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

Mehboob, Riffat; Ahmad, Fridoon Jawad; Qayyum, Ahad; Rana, Muhammad Asim; Tariq, Muhammad; Akram, Javed

doi:10.1101/2020.08.01.20166678

Cited by 25 publications

(29 citation statements)

References 36 publications

(49 reference statements)

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“…The remaining trial comparisons included: favipiravir versus umifenovir [ 32 ]; umifenovir versus lopinavir-ritonavir [ 39 ]; umifenovir versus standard care [ 39 ]; novaferon versus novaferon plus lopinavir-ritonavir [ 44 ]; novaferon plus lopinavir-ritonavir versus lopinavir-ritonavir [ 44 ]; novaferon versus lopinavir-ritonavir [ 44 ]; alpha lipotic acid versus placebo [ 45 ]; baloxavir marboxil versus favipiravir [ 40 ]; baloxavir marboxil versus standard care [ 40 ]; triple combination of interferon beta-1b plus lopinavir-ritonavir plus ribavirin versus lopinavir-ritonavir [ 37 ]; remdesivir for 5 days versus remdesivir for 10 days [ 36 ]; high-flow nasal oxygenation versus standard bag-valve oxygenation [ 43 ]; hydroxychloroquine versus chloroquine [ 47 ]; chloroquine versus standard care [ 47 ]; high dosage chloroquine diphosphate versus low dosage chloroquine diphosphate [ 49 ]; hydroxychloroquine plus azithromycin versus standard care [ 53 ]; triple combination of darunavir plus cobicistat plus interferon alpha-2b versus interferon alpha-2b [ 60 ]; lopinavir-ritonavir plus interferon alpha versus ribavirin plus interferon alpha [ 60 ]; ribavirin plus lopinavir-ritonavir plus interferon alpha versus ribavirin plus interferon alpha [ 60 ]; ribavirin plus lopinavir-ritonavir plus interferon alpha versus lopinavir-ritonavir plus interferon alpha [ 60 ]; lincomycin versus azithromycin [ 61 ]; 99-mTc-methyl diphosphonate (99mTc-MDP) injection versus standard care [ 62 ]; interferon alpha-2b plus interferon gamma versus interferon alpha-2b [ 63 ]; telmisartan versus standard care [ 65 ]; avifavir 1800/800 versus avifavir 1600/600 [ 66 ]; dexamethasone plus aprepitant versus dexamethasone [ 68 ]; anti-C5a antibody versus standard care [ 69 ]; azvudine versus standard care [ 72 ]; human plasma-derived C1 esterase/kallikrein inhibitor versus standard care [ 71 ]; icatibant acetate versus standard care [ 71 ]; icatibant acetate versus human plasma-derived C1 esterase/kallikrein inhibitor [ 7...…”

Section: Resultsmentioning

confidence: 99%

Interventions for treatment of COVID-19: Second edition of a living systematic review with meta-analyses and trial sequential analyses (The LIVING Project)

et al. 2021

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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; 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. 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.

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Section: Resultsmentioning

confidence: 99%

Interventions for treatment of COVID-19: Second edition of a living systematic review with meta-analyses and trial sequential analyses (The LIVING Project)

et al. 2021

View full text Add to dashboard Cite

show abstract

“…The remaining trial comparisons included: favipiravir versus umifenovir [33]; umifenovir versus lopinavir-ritonavir [40]; umifenovir versus standard care [40]; novaferon versus novaferon plus lopinavir-ritonavir [45]; novaferon plus lopinavir-ritonavir versus lopinavir-ritonavir [45]; novaferon versus lopinavir-ritonavir [45]; alpha lipotic acid versus placebo [46]; baloxavir marboxil versus favipavir [41]; baloxavir marboxil versus standard care [41]; triple combination of interferon beta-1b plus lopinavir-ritonavir plus ribavirin versus lopinavir-ritonavir [38]; remdesivir for 5 days versus remdesivir for 10 days [37]; high-flow nasal oxygenation versus standard bag-valve oxygenation [44]; hydroxychloroquine versus chloroquine [48]; chloroquine versus standard care [48]; high dosage chloroquine diphosphate versus low dosage chloroquine diphosphate [50]; hydroxychloroquine plus azithromycin versus standard care [54]; triple combination of darunavir plus cobicistat plus interferon alpha-2b versus interferon alpha-2b [117]; lopinavir-ritonavir plus interferon alpha versus ribavirin plus interferon alpha [61]; ribavirin plus lopinavir-ritonavir plus interferon alpha versus ribavirin plus interferon alpha [61]; ribavirin plus lopinavir-ritonavir plus interferon alpha versus lopinavir-ritonavir plus interferon alpha [61]; lincomycin versus azithromycin [62];, 99-mTc-methyl diphosphonate (99mTc-MDP) injection versus standard care [63]; interferon alpha-2b plus interferon gamma versus interferon alpha-2b [64]; telmisartan versus standard care [66]; avifavir 1800/800 versus avifavir 1600/600 [67]; dexamethasone plus aprepitant versus dexamethasone [69]; anti-C5a antibody versus standard care [70]; azvudine versus standard care [73]; human plasma-derived C1 esterase/kallikrein inhibitor versus standard care [72]; icatibant acetate versus standard care [72]; icatibant acetate versus human plasma-derived C1 esterase/kallikrein inhibitor [72]; pulmonary rehabilitation program versus isolation at home [71]; auxora (calcium release-activated calcium channel inhibitors) versus standard care [74]; umbilical cord stem cell infusion versus standard care [75]; vitamin C versus placebo [76]; sofosbuvir plus daclatasvir versus standard care [80]; sofosbuvir plus daclatasvir plus ribavirin versus hydroxychloroquine plus lopinavir-ritonavir with or without ribavirin [79]; interferon beta-1b versus standard care [81]; calcifediol versus standard care [84]; recombinant human granulocyte colony–stimulating factor versus standard care [85]; intravenous and/or nebulized electrolyzed saline w...…”

Section: Resultsmentioning

confidence: 99%

“…Third, it was not relevant to perform individual patient data meta-analyses, network-meta-analysis, or several of the planned subgroup analyses due to lack of relevant data. We contacted all trial authors requesting individual patient data, but until now we only received five datasets [38,69,79,80,107]. We did not perform network meta-analysis because the ranking of the interventions is not unclear, i.e., no evidence-based intervention currently exits for COVID-19.…”

Section: Discussionmentioning

confidence: 99%

Interventions for treatment of COVID-19: second edition of a living systematic review with meta-analyses and trial sequential analyses (The LIVING Project)

Juul

Feinberg

Siddiqui

et al. 2020

Preprint

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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 bromhexidine 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 intraveneous 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 bromhexidine 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 CRD42020178787Author summaryWhy was this study done?Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has spread rapidly worldwide, causing an international outbreak of the corona virus disease 2019 (COVID-19).There is a need for a living systematic review evaluating the beneficial and harmful effects of all possible interventions for treatment of COVID-19.What did the researchers do and find?We conducted the second edition of our living systematic review with meta-analyses and Trial sequential analyses to compare the effects of all treatment interventions for COVID-19.Very low certainty evidence indicated 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 intraveneous 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 bromhexidine might reduce the risk of non-serious adverse events.Nine single trials showed statistically significant results on our predefined outcomes but were underpowered to confirm or reject realistic intervention effects.None of the remaining trials showed evidence of a difference of the experimental interventions on our predefined outcomes.What do these findings mean?No evidence-based treatment for COVID-19 currently existsMore high quality, low risk of bias randomized clinical trials are urgently needed.

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“…45, 46, 64, 71 Eight trials did not specify the outcomes of interest. 55, 58, 68, 81, 93, 101, 122, 123 Treatments in four trials were not connected in the network. 73, 77, 86, 98…”

Section: Resultsmentioning

confidence: 99%

A Systematic Review and Network Meta-Analysis for COVID-19 Treatments

Zhang

Jin

Wen

et al. 2020

Preprint

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BackgroundNumerous interventions for coronavirus disease 2019 (COVID-19) have been investigated by randomized controlled trials (RCTs). This systematic review and Bayesian network meta-analysis (NMA) aim to provide a comprehensive evaluation of efficacy of available treatments for COVID-19.MethodsWe searched for candidate COVID-19 studies in WHO COVID-19 Global Research Database, PubMed, PubMed Central, LitCovid, Proquest Central and Ovid up to December 19, 2020. RCTs for suspected or confirmed COVID-19 patients were included, regardless of publication status or demographic characteristics. Bayesian NMA with fixed effects was conducted to estimate the effect sizes using posterior means and 95% equal-tailed credible intervals (CrIs), while that with random effects was carried out as well for sensitivity analysis. Bayesian hierarchical models were used to estimate effect sizes of treatments grouped by their drug classifications.ResultsWe identified 96 eligible RCTs with a total of 51187 patients. Compared with the standard of care (SOC), this NMA showed that dexamethasone led to lower risk of mortality with an odds ratio (OR) of 0.85 (95% CrI [0.76, 0.95]; moderate certainty) and lower risk of mechanical ventilation (MV) with an OR of 0.68 (95% CrI [0.56, 0.83]; low certainty). For hospital discharge, remdesivir (OR 1.37, 95% CrI [1.15, 1.64]; moderate certainty), dexamethasone (OR 1.20, 95% CrI [1.08, 1.34]; low certainty), interferon beta (OR 2.15, 95% CrI [1.26, 3.74]; moderate certainty), tocilizumab (OR 1.40, 95% CrI [1.05, 1.89]; moderate certainty) and baricitinib plus remdesivir (OR 1.75, 95% CrI [1.28, 2.39]; moderate certainty) could all increase the discharge rate respectively. Recombinant human granulocyte colony-stimulating factor indicated lower risk of MV (OR 0.20, 95% CrI [0.10, 0.40]; moderate certainty); and patients receiving convalescent plasma resulted in better viral clearance (OR 2.28, 95% CrI [1.57, 3.34]; low certainty). About two-thirds of the studies included in this NMA were rated as high risk of bias, and the certainty of evidence was either low or very low for most of the comparisons.ConclusionThe Bayesian NMA identified superiority of several COVID-19 treatments over SOC in terms of mortality, requirement of MV, hospital discharge and viral clearance. These results provide a comprehensive comparison of current COVID-19 treatments and shed new light on further research and discovery of potential COVID-19 treatments.

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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

Cited by 25 publications

References 36 publications

Interventions for treatment of COVID-19: Second edition of a living systematic review with meta-analyses and trial sequential analyses (The LIVING Project)

Interventions for treatment of COVID-19: Second edition of a living systematic review with meta-analyses and trial sequential analyses (The LIVING Project)

Interventions for treatment of COVID-19: second edition of a living systematic review with meta-analyses and trial sequential analyses (The LIVING Project)

A Systematic Review and Network Meta-Analysis for COVID-19 Treatments

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