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expert reaction to preprint from the REMAP-CAP trial looking at tocilizumab and sarilumab in critically ill COVID-19 patients

A preprint, an unpublished non-peer reviewed study, looks at Interleukin-6 receptor agonists, tocilizumab and sarilumab, in critically ill COVID-19 patients.

This Roundup accompanied an SMC Briefing

 

Dr Adam Jacobs, Director of Biostatistics at Premier Research, said:

“This paper has not yet been peer reviewed, which is an important limitation.

“There are some quite complex statistical methods, which would benefit from robust peer review (certainly a more thorough look than I’ve had time to do today).  But one thing that seems odd is that they report odds ratios for death > 1, which suggests increased mortality in the experimental groups compared with the control.  In fact, their descriptive statistics show decreased mortality in the experimental groups, consistent with the conclusions of the paper.  This is the sort of thing that would no doubt be sorted out in peer review.

“This is a randomised controlled trial (we absolutely do need these trials) and seems to be well conducted, by a team with a good reputation.  The treatment groups were well balanced at baseline.

“I am a bit sceptical of their primary outcome measure of ‘organ support-free days’.  They have created a score that combined mortality with the number of days without organ support, and those are really not comparable outcomes.  Mortality is clearly far more important than one extra day of organ support, but the way they have constructed their score blurs that distinction.  Nonetheless, if we believe their primary outcome measure tells us anything useful, it does show substantial differences between the experimental treatments and the control.

“That said, they do report mortality as an outcome in its own right, and that supports the conclusions, at least for tocilizumab.  In-hospital mortality was 28% for tocilizumab, 22% for sarilumab, and 36% for control.  On the face of it, that would seem to imply that sarilumab is the better treatment, but it is important to note that the sample size for sarilumab was very small.  According to their Bayesian analysis, this means that there is a 99.6% chance that tocilizumab is better than placebo and a 99.5% chance that sarilumab is better than placebo.  I am not an expert in Bayesian statistics so can’t comment on whether that is correct: this is one of the reasons why the paper really needs some serious peer review.  I do find it surprising that sarilumab is claimed to have such a high probability of being effective given the small sample size.  I ran my own simple frequentist analysis, and while tocilizumab was significantly better than placebo (although not highly significant: P = 0.03, so only just meeting conventional levels of statistical significance), sarilumab was not significantly better (P = 0.10).

“The magnitude of the effect for tocilizumab does not make it a miracle cure, but certainly makes it enough to be clearly useful.  There is an 8% absolute risk difference between tocilizumab and the control treatment.  That means that if you gave it to 100 people in intensive care with Covid infection, then you would expect 8 more of them to survive than would have done otherwise.  Or to put it another way, you would save one life for approximately each 12 patients you treat.

“It’s worth noting that most patients were already being treated with steroids, which have previously been shown to improve mortality in this group, so the benefit of tocilizumab is in addition to that.  This kind of incremental improvement can make a big difference if we continue to accumulate more of them as more trials are done.

“This was in patients in intensive care.  The results cannot be generalised to a less severely ill population.  This study would absolutely not support anyone who thinks they might have Covid treating themselves with tocilizumab at home (even if they could get hold of it, which of course would need a prescription anyway).

“The results were robust in that they were supported by various sensitivity analyses.

“Bottom line is that although I have a few concerns about the details of this study, if I were in intensive care with Covid, I would definitely want my doctors to give me tocilizumab now that I’ve read this paper.”

 

Dr Nick Cammack, Covid-19 Therapeutics Accelerator Lead at Wellcome, said:

“This is a potentially encouraging step in the search for Covid-19 treatments.  If tocilizumab and sarilumab were to reduce mortality from Covid-19, this would be a promising result and could potentially save thousands of lives.  If patients were able to leave intensive care around a week earlier after taking the treatment, this would significantly alleviate pressure on overstretched healthcare systems.

“To have two additional treatment options for critically ill patients with Covid-19, as well as dexamethasone, would have a strong impact on the search for effective treatments.  We await the final results from the RECOVERY trial, which will give us additional data on the efficacy of tocilizumab and convalescent plasma.

“As hospitalisations and deaths from Covid-19 skyrocket in the UK and the new strains make the pandemic more challenging, finding effective treatments is more urgent than ever.  We must keep up the rapid pace of research, continuing to invest in large-scale clinical trials, and find treatments that can prevent mild symptoms becoming more severe.”

 

Prof Robin Ferner, Honorary Professor of Clinical Pharmacology, University of Birmingham & Honorary Consultant Physician, City Hospital Birmingham, said:

“There are few treatments for severe COVID-19.  The IL-6 receptor antagonists (monoclonal antibodies directed against the interleukin-6 receptors) should theoretically help to damp down the ‘cytokine storm’ of fatal COVID-19.  Previous studies have shown no clear survival benefit.  If the published data from REMAP-CAP are supported by further studies, this suggests that two IL-6 receptor antagonists can reduce the death rate in the most severely ill patients, but are no magic cure: of 401 patients given the drugs, 109 died.  With standard treatment, 144 out of 402 died.”

 

Prof Martin Landray, Professor of Medicine & Epidemiology, Nuffield Department of Population Health, University of Oxford, said:

“Today’s result from REMAP-CAP is good news.  It shows that tocilizumab reduces length of time that critically ill patients require mechanical ventilators and other forms of organ support.  In contrast to previous trials, REMAP-CAP also reports lower mortality among patients given tocilizumab.  There are, of course, still unanswered questions.  For example, exactly how well does tocilizumab work in different types of patients?  And if given earlier, might it reduce the need for patients to require mechanical ventilation in the first place?

“The RECOVERY trial, which has now enrolled over 2800 patients to the assessment of tocilizumab, should help answer those questions.  We don’t yet know the answers.  But, REMAP-CAP has injected that bit of optimism we all need.

“Once again, we are seeing the incredible power of well-conducted randomised trials, delivered by frontline NHS staff at the bedside, to identify which of the many treatments we hope might work actually have real benefits for patients.  Congratulations and many thanks to the REMAP-CAP team – researchers, medical staff, and most especially the patients and their families.”

 

Prof Peter Horby, Professor of Emerging Infectious Diseases, Centre for Tropical Medicine and Global Health, University of Oxford, said:

“It is great to see a positive result at a time that we really need good news and more tools to fight COVID.  This is great achievement for REMAP-CAP; it demonstrates the power of adaptive platform trials.  Importantly, the findings of a benefit are in addition to corticosteroids, which were taken by 93% of the participants.  This means we now have two drugs, which combined have a greater effect.  This result is for critically ill patients and we hope to soon have results from RECOVERY on the effect of tocilizumab in less severely ill patients in hospital.”

 

Prof Stephen Evans, Professor of Pharmacoepidemiology, London School of Hygiene & Tropical Medicine, said:

“This is a high-quality trial, and although published as a pre-print is of much higher quality than many non-peer-reviewed papers.

“The trial of these two drugs, which are licensed as (fairly expensive) treatments for arthritis, was based on the possibility that they would have efficacy as suppressing the extreme immune response seen in many patients with Covid-19 who become critically ill.

“Part way through the trial, the RECOVERY trial findings showed that the (cheap) corticosteroid drug dexamethasone had notable mortality benefits.  Consequently, quite a number of the patients in this trial had also received a corticosteroid, either as being in an early trial as well as this one, or by being given them as routine when the RECOVERY results became available.

“It does look as though these drugs give some additional benefit beyond that given by dexamethasone.

“It is encouraging to find good evidence being generated in well conducted randomised trials to show extra treatments that provide benefit for patients in the critical stages of Covid-19 illness.  It must be emphasised that there is no suggestion that these treatments have any role in the early stages of disease.

“The fairly complex Bayesian analysis that was used is a reliable method, though some of the presentation is not what most readers are used to (such as presenting odds ratios of survival when most present odds ratios for mortality, so that odds ratios greater than 1 show benefit, which is not the usual presentation).  None of this in any way casts doubt on the validity of the results.”

 

 

Preprint (not a paper): ‘Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19–Preliminary report’ by The REMAP-CAP Investigators was posted on medRxiv.  This work is not peer-reviewed.

https://www.medrxiv.org/content/10.1101/2021.01.07.21249390v1

 

 

Declared interests

Dr Adam Jacobs: “No COI to declare.”

Dr Nick Cammack: “The RECOVERY trial receives core funding from a number of funders, including Wellcome.”

Prof Robin Ferner: “No conflicts.”

Prof Martin Landray: “- Co-chief investigator of the RECOVERY trial of potential treatments for COVID-19 (funded by UKRI and NIHR; contributions to supply of study treatment from Abbvie, Roche, and Regeneron).

– Research funding to University of Oxford received from Novartis, Boehringer Ingelheim, and Merck Sharp & Dohme.

– Infrastructure and core funding received from Health Data Research UK, NIHR Oxford Biomedical Research Centre, UK Biobank Ltd, MRC Population Health Research Unit, and British Heart Foundation Centre for Research Excellence.

– Employee of University of Oxford with salary supported by Li Ka Shing Foundation, Health Data Research UK, NIHR Oxford Biomedical Research Centre, Wellcome Trust, and National Health Service.

– I do not accept personal honoraria payments directly or indirectly from the pharmaceutical, biotechnology, or food industries although reimbursement to the University of Oxford for the costs of travel and accommodation to participate in scientific meetings may be accepted. I hold no shares in and receive no consultancy payments directly or indirectly from tobacco, pharmaceutical, biotechnology, or food companies. I comply with the Independence of Research Policy of the Nuffield Department of Population Health, Universityy of Oxford. For details see: https://www.ndph.ox.ac.uk/files/about/ndph-independence-of-research-policy-jun-20.pdf/@@download.”

Prof Peter Horby: “- Co-Chief Investigator of the RECOVERY trial. The RECOVERY trial is supported by a grant to the University of Oxford from UK Research and Innovation and NIHR (MC_PC_19056 ). Tocilizumab is being studied in RECOVERY. Tocilizumab was provided free of charge for this study by Roche. Lopinavir–ritonavir was provided free of charge for this study by Abbvie.  REGN-COV2 was provided free of charge for this study by Regeneron.

– Employee of University of Oxford with salary supported by Wellcome Trust and NIHR.

– I do not accept any personal honoraria payments directly or indirectly from the pharmaceutical, biotechnology, or food industries.

–  I hold no shares in and receive no consultancy payments directly or indirectly from tobacco, pharmaceutical, biotechnology, or food companies.”

Prof Stephen Evans: “No conflicts of interest.  I am funded (one day per week) by LSHTM.  They get funding from various companies, including Astra Zeneca and GSK but I am not funded by them, I have no involvement in obtaining funding from them and I am not an investigator on any grants obtained from them.  I am the statistician to the ‘meta-Data Safety and Monitoring Board’ for CEPI.  I am paid for my attendance at those meetings and will be paid expenses for travel if that occurs.  I am a participant in the Oxford/Astra Zeneca trial, but am still “blind” to the vaccine received.”

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