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Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): preliminary results of a randomised, controlled, open-label, platform trial

Our take —

Prior studies of tocilizumab were not sufficiently large enough to show a significant mortality improvement associated with tocilizumab. This interim report, available as a preprint and thus not yet peer-reviewed, showed that tocilizumab reduces mortality in hospitalized COVID-19 patients, taken both on its own and as part of a meta-analysis including prior studies. The mortality benefit conferred by tocilizumab is in addition to that which is conferred by systemic corticosteroids, which are now considered part of the usual standard of care. Finally, the absolute risk reductions for primary and secondary outcomes were small in this interim report: it is possible that the magnitude of improvement conferred by tocilizumab may diminish when all follow-up is complete for all participants.

Study design

Randomized Controlled Trial

Study population and setting

This study was a subset of the broader Randomized Evaluation of Covid-19 Therapy (RECOVERY) trial, which compares various therapies for the treatment of hospitalized COVID-19 patients. The study described in this article was an open label randomized controlled trial that recruited 4116 patients (out of 21550) hospitalized with suspected or confirmed COVID-19 infection across 131 hospitals in the United Kingdom. The study compared the 28-day mortality of patients receiving usual care (n = 2094) to patients receiving the anti-IL-6R antibody tocilizumab in addition to usual care (n = 2022). Tocilizumab was given via 60 minute IV infusion of approximately 8 mg/kg, with a second infusion given 12-24 hours later if the patient’s condition was not deemed to be improving by their attending physician. In addition to the primary outcome of 28-day mortality, the study measured secondary outcomes including time to discharge, and among patients not receiving invasive ventilation, progression to invasive mechanical ventilation, extracorporeal membrane oxygenation, or death.

Summary of Main Findings

This was an interim analysis as follow-up is only complete for 79% of participants in the tocilizumab group, and 79% in the usual care group: >95% follow-up forms are expected at the conclusion of the study. Among the restricted group of people with completed follow-up forms, 83% of people assigned to receive tocilizumab received at least one dose, while 3% of persons assigned to usual care received at least one dose of tocilizumab. Intention to treat with tocilizumab was associated with a significant reduction in 28-day mortality compared to usual care alone (29% in the tocilizumab group vs. 33% in the control group; rate ratio 0.86; 95%CI = 0.77-0.96; p 0.007). Of the patients enrolled in the study, 94% of them had a lab-confirmed positive test for COVID-19; in a post hoc analysis of exclusively these patients, the rate ratio was similar (0.86; 95%CI 0.78 to 0.98; p 0.02). Patients who were allocated tocilizumab were significantly more likely to be discharged alive within 28 days (54% vs. 47%; rate ratio 1.22; 95%CI 1.12-1.34; p < 0.0001) and significantly less likely to progress to needing invasive ventilation if they did not need it at baseline (33% vs. 38%; risk ratio 0.95; 95%CI 0.78-0.93; p 0.0005). The need for hemodialysis or hemofiltration was lower in the tocilizumab group (5% vs. 7%; risk ratio 0.75; 95%CI 0.59-0.96; p 0.02). Rates of cardiac arrythmias were comparable between the two groups. There was one case each of otitis externa, S. aureus bacteremia, and lung abscess documented as adverse reactions to tocilizumab, all of which resolved with the appropriate respective treatments. In a subgroup analysis, persons who received corticosteroids and tocilizumab appeared to benefit more than persons who received tocilizumab alone.

Study Strengths

The study as reported in this article enrolled 4,116 patients, but this selection was part of the larger RECOVERY trial which recruited 21,550 total patients across 131 hospitals. This scale allows for a reasonable balance of patients between most randomized treatments. The ethnic backgrounds of participants appeared representative: 17% of the patients in the study had a Black, Asian, or other minority ethnic background, although the specific breakdown between minority background is not explicitly provided. In addition, persons with comorbidities (such as HIV and severe liver disease) were permitted in this trial. Although the double randomization design was complicated, persons who received tocilizumab were comparable with regards to several other randomized treatments to persons who received usual care.

Limitations

The study was open label and not blinded. As a result, bias may be imparted by providers, who may consciously or subconsciously change the way care is provided to patients in different arms of the trial. No children were enrolled in the study, which limits the generalizability of the findings to adult patients. 17% of the patients who were allocated to the tocilizumab group did not end up receiving the treatment, for reasons that were not documented in the study. Since this was an open-label study, treating physicians could overrule the randomization assignment, limiting the effects of randomization. Thus, a per protocol analysis is also warranted for this study. Furthermore, this data is still preliminary, as 8% of the patients have not yet reached the 28-day checkpoint, and 21% of participants in both arms did not have complete follow-up forms. In addition, the median hospital stay for the enrolled patients is longer than 28-days, meaning the results of a planned six-month follow up should provide more information. There are no details on the receipt of antivirals such as monoclonal antibodies, convalescent plasma, or remdesivir, and whether this was balanced between groups.

Value added

The preliminary findings of this RCT provide supportive evidence that the use of the anti-IL-6R antibody tocilizumab reduces 28-day mortality in hospitalized COVID-19 patients.

This review was posted on: 5 March 2021