key: cord-0778273-oco58jug
authors: Kaye, A. G.; Siegel, R.
title: The Efficacy of IL-6 Inhibitor Tocilizumab in Reducing Severe COVID-19 Mortality: A Systematic Review
date: 2020-07-14
journal: nan
DOI: 10.1101/2020.07.10.20150938
sha: 9018375e288b2ebb698f890184421c34c1919aa8
doc_id: 778273
cord_uid: oco58jug

Without proven, targeted therapies against SARS-CoV-2, it is crucial to counter the known pathophysiological causes of severe COVID-19, potentially utilizing existing drugs. Severe COVID-19 is largely the result of a dysregulated immune response characterized by lymphocytopenia, neutrophilia and critical hypercytokinemia, also called a cytokine storm. The IL-6 inhibitor tocilizumab (TCZ) could potentially suppress effects of the pro-inflammatory cytokine which drives the cytokine storm and thereby lower mortality from the disease. This systematic analysis aimed to investigate and synthesize existing evidence for the efficacy of TCZ in reducing COVID-19 mortality. PubMed and SearchWorks searches were performed to locate clinical studies with primary data on TCZ treatment for severe COVID-19. 9 case-control studies comparing mortality between TCZ and standard of care (SOC) were identified for a qualitative synthesis. In all of the studies, the odds ratio of mortality from COVID-19 pointed towards lower fatality with TCZ versus the SOC and a combined random effects odds ratio calculation yielded an odds ratio of 0.482 (p<0.001, 95% CI 0.326-0.713). Additionally, 12 uncontrolled trials were identified for a qualitative analysis producing a raw combined mortality rate of 13.6%. Results from the systematic analysis provide positive evidence for the potential efficacy of TCZ, validating the merit and need for ongoing clinical trials of the drug to treat severe COVID-19.

neutrophil survival. 12 Furthermore, elevated serum IL-6 is associated with impaired cytotoxic activity of NK cells. 13 IL-6 is also known to increase the rate of fibrotic clot formation, so it may play a role in the thrombotic complications observed in COVID-19. 12 Finally, the reninangiotensin system -which controls blood pressure and electrolyte balance -is an additional important factor in IL-6 modulation and COVID-19 pathology. As the virus binds ACE2, thus reducing its availability, there is an increase of angiotensin II in COVID-19 patients, creating a positive feedback loop that advances pro-inflammatory signaling 12

Devoid a targeted drug for COVID-19, scientists and clinicians are attempting to rapidly find alternative treatments and solutions to combat the disease's lethal immunological effects. 14 In addition to repurposing antivirals such as the RNA-dependent RNA polymerase inhibitor remdesivir -where patients in severe condition upon treatment fare worse than minor cases 15 -there are numerous investigations of immune suppressing and anti-cytokine interventions to counter the dysregulated, excessive immune response. After early evidence and recommendations against the use of corticosteroids to treat severe COVID-19, 16 ,17 a large randomized evaluation of dexamethasone found that the drug significantly reduced 28-day mortality in all patients (rate ratio 0.83; 95% CI 0.74-0.92; p<0.001); however, mortality rate reductions varied depending on baseline respiratory demands upon randomization as there was reduction for patients on mechanical ventilation and oxygen but not for patients without respiratory support. 18 At the time of this paper, the WHO did not alter their recommendation against corticosteroids in most cases except for judicious administration under respiratory failure with ARDS. 19 Lastly, despite common use for COVID-19 patients, there is weak evidence for the clinical efficacy and prophylactic properties of hydroxychloroquine or chloroquine despite their in vitro antiviral and in vivo immunomodulatory properties. 20 Therefore, more options for targeted immune regulation is warranted. Common targets for inhibition include IL-6, IL-1 family (IL-1β and IL-18), TNF-α and IFN-γ cytokines and the JAK pathway. 8 IL-6 is a particularly intriguing target due to its close correlation with ARDS severity and mortality. 21 IL-6 inhibitors are already successfully utilized for other cytokine storm syndromes such as adverse T cell therapy reactions and Still's disease-associated reHLH. 8 Nonetheless, IL-6 inhibitors must be carefully administered with appropriate timing due to its suppression and facilitation of viral replication. 22 Tocilizumab (TCZ) [Actemra] is a recombinant monoclonal antibody with a humanized murine variable domain and a human IgG1 constant domain. TCZ binds to both membranebound and soluble IL-6 receptors, thus preventing IL-6 mediated signal transduction. The drug was initially developed to treat rheumatoid arthritis and now it is also approved for giant cell arteritis and similar autoimmune ailments. Furthermore, its safety profile was analyzed in a phase III double-blind controlled trial and it is reportedly effective in treating other cases severe cytokine release syndrome such as chimeric antigen receptor T-cell immunotherapy. 11 While TCZ is not yet approved for treatment of COVID-19, clinicians across the globe are utilizing the drug under "emergency" use including in the United States following FDA approval.

An early observational study of 547 COVID-19 ICU in New Jersey compared the survival rate of 134 individuals treated with standard of care (SOC) and TCZ compared with SOC controls finding a 46% and 56% mortality rate respectively and a 0.76 adjusted hazard ratio. 23 However, the researchers were unable to conclude clinical efficacy of TCZ with the clinical data and they only focused on the most severe cases. Genentech -the producer of TCZ -and the FDA agreed to commence a phase III clinical trial (called COVACTA) with 450 patients globally to assess the effect of the drug on clinical status, mortality, mechanical ventilation and ICU admission. 24 While a complete randomized controlled trial (RCT) is the only validated method of proving a drug's efficacy, the Genentech trial and analysis are not expected to be completed until late September. Nonetheless, as RCTs remain ongoing for several more months, healthcare providers are still currently administering TCZ globally to combat lethal COVID-19 cases.

Existing systematic reviews only investigate case studies of TCZ treatment without controls. 25, 26 Therefore, this systematic review will synthesize the evidence from individual case-control studies and analyze uncontrolled trials to determine whether the drug is potentially effective at reducing severe COVID-19-related mortality, thus corroborating the logic for ongoing RCTs.

Articles utilized for the systematic review were selected from a PubMed search on July 4 2020. For the initial screening, the primary search terms were COVID-19 or SARS-CoV-2 and tocilizumab. Papers with primary data for a case-control study comparing mortality of severe COVID-19 between TCZ and standard of care (SOC) were included for data synthesis. Uncontrolled studies on severe COVID-19 mortality with TCZ were reviewed separately without data synthesis. Exclusion criteria included papers without primary data, case reports, reviews, protocols, and studies without mortality numbers available or potentially repeating patient data. An additional search was performed on SearchWorks to identify case-control studies not found in PubMed.

For each study included in the synthesis, the mortality rate for the TCZ and SOC group were calculated. In the controlled studies, the odds ratio (RR) of mortality from COVID-19 with TCZ versus the SOC was determined followed by the 95% confidence interval (CI). A two-tailed t-test was performed to identify the p-value. The data from the individual controlled studies were synthesized by a random effects meta-analysis calculation using MedCalc software. MedCalc was also used to perform a sample size calculation with an alpha of 0.01 and power of 90% to detect a difference between the total crude TCZ and SOC mortality rates.

The systematic review protocol was pre-registered with PRISMA and approved on June 22, 2020 (CRD42020193479). 

A total of 186 articles were identified by the initial PubMed search and three additional case-control studies were found on a SearchWorks (Fig. 1) . 24 articles were selected for fulltext review yielding 12 uncontrolled studies for qualitative analysis and 9 case-control studies for both quantitative synthesis and qualitative analysis. The study characteristics for the controlled studies are summarized in Supplementary Table 1 while the uncontrolled studies are outlined in Supplementary Table 3 .

The systematic review of controlled studies encompassed a total of 618 TCZ-treated and 1057 SOC control patients ( Table 1) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 14, 2020. . https://doi.org/10.1101/2020.07.10.20150938 doi: medRxiv preprint patient characteristic for all but one study [Guaraldi et al.] was severe COVID-19, generally qualified by oxygen supplementation needs. Ip et al. only analyzed patients who were already admitted into the ICU while 61% of both cases and controls in Rojas-Marte et al. began the trial in critical condition. There was some variation in TCZ administration and SOC treatments, the most common being hydroxychloroquine -utilized in all but one study -and lopinavir/ritonavir. Length of observation ranged from 7 days to 30 days or until death, discharge or ICU admission. Mean age of participants in the treatment and control groups extended from 55.5 to 76.8 with no more than 6.1 years separating the two groups within one study.

Odds ratio 95% CI Random p Value Klopfenstein et al. 28 All of the studies trended toward lower mortality from severe COVID-19 with TCZ versus the SOC with two studies yielding a statistically significant result [Capra et al. and Guaraldi et al.] (Fig. 2) . A random effects odds ratio analysis generated an odds ratio of 0.482 (95% CI 0.326-0.713) with a p-value less than 0.001. A sample size analysis with alpha of 0.01 and power of 90% affirmed that 392 total case and control patients are needed to detect a difference between 26.1% and 41.5% mortality. The studies also scattered symmetrically around the overall odds ratio from the analysis signifying a low likelihood of publication bias (Fig. 3) . TCZ patients in two studies had secondary bacteremia but one reported a lower rate than the SOC [Rojas Marte et al.]. 4 studies reported no adverse effects from TCZ.

. 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.

The copyright holder for this preprint this version posted July 14, 2020. . https://doi.org/10.1101/2020.07.10.20150938 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.

The copyright holder for this preprint this version posted July 14, 2020. . https://doi.org/10.1101/2020.07.10.20150938 doi: medRxiv preprint

The 12 uncontrolled trials encompassed 803 total patients who received TCZ. The mortality rate from severe COVID-19 ranged from 0% to 27.5% (SD 7.78), although the two studies with 0% had relatively small sample sizes [20 and 12 for Xu et al. and Borku Uysal et al. respectively]. The raw overall mortality rate from the 12 studies is 13.6%. The initial patient severity level ranged from "severe" -requiring supplemental oxygen -to ICU admission. No study only investigated ICU patients. SOC varied more widely in the uncontrolled trials than the controlled, but hydroxychloroquine was still the most common additional drug used. Few major side effects such as bacterial/fungal infections and increased hepatic enzymes were reported.

In crude comparison between uncontrolled (n=12) and controlled trials (n=7) with TCZ ( Table 2) , excluding controlled studies with over 50% of patients initially in the ICU, the mortality rate was 15.1% and 12.6% respectively (p=0.808). 

The purpose of this systematic analysis was to analyze and synthesize clinical data on the efficacy of TCZ treatment against severe COVID-19. In the 9 case-control trials published by June 6, 2020, all of the studies at least trended towards reduced mortality with TCZ ( Fig. 2) including two with statistical significance [Capra et al. and Guaraldi et al.] . After performing a qualitative synthesis, the random effects odds ratio of mortality with TCZ versus the SOC was 0.482 (95% CI 0.326-0.713, p<0.001) illustrating a stark difference in patient outcomes ostensibly improved by TCZ. There was no indication of publication bias (Fig. 3) and there were well over the 392 required total case and control patients to detect the difference in mortality rate. It is important to acknowledge that only one of the studies [Guaraldi et al.] randomized who received TCZ. Specific strengths and shortcomings for the controlled trials are outlined in Supplementary Table 2 . Although the value of any single controlled clinical study does not hold definitive proof of efficacy, the consistent qualitative trend and strong statistical significance from the combined data in this analysis corroborates TCZ's potential positive effects and adds merit to systematic clinical investigations.

Secondarily, the uncontrolled trials were analyzed separately to explore trends in treatment data. Recognizing the variation in patient outcomes between the studies, the combined mortality rate from 12 single-arm studies using TCZ against severe COVID-19 was . 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.

The copyright holder for this preprint this version posted July 14, 2020. . https://doi.org/10.1101/2020.07.10.20150938 doi: medRxiv preprint 13.6% (SD 7.51%). As a comparison, in a review of clinical data from 5700 individuals hospitalized from COVID-19 in New York, 21% of the patients passed away 36 . On the surface, the combined mortality rate with TCZ in single-arm trials does appear lower, but participants must be matched to controls to eliminate bias and account for other confounding factors to draw any conclusions. When excluding controlled trials with over 50% of patients initially in the ICU [Ip et al. and Rojas-Marte et al.] , there was an insignificant difference in mortality rate between the uncontrolled and controlled trials (p=0.808). This observation provides minor evidence that the reported results from the uncontrolled experimental trials in this review are potentially accurate and have merit in evaluating TCZ efficacy. Nonetheless, the uncontrolled trials should still be evaluated with some degree of skepticism. Specific shortcomings for the individual uncontrolled trials are delineated in Supplementary Table 4 .

There is also a question of timing for the IL-6 blocking treatment. All of the studies observed only included patients who were already in a severe disease state. Given the patterns of COVID-19 pathology and immune dysregulation, it is logical to defer TCZ until the inflammatory phase due to the positive effects of IL-6 release in the acute infection stage which theoretically prevents SARS-CoV-2 proliferation. Given the unique, aberrant immune reaction in COVID-19, in order to curtail and not enhance mortality, some researchers argue that the optimal time to employ targeted immune suppressants such as TCZ is when patients begin to trend towards hypoxia and inflammation. 3 However, this timing is only a theory that must be proven in a randomized controlled trial (RCT) to be definitive.

There are multiple RCTs in progress to evaluate the efficacy of TCZ (NCT04320615, NCT04317092, NCT04363853). RCTs were also initiated to assess another IL-6 inhibitor, sarilumab, (NCT04322773, NCT04327388), however, the drug failed its Phase III in the United States 37 . Nevertheless, it is encouraging that preliminary data from this systematic analysis appear promising for the prospects of TCZ reinforcing support for efforts to continue RCTs for the IL-6 inhibitor.

There are notable limitations to this systematic analysis and the qualitative synthesis alluded to in the Discussion above. First, only one of the studies presented randomized who received TCZ, opening the possibility for selection bias and confounding factors that cannot be accounted for statistically. This systematic analysis synthesizes data from studies with different SOCs, geographies, resources, demographics, and TCZ dosing amount, number and timing. Therefore, it is not possible to conclude that TCZ is efficacious in reducing COVID-19 mortality, simply that the data trends towards a lower odds ratio for mortality with incomplete generalizability. On a similar note, while patients across all of the studies were at least in severe condition, the combined data still represents individuals at various stages of COVID-19. Not all of the studies offered a longitudinal time component, so an overall hazard ratio or Kaplan-Meir survival curve cannot be produced. Additionally, many patients were still in the hospital at the end of the observation period potentially skewing the mortality rate. Finally, in the random effects odds ratio calculation, there was no control for age, sex and baseline characteristics like individual studies were able to accomplish. It is also worth repeating that the uncontrolled trials on TCZ cannot be adequately evaluated without direct comparison to a control group.

. 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.

The copyright holder for this preprint this version posted July 14, 2020. . https://doi.org/10.1101/2020.07.10.20150938 doi: medRxiv preprint

After reviewing the clinical data of the IL-6 inhibitor tocilizumab (TCZ) for severe COVID-29, the evidence points towards efficacy in reducing mortality from the disease. The results from this systematic analysis corroborate the logic for ongoing phase III, RCT clinical trials on TCZ. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 14, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 14, 2020. 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)

The copyright holder for this preprint this version posted July 14, 2020. . 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)

The copyright holder for this preprint this version posted July 14, 2020. . https://doi.org/10.1101/2020.07.10.20150938 doi: medRxiv preprint

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Primary goal of study was to identify laboratory features to predict CODI-19 severity. "Controls" for trial who did not receive TCZ were patients who did not need oxygen support at baseline (therefore, the study was considered uncontrolled and only TCZ patients were assessed). Variation in glucocorticoid administration.

SOC not provided other than corticosteroids, which varied amongst patients and could confound results. Inclusion criteria not outlined. Limited data provided in report.

Very small sample. Does not delineate inclusion criteria.