Adding the arthritis drug tocilizumab to standard care for patients in hospital with severe or critical COVID-19 is no better than standard care alone in improving clinical outcomes at 15 days, finds a new trial published by The BMJ today.
There was an increased number of deaths at 15 days in patients receiving tocilizumab, resulting in the trial being stopped early.
Today’s results contradict earlier observational studies suggesting a benefit of tocilizumab. However, observational effects are limited by a high risk that they may be due to other unknown (confounding) factors—and some studies have not yet been peer reviewed or published in a medical journal.
A randomised trial assessing tocilizumab in critically ill patients with COVID-19 (REMAP-CAP) published as a preprint earlier this month, found a beneficial effect of the drug on days free from organ support within 21 days and mortality. Reasons for these apparently contradictory effects, for example differences between patients’ characteristics, need to be assessed in future analysis, say the researchers.
Tocilizumab blocks a specific part of the immune system (interleukin 6) that can go into overdrive in some patients with COVID-19. Doctors think this might help lessen the body’s inflammatory response to the virus and avert some of the more dire consequences of the disease, but its effects are not well defined.
To test this theory, researchers based in Brazil 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.
Their findings are based on 129 relatively young adults (average age 57 years) with confirmed COVID-19 at nine hospitals in Brazil between 8 May and 17 July 2020.
Patients were receiving supplemental oxygen or mechanical ventilation and had abnormal levels of at least two chemicals linked to inflammation in their blood.
Patients were randomly divided into two groups: 65 received tocilizumab plus standard care and 64 received standard care alone.
Other potentially important factors, such as underlying conditions and use of other medication, were taken into account and all patients were monitored for 15 days.
By day 15, 18 (28%) patients in the tocilizumab group and 13 (20%) in the standard care group were receiving mechanical ventilation or died.
Death at 15 days occurred in 11 (17%) patients in the tocilizumab group compared with 2 (3%) in the standard care group.
The increased number of deaths in the tocilizumab group raised safety concerns and the trial was stopped early. In both groups, deaths were attributed to COVID-19 related acute respiratory failure or multiple organ dysfunction.
The researchers point to some limitations including the small sample size, which affects the chances of detecting a true effect. However, results were consistent after adjusting for levels of respiratory support needed by patients at the start of the trial, suggesting that the findings withstand scrutiny.
As such, the researchers conclude that in 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 might increase mortality.”
And they say these results “raise questions about an anti-inflammatory approach in the treatment of COVID-19 beyond corticosteroids.”
Tocilizumab is a recombinant humanized monoclonal antibody directed against both the soluble and the membrane-bound IL-6 receptor. It is indicated for the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, giant cell arteritis, and life-threatening cytokine release syndrome induced by chimeric antigen receptor T-cells.9–12
Recent retrospective studies have suggested that tocilizumab may be associated with lower risk of death or intubation in patients with severe COVID-19 pneumonia.13–17
However, the observational nature of these studies hampers the assessment of the effect of tocilizumab. To evaluate the efficacy and safety of early administration of tocilizumab in hospitalized patients with COVID-19 pneumonia, we designed and conducted a multicentric randomized clinical trial (eMethods in Supplement 1).
Objective: To evaluate the effect of early tocilizumab administration vs standard therapy in preventing clinical worsening in patients hospitalized with COVID-19 pneumonia.
Design, setting, and participants: Prospective, open-label, randomized clinical trial that randomized patients hospitalized between March 31 and June 11, 2020, with COVID-19 pneumonia to receive tocilizumab or standard of care in 24 hospitals in Italy. Cases of COVID-19 were confirmed by polymerase chain reaction method with nasopharyngeal swab. Eligibility criteria included COVID-19 pneumonia documented by radiologic imaging, partial pressure of arterial oxygen to fraction of inspired oxygen (Pao2/Fio2) ratio between 200 and 300 mm Hg, and an inflammatory phenotype defined by fever and elevated C-reactive protein.
Interventions: Patients in the experimental arm received intravenous tocilizumab within 8 hours from randomization (8 mg/kg up to a maximum of 800 mg), followed by a second dose after 12 hours. Patients in the control arm received supportive care following the protocols of each clinical center until clinical worsening and then could receive tocilizumab as a rescue therapy.
Main outcome and measures: The primary composite outcome was defined as entry into the intensive care unit with invasive mechanical ventilation, death from all causes, or clinical aggravation documented by the finding of a Pao2/Fio2 ratio less than 150 mm Hg, whichever came first.
Results: A total of 126 patients were randomized (60 to the tocilizumab group; 66 to the control group). The median (interquartile range) age was 60.0 (53.0-72.0) years, and the majority of patients were male (77 of 126, 61.1%). Three patients withdrew from the study, leaving 123 patients available for the intention-to-treat analyses. Seventeen patients of 60 (28.3%) in the tocilizumab arm and 17 of 63 (27.0%) in the standard care group showed clinical worsening within 14 days since randomization (rate ratio, 1.05; 95% CI, 0.59-1.86). Two patients in the experimental group and 1 in the control group died before 30 days from randomization, and 6 and 5 patients were intubated in the 2 groups, respectively. The trial was prematurely interrupted after an interim analysis for futility.
Conclusions and relevance: In this randomized clinical trial of hospitalized adult patients with COVID-19 pneumonia and Pao2/Fio2 ratio between 200 and 300 mm Hg who received tocilizumab, no benefit on disease progression was observed compared with standard care. Further blinded, placebo-controlled randomized clinical trials are needed to confirm the results and to evaluate possible applications of tocilizumab in different stages of the disease.
Trial registration: ClinicalTrials.gov Identifier: NCT04346355; EudraCT Identifier: 2020-001386-37.
reference link: https://pubmed.ncbi.nlm.nih.gov/33080005/
More information: Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial, BMJ (2021). DOI: 10.1136/bmj.n84
