Tocilizumab Does Not Improve Outcomes for Patients With Severe COVID-19

According to a study published in The BMJ,^{1 t} tocilizumab, in conjunction with standard care, was not superior to standard care alone for patients with severe or critical coronavirus disease 2019 (COVID-19). In fact, in some cases it may actually increase mortality rates.

Tocilizumab is an interleukin 6 (an inflammatory cytokine) inhibitor approved for treating a variety of rheumatic diseases, including rheumatoid arthritis. As studies have shown that an increased level of interleukin 6 directly correlates to poor COVID-19 outcomes, investigators speculated that blocking this activity could be a helpful tool in treating the virus and lessening its severity.

Investigators created a randomized, open-label, parallel group, superiority trial (NCT04403685)conducted in 9 hospitals across Brazil, between May 8 and July 17, 2020, to determine the effectiveness of tocilizumab in treating COVID-19. Eligible patients were aged 18 years or older and admitted to a hospital for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with symptoms lasting more than 3 days. Diagnosis was confirmed by reverse transcription-polymerase chain reaction. All patients were receiving supplemental oxygen or had been receiving mechanical ventilation for less than 24 hours before analysis. In order to participate, patients had to have abnormal levels of at least 2 of the following serum biomarkers: C reactive protein, D dimer, lactate dehydrogenase, or ferritin.

Investigators selected 129 patients (mean age 57 [SD 14] years; 68% men) that were then randomized 1:1 to either standard care (n = 64) or tocilizumab plus standard care (n = 65). Patients were further categorized by age (<60 and ≥60 years) and sex. The tocilizumab group received the drug as a single intravenous infusion at a dose of 8 mg/kg (maximum 800 mg). Antibiotics, corticosteroids, and hydroxychloroquine were permitted in accordance with standard care. Comorbidities like hypertension, diabetes, and obesity were documented.

Primary outcome results were evaluated at 15 days using a 7-level ordinal scale. During the study, this 7-level system was fragmented into 2 sections: levels 1 to 5 (alive and not receiving mechanical ventilation) and levels 6-7 (receiving mechanical ventilation or death). Secondary outcomes were analyzed from patient information up to day 28. Investigators kept track of ventilator-free days within 29 days, duration of hospital stay, secondary infections, the use of supplemental oxygen, and other adverse reactions.

An independent data monitoring committee recommended that investigators stop the trial earlier than expected, as the number of deaths in the tocilizumab group significantly increased within the first 15 days, raising safety concerns. For both groups, however, deaths were directly attributed to acute respiratory failure or organ dysfunction, not tocilizumab usage.

In the first 15 days, 18 of 65 (28%) patients receiving tocilizumab and 13 of 64 (20%) patients receiving standard care had either died or switched to mechanical ventilation (OR 1.54, 95% CI 0.66 to 3.66; P = 0.32). Additionally, 11 patients (17%) in the tocilizumab group died within the first 15 days compared to only 2 (3%) in the standard care group (OR 6.42, 95% CI 1.59 to 43.2).

Primary outcomes surprised investigators. “Our results were unexpected given the potent anti-inflammatory activity of tocilizumab in rheumatoid arthritis and CAR-T. The rapid increase in cytokines usually accompanies an increase in inflammatory markers and clinical deterioration in patients with COVID-19, which is reminiscent of CAR-T. Thus, it was plausible that blocking interleukin 6 in patients with COVID-19 could lessen the inflammatory response and avert some of the more dire consequences of the disease,” investigators explained. “However, clinical observation and biological plausibility are often not confirmed by randomized clinical trials.”

During the second half of the study, tocilizumab was not associated with an increased risk of death (OR 2.70, 95% CI 0.97 to 8.35) or in-hospital mortality (2.70, 0.97 to 8.35). Adverse reactions occurred in 29 (43%) patients in the tocilizumab group and 21 (34%) in the standard care group, with no significant difference in the incidences between the two groups. Further, there were no differences in other secondary outcomes, including secondary infections, thromboembolic events, and discontinuation of supplemental oxygen.

The first limitation of the study is that the results are somewhat in the hands of the operator. For example, a physician needs to decide when to perform tracheal intubation, which can throw off the statistics. Second, the sample size (129 patients) was very small. Lastly, the 7-level scale was not compatible with proportional odds assumptions, as it required reclassification of the outcome as a binary variable. This, in turn, hindered detection of treatment effect during the first half of the study.

“These results raise questions about an anti-inflammatory approach in the treatment of COVID-19 beyond corticosteroids, which might also have an immune modulation role in COVID-19,” investigators theorized. “Dexamethasone was found to be associated with a reduction in 28-day mortality in patients with COVID-19 who needed supplemental oxygen or mechanical ventilation. No other anti-inflammatory agents have been shown to be beneficial in COVID-19. A single anticytokine approach might not inhibit the breadth of the inflammatory response in COVID-19 and could have a limited role as a single agent.”

Reference:

Veiga VC, Prats JAGG, Farias DLC, et al. Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial. BMJ. 2021;372:n84. Published 2021 Jan 20. doi:10.1136/bmj.n84