Successful immunomodulators for the treatment of COVID-19 have opened the pathway for comparative trials

Because coronavirus disease 2019 (COVID-19) became a dominant factor in our daily lives, we have learned a tremendous amount about it through both study and shared experience. Therapies for patients hospitalized for COVID-19 have improved from ineffective shots in the dark, through mildly effective antivirals, to mortality-reducing immunomodulatory therapies [[1]McCreary E.K. Pogue J.M. Coronavirus disease 2019 treatment: a review of early and emerging options.Open Forum Infect Dis. 2020; 7 (:ofaa105. https://doi.org/10.1093/ofid/ofaa105)Crossref Scopus (208) Google Scholar]. The widely accepted view of COVID-19 as a dual-phase illness with a viral component and an inflammatory component has led to the successful search for immunomodulatory therapies to attenuate host response and improve outcomes [[2]Gandhi R.T. The multidimensional challenge of treating coronavirus disease 2019 (COVID-19): remdesivir is a foot in the door.Clin Infect Dis. 2021; 73: e4175-e4178https://doi.org/10.1093/cid/ciaa1132Crossref PubMed Scopus (15) Google Scholar,[3]Wiersinga W.J. Rhodes A. Cheng A.C. Peacock S.J. Prescott H.C. Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review.JAMA. 2020; 324: 782-793https://doi.org/10.1001/jama.2020.12839Crossref PubMed Scopus (2826) Google Scholar]. As studies have advanced, our standard of care has advanced as well; patients with severe and critical COVID-19 now receive combinations of these corticosteroids with Janus kinase inhibitors or interleukin 6 inhibitors [4Clinical management of COVID-19: living guideline, 23 june 2022. World Health Organization, 2022https://www.who.int/publications-detail-redirect/WHO-2019-nCoV-clinical-2022-1Google Scholar, 5Bhimraj A. Morgan R.L. Shumaker A.H. Baden L. Cheng V.C.C. Edwards K.M. et al.IDSA guidelines on the treatment and management of patients with COVID-19. Infectious Diseases Society of America, 2022https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/Google Scholar, 6COVID-19 Treatment Guidelines PanelCoronavirus disease 2019 (COVID-19) treatment guidelines. National Institutes of Health, 2022https://www.covid19treatmentguidelines.nih.gov/Date accessed: August 29, 2022Google Scholar]. What have largely not occurred thus far are comparative, head-to-head trials to determine which therapies are best. Two comparison trials exist, only one of which is direct. One is the IL-6 inhibitor arm of the REMAP-CAP trial (Randomised, Embedded, Multi-factorial, Adaptive Platform Trial for Community-Acquired Pneumonia), in which tocilizumab and sarilumab are compared separately to the standard of care [[7]IREMAP-CAP Investigators Interleukin-6 receptor antagonists in critically ill patients with Covid-19.N Engl J Med. 2021; 384: 1491-1502https://doi.org/10.1056/NEJMoa2100433Crossref PubMed Scopus (1039) Google Scholar]. This trial showed improved outcomes in patients with progressive critical COVID-19 receiving tocilizumab or sarilumab with corticosteroids compared with the outcomes in controls, although only 48 patients received sarilumab in the study, whereas 353 patients received tocilizumab [[7]IREMAP-CAP Investigators Interleukin-6 receptor antagonists in critically ill patients with Covid-19.N Engl J Med. 2021; 384: 1491-1502https://doi.org/10.1056/NEJMoa2100433Crossref PubMed Scopus (1039) Google Scholar]. In the other trial, which is available as a preprint, Karampitsakos et al. [[8]Karampitsakos T. Papaioannou O. Tsiri P. Katsaras M. Katsimpris A. Kalogeropoulos A.P. et al.Tocilizumab versus baricitinib in hospitalized patients with severe COVID-19: an open label, randomized controlled trial.Posted June. 2022; 16 (Accessed XXX. Available at)https://www.medrxiv.org/content/10.1101/2022.06.13.22276211v1Date accessed: August 29, 2022Google Scholar] directly compared tocilizumab to baricitinib in patients with a partial pressure of inhaled oxygen to fraction of inhaled oxygen (PaO2-to-FiO2) ratio of <200. This open-label randomized study of 251 patients showed noninferiority of baricitinib to tocilizumab using their criteria (upper bound of the hazard ratio for death or mechanical ventilation not exceeding 1.5) [[8]Karampitsakos T. Papaioannou O. Tsiri P. Katsaras M. Katsimpris A. Kalogeropoulos A.P. et al.Tocilizumab versus baricitinib in hospitalized patients with severe COVID-19: an open label, randomized controlled trial.Posted June. 2022; 16 (Accessed XXX. Available at)https://www.medrxiv.org/content/10.1101/2022.06.13.22276211v1Date accessed: August 29, 2022Google Scholar]. The paucity of head-to-head trials comparing established treatment options has led different guideline panels to make different recommendations even though informed by a similar body of evidence (Table 1) [4Clinical management of COVID-19: living guideline, 23 june 2022. World Health Organization, 2022https://www.who.int/publications-detail-redirect/WHO-2019-nCoV-clinical-2022-1Google Scholar, 5Bhimraj A. Morgan R.L. Shumaker A.H. Baden L. Cheng V.C.C. Edwards K.M. et al.IDSA guidelines on the treatment and management of patients with COVID-19. Infectious Diseases Society of America, 2022https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/Google Scholar, 6COVID-19 Treatment Guidelines PanelCoronavirus disease 2019 (COVID-19) treatment guidelines. National Institutes of Health, 2022https://www.covid19treatmentguidelines.nih.gov/Date accessed: August 29, 2022Google Scholar]. For example, WHO recommends tocilizumab, baricitinib, or sarilumab, whereas the Infectious Diseases Society of America (IDSA) and the US National Institutes of Health (NIH) both recommend tocilizumab and sarilumab but recognize sarilumab as an alternative when tocilizumab is not available instead of recommending it at the same level [4Clinical management of COVID-19: living guideline, 23 june 2022. World Health Organization, 2022https://www.who.int/publications-detail-redirect/WHO-2019-nCoV-clinical-2022-1Google Scholar, 5Bhimraj A. Morgan R.L. Shumaker A.H. Baden L. Cheng V.C.C. Edwards K.M. et al.IDSA guidelines on the treatment and management of patients with COVID-19. Infectious Diseases Society of America, 2022https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/Google Scholar, 6COVID-19 Treatment Guidelines PanelCoronavirus disease 2019 (COVID-19) treatment guidelines. National Institutes of Health, 2022https://www.covid19treatmentguidelines.nih.gov/Date accessed: August 29, 2022Google Scholar]. These stepped recommendations from IDSA and NIH recognize the lack (at the time) of trials directly comparing these treatments and the limited certainty from indirect comparisons.Table 1Guideline recommendations for interleukin 6 inhibitors and baricitinib for COVID-19 [4Clinical management of COVID-19: living guideline, 23 june 2022. World Health Organization, 2022https://www.who.int/publications-detail-redirect/WHO-2019-nCoV-clinical-2022-1Google Scholar, 5Bhimraj A. Morgan R.L. Shumaker A.H. Baden L. Cheng V.C.C. Edwards K.M. et al.IDSA guidelines on the treatment and management of patients with COVID-19. Infectious Diseases Society of America, 2022https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/Google Scholar, 6COVID-19 Treatment Guidelines PanelCoronavirus disease 2019 (COVID-19) treatment guidelines. National Institutes of Health, 2022https://www.covid19treatmentguidelines.nih.gov/Date accessed: August 29, 2022Google Scholar]DrugWHOInfectious diseases society of AmericaNational institutes of health (United States)TocilizumabRecommended for patients with severe or critical COVID-19Suggested for patients with progressive severe or critical COVID-19 and elevated markers of inflammationRecommended for patients with progressive severe or critical COVID-19 and elevated markers of inflammationSarilumabRecommended for patients with severe or critical COVID-19Suggested for patients with progressive severe or critical COVID-19 and elevated markers of inflammation when tocilizumab is not availableRecommended for patients with progressive severe or critical COVID-19 and elevated markers of inflammation when tocilizumab is not availableBaricitinibRecommended for patients with severe or critical COVID-19Suggested for patients with severe COVID-19Recommended for patients with progressive severe or critical COVID-19 and elevated markers of inflammation Open table in a new tab In the absence of a robust body of evidence from trials reporting on direct comparisons, in this issue of Clinical Microbiology and Infection, Albuquerque et al. [[9]Albuquerque A.M. Eckert I. Tramujas L. Butler-Laporte G. McDonald E.G. Brophy J.M. et al.Effect of tocilizumab, sarilumab, and baricitinib on mortality among patients hospitalized for COVID-19 treated with corticosteroids: a systematic review and meta-analysis.Clin Microbiol Infect. 2022; 29: 13-21https://doi.org/10.1016/j.cmi.2022.07.008Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar] propose a Bayesian meta-regression to indirectly assess the efficacy of sarilumab and baricitinib compared with that of tocilizumab [[9]Albuquerque A.M. Eckert I. Tramujas L. Butler-Laporte G. McDonald E.G. Brophy J.M. et al.Effect of tocilizumab, sarilumab, and baricitinib on mortality among patients hospitalized for COVID-19 treated with corticosteroids: a systematic review and meta-analysis.Clin Microbiol Infect. 2022; 29: 13-21https://doi.org/10.1016/j.cmi.2022.07.008Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar]. The authors initially conducted several pairwise Bayesian meta-analyses studying the effects of tocilizumab, sarilumab, and baricitinib versus an inactive comparison (i.e. placebo or standard of care) when added to corticosteroid therapy for COVID-19 on 28-day mortality. The meta-regression, based on multiple levels of assumptions, aimed to determine the probabilities of noninferiority of sarilumab and baricitinib to the reference of tocilizumab. The investigators present four models informed by different priors, including using the results from two recent head-to-head trials comparing the active treatments. While recognizing wide variability, they concluded that sarilumab and baricitinib may have high probabilities of noninferiority compared with that of tocilizumab for the treatment of COVID-19, all in combination with corticosteroids. The authors recognized the heterogeneity in the primary meta-analyses because the methods used for this indirect comparison could not completely account for the differences in study populations across different trials, such as age, the severity of disease, circulating variant, etc. Similarly, it is unclear whether the meta-regression considered the certainty of the evidence for the pairwise meta-analyses because this varied across therapies. Although intra-study differences were small, the studies had different inclusion criteria and, resultantly, different proportions of patients requiring intensive respiratory therapy, which indicate the populations in which tocilizumab shows the greatest benefit. What is a clinician to do with these data? Although it is reassuring that the effectiveness of sarilumab and baricitinib may not be inferior to that of tocilizumab for 28-day mortality, it is still important to take the findings with caution. The interleukin 6 inhibitors in particular have had a difficult road in determining where their utility lies for COVID-19. A quick scan of the meta-analysis shows that there has been no shortage of studies with either tocilizumab or sarilumab. Some of these early studies were underpowered because of low enrollment, low event rates, the inclusion of patients at low risk of poor outcomes, and/or low numbers of patients receiving concomitant corticosteroid therapy, highlighting the importance of pooling the results in a meta-analysis [[5]Bhimraj A. Morgan R.L. Shumaker A.H. Baden L. Cheng V.C.C. Edwards K.M. et al.IDSA guidelines on the treatment and management of patients with COVID-19. Infectious Diseases Society of America, 2022https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/Google Scholar]. Many of the studies on both tocilizumab and sarilumab showed no benefit, and it was not until they were studied in critically ill patients receiving corticosteroids that an effect on mortality was observed. The eligibility for inclusion of primary studies is appropriately limited to evaluating patients who received concomitant corticosteroids; however, this comes with the potential for loss of randomization from trials that did not stratify on the basis of the receipt of corticosteroids and lumping patients from the subgroups of earlier studies with the entire populations of later studies. Both of these have the potential for introducing heterogeneity into the analyses owing to changing study characteristics, such as standards of care, recognition of severe disease, and concomitant therapies. Ultimately, the study is a useful reference but does not supersede the need for direct comparisons and/or fit-for-purpose analyses, such as a network meta-analysis of therapies for patients with severe COVID-19. Separately, there are sufficient data showing the efficacy of both baricitinib and tocilizumab compared with that of the standard of care, and in overlapping levels of severity, both therapies are good options for patients with severe illness. Although studies on baricitinib in populations published earlier in the pandemic included few patients on mechanical ventilators, an analysis of patients on mechanical ventilators or receiving extracorporeal membrane oxygenation in the COV-BARRIER study showed a reduction in mortality [[10]Ely E.W. Ramanan A.V. Kartman C.E. de Bono S. Liao R. Piruzeli M.L.B. et al.Efficacy and safety of baricitinib plus standard of care for the treatment of critically ill hospitalised adults with COVID-19 on invasive mechanical ventilation or extracorporeal membrane oxygenation: an exploratory, randomised, placebo-controlled trial.Lancet Respir Med. 2022; 10: 327-336https://doi.org/10.1016/S2213-2600(22)00006-6Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar]. The data supporting sarilumab are sparser; hence, recommendations by IDSA and NIH guideline panels are measured and these panels recommend sarilumab only when better-studied therapies are not available. In the absence of more robust studies, to recommend it on parity with tocilizumab and baricitinib is premature. As our standards of care for severe COVID-19 have advanced, our standards of evidence should advance as well. JCG is the lead and corresponding author. JCG wrote the original draft of the article. JCG and RLM reviewed and edited the article. JCG has received royalties for book authorship from Jones and Bartlett Learning; consulting fees from Qpex, Shionogi, Merck, Accelerate Diagnostics, Achaogen, Astellas Pharma, Melinta Therapeutics, Nabriva Therapeutics, Paratek Pharma, scPharmaceuticals, Spero Therapeutics, and Tetraphase Pharmaceuticals; speaker honoraria from Astellas Pharma, Melinta Therapeutics, Merck, and Shionogi; travel support from Merck; and research support from Merck. R.M. declares that she has no conflicts of interest. Effect of tocilizumab, sarilumab, and baricitinib on mortality among patients hospitalized for COVID-19 treated with corticosteroids: a systematic review and meta-analysisClinical Microbiology and InfectionVol. 29Issue 1PreviewRandomized controlled trials (RCT) established the mortality reduction by tocilizumab (Actemra), baricitinib (Olumiant), and sarilumab (Kevzara) in hospitalized COVID-19 patients. However, uncertainty remains about which treatment performs best in patients receiving corticosteroids. Full-Text PDF