Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial - The BMJ

Objective To determine whether tocilizumab improves clinical outcomes for patients with severe or critical coronavirus disease 2019 (covid-19).

The data monitoring committee recommended stopping the trial early, after 129 patients had been enrolled, because of an increased number of deaths at 15 days in the tocilizumab group.

Interventions Tocilizumab (single intravenous infusion of 8 mg/kg) plus standard care (n=65) versus standard care alone (n=64).

All patients in the tocilizumab group and two in the standard care group received tocilizumab.

18 of 65 (28%) patients in the tocilizumab group and 13 of 64 (20%) in the standard care group were receiving mechanical ventilation or died at day 15 (odds ratio 1.54, 95% confidence interval 0.66 to 3.66; P=0.32).

Death at 15 days occurred in 11 (17%) patients in the tocilizumab group compared with 2 (3%) in the standard care group (odds ratio 6.42, 95% confidence interval 1.59 to 43.2).

Conclusions In patients with severe or critical covid-19, tocilizumab plus standard care was not superior to standard care alone in improving clinical outcomes at 15 days, and it might increase mortality.

Tocilizumab is an interleukin 6 inhibitor approved for the treatment of rheumatoid arthritis, giant cell arteritis, and cytokine release syndrome during chimeric antigen receptor T cell therapy (CAR-T).9 Interleukin 6 is an inflammatory cytokine that exerts its effects in the liver and on lymphocytes, inducing acute phase reactants such as C reactive protein, fibrinogen, and hepcidin from hepatocytes, and promotes CD4 T helper 17 and CD8 cytotoxic T cell differentiation and antibody production.10 Interleukin 6 plays an important role in controlling viral infections such as influenza A, severe acute respiratory syndrome coronavirus 1, and herpesvirus.11 In covid-19, an increased level of interleukin 6 and C reactive protein correlates with disease severity and mortality.1213 Thus, blocking interleukin 6 activity might play a role in mitigating the inflammatory response and improve clinical outcomes in patients with covid-19.

To test this hypothesis, we conducted a randomised controlled trial comparing tocilizumab plus standard care with standard care alone in patients admitted to hospital with severe or critical covid-19.

Patients were randomised in a 1:1 ratio to receive either standard care or tocilizumab plus standard care, with random blocks of sizes 2, 4, 6, and 8, and stratified by age (<60 and ≥60 years) and sex, according to a computer generated schedule using the sample function of software R 3.6.3 (R Foundation).

The concomitant use of hydroxychloroquine, azithromycin, corticosteroids, and antibiotics was allowed according to standard care per local institutional guidelines for patients with covid-19.

For patients who were discharged before day 15, an interviewer who was unaware of the assigned trial group conducted a structured telephone call with the patient or patient’s proxy on or after day 15 to assess vital status and return to routine activities.

The primary analysis followed the intention-to-treat principle, except for adverse events, which were analysed in a safety population that included patients according to the drug received, regardless of assigned group.

A sensitivity analysis of the treatment effect on the primary outcome was performed using a per protocol population and considering only patients who received the treatment as assigned.

The trial was prematurely interrupted on 17 July 2020, after the first interim analysis, in accordance with the recommendation of the data monitoring committee, owing to an excess number of deaths at 15 days in the tocilizumab group (see supplementary file).

Sixty five patients were assigned to receive tocilizumab plus standard care, and all were treated accordingly (fig 1).

Sixty four patients were assigned to receive standard care alone; however, two patients received tocilizumab at the discretion of the treating doctors.

Baseline characteristics of patients with severe or critical coronavirus disease 2019 and assigned to tocilizumab plus standard care or standard care alone.

The use of tocilizumab was not associated with an improvement in mechanical ventilation or death at 15 days (18 of 65 (28%) patients in the tocilizumab group and 13 of 64 (20%) in the standard care group: odds ratio 1.54, 95% confidence interval 0.66 to 3.66; P=0.32).

Death at 15 days, a component of the primary outcome, occurred in 11 (17%) patients in the tocilizumab plus standard care group compared with two (3%) in the standard care group (odds ratio 6.42, 1.59 to 43.2).

Patients assigned to tocilizumab had a lower duration of hospital stay (mean 11.3 (SD 8.0) v 14.7 (8.2) days; rate ratio 0.70, 95% confidence interval 0.55 to 0.87).

Duration of hospital stay remained lower in patients assigned to tocilizumab in a post hoc analysis including only patients discharged alive (11.9 (8.4) v14.8 (8.6) days; rate ratio 0.75, 0.58 to 0.94).

A total of 29 (43%) patients assigned to tocilizumab and 21 (34%) assigned to standard care had adverse events (P=0.26) (table 3).

Serious adverse events occurred in 11 (16%) patients in the tocilizumab group and seven (11%) in the standard care alone group.

Levels of interleukin 6 were higher among patients assigned to tocilizumab plus standard care compared with those assigned to standard care alone on days 5 and 8 (see supplementary figure S2 and table S9).

Among patients assigned to tocilizumab, interleukin 10 was not significantly different on day 5 but was higher on day 8.

In this open label, multicentre, randomised, controlled trial including relatively young (mean age 57 years) patients admitted to hospital with confirmed severe or critical covid-19, the use of the interleukin 6 inhibitor tocilizumab did not result in better clinical outcomes as assessed by a seven level ordinal scale at 15 days.

Mortality at 15 days was increased in the group assigned to tocilizumab.

Conversely, randomised controlled trials have not shown a beneficial effect of tocilizumab on their respective primary outcomes.20212223 In the Study to Evaluate the Safety and Efficacy of Tocilizumab in Patients With Severe COVID-19 Pneumonia (COVACTA), enrolling 452 hypoxaemic patients, tocilizumab had no effect on clinical outcomes at 28 days, assessed with the seven level ordinal scale.20 Length of intensive care unit and hospital stay, however, were lower among patients assigned to tocilizumab.

The CORIMUNO trial included 131 hypoxaemic patients and did not show an effect of tocilizumab on clinical outcomes at 28 days.21 The Boston Area COVID-19 Consortium (BACC) Bay Tocilizumab Trial randomised 242 hypoxaemic patients and reported no difference in time to intubation or death during 28 days.22 Another study, which enrolled 126 hypoxaemic patients, reported no benefit on disease progression at day 14.23.

Observational studies have suggested that a beneficial effect of tocilizumab is related to starting treatment early in the course of illness.35363738 For example, in the STOP-covid trial35 tocilizumab was associated with decreased mortality only among patients with a time from onset of symptoms to intensive care unit admission equal to or lower than three days.

Conversely, in all randomised trials assessing tocilizumab, including our trial, average duration of symptoms at baseline ranged from 8 to 12 days.20212223 Nevertheless, in a post hoc subgroup analysis, we found no evidence that earlier (≤10 days) versus later (>10 days) initiation of tocilizumab modifies the treatment effect of tocilizumab on clinical outcomes (see supplementary table S10).

The level of respiratory support, an important prognostic marker, was lower among patients assigned to tocilizumab.

Although baseline use of azithromycin was less common among patients assigned to tocilizumab, the drug has proven to be ineffective for patients admitted to hospital with covid-19.394041.

In this trial including patients admitted to hospital with severe or critical covid-19, the use of tocilizumab plus standard care was not superior to standard care alone in improving patients’ clinical status at 15 days, and might have increased mortality.

The interleukin 6 inhibitor tocilizumab might mitigate the inflammatory response and improve clinical outcomes of patients with severe or critical covid-19.

Among patients with severe or critical covid-19, tocilizumab plus standard care was not superior to standard care alone in improving clinical status at 15 days, and it might increase mortality.

ABC, RGR, FRM, FGZ, OB, LCPA, RDL, AA, LKD, and CGC developed the protocol and approved the final version for the Coalition covid-19 Brazil Group, recruited patients, participated in interim discussions, and reviewed the manuscript.