The use of intravenous immunoglobulin gamma for the treatment of severe coronavirus disease 2019: A randomised placebo-controlled double-blind clinical trial

Gharebaghi, Naser; Nejadrahim, Rahim; Mousavi, Seyed Jalil; Sadat-Ebrahimi, Seyyed-Reza; Hajizadeh, Reza

doi:10.21203/rs.3.rs-40899/v2

Cited by 1 publication

(3 citation statements)

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“…The identified trials compared the following interventions: 10 trials compared corticosteroids versus standard care [52,56,87,89,96–99] or placebo [68, 88]; four trials compared remdesivir versus standard care [86, 110] or placebo [43, 65]; 13 trials compared hydroxychloroquine versus standard care [34,35,42,48,54,55,58,59,105,110], or placebo [53, 108]; five trials compared lopinavir-ritonavir versus standard care [32,40,106,110] or a co-intervention alone [45]; two trials compared interferon beta-1a versus standard care [36, 110]; four trials compared convalescent plasma versus standard care [39,51,78,91]; three trials compared azithromycin versus standard care [83] or co-interventions with standard care [54] or without standard care [82]; three trials compared colchicine versus standard care [49], placebo plus standard care [92], or placebo plus a co-intervention [107]; two trials compared immunoglobulin versus standard care [57] or placebo [95]; six trials compared tocilizumab versus standard care [93,111–113], placebo with standard care [90] or favipiravir alone as co-intervention [114];two trials compared bromhexine versus standard care [94, 104]; and three trials compared favipiravir versus standard care [41, 67] or a co-intervention alone [114].…”

Section: Resultsmentioning

confidence: 99%

“…We identified two trials randomizing 93 participants to intravenous immunoglobulin versus standard care [57] or placebo [95]. Both trials included immunoglobulin from healthy donors [57, 95]. Both trials were assessed at high risk of bias ( S3 Table ).…”

Section: Resultsmentioning

confidence: 99%

“…Visual inspection of the forest plot and measures to quantify heterogeneity (I 2 = 0%) indicated no heterogeneity. The outcome was assessed only in hospital in the first trial [95] and up to 30 days in the second trial [57]. The trial sequential analysis showed that we did not have enough information to confirm or reject that intravenous immunoglobulin versus control reduces the risk of all-cause mortality with a relative risk reduction of 20% ( S52 Fig ).…”

Section: Resultsmentioning

confidence: 99%

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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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