Is There Still a Place for Tocilizumab in Coronavirus Disease 2019?

Abstract In this article, we sought to summarize the available evidence of tocilizumab as a treatment for coronavirus disease 2019. Recent tocilizumab randomized trials have not shown clear evidence of efficacy, especially on mortality, in contrast to observational studies. These clinical trials focus on a heterogeneous population of patients (clinical severity and inflammatory stage), and this is possibly one of the reasons that explain heterogeneity of results. However, these same trials have shown some evidence that tocilizumab may reduce intensive care unit admissions and/or mechanical ventilation incidence, which are huge challenges in the severe acute respiratory syndrome coronavirus 2 pandemic. Future clinical trials with primary endpoint built on this assumption are needed (1) to confirm whether tocilizumab reduces mechanical ventilation requirement and (2) to describe the right patient population and optimal timing for tocilizumab administration. Finding the optimal timing for tocilizumab administration and the group of patients who are susceptible to having the greatest benefit are probably the main challenge.


Is There Still a Place for Tocilizumab in Coronavirus Disease 2019?
Timothée Klopfenstein, 1 Thierry Conrozier, 2 N'dri Juliette Kadiane-Oussou, 1 Vincent Gendrin, 1 and Souheil Zayet 1; for the HNF Hospital Tocilizumab multidisciplinary team 1 Infectious Disease Department, Nord Franche-Comté Hospital, Trévenans, France, 2 Rheumatology Department, Nord Franche-Comté Hospital, Trévenans, France In this article, we sought to summarize the available evidence of tocilizumab as a treatment for coronavirus disease 2019. Recent tocilizumab randomized trials have not shown clear evidence of efficacy, especially on mortality, in contrast to observational studies. These clinical trials focus on a heterogeneous population of patients (clinical severity and inflammatory stage), and this is possibly one of the reasons that explain heterogeneity of results. However, these same trials have shown some evidence that tocilizumab may reduce intensive care unit admissions and/or mechanical ventilation incidence, which are huge challenges in the severe acute respiratory syndrome coronavirus 2 pandemic. Future clinical trials with primary endpoint built on this assumption are needed (1) to confirm whether tocilizumab reduces mechanical ventilation requirement and (2) to describe the right patient population and optimal timing for tocilizumab administration. Finding the optimal timing for tocilizumab administration and the group of patients who are susceptible to having the greatest benefit are probably the main challenge.
At this time, the second wave of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is ongoing in Europe, including France, and we are facing a huge challenge in terms of places in hospitals; intensive care unit (ICU) capacities are especially challenged while facing this outbreak. Until now, corticosteroids have been the only treatment, which have proven to reduce mortality [1]. Indeed, several arguments showed that tocilizumab, "a recombinant humanized anti-interleukin-6 receptor monoclonal antibody", which is usually used in the treatment of rheumatoid arthritis [2], could be an effective treatment in severe novel coronavirus disease 2019 (COVID-19). By neutralizing a key inflammatory factor in the cytokine release syndrome, this molecule can theoretically block the cytokine storm during the systemic hyperinflammation stage and reduce the severity of the disease [3]. In October 2020, in a cohort of 206 patients with COVID-19, we published a paper showing that tocilizumab can be an effective treatment to reduce mortality and/or invasive mechanical ventilation requirement in COVID-19 [4]. In our study [4], tocilizumab was used in 30 patients in critical condition (oxygen therapy flow at tocilizumab onset was 10.5 L/minute) as a rescue treatment (8 of 30 patients who died were not admitted in ICU in regard to their comorbidities). However, mortality and/or mechanical ventilation requirement were lower in patients with tocilizumab than in 176 patients without tocilizumab (27% vs 52%, P = .009). However, since the results of randomized prospective clinical trials [5][6][7], tocilizumab has disappointed medical community's hope on this drug due to the lack of impact on mortality (during the first month after administration), in contrast to observational studies. For example, in a randomized clinical trial, Stone et al [5] showed no benefit of tocilizumab versus placebo on mechanical ventilation or death on day 28 in a population at inflammatory stage (median C-reactive protein level at 110.0 mg/L) of moderate to severe pneumonia (>95% of patients had a level of O 2 <6l/minute delivered by nasal cannula or no O 2 administration). Likewise, Salvarani et al [6] showed no benefit of tocilizumab early administration in a selected population of severe (but not critical) pneumonia (median PaO 2 /FiO 2 at 264.5 mmHq), which had a very low level of systemic inflammation (median C-reactive protein at 8.2 mg/L). Recent tocilizumab randomized trials have not shown clear evidence of efficacy, especially on mortality [5][6][7][8][9]. However, these same trials have shown some evidence that tocilizumab may reduce ICU admissions and/or mechanical ventilation incidence. In this way, EMPACTA [8]  ). This is explained by a lower incidence of ICU stays among patients not in ICU at baseline in the tocilizumab arm compared with the placebo arm (23.6%, n = 30 of 127 vs 40.6%, n = 26 of 64; P = .01). These clinical trials (5-9) focus on a heterogeneous population of patients (clinical severity and inflammatory stage); this is possibly one of the reasons that explain heterogeneity of results. However, most of these trials (except Stone et al [5]) have shown some encouragement about secondary endpoints, especially ICU care characteristics. No safety signal for tocilizumab emerged from the 5 clinical trials. All endpoints of the 5 randomized clinical trials are summarized in the Table 1.
Finding the optimal, timing of tocilizumab administration and the group of patients who are susceptible to have the greatest benefit are probably the main challenge. For example, in our retrospective cohort [4], patients had a high level of oxygen therapy (mean oxygen therapy flow at tocilizumab onset was 10.5 liters/ minute) at a high inflammatory stage (mean serum levels of C-reactive protein and ferritin was 142 mg/L and 1496 ng/ mL, respectively, at tocilizumab onset). Our patients were more severe than patients described by Stone et al [5] and Salvarani et al [5] in their cohorts. For example, in Stone et al trial [5], patients were excluded if they were receiving supplemental oxygen ≥10 liters/minute. Our patients were more like CORIMUNO-TOCI-1 patients (oxygen therapy flow ≥3 liter/minute but no patients on invasive mechanical ventilation) [4,9]. In COVACTA [7], the population was heterogeneous; however, if, at baseline, we selected the patients who were similar to our patients in term of severity (category 4 of the 7-category ordinal scale: ICU or non-ICU hospital ward, requiring high-flow oxygen or noninvasive ventilation), then this category is the only category (among the 7 categories) that has improved their clinical status on day 28 compared with placebo: 1.0 (1.0 to 2.0) for tocilizumab and 2.0 (1.0 to 6.0) for placebo (odds ratio, 1.59 [95% CI, 0.78 to 3.24]). The lack of statistical significance is probably due to the lack of evaluated impact on ICU admissions/characteristic on day 28 by the 7-category ordinal scale (most of the survival patients would be out of ICU) as we discussed above. We do not have the detailed 7-category ordinal scale on day 14 (according to baseline ordinal scale category), which would be interesting.

PATIENT CONSENT STATEMENT
Due to the retrospective nature of the study, the Ethics & Scientific Committee of Nord Franche Comté Hospital determined that patients consent was required only for the off-label use Tocilizumab. We made sure to keep patient data confidential and in compliance with the Declaration of Helsinki.

CONCLUSIONS
To conclude, randomized trials with tocilizumab in COVID-19 pneumonia have not shown an impact on mortality. However, tocilizumab might have some benefit in patients with severe COVID-19 in reducing mechanical ventilation incidence or ICU admissions, which are huge challenges in the SARS-CoV-2 pandemic. A recent meta-analysis about these randomized trials confirmed our conclusion [10]. Furthermore, although tocilizumab had no impact on mortality during the first month (after administration), it may decrease the risk of longterm complications and possibly death by reducing mechanical ventilation incidence or ICU admissions. Future clinical trials with primary endpoint built on this assumption are needed to confirm whether tocilizumab reduces mechanical ventilation requirement and to describe the right population and optimal timing administration with expected benefits of tocilizumab use. If tocilizumab is effective, it is probably on severe/critical COVID-19 pneumonia patients with a high level of oxygen therapy or noninvasive ventilation (before intubation stage).  [5] , EMPACTA, and COVACTA trials were blinded with placebo controlled (but not Salvarani et al [6] and Hermine et al [9] trials). Clinical severity definition changed by study, so we used the classification of the National Institutes of Health COVID-19 management categories: moderate (SpO 2 ≥94% on room air) or severe (SpO 2 <94% on room air) or critical (respiratory failure, septic shock, and/or multiple organ dysfunction). b Stone et al [5], Salvarani et al [6], and COVACTA trials did not reach the primary endpoint. The results of secondary endpoints need to be taken carefully in these studies, stricto sensu the difference cannot be considered statistically significant because the primary endpoint was not met. indication. Finally, we especially acknowledge all of the physicians, caregivers (nurses and orderlies), and patients. Author contributions. All authors contributed to data analysis, drafting or revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.
Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.