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EXPERT REACTION: Is arthritis drug tocilizumab another treatment for COVID-19?

Embargoed until: Publicly released:
Peer-reviewed: This work was reviewed and scrutinised by relevant independent experts.

Randomised controlled trial: Subjects are randomly assigned to a test group, which receives the treatment, or a control group, which commonly receives a placebo. In 'blind' trials, participants do not know which group they are in; in ‘double blind’ trials, the experimenters do not know either. Blinding trials helps removes bias.

Observational study: A study in which the subject is observed to see if there is a relationship between two or more things (eg: the consumption of diet drinks and obesity). Observational studies cannot prove that one thing causes another, only that they are linked.

People: This is a study based on research using people.

Across a series of studies, international researchers have investigated whether tocilizumab, an immunosuppressive drug used mainly for the treatment of rheumatoid arthritis, is an effective treatment against COVID-19 and its associated pneumonia. Using a randomised control trial, one study looked at whether the drug could reduce mortality for patients hospitalised with COVID-19, while two other studies investigated whether the drug could reduce the symptoms and severity of patients diagnosed with COVID-19-associated pneumonia. The initial findings suggest that amongst critically ill patients, early treatment with tocilizumab may reduce mortality, while the treatment did not appear to impact the severity of pneumonia but may reduce the need for ventilation among pneumonia patients. All three studies stress the need for further research to fully investigate the drug's potential.

Journal/conference: JAMA Internal Medicine

Link to research (DOI): 10.1001/jamainternmed.2020.6252

Organisation/s: Brigham and Women’s Hospital, US, Unita Operativa di Reumatologia in Reggio Emilia, Italy, Université de Paris, France

Funder: See individual papers

Media release

From: JAMA

Paper 1

Examining Association Between Early Treatment WithTocilizumab, Risk of Death Among Critically Ill COVID-19Patients

What The Study Did:
Whether treatment with tocilizumab in the first two days after being admitted to an intensivecare unit was associated with a reduced risk of death among critically ill patients with COVID-19 was investigated inthis study.

Authors: David E. Leaf, M.D., M.M.Sc., of Brigham and Women’s Hospital in Boston, is the corresponding author.

Paper 2

Tocilizumab vs Standard Care on Preventing Worsening inPatients Hospitalized With COVID-19 Pneumonia

What The Study Did:
Researchers in this randomized clinical trial compared the effect of early administration oftocilizumab with standard therapy in preventing clinical worsening in patients hospitalized with COVID-19pneumonia.

Authors: Carlo Salvarani, M.D., of Unita Operativa di Reumatologia in Reggio Emilia, Italy, is the corresponding author.

Paper 3

Effect of Tocilizumab in Adults Hospitalized With COVID-19With Moderate or Severe Pneumonia

What The Study Did:
This randomized clinical trial assessed whether tocilizumab improves outcomes of patientshospitalized with moderate-to-severe COVID-19 pneumonia compared to usual care.

Authors: Olivier Hermine, M.D., Ph.D., of the Université de Paris, is the corresponding author.

Attachments:

  • JAMA
    Web page
    Paper 1 - The URL will go live after the embargo ends
  • JAMA
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    Paper 2 - The URL will go live after the embargo ends
  • JAMA
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    Paper 3 - The URL will go live after the embargo ends

Expert Reaction

These comments have been collated by the Science Media Centre to provide a variety of expert perspectives on this issue. Feel free to use these quotes in your stories. Views expressed are the personal opinions of the experts named. They do not represent the views of the SMC or any other organisation unless specifically stated.

Professor Stuart Tangye is Leader of the Immunity & Inflammation Theme and Head of the Immunology & Immunodeficiency Lab at the Garvan Institute of Medical research. He is also a Professor (Conjoint) at St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney

Ongoing infection with SARS-CoV-2 can lead to a high production of pro-inflammatory molecules, which can cause tissue damage to the host – commonly referred to as a 'cytokine storm'. One of these pro-inflammatory molecules is interleukin-6 (IL-6), which early studies have revealed is elevated in patients with a SARS-CoV-2 infection.

Tocilizumab is a biological inhibitor of IL-6 function, which shuts down the IL-6-induced inflammatory response and has been used to treat several known autoimmune diseases such as rheumatoid arthritis. 

The three studies published in JAMA Internal Medicine report clinical trials testing the effects of tocilizumab in patients with SARS-CoV-2 infection, revealing a favourable – albeit relatively mild – effect on COVID-19. The best results are seen when the treatment was administered early.

These results are consistent with another recent study (on which I am an author), which revealed that patients who have defects in the receptor for IL-6 develop mild or asymptomatic COVID-19.

It will be important for further clinical trials to test tocilizumab in combination with other potential therapies, such as steroids and dexamethasone.

Last updated: 20 Oct 2020 5:09pm
Declared conflicts of interest:
None declared.
Professor David Henry is in the Institute for Evidence-Based Healthcare at Bond University

Tocilizumab (TCZ) is an anti-inflammatory drug that is used to treat severe active rheumatoid arthritis. It acts by blocking a type of cytokine which is present in elevated concentrations in some forms of arthritis. Cytokines are also thought to be important in producing the severe inflammation in the later stages of COVID-19, worsening damage in the lungs and other organs. To date, over 20 studies have investigated the effects of TCZ in COVID-19 and a meta-analysis of these suggested that treatment might reduce mortality and need for mechanical ventilation. However, the studies were not randomised trials and were subject to biases that might weaken their conclusions.

Today, three new studies of TCZ in patients with COVID-19 and respiratory impairment are reported in JAMA Internal Medicine. The largest is an observational study from the USA that used sophisticated design and analysis methods to emulate a randomised trial. The investigators found that TCZ was associated with a 9.6 percent reduction in mortality at 30 days. However, patients were not randomised to tocilizumab and the authors caution that residual confounding may have distorted the results.

In the second report, the RCT-TCZ-COVID-19 Study Group publish the results of a small randomised trial (126 patients) conducted in 24 Italian hospitals that found no effect of TCZ on the rate of worsening of the disease. The trial was terminated early because an interim analysis showed there was no reasonable prospect of finding a positive result (futility).

The third study conducted in nine university hospitals in France was also a small (131 patients) randomised trial. Patients requiring oxygen but not in intensive care received TCZ or usual care. TCZ might have reduced the need for invasive or non-invasive ventilatory support but it had no effect on mortality at 14 or 28 days. However, the numbers of deaths were too small to draw confident conclusions about the effect of TCZ.

These studies have to be viewed against a background of larger randomised trials that have not yet reported in full. The COVACTA study conducted by the manufacturer of TCZ (Roche) appears not to have met its primary endpoint of improved clinical status in COVID-19 pneumonia. Sarilumab, a drug similar in effect to TCZ, has been investigated in COVID-19, but the trial stopped recruiting patients with less advanced disease because of futility in this group. The largest ongoing trial of TCZ (over 850 patients) is the Recovery Trial being coordinated by Oxford University, and the results have not yet been reported. So, while the results of non-randomised studies have suggested possible benefits of TCZ, the two small randomised trials reported today are inconclusive about mortality. As with other drugs in COVID-19 we must wait for the results of large definitive randomised trials.

Last updated: 20 Oct 2020 5:08pm
Declared conflicts of interest:
None declared.
Associate Professor Sanjaya Senanayake is a specialist in Infectious Diseases and Associate Professor of Medicine at The Australian National University

Management of patients with COVID-19 has either targeted the virus or the exuberant immune response to it. Tocilizumab has been used to treat the latter. One advantage of tocilizumab is that it has been used for many years, and we therefore already understand its side effect profile. However, it hasn't been used to treat infections, rather conditions like rheumatoid arthritis. Also, these three studies used tocilizumab in sick hospitalised patients with COVID-19, whereas tocilizumab is often given in the outpatient setting to stable patients.

The gold standard for assessing a medication is through a randomised controlled trial. Out of these three newly published studies, one was not randomised and the other two were; however, in the two randomised trials, investigators knew whether the placebo or tocilizumab was being given [which can bias results]. Also, the numbers were small. The results of both randomised trials did not show a definite benefit in death rates or clinical progression with tocilizumab, although the French trial raised the possibility of this at the 14-day mark. The US non-randomised trial showed a mortality benefit with tocilizumab; however, the lack of a randomised trial makes it difficult to interpret these findings.

In summary, the results of these trials will not lead to a universal recommendation of tocilizumab use in hospitalised patients with COVID-19; but, it would be reasonable to proceed with large-scale randomised trials (such as we have seen with RECOVERY and SOLIDARITY) to definitively answer the questions of whether it has a role in COVID-19.

Last updated: 20 Oct 2020 5:06pm
Declared conflicts of interest:
None declared.

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