Tocilizumab reduces deaths in hospitalised COVID-19 patients — RECOVERY trial

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The an anti-inflammatory treatment, tocilizumab, reduces the risk of death when given to hospitalised patients with severe COVID-19, shows the  RECOVERY trial, writes MedicalBrief. It also shortens the time until patients are successfully discharged from hospital and reduces the need for a mechanical ventilator.

Prof Stephen Evans, a pharmacoepidemiologist at the London School of Hygiene & Tropical Medicine who was not directly involved in the trial, said in a Reuters report, its results were important. "It is a large trial and the benefits were seen both on earlier discharge from hospital and mortality," he said. "The magnitude of benefit is not startling but is clinically important, with a reduction in deaths from 33% to 29%."

It is the second treatment that Recovery – the world's largest randomised controlled clinical trial – has found to be effective against COVID, following its discovery of the world-first treatment with dexamethasone in June, which reduces the risk of death by 20% for patients on oxygen and 35% for ventilated patients.

The Randomised Evaluation of COVID-19 Therapy  trial has demonstrated that trial has been testing a range of potential treatments for COVID-19 since March 2020. Tocilizumab, an intravenous drug used to treat rheumatoid arthritis, was added to the trial in April 2020 for patients with COVID-19 who required oxygen and had evidence of inflammation. Recruitment to the tocilizumab arm stopped on 24 January 2021 since, in the view of the trial Steering Committee, sufficient patients had been enrolled to establish whether or not the drug had a meaningful benefit.

A total of 2022 patients were randomly allocated to receive tocilizumab by intravenous infusion and were compared with 2094 patients randomly allocated to usual care alone. 82% of patients were taking a systemic steroid such as dexamethasone.

Treatment with tocilizumab significantly reduced deaths: 596 (29%) of the patients in the tocilizumab group died within 28 days compared with 694 (33%) patients in the usual care group (rate ratio 0·86; [95% confidence interval [CI] 0·77 to 0·96]; p=0·007), an absolute difference of 4%. This means that for every 25 patients treated with tocilizumab, one additional life would be saved. Tocilizumab also increased the probability of discharge alive within 28 days from 47% to 54% (rate ratio 1·23, [95% CI 1·12 to 1·34], p<0·0001). These benefits were seen in all patient subgroups, including those requiring oxygen via a simple face mask through to those requiring mechanical ventilators in an intensive care unit.

Among patients not on invasive mechanical ventilation when entered into the trial, tocilizumab significantly reduced the chance of progressing to invasive mechanical ventilation or death from 38% to 33% (risk ratio 0·85, [95% CI 0·78 to 0·93], p=0·0005). However, there was no evidence that tocilizumab had any effect on the chance of successful cessation of invasive mechanical ventilation. In June 2020, the RECOVERY trial found that the inexpensive and widely available steroid dexamethasone reduces death for patients with severe COVID-19. This rapidly became part of standard-of-care given to all such patients. The benefits of tocilizumab were clearly seen to be in addition to those of steroids.

The data suggest that in COVID-19 patients with hypoxia (requiring oxygen) and significant inflammation, treatment with the combination of a systemic corticosteroid (such as dexamethasone) plus tocilizumab reduces mortality by about one third for patients requiring simple oxygen and nearly one half for those requiring invasive mechanical ventilation.

Peter Horby, professor of emerging infectious diseases in the Nuffield Department of Medicine, University of Oxford, and joint chief investigator for RECOVERY, said: “Previous trials of tocilizumab had shown mixed results, and it was unclear which patients might benefit from the treatment. We now know that the benefits of tocilizumab extend to all COVID patients with low oxygen levels and significant inflammation. The double impact of dexamethasone plus tocilizumab is impressive and very welcome.”

Martin Landray, professor of medicine and epidemiology at the Nuffield Department of Population Health, University of Oxford, and joint chief investigator, said: “The results from the RECOVERY trial clearly show the benefits of tocilizumab and dexamethasone in tackling the worst consequences of COVID-19 – improving survival, shortening hospital stay, and reducing the need for mechanical ventilators. Used in combination, the impact is substantial. This is good news for patients and good news for the health services that care for them in the UK and around the world. We simply would not know this if it wasn’t for the incredible support of NHS patients and staff in the most challenging of circumstances.”

Professor Nick Lemoine, medical director of the National Institute for Health Research (NIHR) Clinical Research Network said: “Through our programme of urgent public research – working closely with the RECOVERY team and NHS hospital staff right across the UK – the NIHR has helped over 35,000 patients take part in this flagship treatment study. In doing so, the RECOVERY trial has been able to provide data which has now given the world two life-saving treatments against this dreadful disease.”

Professor Fiona Watt, executive chair of the Medical Research Council, which funded the study with the NIHR, said: “It’s incredibly encouraging that doctors now have an additional COVID-19 treatment that can save lives and reduce the length of hospital stays. We’ve been funding the RECOVERY trial since early last year and were delighted when the RECOVERY team identified the first drug to substantially reduce COVID-19 deaths, dexamethasone. Importantly, the benefits from tocilizumab are in addition to those provided by dexamethasone – patients receiving both drugs do even better than patients on dexamethasone alone. This world-leading study shows the power of well-designed clinical trials to discover which drugs can help patients.”

The preliminary results will be made available via medRxiv shortly and submitted to a peer-reviewed medical journal. For this preliminary report, information on the primary outcome was available for 92% of patients.

 

 

The Reuters report notes that Roche's drug division chief Bill Anderson said that previous mixed results were likely due to differences in the type of patients studied, when they were treated, and the endpoint – the juncture at which success or failure is measured.

"We think we're sort of zooming in on both the most relevant endpoints and relevant patient population," Anderson said. "It seems like the ideal candidates are patients who are really in that acute phase of inflammatory attack."

The report says Actemra, along with Sanofi's similar drug Kevzara, was authorised by Britain's National Health Service (NHS) in early January for COVID-19 patients in intensive care units after preliminary data from a smaller study called REMAP-CAP indicated it could reduce hospital stays by about 10 days.

 

Anthony Gordon, professor of anaesthesia and critical care and NIHR Research professor at Imperial College London, welcomed the results. "This is great news," he said. "We know approximately 4,000 critically ill patients have already been treated with tocilizumab in the UK. "Now even more patients will benefit from this treatment," added Gordon, who was not involved in the research.

Medical Xpress reports that the pandemic has seen a global race to identify effective treatments for serious cases that don't risk other adverse outcomes in patients. Despite dozens of trials using a host of existing medicines, until Thursday the only drug that had showed significant efficacy in treating COVID-19 was dexamethasone.

"After dexamethasone, this is the most significant advance in the treatment of COVID that has an impact in reducing deaths," said Athimalaipet Ramanan, professor of paediatric rheumatology at the University of Bristol.

Landray said that compared with the first pandemic wave, where there were no proven COVID-19 treatments for hospitalised patients, both tocilizumab and dexamethasone offered some hope. "We can now reduce the risk of death from anything from one third to up to a half, depending on the patient," he said. "That's good for patients, and good for the health service both here in the UK and internationally."

 

The Daily Telegraph reports that this second coronavirus treatment will be given to NHS patients after the successful trials.

Professor Jonathan Van-Tam, the deputy chief medical officer, said: "These results present another important advance in our fight against COVID-19 and are good news for patients and clinicians around the world. It's a combination of both effective therapeutics and vaccines that will mean an end to this pandemic."

The report says the UK government is working closely with the manufacturer Roche to ensure the drug is available across NHS healthcare settings.

It is the second treatment that Recovery – the world's largest randomised controlled clinical trial – has found to be effective against COVID, following its discovery of the world-first treatment with dexamethasone in June, which reduces the risk of death by 20% for patients on oxygen and 35% for ventilated patients.

Scientists say the benefits of using tocilizumab with dexamethasone are in addition to the benefits shown by dexamethasone alone.

 

University of Oxford material

 

Full Reuters report (Open access)

 

Full Medical Xpress report (Open access)

 

Full report in The Daily Telegraph (Restricted access)

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