Early RCT evidence suggests tocilizumab may not be beneficial for COVID-19
medwireNews: Findings from three randomized controlled trials (RCTs) suggest that treatment with the interleukin (IL)-6 inhibitor tocilizumab has little benefit for hospitalized patients with COVID-19.
The first – the BACC Bay Tocilizumab Trial – included 242 patients aged an average of 60 years (58% men) who were hospitalized with confirmed SARS-CoV-2 infection in the USA and were not receiving mechanical ventilation. Participants were randomly assigned to receive a single dose of tocilizumab 8 mg/kg (maximum dose 800 mg; n=161) or placebo (n=81) in addition to standard care.
As reported in The New England Journal of Medicine, a comparable proportion of participants in the tocilizumab and placebo arms experienced the primary endpoint of intubation or death over 28 days of follow-up, with rates of 10.6% and 12.5%, respectively. Rates of clinical worsening on an ordinal scale were also similar in the two groups, at a corresponding 19.3% and 17.4%.
“Our data do not provide support for the concept that early interleukin-6 receptor blockade is an effective treatment strategy in moderately ill patients hospitalized with Covid-19,” conclude John Stone (Harvard Medical School, Boston, Massachusetts, USA) and co-investigators.
In the second trial, investigators from the RCT-TCZ-COVID-19 Study Group evaluated the efficacy of tocilizumab compared with standard care in 123 patients from Italy who were hospitalized with COVID-19 pneumonia. Participants were aged a median of 60 years, and 61% were men.
Carlo Salvarani (Azienda USL-IRCCS di Reggio Emilia, Italy) and team report in JAMA Internal Medicine that the composite primary endpoint of clinical worsening over 14 days occurred in 28.3% of 60 patients who were randomly assigned to receive tocilizumab (8 mg/kg within 8 hours of randomization and a second dose after 12 hours), compared with 27.0% of the 63 patients given standard care, a nonsignificant difference. Clinical worsening was defined as admission to the intensive care unit (ICU) with invasive mechanical ventilation, all-cause mortality, or clinical aggravation according to a ratio of arterial oxygen partial pressure to fractional inspired oxygen of less than 150 mmHg.
Salvarani et al say that the RCT-TCZ-COVID-19 trial was prematurely discontinued following an interim analysis for futility.
The third trial, also published in JAMA Internal Medicine, was conducted in France and involved 130 patients (median age 64 years, 68% men) with COVID-19 and moderate-to-severe pneumonia who required at least 3 L/min of oxygen but not mechanical ventilation or ICU admission. CORIMUNO-19 participants were randomly assigned to receive standard care plus tocilizumab 8 mg/kg on day 1, with a second dose on day 3 if oxygen requirement was not decreased by at least 50%, or to receive standard care only.
In all, 19% of 63 participants in the tocilizumab arm had a score of higher than 5 points on the World Health Organization 10-point Clinical Progression Scale (WHO-CPS) at day 4, compared with 28% of 67 patients in the control group, a nonsignificant difference.
Although tocilizumab did not significantly reduce clinical progression according to WHO-CPS scores, the IL-6 inhibitor “might have reduced the risk” for the coprimary endpoint of noninvasive mechanical ventilation, mechanical ventilation, or death in the study population, say Olivier Hermine (Hôpital Necker, Paris, France) and fellow investigators. Cumulative rates of this composite endpoint during 14 days of follow-up were numerically lower in the tocilizumab arm compared with the control group, at 24% versus 36%.
Using Markov chain Monte Carlo methods, Hermine and team estimated that the posterior probability of achieving a hazard ratio of less than 1 was 95% for the second coprimary endpoint, which they say met the predefined efficacy threshold. However, they note that 28-day mortality rates were comparable in the tocilizumab and control arms (89 vs 88%).
Commenting on the RCT-TCZ-COVID-19 and CORIMUNO-19 trials in an accompanying editorial published in JAMA Internal Medicine, Jonathan Parr (University of North Carolina at Chapel Hill, USA) says that the results “do not show clear evidence of efficacy, in contrast to observational studies,” and “do not support routine tocilizumab use in COVID-19.”
However, he notes that “[a]s with everything in the COVID-19 era, things may change,” highlighting the need for further studies to evaluate longer-term outcomes in tocilizumab-treated patients.
Moreover, in a statement to the media about these trials, Martin Landray, Professor of Medicine & Epidemiology from the University of Oxford in the UK, said that the studies “are too small to give robust answers” and “[w]hat is needed is evidence from randomised trials that are sufficiently large to provide doctors the information they need to treat future patients.”
Landray says that “[t]he RECOVERY trial will provide this information,” with results anticipated by the end of 2020, but “[u]ntil that time, Tocilizumab remains promising but unproven.”
medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2020 Springer Healthcare Ltd, part of the Springer Nature Group
22 October 2020: The coronavirus pandemic is affecting all healthcare professionals across the globe. Medicine Matters’ focus, in this difficult time, is the dissemination of the latest data to support you in your research and clinical practice, based on the scientific literature. We will update the information we provide on the site, as the data are published. However, please refer to your own professional and governmental guidelines for the latest guidance in your own country.
NEJM 2020; doi:10.1056/NEJMoa2028836
JAMA Intern Med 2020; doi:10.1001/jamainternmed.2020.6615
JAMA Intern Med 2020; doi:10.1001/jamainternmed.2020.6820
JAMA Intern Med 2020; doi:10.1001/jamainternmed.2020.6557