PLoS ONE plos plosone PLOS ONE 1932-6203 Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0270668 PONE-D-22-07351 Research Article Research and analysis methodsMathematical and statistical techniquesStatistical methodsMetaanalysis Physical sciencesMathematicsStatisticsStatistical methodsMetaanalysis Medicine and health sciencesMedical conditionsInfectious diseasesViral diseasesCOVID 19 Computer and information sciencesNetwork analysis Medicine and health sciencesPharmaceuticsDrug therapyReceptor antagonist therapy Medicine and health sciencesPharmaceuticsDrug therapySteroid therapyCorticosteroid therapy Physical sciencesChemistryChemical elementsOxygen Biology and life sciencesPopulation biologyPopulation metricsDeath rates Medicine and health sciencesEpidemiologyMedical risk factors Association between tocilizumab, sarilumab and all-cause mortality at 28 days in hospitalised patients with COVID-19: A network meta-analysis Tocilizumab or sarilumab for hospitalised patients with COVID-19 https://orcid.org/0000-0003-0648-0992 Godolphin Peter J. Conceptualization Data curation Formal analysis Investigation Writing – original draft Writing – review & editing 1 * Fisher David J. Conceptualization Data curation Formal analysis Investigation Writing – original draft Writing – review & editing 1 Berry Lindsay R. Data curation Investigation Writing – review & editing 2 Derde Lennie P. G. Data curation Investigation Writing – review & editing 3 4 Diaz Janet V. Investigation Supervision Writing – review & editing 5 Gordon Anthony C. Data curation Investigation Writing – review & editing 6 Lorenzi Elizabeth Data curation Investigation Writing – review & editing 2 Marshall John C. Investigation Supervision Writing – review & editing 7 Murthy Srinivas Investigation Supervision Writing – review & editing 8 Shankar-Hari Manu Conceptualization Data curation Investigation Supervision Writing – review & editing 9 10 Sterne Jonathan A. C. Conceptualization Data curation Formal analysis Investigation Supervision Writing – original draft Writing – review & editing 11 12 13 Tierney Jayne F. Investigation Supervision Writing – review & editing 1 Vale Claire L. Conceptualization Data curation Investigation Supervision Writing – original draft Writing – review & editing 1 MRC Clinical Trials Unit at University College London, Institute of Clinical Trials and Methodology, London, United Kingdom Berry Consultants, Austin, Texas, United States of America Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, The Netherlands University Medical Center Utrecht, Julius Center for Health Sciences and Primary Care, Utrecht, The Netherlands Clinical Unit, Health Emergencies Programme, World Health Organization, Geneva, Switzerland Division of Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, London, United Kingdom Li Ka Shing Knowledge Institute, St Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada Department of Pediatrics, University of British Columbia, Vancouver, Canada Centre for Inflammation Research, The University of Edinburgh, Edinburgh, United Kingdom Department of Critical Care Medicine, Royal Infirmary of Edinburgh, NHS Lothian, Edinburgh, United Kingdom Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom NIHR Bristol Biomedical Research Centre, Bristol, United Kingdom Health Data Research UK South West, Bristol, United Kingdom Cortegiani Andrea Editor University of Palermo, ITALY

LPGD is a member of the COVID-19 guideline committee for the Society of Critical Care Medicine/European Society of Intensive Care Medicine/Surviving Sepsis Campaign. ACG has received personal fees from Thirty Respiratory Ltd and GlaxoSmithKline. JCM received personal fees from AM Pharma (for serving as the chair of a data and safety monitoring board), Gilead (for serving as a consultant), and Critical Care Medicine (for serving as associate editor). This does not alter our adherence to PLOS ONE policies on sharing data and materials.

 * E-mail: p.godolphin@ucl.ac.uk 8 7 2022 2022 17 7 e0270668 11 3 2022 14 6 2022 2022 Godolphin et al This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background

A recent prospective meta-analysis demonstrated that interleukin-6 antagonists are associated with lower all-cause mortality in hospitalised patients with COVID-19, compared with usual care or placebo. However, emerging evidence suggests that clinicians are favouring the use of tocilizumab over sarilumab. A new randomised comparison of these agents from the REMAP-CAP trial shows similar effects on in-hospital mortality. Therefore, we initiated a network meta-analysis, to estimate pairwise associations between tocilizumab, sarilumab and usual care or placebo with 28-day mortality, in COVID-19 patients receiving concomitant corticosteroids and ventilation, based on all available direct and indirect evidence.

 Methods

Eligible trials randomised hospitalised patients with COVID-19 that compared tocilizumab or sarilumab with usual care or placebo in the prospective meta-analysis or that directly compared tocilizumab with sarilumab. Data were restricted to patients receiving corticosteroids and either non-invasive or invasive ventilation at randomisation.

Pairwise associations between tocilizumab, sarilumab and usual care or placebo for all-cause mortality 28 days after randomisation were estimated using a frequentist contrast-based network meta-analysis of odds ratios (ORs), implementing multivariate fixed-effects models that assume consistency between the direct and indirect evidence.

 Findings

One trial (REMAP-CAP) was identified that directly compared tocilizumab with sarilumab and supplied results on all-cause mortality at 28-days. This network meta-analysis was based on 898 eligible patients (278 deaths) from REMAP-CAP and 3710 eligible patients from 18 trials (1278 deaths) from the prospective meta-analysis. Summary ORs were similar for tocilizumab [0·82 [0·71–0·95, p = 0·008]] and sarilumab [0·80 [0·61–1·04, p = 0·09]] compared with usual care or placebo. The summary OR for 28-day mortality comparing tocilizumab with sarilumab was 1·03 [95%CI 0·81–1·32, p = 0·80]. The p-value for the global test of inconsistency was 0·28.

 Conclusions

Administration of either tocilizumab or sarilumab was associated with lower 28-day all-cause mortality compared with usual care or placebo. The association is not dependent on the choice of interleukin-6 receptor antagonist.

 http://dx.doi.org/10.13039/501100000771 Prostate Cancer UK RIA 16-ST2-020 https://orcid.org/0000-0003-0648-0992 Godolphin Peter J. http://dx.doi.org/10.13039/501100000771 Prostate Cancer UK RIA 16-ST2-020 Fisher David J. http://dx.doi.org/10.13039/501100000272 National Institute for Health Research NIHR301653 https://orcid.org/0000-0003-0648-0992 Godolphin Peter J. http://dx.doi.org/10.13039/501100000265 Medical Research Council MC_UU_00004/06 Vale Claire L. http://dx.doi.org/10.13039/501100000265 Medical Research Council MC_UU_00004/06 Tierney Jayne F. http://dx.doi.org/10.13039/501100000265 Medical Research Council MC_UU_00004/06 Fisher David J. http://dx.doi.org/10.13039/501100000272 National Institute for Health Research NIHR-CS-2016-16-011 Shankar-Hari Manu http://dx.doi.org/10.13039/100012411 School for Social Care Research RP-2015-06-018 Gordon Anthony C. This study was funded by Prostate Cancer UK in the form of funds to PJG and DJF [RIA 16-ST2-020], by the National Institute for Health Research in the form of funds to PJG [NIHR301653], by the Medical Research Council in the form of funds to DJF, JFT, and CLV [MC_UU_00004/06], by the National Institute for Health Research in the form of funds to MS-H [NIHR-CS-2016-16-011], and by the National Institute for Health Research in the form of funds to ACG [RP-2015-06-018]. Data Availability All relevant data are within the article and its Supporting information files. Outbreaks COVID-19 Introduction

Following the recent publication of results from a prospective meta-analysis [1] and an updated guideline from the WHO [2], the interleukin-6 receptor antagonists, tocilizumab and sarilumab, have been recommended alongside corticosteroids for the routine treatment of hospitalised patients requiring oxygen support for COVID-19.

Findings from the prospective meta-analysis, which unlike standard meta-analysis is planned whilst trials are ongoing, preceding any knowledge of trial results and therefore less prone to biases sometimes associated with standard meta-analysis of aggregate data [3], showed that the interleukin-6 antagonists were associated with lower all-cause mortality 28 days after randomisation than standard care alone. In a prespecified analysis stratified by individual interleukin-6 receptor antagonists, whilst there was a clear association between reduced mortality and tocilizumab (based on the results of 8048 patients from 19 randomised trials), the evidence supporting the use of sarilumab (based on 2826 patients from 9 randomised trials) was less certain. In further pre-specified analyses, a stronger association between the interleukin-6 antagonists and reduced mortality was observed among patients receiving concomitant corticosteroids at randomisation than those not receiving corticosteroids, and the proportion of patients receiving concomitant corticosteroids at randomisation was lower in sarilumab trials than tocilizumab trials. If, based on these findings, clinicians and healthcare providers tend to favour the use of tocilizumab, there will inevitably be implications on demand and availability, potentially limiting patient access to tocilizumab.

The best way to resolve this uncertainty is to compare the relative effectiveness of tocilizumab with sarilumab. However, because the prospective meta-analysis set out to compare interleukin-6 antagonists with standard of care, trials that directly compared individual agents were excluded. Therefore, only indirect comparisons between tocilizumab and sarilumab, summarised as a ratio of odds ratios, were possible. An indirect comparison of the two agents, in patients receiving corticosteroids as part of usual care, suggested similar associations for both agents with 28-day all-cause mortality (Ratio of odds ratios, 0·77 [95%CI 0·44–1·33, p = 0·34]), but this comparison was not precisely estimated. To better compare the effectiveness of these two agents, direct randomised comparisons are needed. The Randomised, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) trial, which randomised critically ill patients with COVID-19 requiring either non-invasive ventilation (NIV) or invasive mechanical ventilation (IMV) including Extracorporeal Membrane Oxygenation (ECMO) [4] is, to date, the only reported randomised clinical trial that has directly compared tocilizumab and sarilumab [5]. Analysed as part of the immune modulation therapy domain of the trial, pre-defined triggers for equivalence between tocilizumab and sarilumab were met. The investigators reported beneficial effects of both tocilizumab and sarilumab on the primary outcome, organ support-free days, as well as on all pre-planned secondary outcomes including in hospital survival; 90-day survival; and both intensive care unit and hospital discharge. Furthermore, they reported that in their Bayesian analysis, the probability that sarilumab was non-inferior to tocilizumab was 98.9%.

Therefore, to inform clinical practice more fully and to clarify the evidence regarding these two treatments, we planned a network meta-analysis, bringing together the relevant data on tocilizumab and sarilumab from all randomised clinical trials. The aim of this new analysis is to estimate the pairwise associations between administration of tocilizumab, sarilumab or usual care or placebo and 28-day mortality, in COVID-19 patients receiving concomitant corticosteroids and NIV, IMV or ECMO, based on all the available direct and indirect evidence.

 Methods

This network meta-analysis is reporting according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension statement to Network Meta-Analyses [6] (see S1 Checklist).

Eligible randomised trials that aimed to compare tocilizumab or sarilumab with standard care in the treatment of hospitalised patients with COVID-19 were identified from the searches conducted by the same authors for a recently published systematic review and prospective meta-analysis [1]. Full details of the methods used have been previously reported [1], and are included in the prospectively registered protocol (CRD42021230155) [7].

For this network meta-analysis, we also carried out searches of trial registers (Clinicaltrials.gov and the EU Clinical Trials Register, most recent search 27th August 2021) to identify any randomised trials in addition to REMAP-CAP that directly compared tocilizumab with sarilumab in a similar population, using the search terms sarilumab, tocilizumab, random* and COVID. Patients were eligible for inclusion in this network meta-analysis if they were included in any of the eligible randomised trials and received either NIV (including high-flow nasal canula), IMV or ECMO at randomisation. Furthermore, because the prospective meta-analysis demonstrated that corticosteroid use modifies the association of interleukin-6 antagonists with mortality, patients also needed to have received corticosteroids as part of usual care to be eligible.

The primary outcome was all-cause mortality up to 28 days after randomisation. Data on all eligible patients included in the prospective meta-analysis were extracted from the summary data supplied. We requested data using bespoke data collection forms (developed for the prospective meta-analysis) for any trials identified as having made a direct comparison between tocilizumab and sarilumab.

All included trials secured institutional review board approval, and informed consent for participation in each trial was obtained, consistent with local institutional review board requirements. Approval was not required for these secondary analyses as all data were published either as part of the prospective meta-analysis and/or in individual trial reports.

Risk of bias

Risk of bias for each trial included in the prospective meta-analysis had already been assessed for all-cause mortality 28 days after randomisation as part of the prospective meta-analysis and was not repeated here. We planned to similarly assess risk of bias for any additional eligible trials identified for the network meta-analysis for this outcome using version 2 of the Cochrane Risk of Bias Assessment Tool [8].

 Contemporaneous randomisation in REMAP-CAP

Because REMAP-CAP is a multi-arm trial with an adaptive non-parallel design, for the purposes of this analysis it is represented as three independent observations in the model (tocilizumab vs usual care or placebo, sarilumab vs usual care or placebo, sarilumab vs tocilizumab). A small group of patients (21, 4 deaths by 28 days) were randomised to usual care or placebo contemporaneously with both treatment arms. We re-allocated these patients (and events) to the tocilizumab vs usual care or placebo and sarilumab versus usual care or placebo observations in proportion to their total counts and events, and thereafter assumed independence between these observations.

 Statistical analysis

Pairwise associations between tocilizumab, sarilumab and usual care or placebo were estimated using a network meta-analysis of odds ratios (ORs), using a frequentist contrast-based approach implemented in multivariate fixed-effects meta-analysis models [9]. These models assume consistency between ‘direct evidence’ (associations estimated in trials directly comparing the pair of interventions) and ‘indirect evidence’ (associations estimated through the network). The ‘net evidence’ from the network meta-analysis is a weighted average of the direct and indirect evidence. Inconsistency between direct and indirect evidence was examined locally using symmetrical node-splitting [10] and globally using a design-by-treatment interaction model [9,11]. Borrowing of strength statistics were calculated using the score decomposition method [12] to illustrate the proportion of information for each net estimate that is due to indirect evidence. Treatment rankings were also calculated and are summarised according to the surface under the cumulative ranking curve (SUCRA) value, which represents the re-scaled mean ranking [13,14]. Following the approach in the prospective meta-analysis [1], we report precise p values and do not set a threshold for statistical significance. The certainty of evidence in each comparison was rated following the GRADE approach to network meta-analysis [15,16], with this completed independently by two reviewers [PJG and CLV] and any discrepancies resolved through discussion. The certainty of evidence was rated as either High, Moderate, Low or Very Low. All analyses were conducted in Stata statistical software version 16.1 [StataCorp, USA] using the ‘network’ user-written command suite [17].

 Results Study selection and description of eligible trials

Of the 27 trials included in the prospective meta-analysis, nine randomised patients prior to guidance to include corticosteroids as part of routine care, or excluded patients requiring non-invasive or mechanical ventilation, or used an interleukin-6 agent other than tocilizumab or sarilumab. Thus, these trials are ineligible for the network meta-analysis (Fig 1). Of the nine trials, a similar number compared tocilizumab (5 trials, 848 patients) to usual care or placebo as compared sarilumab (4 trials, 815 patients) to usual care or placebo. The remaining 18 trials contained at least one eligible patient and are included in this network meta-analysis. 14 trials are published [4,18–28], one is reported on a pre-print server [29] and three are not yet published (see Table 1 for trial registration numbers). These 18 trials had compared tocilizumab (13 trials) or sarilumab (4 trials) or both (1 trial) with usual care or placebo and include 3710 patients (40%; 1278 deaths by 28 days) who received corticosteroids and either non-invasive or mechanical ventilation and were therefore eligible for inclusion in the network meta-analysis (Fig 1).

10.1371/journal.pone.0270668.g001 Flow diagram showing the identification of eligible trials and patients. 10.1371/journal.pone.0270668.t001 Summary of included trials, patient characteristics and all-cause mortality 28 days after randomisation.
Trial name Trial registration No. No. of eligible patients / total randomised For eligible patients, concomitant therapy at randomisation (%) For eligible patients, 28-day mortality (Deaths / Patients)
Corticosteroids Non-invasive ventilation Invasive mechanical ventilation Usual care or Placebo Tocilizumab Sarilumab
Tocilizumab versus usual care or placebo
ARCHITECTS NCT04412772 19/21 19 (100%) 0 (-) 19 (100%) 1/10 0/9
CORIMUNO-TOCI-ICU NCT04331808 12/92 12 (100%) 3 (25%) 9 (75%) 2/4 4/8
COV-AID NCT04330638 42/153 42 (100%) 31 (74%) 11 (26%) 3/20 5/22
COVACTA NCT04320615 69/438 69 (100%) 27 (39%) 42 (61%) 11/26 13/43
COVIDOSE2-SS-A NCT04479358 1/27 1 (100%) 1 (100%) 0 (-) 0/1 0/0
COVIDSTORM NCT04577534 10/39 10 (100%) 10 (100%) 0 (-) 0/4 0/6
EMPACTA NCT04372186 94/377 94 (100%) 94 (100%) 0 (-) 7/33 13/61
HMO-020-0224 NCT04377750 46/54 46 (100%) 19 (41%) 27 (59%) 8/15 10/31
ImmCoVA EudraCT 2020-001748-24 29/49 29 (100%) 29 (100%) 0 (-) 2/18 2/11
PreToVid EudraCT 2020-001375-32 82/354 82 (100%) 79 (96%) 3 (4%) 12/43 8/39
RECOVERY NCT04381936 1849/4116 1849 (100%) 1444 (78%) 405 (22%) 427/954 356/895
REMAP-CAP (a) NCT02735707 429/711 429 (100%) 314 (73%) 115 (27%) 70/201a 53/213a
REMDACTA NCT04409262 523/640 523 (100%) 445 (85%) 78 (15%) 39/179 68/344
TOCIBRAS NCT04403685 31/129 31 (100%) 20 (65%) 11 (35%) 5/20 7/11
Sarilumab versus usual care or placebo
CORIMUNO-SARI-ICU NCT04324073 2/81 2 (100%) 1 (50%) 1 (50%) 0/2 0/0
REGENERON-P2 NCT04315298 63/457 63 (100%) 19 (30%) 44 (70%) 4/10 26/53
REGENERON-P3 NCT04315298 328/1330 328 (100%) 178 (54%) 150 (46%) 21/71 79/257
REMAP-CAP (b) NCT02735707 96/113 96 (100%) 84 (88%) 12 (13%) 13/49a 8/44a
SARCOVID NCT04357808 3/30 3 (100%) 3 (100%) 0 (-) 0/0 1/3
Tocilizumab versus sarilumab
REMAP-CAP (c) NCT02735707 898/1018 898 (100%) 596 (66%) 302 (34%) 169/529 109/369

aREMAP-CAP has a small group of patients and events (21, 4 deaths by 28 days) randomised to usual care or placebo contemporaneously with both Tocilizumab and Sarilumab. These patients are events are re-allocated in proportion to their total counts and events.

Searches of trial registers for eligible randomised trials that had directly compared tocilizumab with sarilumab in a similar patient population did not return any further trials in addition to the recently published REMAP-CAP trial [5]. Full details of search results are given in Fig 1. Trial investigators for REMAP-CAP obtained approval from the International Trial Steering Committee to supply data for this analysis. Data were supplied on June 12th, 2021 using a standardised outcome data collection form (developed for use in the prospective meta-analysis) and finalised data were subsequently verified by the trial team prior to inclusion in this analysis. Of 1018 patients from the REMAP-CAP trial who were randomised to receive either tocilizumab or sarilumab, 898 (88%; 278 deaths by 28 days) received NIV, IMV or ECMO plus corticosteroids at randomisation and were eligible for inclusion in the network meta-analysis.

 Risk of bias within studies

Detailed risk of bias assessments for the 18 included trials that contributed to the prospective meta-analysis have already been reported [1]. In summary, 12 were assessed as low risk of bias (1003 deaths by 28 days, 65% of total deaths); five were judged to have some concerns (257 deaths by 28 days, 17% of total deaths) largely as small numbers of patients who did not receive their assigned interventions were excluded. One trial (18 deaths by 28 days, 1% of total deaths) was judged as high risk of bias as the usual procedures to ensure concealment of the allocation sequence were not in place; however, concealed allocation did appear to have been implemented as intended. Risk of bias for the additional REMAP-CAP direct comparison was judged as low risk of bias. Thus, in total, 12 trials (14 comparisons, 1281 deaths by 28 days, 82% of total deaths) were judged as low risk of bias.

 Synthesis of results

The direct comparison with the greatest amount of information was tocilizumab versus usual care or placebo (Fig 2, 3221 patients, 1126 deaths by 28 days). There was relatively little information for the direct comparison of sarilumab with usual care or placebo (489 patients, 152 deaths by 28 days). The direct comparison of tocilizumab with sarilumab was from REMAP-CAP (898 patients, 278 deaths by 28 days). Fig 3 presents the direct evidence for each of the included trials. For both the tocilizumab versus usual care or placebo and sarilumab versus usual care or placebo comparisons, a single trial contributed approximately two-thirds of the information for the direct estimate (RECOVERY for the tocilizumab comparison and REGENERON-P3 for the sarilumab comparison).

10.1371/journal.pone.0270668.g002 Network map showing numbers of trials in each direct treatment comparison.

The node size is proportional to the number of trials that include this treatment. The width of the lines is proportional to the total number of events involved in each direct comparison.

 10.1371/journal.pone.0270668.g003 Summary of the direct evidence from each included trial for all-cause mortality 28 days after randomisation.

The % weight corresponds to the contribution each trial makes to the pooled direct evidence for each treatment comparison.

Based on the network meta-analysis, the net ORs for 28-day mortality were similar for tocilizumab [95%CI 0·82 [0·71–0·95, p = 0·008]] and sarilumab [95%CI 0·80 [0·61–1·04, p = 0·09]] compared with usual care or placebo (Table 2, Fig 4), although the tocilizumab comparison borrowed less strength from the network (borrowing of strength 7%) than the sarilumab comparison (borrowing of strength 67%). The net OR for 28-day mortality comparing tocilizumab with sarilumab was 1·03 [95%CI 0·81–1·32, p = 0·80], with this comparison borrowing 26% of strength from the network. The global p value for inconsistency was 0·28. Both tocilizumab and sarilumab were ranked similarly with high SUCRA values (70% and 78% respectively, Table 3). Usual care or placebo had a 95% probability of being the least effective treatment. The certainty of evidence for each comparison is displayed in S1 Table. Tocilizumab versus usual care was rated as High, with sarilumab versus usual care and tocilizumab versus sarilumab both rated as Moderate (both downgraded due to Imprecision).

10.1371/journal.pone.0270668.g004 Network associations of tocilizumab, sarilumab and usual care or placebo for patients receiving corticosteroids and either NIV, IMV or ECMO at randomisation with all-cause mortality 28 days after randomisation.

NIV: Non-invasive ventilation. IMV: Invasive mechanical ventilation. ECMO: Extracorporeal Membrane Oxygenation. Size of markers is proportional to the inverse of the variance from the net estimate. Borrowing of strength illustrates the proportion of information for each net odds ratio that is due to indirect evidence.

 10.1371/journal.pone.0270668.t002 Summary of direct, indirect, and net evidence for the associations of tocilizumab, sarilumab and usual care or placebo with all-cause mortality 28 days after randomisation for patients receiving corticosteroids and either NIV, IMV or ECMO at randomisation.
Comparison Number of trials Deaths / patients from direct evidence OR (95% CI), p from direct evidence OR (95% CI), p from indirect evidence Net OR (95% CI), p from network meta-analysis Inconsistency p value
Intervention 1a Intervention 2a
Tocilizumab vs usual care or placebo 14 539/1693 587/1528 0·80 (0·69, 0·93), p = 0·004 1·10 (0·64, 1·90), p = 0·74 0·82 (0·71, 0·95), p = 0·008 p = 0·28
Sarilumab vs usual care or placebo 5 114/357 38/132 0·98 (0·62, 1·56), p = 0·94 0·72 (0·52, 0·99), p = 0·05 0·80 (0·61, 1·04), p = 0·09
Tocilizumab vs sarilumab 1 169/529 109/369 1·12 (0·84, 1·49), p = 0·44 0·82 (0·50, 1·33), p = 0·42 1·03 (0·81, 1·32), p = 0·80

NIV: Non-invasive ventilation. IMV: Invasive mechanical ventilation. ECMO: Extracorporeal Membrane Oxygenation.

Note, the REMAP-CAP trial contributes to all three comparisons for each network.

aIntervention 1 refers to the treatment listed first, while Intervention 2 is the treatment listed second. For example, for the comparison of tocilizumab versus usual care or placebo, Intervention 1 is tocilizumab and Intervention 2 is usual care or placebo.

Local tests for inconsistency, p = 0·28 for all three comparisons.

 10.1371/journal.pone.0270668.t003 Ranking of interventions (% probability) and SUCRA values for all-cause mortality 28 days after randomisation.
Rank Sarilumab Tocilizumab Usual care or placebo
Best 59.7 40.1 0.1
Second 35.5 59.5 5.0
Worst 4.8 0.3 94.9
SUCRA 78% 70% 26%

SUCRA: Surface under the cumulative ranking curve.

 Discussion

In this network meta-analysis of patients receiving both corticosteroids and either NIV, IMV or ECMO at randomisation, both tocilizumab and sarilumab were associated with lower all-cause mortality 28 days after randomisation compared with usual care or placebo. The associations of these agents with all-cause mortality appeared similar, consistent with the direct findings from the REMAP-CAP trial [5] in which tocilizumab and sarilumab met the criteria for equivalence. More generally, these results confirm a clear association of interleukin-6 receptor antagonists with lower all-cause mortality in this patient population.

The comparison of tocilizumab versus usual care or placebo was based mainly on direct evidence from the prospective meta-analysis, with only limited additional information from the network. By contrast, for sarilumab versus usual care or placebo, the direct comparison was limited to fewer than 500 patients from the prospective meta-analysis. Therefore, the indirect evidence (arising from the association of tocilizumab with reduced all-cause mortality compared to usual care or placebo and the direct comparison of tocilizumab with sarilumab) has a substantial impact on the net estimate for this comparison. In the absence of any other direct comparisons of tocilizumab with sarilumab, this network meta-analysis provides the strongest evidence in support of the hypothesis that both agents are similarly associated with lower all-cause mortality at 28-days in this patient population.

A separate living network meta-analysis found that both tocilizumab and sarilumab added to usual care including corticosteroids “probably reduce mortality” in patients with severe or critical COVID-19 [30] based on results for all patients from 36 randomised trials, irrespective of corticosteroid use or extent of oxygen support at randomisation. Including all patients increases the possibility of inconsistency between patients included in the indirect and direct comparisons of tocilizumab and sarilumab, as patients in the direct comparison (i.e. from the REMAP-CAP trial), all received both corticosteroids and invasive or non-invasive ventilation. The authors also down-rated the certainty of evidence for tocilizumab versus usual care, sarilumab versus usual care and tocilizumab versus sarilumab, as Moderate, Low and Low respectively, based on a lack of blinding in many of the included trials.

In contrast, we restricted the network to the subset of patients receiving both oxygen support and corticosteroids, making them more comparable with each other and to the REMAP-CAP direct tocilizumab and sarilumab comparison. Therefore, variability of the population within the network and resulting inconsistency was reduced, and interpretability was increased. This was only possible through the prospective and collaborative approach [3] we adopted as part of the prospective meta-analysis [1], collecting detailed data on both oxygen support and corticosteroid use subgroups. This enabled us to make decisions often only available in an individual participant data meta-analysis [31] and resulted in increased consistency and harmonisation. Furthermore, given that over 80% of the total events included in this network were from trials judged to be at low risk of bias, and because of a lack of subjectivity in the assessment of a mortality outcome, we have kept our risk of bias assessments consistent with the approach used in the prospective meta-analysis [1] and by the WHO guideline panel [2]. Consequently, we rated the certainty of evidence as High, Moderate and Moderate for the comparisons of tocilizumab versus usual care, sarilumab versus usual care and tocilizumab versus sarilumab, respectively.

This study has some limitations. First, because these results are focused on patients treated with corticosteroids and either NIV, IMV or ECMO, alongside interleukin-6 receptor antagonists, they may not be generalised to less critically ill patients or to those not receiving steroids or non-invasive or mechanical ventilation. Second, the direct evidence in each of the three comparisons included in this network meta-analysis came predominantly from a single trial (either RECOVERY, REGENERON-P3 or REMAP-CAP), with these three trials primarily conducted in high income countries. With the direct evidence limited to only high-income counties we cannot be certain how their results might translate into lower income settings. Third, four of the included trials have not yet been published in peer-reviewed journals, either available as pre-print publications or currently unpublished. However, thorough checking and verification was carried out as part of the original prospective meta-analysis procedure, with the same process applied to the new REMAP-CAP trial data, and we have no concerns about the conduct or quality of the data from any of the as yet unpublished trials.

In conclusion, this network meta-analysis of clinical trials of hospitalised patients with COVID-19 receiving ventilation and corticosteroids at randomisation, confirms that administration of tocilizumab or sarilumab, compared with usual care or placebo, is associated with similarly lower 28-day all-cause mortality.

 Supporting information PRISMA NMA checklist of items to include when reporting a systematic review involving a network meta-analysis.

(DOCX)

 Certainty assessment for each comparison.

(DOCX)

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Consistency and inconsistency in network meta-analysis: model estimation using multivariate meta-regression. Research Synthesis Methods 2012;3:111–25. doi: 10.1002/jrsm.1045 26062085 Dias S, Welton NJ, Caldwell DM, Ades AE. Checking consistency in mixed treatment comparison meta-analysis. Stat Med. 2010;29(7–8):932–44. Epub 2010/03/10. doi: 10.1002/sim.3767 20213715. Higgins JPT, Jackson D, Barrett JK, Lu G, Ades AE, White IR. Consistency and inconsistency in network meta-analysis: concepts and models for multi-arm studies. Research Synthesis Methods 2012;3:98–110. doi: 10.1002/jrsm.1044 26062084 Jackson D, White IR, Price M, Copas J, Riley RD. Borrowing of strength and study weights in multivariate and network meta-analysis. Statistical Methods in Medical Research 2017:First Published November 6, 2015 doi: 10.1177/0962280215611702 26546254 White IR. Multivariate Random-effects Meta-regression: Updates to Mvmeta. The Stata Journal. 2011;11(2):255–70. doi: 10.1177/1536867X1101100206 Salanti G, Ades AE, Ioannidis J. Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial. J Clin Epidemiol. 2011;64:163–71. doi: 10.1016/j.jclinepi.2010.03.016 20688472 Zeng L, Brignardello-Petersen R, Hultcrantz M, Siemieniuk RAC, Santesso N, Traversy G, et al. GRADE guidelines 32: GRADE offers guidance on choosing targets of GRADE certainty of evidence ratings. J Clin Epidemiol. 2021;137:163–75. doi: 10.1016/j.jclinepi.2021.03.026 33857619 Puhan MA, Schünemann HJ, Murad MH, Li T, Brignardello-Petersen R, Singh JA, et al. A GRADE Working Group approach for rating the quality of treatment effect estimates from network meta-analysis. BMJ: British Medical Journal. 2014;349:g5630. doi: 10.1136/bmj.g5630 25252733 White IR. Network meta-analysis. Stata Journal 2015;15:951–85. RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. The Lancet. 2021;397(10285):1637–45. doi: 10.1016/S0140-6736(21)00676-0 33933206 Rosas IO, Bräu N, Waters M, Go RC, Hunter BD, Bhagani S, et al. Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia. N Engl J Med. 2021;384(16):1503–16. doi: 10.1056/NEJMoa2028700 33631066 Salama C, Han J, Yau L, Reiss WG, Kramer B, Neidhart JD, et al. Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia. N Engl J Med. 2020;384(1):20–30. doi: 10.1056/NEJMoa2030340 33332779 Veiga VC, Prats JAGG, Farias DLC, Rosa RG, Dourado LK, Zampieri FG, et al. Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial. BMJ. 2021;372:n84. doi: 10.1136/bmj.n84 33472855 Declercq J, Van Damme KFA, De Leeuw E, Maes B, Bosteels C, Tavernier SJ, et al. Effect of anti-interleukin drugs in patients with COVID-19 and signs of cytokine release syndrome (COV-AID): a factorial, randomised, controlled trial. The Lancet Respiratory Medicine. 2021;9(12):1427–38. doi: 10.1016/S2213-2600(21)00377-5 34756178 Rosas IO, Diaz G, Gottlieb RL, Lobo SM, Robinson P, Hunter BD, et al. Tocilizumab and remdesivir in hospitalized patients with severe COVID-19 pneumonia: a randomized clinical trial. Intensive Care Med. 2021;47(11):1258–70. doi: 10.1007/s00134-021-06507-x 34609549 Hermine O, Mariette X, Porcher R, Resche-Rigon M, Tharaux P-L, Ravaud P. Effect of Interleukin-6 Receptor Antagonists in Critically Ill Adult Patients with COVID-19 Pneumonia: two Randomised Controlled Trials of the CORIMUNO-19 Collaborative Group. Eur Respir J. 2022:2102523. doi: 10.1183/13993003.02523-2021 35115337 García-Vicuña R, Rodriguez-García SC, Abad-Santos F, Bautista Hernández A, García-Fraile L, Barrios Blandino A, et al. Subcutaneous IL-6 Inhibitor Sarilumab vs. Standard Care in Hospitalized Patients With Moderate-To-Severe COVID-19: An Open Label Randomized Clinical Trial. Frontiers in Medicine. 2022;9. doi: 10.3389/fmed.2022.819621. pub.1145799177. 35280907 Sivapalasingam S, Lederer DJ, Bhore R, Hajizadeh N, Criner G, Hosain R, et al. Efficacy and Safety of Sarilumab in Hospitalized Patients With COVID-19: A Randomized Clinical Trial. Clin Infect Dis. 2022:ciac153. doi: 10.1093/cid/ciac153 35219277 Broman N, Feuth T, Vuorinen T, Valtonen M, Hohenthal U, Löyttyniemi E, et al. Early administration of tocilizumab in hospitalized COVID-19 patients with elevated inflammatory markers; COVIDSTORM—a prospective, randomized, single-centre, open-label study. Clinical Microbiology and Infection. 2022. doi: 10.1016/j.cmi.2022.02.027 35259529 Rosas IO, Bräu N, Waters M, Go RC, Malhotra A, Hunter BD, et al. Tocilizumab in patients hospitalised with COVID-19 pneumonia: Efficacy, safety, viral clearance, and antibody response from a randomised controlled trial (COVACTA). eClinicalMedicine. 2022;47:101409. doi: 10.1016/j.eclinm.2022.101409 35475258 Rutgers A, Westerweel P, Holt Bvd, Postma S, Vonderen MGAv, Piersma D, et al. Timely Administration of Tocilizumab Improves Survival of Hospitalized COVID-19 Patients. SSRN; 2021. Zeraatkar D, Cusano E, Martínez JPD, Qasim A, Mangala S, Kum E, et al. Use of tocilizumab and sarilumab alone or in combination with corticosteroids for covid-19: systematic review and network meta-analysis. BMJ Medicine. 2022;1(1):e000036. doi: 10.1136/bmjmed-2021-000036 Godolphin PJ, Rogozińska E, Fisher DJ, Vale CL, Tierney JF. Meta-analyses based on summary data can provide timely, thorough and reliable evidence: don’t dismiss them yet. Nat Med. 2022;28(3):429–30. doi: 10.1038/s41591-021-01675-1 35145306 10.1371/journal.pone.0270668.r001 Decision Letter 0 Cortegiani Andrea Academic Editor 2022 Andrea Cortegiani This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version 0 Transfer Alert

This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present.

21 Apr 2022

PONE-D-22-07351Association between tocilizumab, sarilumab and all-cause mortality at 28 days in hospitalised patients with COVID-19: A network meta-analysisPLOS ONE

Dear Dr. Godolphin,

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Both reviewers, experts in SR methodology, underlined the importance of the topic. However, both recommended the GRADE assessment of the certainty of evidence according to current standard for GRADE NMA. 

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Reviewer #1: Yes

Reviewer #2: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

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Reviewer #1: Thank you for the opportunity to review this rigorous and well-conducted network meta-analysis. I have only a few minor points for the authors to consider to enhance the interpretation of the study. One of the major rationales for addressing the question of tocilizumab vs. sarilumab is that clinicians tend to favour the former. The study partially addresses this question, but a few issues remain.

1) No evidence for this claim (page 3, lines 71-72) "Possibly related to interpretations of these findings, there is some emerging evidence to suggest that clinicians and healthcare providers have tended to favour the use of tocilizumab, with potential implications on patient access to these treatments." Anecdotally, this statements aligns with my experience but I am not sure whether it is true or not, and no citation is provided.

2) There was no consideration of the quality/certainty of evidence across studies, eg. GRADE. This is quite feasible to do even in the NMA setting (https://www.bmj.com/content/349/bmj.g5630). Consideration of imprecision, inconsistency, indirectness, incoherence, etc. in a structured way (I would advocate for GRADE) could provide the reader with a better sense of how confident we should be in these results. For instance the confidence intervals for the T vs. S comparisons are very wide in all 3 comparisons (direct, indirect, net); the potential for incoherence between direct vs. indirect T vs. S comparisons, etc. This is not merely a matter of academic interest, but also important in exploring the study question regarding why clinicians may favour T vs. S (eg. direct evidence is less precise, etc.)

3) Lastly, the discussion does lit tle to address the question which the NMA claims to address, re: clinician practice. While making such recommendations is more likely to be done in the setting of a guideline, it is important to note that the rationale for clinicians and patients choosing a treatment is based upon many factors (desirable effects; undesirable effects for sure; but also certainty of those effects, the balance, the feasibility, cost, acceptability etc.). While the review does not really address all these other issues, the discussion could note that these are also important, not just the mortality rate alone (as important as that is).

These are fairly minor concerns in a wonderful paper. Butt as it quite explicitly asks one question, I expected there to be greater exploration of the certainty of the effects of T vs. S and some discussion on the topic (including all the various factors for choosing a treatment which are not really addressed in this NMA).

Reviewer #2: The authors did not assess the certainty of the evidence, which- according to Cochrane- is considered a methodological standard for all systematic reviews. This can be done using GRADE or CINEMA They should not only add this assessment (which includes specifying the degree of contextualization they will use and their target of certainty), but incorporate it formally in the drawing of their conclusions regarding the effects of the interventions. They can find detailed information about certainty of evidence assessment process and drawing conclusions from NMA in the GRADE for NMA papers, making narrative statements/ conclusions in GRADE guidelines 26, and contextualization/ target of certainty rating in GRADE guidelines 32.

In addition, authors should follow the prisma statement for NMA for reporting.

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Reviewer #1: No

Reviewer #2: Yes: Romina Brignardello-Petersen

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 10.1371/journal.pone.0270668.r002 Author response to Decision Letter 0 Submission Version 1

1 Jun 2022

Please see attached file for our response to reviewers

Submitted filename: IL6 NMA response to reviewers_v3.docx

 10.1371/journal.pone.0270668.r003 Decision Letter 1 Cortegiani Andrea Academic Editor 2022 Andrea Cortegiani This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version 1

15 Jun 2022

Association between tocilizumab, sarilumab and all-cause mortality at 28 days in hospitalised patients with COVID-19: A network meta-analysis

PONE-D-22-07351R1

Dear Dr. Godolphin,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Thank you for the thoughtful and comprehensive responses to the reviewer comments. The manuscript has benefited from the use of a standardized reporting approach for the quality/certainty of evidence using GRADE. It is excellent and I have no further comments-- thank you.

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Reviewer #1: Yes: Simon JW Oczkowski

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 10.1371/journal.pone.0270668.r004 Acceptance letter Cortegiani Andrea Academic Editor 2022 Andrea Cortegiani This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

30 Jun 2022

PONE-D-22-07351R1

Association between tocilizumab, sarilumab and all-cause mortality at 28 days in hospitalised patients with COVID-19: A network meta-analysis

Dear Dr. Godolphin:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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PLOS ONE