Tocilizumab in COVID-19: some clarity amid controversy
Shruti Gupta, David E Leaf
Lancet 2021; 397: 1599-1601
Hyperactivation of the immune response, including release of pro-inflammatory cytokines such as interleukin-6 (IL-6), might play a key role in the pathophysiology of severe illness from COVID-19.1Consistent with this notion, one of the few therapies that reduces mortality in hospitalised patients with COVID-19 is the corticosteroid, dexamethasone.2 Accordingly, there has been great interest in examining whether treatment with additional, more targeted anti-inflammatory agents beyond steroids could provide further benefit.
Tocilizumab is a recombinant humanised monoclonal antibody that inhibits binding of IL-6 to both membrane and soluble IL-6 receptors. Early observations from China suggested improved outcomes in hospitalised patients with COVID-19 who received tocilizumab.3These preliminary reports were followed by large observational studies in critically ill patients with COVID-19, which suggested a mortality benefit with tocilizumab.4 Subsequent randomised clinical trials examining tocilizumab reported conflicting results, but these trials differed considerably in size, study design, and illness severity of the patients enrolled. For instance, several initial trials5, 6, 7 failed to show a mortality benefit for tocilizumab, but these trials enrolled fewer than 300 patients each and were thus underpowered to detect differences in death between groups.8 Additional limitations of early trials were exclusion of critically ill patients5, 7 and imbalances in the use of steroids between tocilizumab-treated and tocilizumab-untreated patients.9 The Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) study published in 2021 was, until now, the largest trial (n=803) to examine tocilizumab in COVID-19, and showed a survival benefit.10 However, as REMAP-CAP was limited to critically ill patients, the role of tocilizumab for hospitalised but non-critically ill patients with COVID-19 remained unclear.
In The Lancet, the Randomised Evaluation of COVID-19 Therapy (RECOVERY) Collaborative Group reports its findings from the largest trial of tocilizumab to date.11 Particularly in light of the conflicting findings from the heterogeneous and generally underpowered studies described in the foregoing, the importance of the findings from the RECOVERY trial cannot be overstated. RECOVERY is a multicentre, randomised, controlled, open-label, platform trial that was designed to examine the role of several treatments in patients hospitalised with COVID-19 in the UK. In a herculean effort, the investigators recruited more than 27 000 hospitalised adults with clinically suspected or confirmed SARS-CoV-2 infection from 177 sites in the UK between April 14, 2020, and Jan 24, 2021, randomly assigning them to one of several treatment groups. Patients were eligible for random assignment to tocilizumab versus usual care if they had hypoxia (oxygen saturation <92% on room air or requirement for supplemental oxygen), systemic inflammation (C-reactive protein ≥75 mg/L), and no clear evidence of an active infection other than SARS-CoV-2.
In total, 4116 adults were randomly assigned to tocilizumab (n=2022) or usual care (n=2094), several times more patients than in all previous randomised trials of tocilizumab combined. The mean age was 63·6 years (SD 13·6), 2774 patients (67%) were male, and 3018 (73%) were White. The median time from hospitalisation to random assignment was 2 days (IQR 1–5 days), and 562 patients (14%) were receiving invasive mechanical ventilation at the time of random assignment. Most patients (82% in both groups) were receiving systemic corticosteroids at the time of random assignment, in contrast to some earlier tocilizumab trials. The primary outcome, all-cause mortality within 28 days of random assignment, occurred in 35% of patients allocated to usual care and 31% of patients allocated to tocilizumab (rate ratio 0·85; 95% CI, 0·76–0·95; p=0·0028). Patients in the tocilizumab group were also more likely to be discharged from the hospital within 28 days than patients in the usual care group.
The RECOVERY trial investigators should be commended for this substantial investigation, the results of which will undoubtedly have major implications for the treatment of hospitalised patients with COVID-19. However, several limitations should be mentioned. First, the study was open label, and thus participants and local study staff were unmasked to the treatment allocation. Second, one of the concerns surrounding tocilizumab use in patients with COVID-19 is the risk of secondary infection, and although tocilizumab did not result in any deaths from secondary infection, the investigators did not collect data on non-fatal infections or other adverse events. Third, important physiological data regarding hypoxaemia, such as longitudinal assessment of the partial pressure of arterial oxygen to the fraction of inspired oxygen, were not collected. Fourth, only 1837 (91%) of 2022 patients in the tocilizumab group and 1918 (92%) of 2094 patients in the usual care group had data available on study drug receipt. Fifth, among the 1837 patients assigned to tocilizumab with data available on study drug receipt, only 1534 (84%) actually received the drug. However, the net effect of this crossover in an intention-to-treat analysis would be to bias the results toward the null, and thus the reported results are probably an underestimate of the true benefit of tocilizumab in reducing death. Finally, given that patients with COVID-19 often have a prolonged hospital course, it is unclear whether a reduction in 28-day mortality will translate into longer-term mortality benefit, and we look forward to the preplanned analyses at 6 months.
In summary, the RECOVERY trial provides the most definitive evidence thus far to address the controversy over whether tocilizumab should be added to our armamentarium of treatments for severely ill patients with COVID-19. The answer is yes. Questions remain about tocilizumab's efficacy and safety in other settings, such as those with C-reactive protein concentrations of less than 75 mg/L and among paediatric patients (the RECOVERY group is doing a separate trial in children, which is ongoing), and among more gender and racially diverse populations. Importantly, the 28-day mortality rate of 31% in the tocilizumab group, although lower than the placebo group, remains unacceptably high, and thus additional therapies are urgently needed to further reduce mortality in severely ill patients with COVID-19. Several treatments, including other immunomodulators and antibodies against the spike protein of SARS-CoV-2, are under investigation.12
