key: cord-0959651-bls5qllx
authors: Zhang, C.; Jin, H.; Wen, Y.; Yin, G.
title: A Systematic Review and Network Meta-Analysis for COVID-19 Treatments
date: 2020-12-22
journal: nan
DOI: 10.1101/2020.12.21.20248621
sha: 31da5d49af8f2ecf9ac1d5fb5500073b5a13b889
doc_id: 959651
cord_uid: bls5qllx

Background: Numerous 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. Methods: We 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. Results: We 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. Conclusion: The 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.

The pandemic of novel coronavirus disease 2019 (COVID- 19) , first identified at the end of 2019 in Wuhan, China, has become a global threat to public health. By December 20, 2020, over 76.4 million confirmed cases including 1.69 million deaths have been reported. 1 Faced with such a global crisis, identifying effective treatments for COVID -19 is of urgent need and paramount importance for clinical researchers. Development of novel drugs typically takes years of concerted efforts and thus most of current research in COVID-19 treatment has been focused on drug repositioning, i.e., investigating the treatment effect of drugs approved for other diseases on COVID-19 patients.

Till December 2020, over 7000 clinical trials related to COVID-19 have been registered worldwide. Although numerous medications have been investigated by randomized controlled trials (RCTs), only dexamethasone 2, 3 and remdesivir 4, 5 were proven to be clinically effective, while several other antiviral medications were approved for emergency or compassionate use.

During the drug repurposing process, clinicians identify candidate drugs for a specific disease by estimating drug-disease or drug-drug similarities. Drugs with shared chemical structures and mechanisms of action are supposed to deliver similar therapeutic applications. 6 Not only should research focus on individual treatment for COVID -19, but it is also of great interest to evaluate a class of treatments with shared clinical properties and biochemical structures. For example, systemic corticosteroids including methylprednisolone, dexamethasone and hydrocortisone were reported to be associated with reduced 28-day mortality for COVID-19 patients of critical illness. 7 With global efforts on pursuing effective treatments during the pandemic, many shortterm RCTs of small size were conducted and published at a high rate, and some trials were carried out in a rather rush manner which might cause deterioration of trial quality.

Timely summaries and analyses on existing clinical trial results can help to better understand various treatments, early terminate investigation on proven ineffective treatments and provide necessary guidelines for further research and discovery of new treatment. However, with a large number of treatments evaluated against the standard of care (SOC) or other active comparators in RCTs, the conventional pairwise meta-analysis is limited in simultaneous comparisons among multiple trials and fails to capture indirect evidence for treatments that have not been tested in a head-to-head comparison. A network meta-analysis (NMA) which combines both direct and indirect information in a network would be more appropriate to accommodate such complex environments.

Several NMA publications provided useful information on the comparative effectiveness of common repurposed drugs for patients with 9 Our work formulated Bayesian hierarchical models using fixed and random effects respectively, which could effectively borrow information across different trials in the NMA. Not only does our NMA evaluate treatments at the drug level, but it also provides an overall estimated effect at the class level which may contain several drugs of a similar type.

This NMA simultaneously evaluates the clinical benefits of individual treatments and classifications of multiple treatments for COVID-19. We construct a Bayesian hierarchical framework on the effect sizes of treatments and classes, and results were presented and interpreted on both the individual drug level and the class level.

This systematic review and NMA were conducted and reported in accordance with the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) for NMAs 10 .

We only included RCTs for suspected or confirmed COVID-19 patients in the systematic review and meta-analysis, because non-randomized trials and observational studies were considered of low certainty of evidence 11 . We included trials published in English and Chinese regardless of the publication status (peer-reviewed or preprint), ways of randomization (double-blind, single-blind or open-label) or study location. Patients in all age groups and of all baseline severities of illness were considered eligible.

We examined treatments for COVID-19 irrespective of dose or duration of administration.

Exclusion criteria for the interventions were given as follows: (i) herbal medicine; (ii) preventive interventions (e.g., vaccination and mask wearing); (iii) non-drug supportive care; (iv) exercise, psychological and educational treatments. No restrictions were placed on the control group and we included studies comparing drugs to other active comparator, placebo, SOC or no intervention.

The outcomes of interest in the NMA included overall mortality, requirement for mechanical ventilation (MV), discharge from hospital on day 14 or the day closest to that, and viral clearance on day 7 or the day closest to that. We evaluated only binary . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted December 22, 2020. ; https://doi.org/10.1101/2020.12.21.20248621 doi: medRxiv preprint outcomes since most COVID-19 trials had a less than one-month follow-up, 8 and for such short-term studies, continuous or survival outcomes might not provide a clinically meaningful and relevant summary for treatment effect 12 . In addition, the clinical definitions of several continuous outcomes, e.g., time to clinical improvement, deterioration and symptom resolution, were not consistent across trials. Different reporting patterns of point and interval estimates for continuous outcomes may also cause additional difficulties and biases in the NMA.

To solve inconsistent reporting for the requirement of MV across trials, we adopted a hierarchical data extraction approach. 8 We updated the literature search weekly to include newly published trials. The current version of manuscript included studies from January 1, 2020 to December 19, 2020. The update of our NMA results will continue on the monthly basis to provide timely assessment on all therapeutic treatments for COVID-19.

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The copyright holder for this this version posted December 22, 2020. ; https://doi.org/10.1101/2020.12.21.20248621 doi: medRxiv preprint Two reviewers independently screened the titles and abstracts using the inclusion criteria.

Studies identified as relevant with full text available were further assessed for eligibility.

Discrepancies were resolved by the same two reviewers via discussion and, if necessary, a third senior investigator would make the final decision.

Data extraction was conducted by two investigators independently. For each eligible study, we collected trial characteristics (e.g., the trial registration number, publication status, study status, randomization), interventions, characteristics of participants at baseline (e.g., age, sex, severity of illness, etc.) and outcomes of interest. For the four binary outcomes (mortality, MV, discharge and viral clearance), numbers of events and overall numbers of patients were collected. Two reviewers resolved discrepancies if any via discussion and a third party would adjudicate the conflict. For multiple reports on the same trial, we adopted the peer-reviewed publication if available, or the latest preprint.

For each eligible trial, we used a revision 8 of version 2 of the Cochrane risk of bias tool (RoB 2.0) 14 to assess risk of bias in RCTs. Trials were evaluated on five bias domains including bias arising from the randomization process, bias due to deviations from intended interventions, bias due to missing outcome data, bias in measurement of the outcome and bias in selection of the reported result, and for each domain it was labelled as low, probably low, probably high or high risk of bias. A trial would be rated as low risk if all of five domains were labelled as probably low or low risk of bias; otherwise, it . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted December 22, 2020. ; https://doi.org/10.1101/2020.12.21.20248621 doi: medRxiv preprint would be rated as high risk. Detailed risk-of-bias judgments were listed in Supplementary Materials. Two reviewers separately completed the RoB assessment and, in presence of any disagreement, a third party would make the final decision.

We conducted a fixed-effects NMA under a Bayesian hierarchical framework. A randomeffects NMA was adopted if there existed heterogeneity among trials. However, for most of the comparisons between two treatments, only a few studies were reported and the assessment of heterogeneity might not be reliable. Moreover, sample sizes of trials varied dramatically within some comparisons; for example, the relatively large trials, RECOVERY 2, 15, 16 and SOLIDARITY 17 , would typically dominate the estimates. In the network, each node represents a treatment, regardless of dose or duration of administration. For the studies involving different doses or durations of the same drug 18 , we aggregated data of the same drug into one arm. Each multi-arm trial was treated as a single study in the network analysis, instead of splitting it into several two-arm sub-trials.

Interventions composed of more than one drug were treated as separate nodes with each corresponding to one drug. In addition, interval estimates could be imprecise for treatments tested with small sample size 8, 19 . Therefore, for each clinical outcome, we excluded the treatments appearing in only one trial with fewer than 100 patients to alleviate potential risk caused by inadequate information. We plotted the network for each outcome of interest using the igraph 20 we considered the node-splitting method 23 . The MCMC sampling was performed using . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted December 22, 2020. ; the jagsUI 24, 25 package of R, and further network analyses were performed using the gemtc 26 package of R.

The grading of recommendations assessment, development and evaluation (GRADE) approach for NMA 11 was used to rate the certainty of evidence of NMA estimates. Two investigators rated the certainty of each treatment comparison independently and resolved discrepancies by discussions and, if necessary, consulted with a third party. We considered each of the following seven criteria: RoB 27 , inconsistency 28 , indirectness 29 , publication bias 30 , intransitivity 11 , incoherence 31 and imprecision 32 , to evaluate the certainty of NMA estimates as high, moderate, low and very low. The certainty would be rated down by one scale if no less than half of the trials directly comparing two treatments were of high RoB. The inconsistency was assessed by the Higgins I 2 statistics and the Cochran Q test 33 and we identified inconsistency if I 2 >50% or p-value<0.05 from the Cochran Q test. We rated down by one scale for publication bias due to asymmetric funnel plots or industry sponsorship. 30 Baseline patient characteristics, especially the severity of illness, were used for the evaluation of intransitivity. The minimally contextualised approach 34 considering only the CrI and null effect was used for assessing imprecision. We set a threshold of 0.02 rather than the null value 0 in the log OR scale in order to demonstrate more convincing evidence in each paired comparison. Detailed ratings and rationales for downgrading were provided in the Supplementary Materials.

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The copyright holder for this this version posted December 22, 2020. ;

Planned subgroup analyses were conducted for peer-reviewed studies only and mild/moderate versus severe/critical COVID-19 patients at baseline. In addition to Bayesian fixed-effects NMA, we also performed Bayesian random-effects NMA and presented results in Supplementary Materials. In the primary analysis, we treated three published studies for the RECOVERY trial 2, 15, 16 which respectively compared lopinavir/ritonavir, dexamethasone and hydroxychloroquine versus SOC, as a four-arm trial according to the RECOVERY protocol v6.0. 35 The SOC group with the largest number of participants 2 was used in the primary analysis. Similarly, although the SOLIDARTIY trial 17 reported four pairwise comparisons between interventions and SOC, we treated it as a five-arm trial due to substantial overlap across SOC groups.

Furthermore, we performed a sensitivity analysis by treating RECOVERY as three twoarm trials and SOLIDARITY as four two-arm trials.

According to the prespecified inclusion and exclusion criteria, we identified and screened 4563 titles and abstracts after de-duplication. Out of these, 146 studies were further 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 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint 

The hospital discharge rate was reported in 36 studies including 31436 patients and 19365 events. 2, 5, 15, 16, 36, 43, 47, 48, 50, 54, 60, 65, 66, 69, 75, 76, 79, 80, 83, 85, 88, 89, 91, 92, 96, 100, 103, 107-110, 112, 113, 116, 117, 120 Treatment nodes included in the network were azithromycin, hydroxychloroquine, hydroxychloroquine plus azithromycin, favipiravir, remdesivir, . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint 

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted December 22, 2020. ; https://doi.org/10.1101/2020.12.21.20248621 doi: medRxiv preprint Twenty-one studies including 3183 patients and 1403 events reported viral clearance rates. 39, 43, 52, 53, 65, 67, 79, 80, 82, 84, 88, 90, 92, 99, 102, 115, 117, [119] [120] [121] 124 Treatment nodes in the network included hydroxychloroquine, nitazoxanide, hydroxychloroquine plus azithromycin, favipiravir, remdesivir, convalescent plasma, methylprednisolone and SOC.

Out of these 15 trials included in the NMA, six were judged at low risk of bias. Under the fixed-effects NMA, the OR of nitazoxanide versus SOC was 1.72 (95% CrI [1.13, 2.80];

low certainty) and that of convalescent plasma was 2.28 (95% CrI was still effective in virus elimination. The RECOVERY trial did not report viral clearance and thus no sensitivity analysis was carried out.

In this systematic review and NMA, we provided a detailed summary of trial characteristics of published RCTs for COVID-19 patients up to December 7, 2020 and reported effectiveness of treatments at both the drug and class levels compared with SOC . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 

Not only was this NMA timely conducted, but it also included a wide range of RCTs, which contained not only common drugs but also interferons, blood products, mineral and vitamin supplementations without restrictions on publication status. Risk of bias for individual studies and rating of certainty for NMA estimates were carefully conducted and detailed information and reasons for corresponding assessments are given in . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint With a large number of completed COVID-19 trials, studies reporting positive results or with large sample size were more likely to be published, leading to possible publication bias. 30 We considered studies irrespective of publication status to alleviate publication bias and obtained as much information as possible. While extra attention should be paid on the evidence implied by only preprints. For example, the significant benefit of nitazoxanide on viral clearance was shown in only one preprint, 102 and clinical results without peer-reviews should not be trusted equally as those published.

Different approaches to dealing with the RECOVERY trial led to discrepancies between the results of the primary and sensitivity analyses, especially for lopinavir/ritonavir. The RECOVERY trial was designed as a multi-arm trial 35 

This systematic review and meta-analysis showed that dexamethasone could reduce the mortality, requirements of MV and increase the discharge rate. Administration of remdesivir led to a higher discharge rate, but showed no difference from SOC for mortality, MV and viral clearance. Patients receiving recombinant GCSF had lower risk of MV. Nitazoxanide and convalescent plasma could improve the viral elimination, although the evidence of nitazoxanide was supported solely by one preprint.

Lopinavir/ritonavir showed clinical benefits on the increase of the discharge rate and . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint Studies included in this meta-analysis (n = 80 ) 4 Different doses/durations of the same drug 9 Not reported outcomes of interest 3 Not connected to the network . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted December 22, 2020. ; https://doi.org/10.1101/2020.12.21.20248621 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

(which was not certified by peer review) preprint

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The copyright holder for this this version posted December 22, 2020. ; https://doi.org/10.1101/2020.12.21.20248621 doi: medRxiv preprint

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