key: cord-1002426-bcv49rmo
authors: Welte, T.; Ambrose, L. J.; Sibbring, G. C.; Sheikh, S.; Müllerova, H.; Sabir, I.
title: Current evidence for COVID-19 therapies: a systematic literature review
date: 2020-12-19
journal: nan
DOI: 10.1101/2020.12.18.20248452
sha: 476c77c6f88a773b1bd114c232b939f73bab2faf
doc_id: 1002426
cord_uid: bcv49rmo

Effective therapeutic interventions for the treatment and prevention of COVID-19 are urgently needed. A systematic review was conducted to identify clinical trials of pharmacological interventions for COVID-19 published between 1 December 2019 and 14 October 2020. Data regarding efficacy of interventions, in terms of mortality, hospitalisation and need for ventilation, were extracted from identified studies and synthesised qualitatively. In total, 42 clinical trials were included. Interventions assessed included antiviral, mucolytic, anti-malarial, anti-inflammatory and immunomodulatory therapies. Some reductions in mortality, hospitalisation and need for ventilation were seen with interferons and remdesivir, particularly when administered early, and with the mucolytic drug, bromhexine. Most studies of lopinavir/ritonavir and hydroxychloroquine did not show significant efficacy over standard care/placebo. Dexamethasone significantly reduced mortality, hospitalisation and need for ventilation versus standard care, particularly in patients with severe disease. Evidence for other classes of interventions was limited. Many trials had a moderate-to-high risk of bias, particularly in terms of blinding; most were short-term; and some included low patient numbers. This review highlights the need for well-designed clinical trials of therapeutic interventions for COVID-19 to increase the quality of available evidence. It also emphasises the importance of tailoring interventions to disease stage and severity for maximum efficacy.

This SLR (registered with the Research Registry, unique identifying number: reviewregistry1019) evaluated studies of pharmacological options for the treatment and prevention of COVID-19. The review was conducted according to the principles embodied in the Cochrane Handbook for Systematic Reviews of Interventions [26] and guidance published by the Centre for Reviews and Dissemination [27] .

The Exclusion criteria included studies of non-pharmacological interventions; traditional or herbal medicines; studies that reported on in vitro or in silico investigations; guidelines; clinical trial protocols or projection studies; or observational studies, such as prospective and retrospective cohort studies, case-control studies, cross-sectional studies, case reports and case series. Articles that were not written in English, reviews, comments, editorials, congress abstracts, and articles that had not undergone peer review were also excluded.

After removal of duplicates, records identified in the electronic database searches were manually screened for eligibility on the basis of titles and abstracts by a single reviewer, with a second reviewer screening ≥10% of records selected at random.

Any disagreements or uncertainties were discussed with a third reviewer to achieve a consensus. Subsequently, full texts of potentially relevant studies were obtained and reviewed for eligibility as for the first-pass screening. Studies containing duplicate information or not meeting the inclusion criteria upon further review were excluded.

Details of study design and population, interventions, comparators, follow-up duration and safety and efficacy outcomes were extracted from identified articles using a pilot-tested data extraction spreadsheet constructed in Microsoft Excel ® . If available, information on statistical comparisons between interventions was recorded; any studies reporting insufficient data meeting the inclusion criteria were All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 19, 2020. ;  https://doi.org/10.1101/2020.12. 18.20248452 doi: medRxiv preprint excluded at the data extraction stage. All extracted data were cross-checked by an independent reviewer.

Included studies were reviewed and assessed for comparability in terms of study design and outcomes reported. Randomised studies were included in the qualitative synthesis if they reported ≥1 of the selected outcomes: mortality, hospitalisation (any reported outcome, including duration, proportion of patients discharged and incidence) and need for ventilation (use of oxygen, non-invasive ventilation and intensive mechanical ventilation). Non-randomised trials reporting these outcomes were only included if no randomised trial evidence was available for a particular intervention.

Studies were grouped according to intervention and the disease phase targeted by the intervention; details of the categorisation used are presented in supplementary table 1. Studies reporting similar outcome measures were summarised descriptively according to the type of intervention. Studies with outcomes that were defined differently to other studies (e.g. event-free survival rather than percentage mortality, or outcomes reported for the overall population rather than according to treatment with [or allocation to] specific interventions) could not be grouped, and these were assessed separately.

Each study was assessed in terms of methodological quality based on criteria consistent with those in the Cochrane Handbook for Systematic Reviews of Interventions and the Cochrane risk-of-bias tool [26, 29] . All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 19, 2020. ;  https://doi.org/10.1101/2020.12.18.20248452 doi: medRxiv preprint

The literature searches identified 33,674 unique citations, and from these, 436 fulltext articles were assessed for eligibility (supplementary figure 1) . A total of 375 articles were excluded as they did not meet eligibility criteria for reasons such as (supplementary figure 2). Most trials used either standard care, which differed between trials, or placebo as a comparator.

In total, 39 randomised and one non-randomised trial reported on mortality, either as the number of deaths that occurred during the study or as a pre-specified study endpoint, with or without a statistical comparison between groups [30-36, 38-56, 58-All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in 

In total, 36 randomised trials and one non-randomised trial reported on hospitalisation, either as a pre-specified study endpoint or the number of patients All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in 

One trial (N=6425) reported a numerically shorter median duration of hospitalisation (12 versus 13 days) and a greater probability of discharge alive within 28 days with All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in 

In total, 30 randomised and one non-randomised trial, and one re-analysis of the study by Wang et al. [46] , reported outcomes relating to the need for oxygen, non-All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 19, 2020. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 19, 2020. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in 

There was variation among trials in terms of the risk of bias in the various domains assessed (supplementary figure 4) . Most trials were deemed at low risk of bias in terms of complete reporting of patient and outcomes data. However, most trials were also judged to be at high risk of bias in terms of blinding of participants and researchers to the intervention received. Only four randomised double-blind trials were considered to be at low risk of bias for all domains assessed [44, 46, 52, 68].

All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in Of 42 included trials, all but one assessed a treatment or treatment combination for patients with established COVID-19. One trial assessed the use of hydroxychloroquine as post-exposure prophylaxis in patients (N=821) with high-risk or moderate exposure to COVID-19 versus placebo. There was no difference in mortality or incidence of hospitalisation between groups, but the numbers of patients experiencing these events were very low (no deaths occurred and only one hospitalisation was reported in each group).

Among the trials assessing treatments in patients with COVID-19, interventions from several treatment classes showed significant effects in improving one or more of mortality, hospitalisation or need for ventilation outcomes. The most consistent effect across all outcomes assessed was reported for the corticosteroid, dexamethasone, in a preliminary report from the Randomised Evaluation of COVid-19 thERapY (RECOVERY) trial (Clinical Trials.gov: NCT04381936). The study investigators reported a significant reduction in mortality and a greater probability of discharge alive within 28 days with dexamethasone plus standard care versus standard care All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in [68] . Further well-designed and adequately powered studies are needed to increase the body of evidence for anti-inflammatory drugs as treatment for COVID-19.

In this review, findings from trials assessing drugs acting in the early infection or early pulmonary disease phase varied depending on the type of agent evaluated, the disease stage of patients enrolled in the study and the timing of drug administration. Some efficacy in reducing mortality, hospitalisation duration and need for ventilation was seen with IFN therapies [66, 67, 69] ; conversely, most trials of lopinavir/ritonavir Trials that assessed remdesivir compared with placebo or standard care also failed All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 19, 2020. treatments concluded that all four treatments evaluated (remdesivir, hydroxychloroquine, lopinavir/ritonavir and interferons) had little or no effect on overall mortality, initiation of ventilation and hospitalisation duration in patients hospitalised with COVID- 19 [76] . A notable difference is that some studies in the present review did show some efficacy of interferon therapies in reducing mortality and improving hospitalisation outcomes [66, 67, 69] , suggesting that these therapies may warrant further investigation.

A key finding from this review was the relationship between the disease phase of All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 19, 2020. ; https://doi.org/10.1101/2020.12.18.20248452 doi: medRxiv preprint Our ability to analyse and compare the data collected was limited by the significant variation between the trials identified, owing to differences in study design, blinding of participants, severity of illness of participants, drug doses and timing, days, and most studies did not report any longer-term data. This might have limited the ability to assess mortality and hospital discharge, particularly in patients with severe COVID-19 who often have a prolonged duration of illness.

These findings are in agreement with those reported in a living systematic review and meta-analysis of drug treatments for COVID-19, last updated in September 2020

[80]. The authors concluded that the effectiveness of most of the interventions that All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in 

This SLR summarises evidence regarding efficacy of pharmacological interventions in terms of mortality, hospitalisation and need for ventilation in patients with COVID-19, and highlights the need for adequately powered, well-designed clinical trials to increase the quality of available evidence. The summary of findings also suggests the need to use interventions appropriate for the disease stage of COVID-19, to maximise treatment efficacy. Although no relevant data from vaccine, antibody and other novel COVID-19-specific treatments were available at the time of conducting this review, the findings from ongoing clinical trials are awaited with interest.

All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 19, 2020. ; https://doi.org/10.1101/2020.12.18.20248452 doi: medRxiv preprint Acknowledgements Editorial support was provided by Rachael Cazaly, of Core Medica, London, UK, supported by AstraZeneca according to Good Publication Practice guidelines (Link).

The Sponsor was involved in the study design, analysis and interpretation of data.

However, ultimate responsibility for opinions, conclusions and data interpretation lies with the authors.

All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 19, 2020. Sibbring are employees of Prime Global, which received funding from AstraZeneca for medical writing and editorial support for this manuscript and other projects.

All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in All rights reserved. No reuse allowed without permission.

perpetuity.

preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in All rights reserved. No reuse allowed without permission.

perpetuity.

preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in

The copyright holder for this this version posted December 19, 2020. perpetuity.

preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in 

All rights reserved. No reuse allowed without permission.

perpetuity.

preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in

The copyright holder for this this version posted December 19, 2020. ; https://doi.org/10.1101/2020.12. 18.20248452 doi: medRxiv preprint Other therapies include anti-inflammatory drugs, anticoagulants, kinase inhibitors, CRAC channel inhibitors, anticoagulants, immunomodulatory therapies and repair therapies. *: Indicates a statistically significant P-value.

Results from one study are not presented graphically. Deftereos et al. [38] reported event-free survival as a primary outcome, which was defined as survival without meeting the primary clinical endpoint (deterioration by 2 points on a 7-grade clinical status scale, ranging from able to resume normal activities to death). a : Treatment administered in addition to standard care, as defined by the investigators in each trial; b : No between-group comparison; c : Treatment on day 1 of study participation; d : Treatment on day 6 of study participation; e : Outcome was disease progression or death; f : P-value for comparison of 7-level ordinal outcome (including death) at 14 days; g : Treatment ≤10 days of symptom onset; h : Treatment >10 days of symptom onset; i : Re-analysis of data from Wang Y, et al. using different criteria; j : Outcome was incidence of hospitalisation or death; k : P-value for comparisons of the 7-level ordinal outcome (including death) at 15 days; l : Participants could be randomly assigned to other interventions within other therapeutic domains; m : Median (95% CI) adjusted odds ratios versus the no-hydrocortisone group were 1.03 (0.53, 1.95) and 1.10 (0.58, 2.11) for the fixed-dose and shock-dependent dosing hydrocortisone groups, respectively. These yielded 54% and 62% Bayesian posterior probabilities of superiority. AZ: azithromycin; CI: confidence interval; CRAC: calcium release-activated calcium; F/U: follow-up; HR: hazard ratio; IFN: interferon; rhG-CSF: recombinant human granulocyte colony-stimulating factor; RR: rate ratio; RBV: ribavirin; TFF2: trefoil factor 2.

All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 19, 2020. ; https://doi.org/10.1101/2020.12.18.20248452 doi: medRxiv preprint perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 19, 2020. ; https://doi.org/10.1101/2020.12.18.20248452 doi: medRxiv preprint each trial; c : Data are mean (95% CI); d : Post-hoc analysis; e : Treatment on day 1 of study participation; f : Treatment on day 6 of study participation; g : Treatment, <7 days from symptom onset; h : Treatment ≥7 days from symptom onset; i : No between-group comparison; j : Outcome only assessed in survivors; k : No IQR reported; l :

Per hospital protocol, all patients meeting ARDS criteria were given pre-emptively intravenous ceftriaxone (1 g 2x for 7 days) plus azithromycin (500 mg 1x for 5 days) or clarithromycin (500 mg 2x for 7 days), starting on day 1; m : Upper IQR limit could not be determined; n : Median value could not be determined, HR: 1.90 (95% CI: 0.45, 8.04); P=0.38.

ARDS: acute respiratory distress syndrome; AZ: azithromycin; CI: confidence interval; HR: hazard ratio; IFN, interferon; IQR: interquartile range; LMW: low molecular weight; RBV: ribavirin; rhG-CSF: recombinant human granulocyte colony-stimulating factor; SD: standard deviation.

All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 19, 2020. ; https://doi.org/10.1101/2020.12.18.20248452 doi: medRxiv preprint perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 19, 2020. ; https://doi.org/10.1101/2020.12.18.20248452 doi: medRxiv preprint

Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review

Organ-specific manifestations of COVID-19 infection

COVID-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal

SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor

The Russian vaccine for COVID-19

Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia

Substantial underestimation of SARS

CoV-2 infection in the United States

Estimates of the severity of coronavirus disease 2019: a model-based analysis

Epidemiology of COVID-19: a systematic review and meta-analysis of clinical characteristics, risk factors, and outcomes

lopinavir/ritonavir plus interferon-alpha, and ribavirin plus lopinavir/ritonavir plus interferon-alpha in patients with mild to moderate coronavirus disease 2019: results of a randomized, open-labeled prospective study

Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial

A randomized clinical trial of the efficacy and safety of interferon β-1a in treatment of severe COVID-19

An open-label, randomized trial of the combination of IFN-κ plus TFF2 with standard care in the treatment of patients with moderate COVID-19

Methylprednisolone as adjunctive therapy for patients hospitalized with COVID-19 (metcovid): a randomised, double-blind, phase iib, placebo-controlled trial

Int Immunopharmacol a : Treatment administered in addition to standard care, as defined by the investigators in each trial; b : No comparison between groups; c : P-value for clinical status at day 14 (composite of death and ventilation requirement outcomes); d : Difference in clinical status distribution versus standard care, odds ratio: 1.65 (95% CI: 1.09, 2.48); e : Outcomes reported in patients not receiving ventilation at baseline; between-group differences (95% CI): oxygen, −8 (−24, -8); non-invasive ventilation/high-flow oxygen

After discharge/death, the proportion of patients requiring supplementary oxygen was significantly decreased compared to baseline in both groups

AZ: azithromycin; CI: confidence interval; ECMO: extracorporeal membrane oxygenation; HR: hazard ratio; IFN: interferon; RBV: ribavirin; rhG-CSF: recombinant human granulocyte colony-stimulating factor