sup.2 = 55.3%; two trials; very low certainty). The fixed-effect meta-analyses showed indications of beneficial effects. Trial sequential analyses showed that the required information size for all three analyses was not reached. Meta-analysis (RR 0.93; 95% CI 0.82 to 1.07; p = 0.31; I.sup.2 = 0%; four trials; moderate certainty) and trial sequential analysis (boundary for futility crossed) showed that we could reject that remdesivir versus control reduced the risk of death by 20%. Meta-analysis (RR 0.82; 95% CI 0.68 to 1.00; p = 0.05; I.sup.2 = 38.9%; four trials; very low certainty) and trial sequential analysis (required information size not reached) showed no evidence of difference between remdesivir versus control on serious adverse events. Fixed-effect meta-analysis showed indications of a beneficial effect of remdesivir on serious adverse events. Meta-analysis (RR 0.40; 95% CI 0.19 to 0.87; p = 0.02; I.sup.2 = 0%; two trials; very low certainty) showed evidence of a beneficial effect of intravenous immunoglobulin versus control on all-cause mortality, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm or reject realistic intervention effects. Meta-analysis (RR 0.63; 95% CI 0.35 to 1.14; p = 0.12; I.sup.2 = 77.4%; five trials; very low certainty) and trial sequential analysis (required information size not reached) showed no evidence of a difference between tocilizumab versus control on serious adverse events. Fixed-effect meta-analysis showed indications of a beneficial effect of tocilizumab on serious adverse events. Meta-analysis (RR 0.70; 95% CI 0.51 to 0.96; p = 0.02; I.sup.2 = 0%; three trials; very low certainty) showed evidence of a beneficial effect of tocilizumab versus control on mechanical ventilation, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm of reject realistic intervention effects. Meta-analysis (RR 0.32; 95% CI 0.15 to 0.69; p < 0.00; I.sup.2 = 0%; two trials; very low certainty) showed evidence of a beneficial effect of bromhexine versus standard care on non-serious adverse events, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm or reject realistic intervention effects. Meta-analyses and trial sequential analyses (boundary for futility crossed) showed that we could reject that hydroxychloroquine versus control reduced the risk of death and serious adverse events by 20%. Meta-analyses and trial sequential analyses (boundary for futility crossed) showed that we could reject that lopinavir-ritonavir versus control reduced the risk of death, serious adverse events, and mechanical ventilation by 20%. All remaining outcome comparisons showed that we did not have enough information to confirm or reject realistic intervention effects. Nine single trials showed statistically significant results on our outcomes, but were underpowered to confirm or reject realistic intervention effects. Due to lack of data, it was not relevant to perform network meta-analysis or possible to perform individual patient data meta-analyses. Conclusions No evidence-based treatment for COVID-19 currently exists. Very low certainty evidence indicates that corticosteroids might reduce the risk of death, serious adverse events, and mechanical ventilation; that remdesivir might reduce the risk of serious adverse events; that intravenous immunoglobin might reduce the risk of death and serious adverse events; that tocilizumab might reduce the risk of serious adverse events and mechanical ventilation; and that bromhexine might reduce the risk of non-serious adverse events. More trials with low risks of bias and random errors are urgently needed. This review will continuously inform best practice in treatment and clinical research of COVID-19. Systematic review registration PROSPERO CRD42020178787. COVID-19 is a rapidly spreading disease that has caused extensive burden to individuals, families, countries, and the world. Effective treatments of COVID-19 are urgently needed. This is the second edition of a living systematic review of randomized clinical trials assessing the effects of all treatment interventions for participants in all age groups with COVID-19. We planned to conduct aggregate data meta-analyses, trial sequential analyses, network meta-analysis, and individual patient data meta-analyses. Our systematic review was based on PRISMA and Cochrane guidelines, and our eight-step procedure for better validation of clinical significance of meta-analysis results. We performed both fixed-effect and random-effects meta-analyses. Primary outcomes were all-cause mortality and serious adverse events. Secondary outcomes were admission to intensive care, mechanical ventilation, renal replacement therapy, quality of life, and non-serious adverse events. According to the number of outcome comparisons, we adjusted our threshold for significance to p = 0.033. We used GRADE to assess the certainty of evidence. We searched relevant databases and websites for published and unpublished trials until November 2, 2020. Two reviewers independently extracted data and assessed trial methodology. We included 82 randomized clinical trials enrolling a total of 40,249 participants. 81 out of 82 trials were at overall high risk of bias. Meta-analyses showed no evidence of a difference between corticosteroids versus control on all-cause mortality (risk ratio [RR] 0.89; 95% confidence interval [CI] 0.79 to 1.00; p = 0.05; I2 = 23.1%; eight trials; very low certainty), on serious adverse events (RR 0.89; 95% CI 0.80 to 0.99; p = 0.04; I2 = 39.1%; eight trials; very low certainty), and on mechanical ventilation (RR 0.86; 95% CI 0.55 to 1.33; p = 0.49; I2 = 55.3%; two trials; very low certainty). The fixed-effect meta-analyses showed indications of beneficial effects. Trial sequential analyses showed that the required information size for all three analyses was not reached. Meta-analysis (RR 0.93; 95% CI 0.82 to 1.07; p = 0.31; I2 = 0%; four trials; moderate certainty) and trial sequential analysis (boundary for futility crossed) showed that we could reject that remdesivir versus control reduced the risk of death by 20%. Meta-analysis (RR 0.82; 95% CI 0.68 to 1.00; p = 0.05; I2 = 38.9%; four trials; very low certainty) and trial sequential analysis (required information size not reached) showed no evidence of difference between remdesivir versus control on serious adverse events. Fixed-effect meta-analysis showed indications of a beneficial effect of remdesivir on serious adverse events. Meta-analysis (RR 0.40; 95% CI 0.19 to 0.87; p = 0.02; I2 = 0%; two trials; very low certainty) showed evidence of a beneficial effect of intravenous immunoglobulin versus control on all-cause mortality, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm or reject realistic intervention effects. Meta-analysis (RR 0.63; 95% CI 0.35 to 1.14; p = 0.12; I2 = 77.4%; five trials; very low certainty) and trial sequential analysis (required information size not reached) showed no evidence of a difference between tocilizumab versus control on serious adverse events. Fixed-effect meta-analysis showed indications of a beneficial effect of tocilizumab on serious adverse events. Meta-analysis (RR 0.70; 95% CI 0.51 to 0.96; p = 0.02; I2 = 0%; three trials; very low certainty) showed evidence of a beneficial effect of tocilizumab versus control on mechanical ventilation, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm of reject realistic intervention effects. Meta-analysis (RR 0.32; 95% CI 0.15 to 0.69; p < 0.00; I2 = 0%; two trials; very low certainty) showed evidence of a beneficial effect of bromhexine versus standard care on non-serious adverse events, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm or reject realistic intervention effects. Meta-analyses and trial sequential analyses (boundary for futility crossed) showed that we could reject that hydroxychloroquine versus control reduced the risk of death and serious adverse events by 20%. Meta-analyses and trial sequential analyses (boundary for futility crossed) showed that we could reject that lopinavir-ritonavir versus control reduced the risk of death, serious adverse events, and mechanical ventilation by 20%. All remaining outcome comparisons showed that we did not have enough information to confirm or reject realistic intervention effects. Nine single trials showed statistically significant results on our outcomes, but were underpowered to confirm or reject realistic intervention effects. Due to lack of data, it was not relevant to perform network meta-analysis or possible to perform individual patient data meta-analyses. No evidence-based treatment for COVID-19 currently exists. Very low certainty evidence indicates that corticosteroids might reduce the risk of death, serious adverse events, and mechanical ventilation; that remdesivir might reduce the risk of serious adverse events; that intravenous immunoglobin might reduce the risk of death and serious adverse events; that tocilizumab might reduce the risk of serious adverse events and mechanical ventilation; and that bromhexine might reduce the risk of non-serious adverse events. More trials with low risks of bias and random errors are urgently needed. This review will continuously inform best practice in treatment and clinical research of COVID-19. PROSPERO CRD42020178787. About the Authors: Sophie Juul Roles Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing * E-mail: sophie.juul@ctu.dk Affiliation: Copenhagen Trial Unit–Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark ORCID logo https://orcid.org/0000-0002-6171-2904 Emil Eik Nielsen Roles Data curation, Formal analysis, Investigation, Methodology, Writing – review & editing Affiliations Copenhagen Trial Unit–Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark, Department of Internal Medicine–Cardiology Section, Holbæk Hospital, Holbæk, Denmark Joshua Feinberg Roles Data curation, Formal analysis, Investigation, Methodology, Writing – review & editing Affiliation: Copenhagen Trial Unit–Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark Faiza Siddiqui Roles Data curation, Formal analysis, Investigation, Methodology, Software, Validation, Visualization, Writing – original draft, Writing – review & editing Affiliation: Copenhagen Trial Unit–Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark Caroline Kamp Jørgensen Roles Data curation, Formal analysis, Investigation, Methodology, Software, Validation, Visualization, Writing – original draft, Writing – review & editing Affiliation: Copenhagen Trial Unit–Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark Emily Barot Roles Data curation, Investigation, Methodology Affiliation: Copenhagen Trial Unit–Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark Johan Holgersson Roles Data curation, Investigation, Methodology, Writing – review & editing Affiliation: Department of Clinical Sciences Lund, Anesthesia & Intensive Care, Helsingborg Hospital, Lund University, Lund, Sweden Niklas Nielsen Roles Conceptualization, Funding acquisition, Supervision, Writing – review & editing Affiliation: Department of Clinical Sciences Lund, Anesthesia & Intensive Care, Helsingborg Hospital, Lund University, Lund, Sweden Peter Bentzer Roles Conceptualization, Funding acquisition, Supervision, Writing – review & editing Affiliation: Department of Clinical Sciences Lund, Anesthesia & Intensive Care, Helsingborg Hospital, Lund University, Lund, Sweden Areti Angeliki Veroniki Roles Conceptualization, Methodology, Supervision, Writing – review & editing Affiliations Department of Primary Education, School of Education, University of Ioannina, Ioannina, Greece, Knowledge Translation Program, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada Lehana Thabane Roles Conceptualization, Supervision, Writing – review & editing Affiliation: Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada Fanlong Bu Roles Data curation, Investigation, Methodology, Writing – review & editing Affiliation: Centre for Evidence-based Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China Sarah Klingenberg Roles Data curation, Writing – review & editing Affiliation: Copenhagen Trial Unit–Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark Christian Gluud Roles Conceptualization, Funding acquisition, Investigation, Methodology, Resources, Supervision, Writing – review & editing Affiliation: Copenhagen Trial Unit–Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark ORCID logo https://orcid.org/0000-0002-8861-0799 Janus Christian Jakobsen Roles Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing Affiliations Copenhagen Trial Unit–Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark Introduction In December 2019, the emergence of a novel coronavirus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), caused a rapid international outbreak of the respiratory illness COVID-19 [1]. Since the initial outbreak in China, SARS-CoV-2 has spread globally and COVID-19 is currently labeled a public health emergency of global concern by the World Health Organization [2]. [...]it is rare that a single trial can sufficiently assess the effects of any intervention. [...]there is an urgent need to continuously surveil the emerging evidence and present aggregate data so that effective treatments, if such exist, are rapidly implemented in clinical practice [7]. An information specialist searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, Medical Literature Analysis and Retrieval System Online (MEDLINE Ovid), Excerpta Medica database (Embase Ovid), Latin American and Caribbean Health Sciences Literature (LILACS; Bireme), Science Citation Index Expanded (SCI-EXPANDED; Web of Science), Conference Proceedings Citation Index–Science (CPCI-S; Web of Science), BIOSIS (Web of Science), CINAHL (EBSCO host), Chinese Biomedical Literature Database (CBM), China Network Knowledge Information (CNKI), Chinese Science Journal Database (VIP), and Wanfang Database to identify relevant trials. Because we primarily considered results of secondary outcomes as hypothesis generating, we did not adjust the |
| Audience | Academic |
| Author | Gluud, Christian Nielsen, Emil Eik Veroniki, Areti Angeliki Bu, Fanlong Jørgensen, Caroline Kamp Bentzer, Peter Barot, Emily Siddiqui, Faiza Feinberg, Joshua Holgersson, Johan Juul, Sophie Thabane, Lehana Nielsen, Niklas Klingenberg, Sarah Jakobsen, Janus Christian |
| AuthorAffiliation | 2 Department of Internal Medicine–Cardiology Section, Holbæk Hospital, Holbæk, Denmark 3 Department of Clinical Sciences Lund, Anesthesia & Intensive Care, Helsingborg Hospital, Lund University, Lund, Sweden 6 Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada Humanitas University, ITALY 1 Copenhagen Trial Unit–Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark 7 Centre for Evidence-based Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China 5 Knowledge Translation Program, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada 4 Department of Primary Education, School of Education, University of Ioannina, Ioannina, Greece 8 Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark |
| AuthorAffiliation_xml | – name: 3 Department of Clinical Sciences Lund, Anesthesia & Intensive Care, Helsingborg Hospital, Lund University, Lund, Sweden – name: 8 Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark – name: 5 Knowledge Translation Program, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada – name: 2 Department of Internal Medicine–Cardiology Section, Holbæk Hospital, Holbæk, Denmark – name: Humanitas University, ITALY – name: 4 Department of Primary Education, School of Education, University of Ioannina, Ioannina, Greece – name: 6 Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada – name: 7 Centre for Evidence-based Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China – name: 1 Copenhagen Trial Unit–Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark |
| Author_xml | – sequence: 1 givenname: Sophie orcidid: 0000-0002-6171-2904 surname: Juul fullname: Juul, Sophie – sequence: 2 givenname: Emil Eik surname: Nielsen fullname: Nielsen, Emil Eik – sequence: 3 givenname: Joshua surname: Feinberg fullname: Feinberg, Joshua – sequence: 4 givenname: Faiza surname: Siddiqui fullname: Siddiqui, Faiza – sequence: 5 givenname: Caroline Kamp surname: Jørgensen fullname: Jørgensen, Caroline Kamp – sequence: 6 givenname: Emily surname: Barot fullname: Barot, Emily – sequence: 7 givenname: Johan surname: Holgersson fullname: Holgersson, Johan – sequence: 8 givenname: Niklas surname: Nielsen fullname: Nielsen, Niklas – sequence: 9 givenname: Peter surname: Bentzer fullname: Bentzer, Peter – sequence: 10 givenname: Areti Angeliki surname: Veroniki fullname: Veroniki, Areti Angeliki – sequence: 11 givenname: Lehana surname: Thabane fullname: Thabane, Lehana – sequence: 12 givenname: Fanlong surname: Bu fullname: Bu, Fanlong – sequence: 13 givenname: Sarah surname: Klingenberg fullname: Klingenberg, Sarah – sequence: 14 givenname: Christian orcidid: 0000-0002-8861-0799 surname: Gluud fullname: Gluud, Christian – sequence: 15 givenname: Janus Christian surname: Jakobsen fullname: Jakobsen, Janus Christian |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/33705495$$D View this record in MEDLINE/PubMed |
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| Cites_doi | 10.1016/S0140-6736(20)30183-5 10.1016/j.ejim.2016.03.020 10.1503/cmaj.120744 10.1016/j.jclinepi.2007.03.013 10.1016/S2213-2600(20)30076-X 10.1186/1471-2288-10-90 10.1136/bmj.m2980 10.1186/s13643-020-01371-0 10.1136/bmj.b2700 10.1016/S0140-6736(20)31042-4 10.1016/S0140-6736(20)31862-6 10.1093/ije/31.1.96 10.1001/jama.2020.16349 10.1016/S2589-7500(20)30086-8 10.1093/ije/dyn188 10.34172/bi.2020.27 10.1186/1471-2288-14-120 10.4269/ajtmh.20-0873 10.1093/ofid/ofaa241 10.1093/ije/dyu115 10.1371/journal.pmed.1003293 10.1056/NEJMoa2007764 10.1136/bmjopen-2016-011890 10.1001/jama.2020.17022 10.1056/NEJMe2002387 10.1016/j.bja.2020.02.020 10.1136/bmj.e1119 10.1093/aje/kwj069 10.1016/j.intimp.2020.106903 10.1371/journal.pmed.1000097 10.15586/jptcp.v27iSP1.684 10.7326/0003-4819-135-11-200112040-00010 10.1001/jamanetworkopen.2020.13136 10.1186/s13287-020-01875-5 10.1186/1471-2288-9-86 10.1016/S0140-6736(98)01085-X 10.1016/j.jclinepi.2007.10.007 10.1186/s13054-020-03220-x 10.1016/S0140-6736(20)31022-9 10.1001/jama.1995.03520290060030 10.1093/ije/dyn179 10.1001/jama.2020.16761 10.1136/bmj.323.7303.42 10.1056/NEJMoa2001282 10.1136/bmj.m1849 10.1056/NEJMoa2002032 10.1016/S0140-6736(20)30154-9 10.1093/jac/dkaa334 |
| ContentType | Journal Article |
| Copyright | COPYRIGHT 2021 Public Library of Science 2021 Juul et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. 2021 Juul et al 2021 Juul et al |
| Copyright_xml | – notice: COPYRIGHT 2021 Public Library of Science – notice: 2021 Juul et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. – notice: 2021 Juul et al 2021 Juul et al |
| CorporateAuthor | Institutionen för kliniska vetenskaper, Lund Infektionsmedicin Sektion II Lunds universitet Section II Lund University Sektion III Cirkulationsfysiologi vid kritisk sjukdom Department of Clinical Sciences, Lund Anesthesiology and Intensive Care Faculty of Medicine Fluid resuscitation in critical illness SEBRA Sepsis and Bacterial Resistance Alliance Section III Infection Medicine (BMC) Medicinska fakulteten Anestesiologi och intensivvård |
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| DOI | 10.1371/journal.pone.0248132 |
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| References | AP Vlaar (pone.0248132.ref069) 2020 AA Ivashchenko (pone.0248132.ref066) 2020 P Horby (pone.0248132.ref057) 2020 Z Chen (pone.0248132.ref034) 2020 R Mehboob (pone.0248132.ref068) 2020 S Juul (pone.0248132.ref008) 2020; 9 BM Tomazini (pone.0248132.ref086) 2020 E Mansour (pone.0248132.ref071) 2020 Y Cao (pone.0248132.ref114) 2020 K Thorlund (pone.0248132.ref028) 2011 K Thorlund (pone.0248132.ref026) 2008; 38 K Thorlund (pone.0248132.ref029) 2010; 2 L Shu (pone.0248132.ref074) 2020; 11 H Rahmani (pone.0248132.ref080) 2020; 88 KF Schulz (pone.0248132.ref126) 1995; 273 MN Lyngbakken (pone.0248132.ref104) 2020 O Mitjà (pone.0248132.ref054) 2020 L Corral-Gudino (pone.0248132.ref055) 2020 L-l Cheng (pone.0248132.ref084) 2020 J Higgins (pone.0248132.ref020) 2011 C Salvarani (pone.0248132.ref111) 2020 RHM Furtado (pone.0248132.ref082) 2020; 396 CN Wu (pone.0248132.ref043) 2020; 125 F Keus (pone.0248132.ref016) 2010; 10 JH Stone (pone.0248132.ref112) 2020 B Cao (pone.0248132.ref003) 2020; 382 P Jüni (pone.0248132.ref124) 2001; 323 M Nojomi (pone.0248132.ref108) 2020 X Wu (pone.0248132.ref101) 2020 M Duarte (pone.0248132.ref065) 2020 H Abbaspour Kasgari (pone.0248132.ref078) 2020 RA Siemieniuk (pone.0248132.ref117) 2020; 370 ME Castillo (pone.0248132.ref083) 2020 MGS Borba (pone.0248132.ref049) 2020; 3 AB Cavalcanti (pone.0248132.ref053) 2020 A Gharbharan (pone.0248132.ref050) 2020 JH Beigel (pone.0248132.ref064) 2020; 383 A Sadeghi (pone.0248132.ref079) 2020; 75 CMP Jeronimo (pone.0248132.ref067) 2020 The Writing Committee for the REMAP-CAP Investigators (pone.0248132.ref088) 2020; 324 Y Wang (pone.0248132.ref042) 2020; 395 L Chen (pone.0248132.ref047) 2020 C Axfors (pone.0248132.ref120) 2020 T Li (pone.0248132.ref093) 2020 J Wetterslev (pone.0248132.ref023) 2008; 61 G Imberger (pone.0248132.ref030) 2016; 6 I Rosas (pone.0248132.ref089) 2020 A Liberati (pone.0248132.ref010) 2009; 339 JP Higgins (pone.0248132.ref021) 2002; 31 J Chen (pone.0248132.ref059) 2020; 7 F Zheng (pone.0248132.ref044) 2020 T Duymaz (pone.0248132.ref070) 2020 Y-K Chen (pone.0248132.ref060) 2020 X Yuan (pone.0248132.ref062) 2020 L Li (pone.0248132.ref038) 2020; 324 J Chen (pone.0248132.ref033) 2020; 49 pone.0248132.ref022 SG Deftereos (pone.0248132.ref048) 2020; 3 JF Chan (pone.0248132.ref005) 2020; 395 J Miller (pone.0248132.ref073) 2020; 24 E Sekhavati (pone.0248132.ref081); 2020 Z Xu (pone.0248132.ref006) 2020; 8 S Abd-Elsalam (pone.0248132.ref076) 2020; 103 W Tang (pone.0248132.ref041) 2020; 369 A Agarwal (pone.0248132.ref090) 2020 Z Ren (pone.0248132.ref072) 2020; 7 pone.0248132.ref018 A Hrobjartsson (pone.0248132.ref129) 2012; 344 P Horby (pone.0248132.ref046) 2020 K Thorlund (pone.0248132.ref013) 2020; 2 M Zhong (pone.0248132.ref045) 2020 J Zhang (pone.0248132.ref075) 2020 F Salehzadeh (pone.0248132.ref106) 2020 PW Horby (pone.0248132.ref105) 2020 C Avendano-Sola (pone.0248132.ref077) 2020 C Chen (pone.0248132.ref032) 2020 LL Kjaergard (pone.0248132.ref123) 2001; 135 O Guvenmez (pone.0248132.ref061) 2020; 27 JH Beigel (pone.0248132.ref031) 2020 M Edalatifard (pone.0248132.ref097) 2020 MIF Lopes (pone.0248132.ref091) 2020 Y Li (pone.0248132.ref039) 2020 RH Farahani (pone.0248132.ref095) 2020 W Guan (pone.0248132.ref001) 2020; 382 J Wetterslev (pone.0248132.ref027) 2009; 9 G Sakoulas (pone.0248132.ref056) 2020 AS Fauci (pone.0248132.ref007) 2020; 382 JD Goldman (pone.0248132.ref036) 2020 L Davoodi (pone.0248132.ref115); 2020 CP Skipper (pone.0248132.ref052) 2020 P-F Dequin (pone.0248132.ref087) 2020; 324 H Zhao (pone.0248132.ref113) 2020 pone.0248132.ref002 S Juul (pone.0248132.ref118) 2020; 17 Y Lou (pone.0248132.ref040) 2020 J Brok (pone.0248132.ref024) 2008; 61 StataCorp (pone.0248132.ref019) 2019 J Brok (pone.0248132.ref025) 2008; 38 A Hrobjartsson (pone.0248132.ref127) 2014; 43 RECOVERY Collaborative Group (pone.0248132.ref051) 2020 K Ansarin (pone.0248132.ref103) 2020; 10 CD Spinner (pone.0248132.ref085) 2020; 324 D Wang (pone.0248132.ref092) 2020 A Hrobjartsson (pone.0248132.ref128) 2013; 185 D Moher (pone.0248132.ref009) 2009; 6 pone.0248132.ref119 pone.0248132.ref015 N Gharebaghi (pone.0248132.ref094) 2020 C Huang (pone.0248132.ref004) 2020; 395 JC Jakobsen (pone.0248132.ref017) 2014; 14 pone.0248132.ref098 E Davoudi-Monfared (pone.0248132.ref035) 2020 E-M Idelsis (pone.0248132.ref063) 2020 RJ Ulrich (pone.0248132.ref107) 2020 pone.0248132.ref012 LL Gluud (pone.0248132.ref122) 2006; 163 pone.0248132.ref130 pone.0248132.ref096 IF-N Hung (pone.0248132.ref037) 2020; 395 I Delgado-Enciso (pone.0248132.ref099) KS Kimura (pone.0248132.ref100) 2020 O Hermine (pone.0248132.ref110) 2020 D Moher (pone.0248132.ref125) 1998; 352 S Garattini (pone.0248132.ref121) 2016; 32 JCG de Alencar (pone.0248132.ref102) 2020 JA Sterne (pone.0248132.ref014) 2019; 366 J Higgins (pone.0248132.ref011) 2019 H Pan (pone.0248132.ref109) 2020 JA Sterne (pone.0248132.ref116) 2020 C-P Chen (pone.0248132.ref058) 2020 |
| References_xml | – volume: 395 start-page: 497 issue: 10223 year: 2020 ident: pone.0248132.ref004 article-title: Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. publication-title: Lancet. doi: 10.1016/S0140-6736(20)30183-5 – year: 2020 ident: pone.0248132.ref039 article-title: Efficacy and safety of lopinavir/ritonavir or arbidol in adult patients with mild/moderate COVID-19: an exploratory randomized controlled trial publication-title: Cell Press – ident: pone.0248132.ref015 – year: 2020 ident: pone.0248132.ref104 article-title: A pragmatic randomized controlled trial reports the efficacy of hydroxychloroquine on coronavirus disease 2019 viral kinetics. publication-title: Research Square. – year: 2020 ident: pone.0248132.ref084 article-title: Effect of recombinant human granulocyte colony–stimulating factor for patients with coronavirus disease 2019 (COVID-19) and lymphopenia: a randomized clinical trial. publication-title: JAMA Intern med – year: 2020 ident: pone.0248132.ref107 article-title: Treating COVID-19 with hydroxychloroquine (TEACH): a multicenter, double-blind, randomized controlled trial in hospitalized patients. publication-title: Open Forum Infect Dis. – ident: pone.0248132.ref018 – volume: 32 start-page: 13 year: 2016 ident: pone.0248132.ref121 article-title: Evidence-based clinical practice: Overview of threats to the validity of evidence and how to minimise them publication-title: Eur J Intern Med doi: 10.1016/j.ejim.2016.03.020 – year: 2020 ident: pone.0248132.ref056 article-title: Intravenous Immunoglobulin (IVIG) significantly reduces respiratory morbidity in COVID-19 pneumonia: a prospective randomized trial. publication-title: medRxiv. – year: 2020 ident: pone.0248132.ref070 article-title: Pulmonary rehabilitation in post-acute period of COVID-19 infection: prospective randomized controleld trial. publication-title: SSRN. – volume: 185 issue: 4 year: 2013 ident: pone.0248132.ref128 article-title: Observer bias in randomized clinical trials with measurement scale outcomes: a systematic review of trials with both blinded and nonblinded assessors. publication-title: CMAJ doi: 10.1503/cmaj.120744 – year: 2020 ident: pone.0248132.ref092 article-title: Tocilizumab ameliorates the hypoxia in COVID-19 moderate patients with bilateral pulmonary lesions: a randomized, controlled, open-label, multicenter trial. publication-title: SSRN – ident: pone.0248132.ref099 article-title: Patient-reported health outcomes after treatment of COVID-19 with nebulized and/or intravenous neutral electrolyzed saline combined with usual medical care versus usual medical care alone: a randomized, open-label, controlled trial. publication-title: Research Square. – year: 2020 ident: pone.0248132.ref100 article-title: Interim analysis of an open-label randomized controlled trial evaluating nasal irrigations in non-hospitalized patients with COVID-19 publication-title: Int Forum Allergy Rhinol – ident: pone.0248132.ref130 – volume: 366 year: 2019 ident: pone.0248132.ref014 article-title: RoB 2: a revised tool for assessing risk of bias in randomised trials publication-title: BMJ – volume: 61 start-page: 64 issue: 1 year: 2008 ident: pone.0248132.ref023 article-title: Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis. publication-title: J Clin Epidemiol doi: 10.1016/j.jclinepi.2007.03.013 – year: 2020 ident: pone.0248132.ref054 article-title: Hydroxychloroquine for early treatment of adults with mild covid-19: a randomized-controlled trial publication-title: Clin Infect Dis – year: 2020 ident: pone.0248132.ref108 article-title: Effect of arbidol on COVID-19: a randomized controlled trial. publication-title: Research Square. – volume: 8 start-page: 420 issue: 4 year: 2020 ident: pone.0248132.ref006 article-title: Pathological findings of COVID-19 associated with acute respiratory distress syndrome publication-title: Lancet Respir Med. doi: 10.1016/S2213-2600(20)30076-X – volume: 10 start-page: 90 issue: 1 year: 2010 ident: pone.0248132.ref016 article-title: Evidence at a glance: error matrix approach for overviewing available evidence publication-title: BMC Med Res Methodol doi: 10.1186/1471-2288-10-90 – volume: 370 start-page: m2980 year: 2020 ident: pone.0248132.ref117 article-title: Drug treatments for covid-19: living systematic review and network meta-analysis publication-title: BMJ doi: 10.1136/bmj.m2980 – volume: 9 start-page: 108 issue: 1 year: 2020 ident: pone.0248132.ref008 article-title: Interventions for treatment of COVID-19: a protocol for a living systematic review with network meta-analysis including individual patient data (The LIVING Project). publication-title: Syst Rev. doi: 10.1186/s13643-020-01371-0 – volume: 2020 start-page: e13600 ident: pone.0248132.ref115 article-title: Febuxostat therapy in outpatients with suspected COVID-19: A clinical trial. publication-title: Int J Clin Pract – volume: 339 start-page: b2700 year: 2009 ident: pone.0248132.ref010 article-title: The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration publication-title: BMJ doi: 10.1136/bmj.b2700 – start-page: 2020 year: 2020 ident: pone.0248132.ref077 article-title: Convalescent plasma for COVID-19: A multicenter, randomized clinical trial. publication-title: medRxiv – start-page: 2020 year: 2020 ident: pone.0248132.ref034 article-title: Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. publication-title: medRxiv – volume: 2 start-page: 57 year: 2010 ident: pone.0248132.ref029 article-title: Interpreting meta-analysis according to the adequacy of sample size. An example using isoniazid chemoprophylaxis for tuberculosis in purified protein derivative negative HIV-infected individuals publication-title: Clin Epidemiol – year: 2020 ident: pone.0248132.ref075 article-title: High-dose vitamin C infusion for the treatment of critically ill COVID-19. publication-title: Research Square. – year: 2020 ident: pone.0248132.ref093 article-title: Bromhexine hydrochloride tablets for the treatment of moderate COVID-19: an open-label randomized controlled pilot study. publication-title: Clin Transl Sci. – ident: pone.0248132.ref022 – volume: 395 start-page: 1695 year: 2020 ident: pone.0248132.ref037 article-title: Triple combination of interferon beta-1b, lopinavir–ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial publication-title: Lancet doi: 10.1016/S0140-6736(20)31042-4 – volume: 7 issue: 19 year: 2020 ident: pone.0248132.ref072 article-title: A randomized, open-label, controlled clinical trial of azvudine tablets in the treatment of mild and common COVID-19, a pilot study. publication-title: Adv Sci. – year: 2011 ident: pone.0248132.ref028 publication-title: User manual for trial sequential analysis (TSA). – year: 2020 ident: pone.0248132.ref062 article-title: Pulmonary radiological change of COVID-19 patients with 99mTc-MDP treatment. publication-title: medRxiv. – year: 2020 ident: pone.0248132.ref111 article-title: Effect of tocilizumab vs standard care on clinical worsening in patients hospitalized with COVID-19 pneumonia: a randomized clinical trial publication-title: JAMA Intern Med – year: 2020 ident: pone.0248132.ref116 article-title: Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis publication-title: JAMA – year: 2020 ident: pone.0248132.ref114 article-title: Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): A multicenter, single-blind, randomized controlled trial. publication-title: J Allergy Clin Immunol – year: 2020 ident: pone.0248132.ref035 article-title: Efficacy and safety of interferon beta-1a in treatment of severe COVID-19: a randomized clinical trial. publication-title: medRxiv. – year: 2020 ident: pone.0248132.ref067 article-title: Methylprednisolone as adjunctive therapy for patients hospitalized with COVID-19 (METCOVID): a randomised, double-blind, phase IIb, placebo-controlled trial. publication-title: Clin Infect Dis – year: 2019 ident: pone.0248132.ref011 article-title: Cochrane Handbook for Systematic Reviews of Interventions version 6.0 (updated July 2019). publication-title: Cochrane – year: 2020 ident: pone.0248132.ref109 article-title: Repurposed antiviral drugs for COVID-19; interim WHO SOLIDARITY trial results. publication-title: medRxiv. – volume: 324 start-page: 1 issue: 5 year: 2020 ident: pone.0248132.ref038 article-title: Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial publication-title: JAMA – volume: 396 start-page: 959 year: 2020 ident: pone.0248132.ref082 article-title: Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial. publication-title: Lancet doi: 10.1016/S0140-6736(20)31862-6 – year: 2020 ident: pone.0248132.ref105 article-title: Lopinavir-ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. publication-title: Lancet – year: 2020 ident: pone.0248132.ref036 article-title: Remdesivir for 5 or 10 days in patients with severe Covid-19 publication-title: N Engl J Med – volume: 31 start-page: 96 issue: 1 year: 2002 ident: pone.0248132.ref021 article-title: Being sceptical about meta-analyses: a Bayesian perspective on magnesium trials in myocardial infarction. publication-title: Int J Epidemiol doi: 10.1093/ije/31.1.96 – volume: 324 start-page: 1048 issue: 11 year: 2020 ident: pone.0248132.ref085 article-title: Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: a randomized clinical trial publication-title: JAMA doi: 10.1001/jama.2020.16349 – volume: 2 start-page: e286 issue: 6 year: 2020 ident: pone.0248132.ref013 article-title: A real-time dashboard of clinical trials for COVID-19 publication-title: Lancet Dig Health. doi: 10.1016/S2589-7500(20)30086-8 – ident: pone.0248132.ref002 – volume: 38 start-page: 287 issue: 1 year: 2008 ident: pone.0248132.ref025 article-title: Apparently conclusive meta-analyses may be inconclusive—trial sequential analysis adjustment of random error risk due to repetitive testing of accumulating data in apparently conclusive neonatal meta-analyses. publication-title: Int J Epidemiol doi: 10.1093/ije/dyn188 – volume: 10 start-page: 209 issue: 4 year: 2020 ident: pone.0248132.ref103 article-title: Effect of bromhexine on clinical outcomes and mortality in COVID-19 patients: a randomized clinical trial. publication-title: BioImpacts doi: 10.34172/bi.2020.27 – year: 2020 ident: pone.0248132.ref031 article-title: Remdesivir for the treatment of Covid-19—Preliminary report publication-title: N Engl J Med – volume: 14 start-page: 120 issue: 1 year: 2014 ident: pone.0248132.ref017 article-title: Thresholds for statistical and clinical significance in systematic reviews with meta-analytic methods. publication-title: BMC Med Res Methodol doi: 10.1186/1471-2288-14-120 – volume: 103 start-page: 1635 issue: 4 year: 2020 ident: pone.0248132.ref076 article-title: Hydroxychloroquine in the treatment of COVID-19: a multicenter randomized controlled study publication-title: Am J Trop Med Hyg doi: 10.4269/ajtmh.20-0873 – year: 2020 ident: pone.0248132.ref113 article-title: Tocilizumab combined with favipiravir in the treatment of COVID-19: A multicenter trial in a small sample size publication-title: Biomed Pharmacother – year: 2020 ident: pone.0248132.ref053 article-title: Hydroxychloroquine with or without azithromycin in mild-to-moderate Covid-19 publication-title: N Engl J Med – year: 2020 ident: pone.0248132.ref045 article-title: A randomized, single-blind, group sequential, active-controlled study to evaluate the clinical efficacy and safety of α-Lipoic acid for critically ill patients with coronavirus disease 2019 (COVID-19). publication-title: medRxiv – year: 2020 ident: pone.0248132.ref055 article-title: GLUCOCOVID: A controlled trial of methylprednisolone in adults hospitalized with COVID-19 pneumonia. publication-title: medRxiv. – year: 2020 ident: pone.0248132.ref050 article-title: Convalescent plasma for COVID-19: a randomized clinical trial. publication-title: medrRxiv – volume: 7 start-page: ofaa241 issue: 7 year: 2020 ident: pone.0248132.ref059 article-title: Antiviral activity and safety of darunavir/cobicistat for the treatment of COVID-19. publication-title: Open Forum Infect Dis. doi: 10.1093/ofid/ofaa241 – year: 2020 ident: pone.0248132.ref060 article-title: Comparative effectiveness and safety of ribavirin plus interferon-alpha, lopinavir/ritonavir plus interferon-alpha and ribavirin plus lopinavir/ritonavir plus interferon-alpha in patients with mild to moderate novel coronavirus pneumonia: results of a randomized, open-labeled prospective study. publication-title: SSRN – volume: 43 start-page: 1272 issue: 4 year: 2014 ident: pone.0248132.ref127 article-title: Bias due to lack of patient blinding in clinical trials. A systematic review of trials randomizing patients to blind and nonblind sub-studies. publication-title: Int J Epidemiol. doi: 10.1093/ije/dyu115 – volume: 17 start-page: e1003293 issue: 9 year: 2020 ident: pone.0248132.ref118 article-title: Interventions for treatment of COVID-19: A living systematic review with meta-analyses and trial sequential analyses (The LIVING Project). publication-title: PLOS Med. doi: 10.1371/journal.pmed.1003293 – volume: 383 start-page: 1813 year: 2020 ident: pone.0248132.ref064 article-title: Remdesivir for the treatment of COVID-19—final report. publication-title: N Eng J Med doi: 10.1056/NEJMoa2007764 – year: 2020 ident: pone.0248132.ref057 article-title: Effect of Hydroxychloroquine in Hospitalized Patients with COVID-19: preliminary results from a multi-centre, randomized, controlled trial. publication-title: medRxiv – year: 2020 ident: pone.0248132.ref063 article-title: Effect and safety of combination of interferon alpha-2b and gamma or interferon alpha-2b for negativization of SARS-CoV-2 viral RNA. Preliminary results of a randomized controlled clinical trial. publication-title: medRxiv – volume: 2020 start-page: 106143 ident: pone.0248132.ref081 article-title: Safety and effectiveness of azithromycin in patients with COVID-19: an open-label randomised trial. publication-title: Int J Antimicrob Agents – year: 2020 ident: pone.0248132.ref044 article-title: A novel protein drug, novaferon, as the potential antiviral drug for COVID-19. publication-title: medRxiv – volume: 6 start-page: e011890 issue: 8 year: 2016 ident: pone.0248132.ref030 article-title: False-positive findings in Cochrane meta-analyses with and without application of trial sequential analysis: an empirical review publication-title: BMJ Open doi: 10.1136/bmjopen-2016-011890 – volume: 324 start-page: 1317 issue: 13 year: 2020 ident: pone.0248132.ref088 article-title: Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: the REMAP-CAP COVID-19 corticosteroid domain randomized clinical trial. publication-title: JAMA doi: 10.1001/jama.2020.17022 – year: 2020 ident: pone.0248132.ref101 article-title: Efficacy and safety of triazavirin therapy for coronavirus disease 2019: a pilot randomized controlled trial. publication-title: Engineering – volume: 382 start-page: 1268 year: 2020 ident: pone.0248132.ref007 article-title: Covid-19—navigating the uncharted publication-title: N Engl J Med doi: 10.1056/NEJMe2002387 – volume: 125 start-page: e166 issue: 1 year: 2020 ident: pone.0248132.ref043 article-title: High-flow nasal-oxygenation-assisted fibreoptic tracheal intubation in critically ill patients with COVID-19 pneumonia: a prospective randomised controlled trial publication-title: Br J Anaesth doi: 10.1016/j.bja.2020.02.020 – volume-title: Stata Statistical Software: Release 16 year: 2019 ident: pone.0248132.ref019 – ident: pone.0248132.ref098 – volume: 344 start-page: e1119 year: 2012 ident: pone.0248132.ref129 article-title: Observer bias in randomised clinical trials with binary outcomes: systematic review of trials with both blinded and non-blinded outcome assessors publication-title: BMJ doi: 10.1136/bmj.e1119 – volume: 163 start-page: 493 issue: 6 year: 2006 ident: pone.0248132.ref122 article-title: Bias in clinical intervention research publication-title: Am J Epidemiol doi: 10.1093/aje/kwj069 – volume: 88 start-page: 106903 year: 2020 ident: pone.0248132.ref080 article-title: Interferon β-1b in treatment of severe COVID-19: a randomized clinical trial publication-title: Int Immunopharmacol doi: 10.1016/j.intimp.2020.106903 – year: 2020 ident: pone.0248132.ref078 article-title: Evaluation of the efficacy of sofosbuvir plus daclatasvir in combination with ribavirin for hospitalized COVID-19 patients with moderate disease compared with standard care: a single-centre, randomized controlled trial publication-title: J Antimicrob Chemother – year: 2020 ident: pone.0248132.ref095 article-title: Evaluation of the efficacy of methylprednisolone pulse therapy in treatment of covid-19 adult patients with severe respiratory failure: randomized, clinical trial. publication-title: Research Square. – year: 2020 ident: pone.0248132.ref094 article-title: The use of intravenous immunoglobulin gamma for the treatment of severe coronavirus disease 2019: a randomised placebo-controlled double-blind clinical trial. publication-title: Research Square. – year: 2020 ident: pone.0248132.ref089 article-title: Tocilizumab in hospitalized patients with COVID-19 pneumonia. publication-title: medRxiv. – volume: 6 issue: 7 year: 2009 ident: pone.0248132.ref009 article-title: Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. publication-title: PLOS Med doi: 10.1371/journal.pmed.1000097 – volume: 27 start-page: e5 issue: SP1) year: 2020 ident: pone.0248132.ref061 article-title: The comparison of the effectiveness of lincocin® and azitro® in the treatment of covid-19-associated pneumonia: A prospective study publication-title: J Popul Ther Clin Pharmacol doi: 10.15586/jptcp.v27iSP1.684 – volume: 135 start-page: 982 issue: 11 year: 2001 ident: pone.0248132.ref123 article-title: Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses publication-title: Ann Intern Med doi: 10.7326/0003-4819-135-11-200112040-00010 – volume: 3 start-page: e2013136 issue: 6 year: 2020 ident: pone.0248132.ref048 article-title: Effect of colchicine vs standard care on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019: the GRECCO-19 randomized clinical trial. publication-title: JAMA Netw Open. doi: 10.1001/jamanetworkopen.2020.13136 – volume: 11 start-page: 361 issue: 1 year: 2020 ident: pone.0248132.ref074 article-title: Treatment of severe COVID-19 with human umbilical cord mesenchymal stem cells publication-title: Stem Cell Res Ther doi: 10.1186/s13287-020-01875-5 – volume: 49 issue: 1 year: 2020 ident: pone.0248132.ref033 article-title: A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19). publication-title: J Zhejiang Univ (Med Sci). – year: 2020 ident: pone.0248132.ref069 article-title: Anti-C5a Antibody (IFX-1) Treatment of severe COVID-19: An exploratory phase 2 randomized controlled trial. publication-title: SSRN. – year: 2020 ident: pone.0248132.ref090 article-title: Convalescent plasma in the management of moderate COVID-19 in India: an open-label parallel-arm phase II multicentre randomized controlled trial (PLACID Trial). publication-title: medRxiv – year: 2020 ident: pone.0248132.ref112 article-title: Efficacy of tocilizumab in patients hospitalized with COVID-19. publication-title: N Eng J Med – year: 2020 ident: pone.0248132.ref047 article-title: Efficacy and safety of chloroquine or hydroxychloroquine in moderate type of COVID-19: a prospective open-label randomized controlled study. publication-title: medRxiv. – year: 2020 ident: pone.0248132.ref102 article-title: Double-blind, randomized, placebo-controlled trial with N-acetylcysteine for treatment of severe acute respiratory syndrome caused by COVID-19 publication-title: Clin Infect Dis – volume: 3 issue: 4 year: 2020 ident: pone.0248132.ref049 article-title: Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. publication-title: JAMA Netw Open – year: 2020 ident: pone.0248132.ref086 article-title: Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomized clinical trial publication-title: JAMA – year: 2020 ident: pone.0248132.ref058 article-title: A Multicenter, randomized, open-label, controlled trial to evaluate the efficacy and tolerability of hydroxychloroquine and a retrospective study in adult patients with mild to moderate coronavirus disease 2019 (COVID-19). publication-title: medRxiv – volume: 9 start-page: 86 issue: 1 year: 2009 ident: pone.0248132.ref027 article-title: Estimating required information size by quantifying diversity in random-effects model meta-analyses. publication-title: BMC Med Res Methodol doi: 10.1186/1471-2288-9-86 – year: 2020 ident: pone.0248132.ref051 article-title: Dexamethasone in hospitalized patients with COVID-19—preliminary report. publication-title: N Engl J Med – volume: 352 start-page: 609 issue: 9128 year: 1998 ident: pone.0248132.ref125 article-title: Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses? publication-title: Lancet doi: 10.1016/S0140-6736(98)01085-X – year: 2020 ident: pone.0248132.ref106 article-title: The impact of colchicine on the COVID-19 patients: a clinical trial study. publication-title: Research Square – volume: 61 start-page: 763 issue: 8 year: 2008 ident: pone.0248132.ref024 article-title: Trial sequential analysis reveals insufficient information size and potentially false positive results in many meta-analyses. publication-title: J Clin Epidemiol doi: 10.1016/j.jclinepi.2007.10.007 – year: 2020 ident: pone.0248132.ref091 article-title: Beneficial effects of colchicine for moderate to severe COVID-19: an interim analysis of a randomized, double-blinded, placebo controlled clinical trial. publication-title: medRxiv – start-page: 2020 year: 2020 ident: pone.0248132.ref032 article-title: Favipiravir versus arbidol for COVID-19: A randomized clinical trial. publication-title: medRxiv – year: 2020 ident: pone.0248132.ref083 article-title: Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: a pilot randomized clinical study publication-title: J Steroid Biochem Mol Biol – ident: pone.0248132.ref012 – year: 2020 ident: pone.0248132.ref040 article-title: Clinical outcomes and plasma concentrations of baloxavir marboxil and favipiravir in COVID-19 patients: an exploratory randomized, controlled trial. publication-title: medRxiv – year: 2020 ident: pone.0248132.ref052 article-title: Hydroxychloroquine in nonhospitalized adults with early COVID-19: a randomized trial publication-title: Ann Intern Med – volume: 24 start-page: 502 issue: 1 year: 2020 ident: pone.0248132.ref073 article-title: Auxora versus standard of care for the treatment of severe or critical COVID-19 pneumonia: results from a randomized controlled trial. publication-title: Crit Care. doi: 10.1186/s13054-020-03220-x – ident: pone.0248132.ref119 – volume: 395 start-page: 1569 issue: 10236 year: 2020 ident: pone.0248132.ref042 article-title: Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial publication-title: Lancet doi: 10.1016/S0140-6736(20)31022-9 – start-page: 2020 year: 2020 ident: pone.0248132.ref066 article-title: AVIFAVIR for treatment of patients with moderate COVID-19: interim results of a phase II/III multicenter randomized clinical trial. publication-title: medRxiv – start-page: 2020 year: 2020 ident: pone.0248132.ref071 article-title: Pharmacological inhibition of the kinin-kallikrein system in severe COVID-19: a proof-of-concept study. publication-title: medRxiv – volume: 273 start-page: 408 issue: 5 year: 1995 ident: pone.0248132.ref126 article-title: Empirical evidence of bias: dimensions of methodological quality associated with estimates of treatment effects in controlled trials publication-title: JAMA doi: 10.1001/jama.1995.03520290060030 – volume: 38 start-page: 276 issue: 1 year: 2008 ident: pone.0248132.ref026 article-title: Can trial sequential monitoring boundaries reduce spurious inferences from meta-analyses? publication-title: Int J Epidemiol doi: 10.1093/ije/dyn179 – ident: pone.0248132.ref096 – start-page: 2020 year: 2020 ident: pone.0248132.ref068 article-title: Aprepitant as a combinant with dexamethasone reduces the inflammation via neurokinin 1 receptor antagonism in severe to critical COVID-19 patients and potentiates respiratory recovery: a novel therapeutic approach. publication-title: medRxiv – year: 2020 ident: pone.0248132.ref110 article-title: Effect of tocilizumab vs usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia: a randomized clinical trial publication-title: JAMA Intern Med – volume: 324 start-page: 1298 issue: 13 year: 2020 ident: pone.0248132.ref087 article-title: Effect of hydrocortisone on 21-Day mortality or respiratory support among critically ill patients with COVID-19: a randomized clinical trial publication-title: JAMA doi: 10.1001/jama.2020.16761 – volume: 323 start-page: 42 issue: 7303 year: 2001 ident: pone.0248132.ref124 article-title: Assessing the quality of controlled clinical trials publication-title: BMJ doi: 10.1136/bmj.323.7303.42 – year: 2020 ident: pone.0248132.ref046 article-title: Effect of dexamethasone in hospitalized patients with COVID-19 –preliminary report. publication-title: medRxiv – start-page: 2020 year: 2020 ident: pone.0248132.ref065 article-title: Telmisartan for treatment of Covid-19 patients: an open randomized clinical trial. Preliminary report. publication-title: medRxiv – year: 2020 ident: pone.0248132.ref097 article-title: Intravenous methylprednisolone pulse as a treatment for hospitalised severe COVID-19 patients: results from a randomised controlled clinical trial. publication-title: Eur Res J. – year: 2020 ident: pone.0248132.ref120 article-title: Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19: an international collaborative meta-analysis of randomized trials. publication-title: medRxiv. – volume: 382 start-page: 1787 year: 2020 ident: pone.0248132.ref003 article-title: A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19 publication-title: N Engl J Med doi: 10.1056/NEJMoa2001282 – year: 2011 ident: pone.0248132.ref020 article-title: Cochrane Handbook for Systematic Reviews of Interventions. publication-title: The Cochrane Collaboration. – volume: 369 start-page: 1849 year: 2020 ident: pone.0248132.ref041 article-title: Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. publication-title: BMJ doi: 10.1136/bmj.m1849 – volume: 382 start-page: 1708 issue: 18 year: 2020 ident: pone.0248132.ref001 article-title: Clinical characteristics of coronavirus disease 2019 in China. publication-title: N Engl J Med doi: 10.1056/NEJMoa2002032 – volume: 395 start-page: 514 issue: 10223 year: 2020 ident: pone.0248132.ref005 article-title: A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. publication-title: Lancet doi: 10.1016/S0140-6736(20)30154-9 – volume: 75 issue: 11 year: 2020 ident: pone.0248132.ref079 article-title: Sofosbuvir and daclatasvir compared with standard of care in the treatment of patients admitted to hospital with moderate or severe coronavirus infection (COVID-19): a randomized controlled trial. publication-title: J Antimicrob Chemother doi: 10.1093/jac/dkaa334 |
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| Snippet | COVID-19 is a rapidly spreading disease that has caused extensive burden to individuals, families, countries, and the world. Effective treatments of COVID-19... Background COVID-19 is a rapidly spreading disease that has caused extensive burden to individuals, families, countries, and the world. Effective treatments of... BackgroundCOVID-19 is a rapidly spreading disease that has caused extensive burden to individuals, families, countries, and the world. Effective treatments of... About the Authors: Sophie Juul Roles Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project... |
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| SubjectTerms | Adenosine Monophosphate - analogs & derivatives Adenosine Monophosphate - therapeutic use Adrenal Cortex Hormones - therapeutic use Alanine - analogs & derivatives Alanine - therapeutic use Anesthesia Antibodies, Monoclonal, Humanized - therapeutic use Antiviral Agents - therapeutic use Bias Biology and Life Sciences Bromhexine - therapeutic use Cardiology Citation analysis Citation indexes Clinical Medicine Clinical trials Clinical Trials as Topic Computer programs Coronaviridae Coronaviruses COVID-19 COVID-19 - mortality COVID-19 - therapy COVID-19 Drug Treatment Data analysis Drafting software Editing Education Engineering and Technology Expectorants - therapeutic use Funding Health risks Health sciences Herbal medicine Hospitals Humans Immunoglobulins, Intravenous - therapeutic use Infectious Medicine Infektionsmedicin Intensive care Intervention Klinisk medicin Medical and Health Sciences Medical research Medicin och hälsovetenskap Medicine Medicine and Health Sciences Medicine, Experimental Meta-analysis Methodology Outbreaks Physical Sciences Public health Research and Analysis Methods Research methods Respiration, Artificial Respiratory diseases Reviews SARS-CoV-2 - drug effects SARS-CoV-2 - isolation & purification Severe acute respiratory syndrome Severe acute respiratory syndrome coronavirus 2 Software Software upgrading Supervision Systematic review Treatment Outcome Viral diseases Visualization |
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| Title | Interventions for treatment of COVID-19: Second edition of a living systematic review with meta-analyses and trial sequential analyses (The LIVING Project) |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/33705495 https://www.proquest.com/docview/2500366883 https://www.proquest.com/docview/2501260515 https://pubmed.ncbi.nlm.nih.gov/PMC7954033 https://doaj.org/article/b2507f15905f41fa8aead3ceb941a1e0 http://dx.doi.org/10.1371/journal.pone.0248132 |
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