REMAP-CAP trial: UK to roll out tocilizumab and sarilumab for ICU patients

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Patients across the UK who are admitted to intensive care units due to COVID-19 are set to receive a treatment that can reduce the time spent in hospital by up to 10 days, an international study supported by the National Institute for Health Research has found.

Results from the REMAP-CAP clinical trial evaluated the effect of treatments on a combination of survival and length of time patients need support in an intensive care unit (ICU). Patients receiving tocilizumab and a second drug called sarilumab – both types of immune modulators – have a significant impact on patient survival and can reduce the relative risk of death by 24% when administered to patients within 24 hours of entering intensive care.

The rollout of these treatments could therefore contribute significantly towards reducing pressures on hospitals over the coming weeks and months.

The latest findings on tocilizumab, an immunosuppressive drug used to treat rheumatoid arthritis, add to REMAP-CAP findings from November last year, which found that tocilizumab significantly improves outcomes for critically ill patients with severe COVID-19.

Due to the clinical implications for patients, the researchers have released the findings before they have been peer reviewed, but are working to analyse and publish them as soon as possible.

Updated guidance will be issued by the government and the NHS to Trusts across the UK, encouraging them to use tocilizumab in their treatment of COVID-19 patients who are admitted to intensive care units, effective immediately.

The REMAP-CAP study, based in 15 countries across Europe, involves more than 3,900 COVID-19 patients. The study is led by Imperial College London and the Intensive Care National Audit & Research Centre (ICNARC) in the UK and Utrecht University in Europe.

As of November, 2020 75% of all study participants had been recruited in the UK through the NIHR’s Clinical Research Network (CRN).

Professor Anthony Gordon, chair in anaesthesia and critical care at Imperial College London, a consultant in intensive care medicine at Imperial College Healthcare NHS Trust and NIHR research professor said: “This is a significant finding which could have immediate implications for the sickest patients with COVID-19. We found that among critically ill adult patients – those receiving breathing support in intensive care – treatment with these drugs can improve their chances of survival and recovery.

“At a time when hospitalisations and deaths from COVID-19 are soaring in the UK, it’s crucial we continue to identify effective treatments which can help to turn the tide against this disease.”

UK Health and Social Care Secretary Matt Hancock said: “The UK has proven time and time again it is at the very forefront of identifying and providing the most promising, innovative treatments for its patients.

“Today’s results are yet another landmark development in finding a way out of this pandemic and, when added to the armoury of vaccines and treatments already being rolled out, will play a significant role in defeating this virus.

“We have worked quickly to ensure this treatment is available to NHS patients without delay, meaning hundreds of lives will be saved. I am hugely proud of the significant role our NHS and its patients have played in this international trial, and grateful to the outstanding scientists and clinicians behind REMAP-CAP who have brought this treatment to our patients.”

Deputy Chief Medical Officer Professor Jonathan Van-Tam said: “This is a significant step forward for increasing survival of patients in intensive care with COVID-19. The data shows that tocilizumab, and likely sarilumab, speed up and improve the odds of recovery in intensive care, which is crucial for helping to relieve pressure on intensive care and hospitals and saving lives.

“This is evidence of the UK’s excellent research infrastructure and life sciences industry advancing global understanding of this disease, which we have done both through our own programme of clinical research and through our ability to make very large contributions to international studies.”

 

The findings, which have not yet been peer-reviewed, come from the REMAP-CAP trial, which evaluates the effect of treatments on a combination of survival and length of time patients need support in an intensive care unit (ICU).

Initial findings reported in November showed that tocilizumab, a drug used to treat arthritis, was likely to improve outcomes among critically ill COVID-19 patients. But the impact on patient survival and length of time on organ support in ICU was not clear at that time.

Now, the latest analysis shows that tocilizumab and a second drug called sarilumab – both types of immune modulators called IL-6 receptor antagonists – have a significant impact on patient survival, reducing mortality by 8.5%

Furthermore, the treatment also improved recovery so that on average patients were able to be discharged from the intensive care unit (ICU) about a week earlier.

“This is a significant finding which could have immediate implications for the sickest patients with COVID-19,” said Gordon. “We found that among critically ill adult patients – those receiving breathing support in intensive care – treatment with these drugs can improve their chances of survival and recovery. At a time when hospitalisations and deaths from COVID-19 are soaring in the UK, it’s crucial we continue to identify effective treatments which can help to turn the tide against this disease.”

At the end of last year, positive early findings on tocilizumab were released before the full data had been collected. With the full analysis now available, researchers are confident the findings could have immediate clinical implications for patients.

Tocilizumab and sarilumab are immunosuppressive drugs used to treat rheumatoid arthritis. They were two of several immune modulation treatments included in the REMAP-CAP trial.

Patients receiving tocilizumab and sarilumab were more likely to improve (measured by a combination of reduced time on organ support, such as a ventilator, in the ICU and surviving the hospital admission) compared to patients who received no immune modulator.

At the time of full analysis 353 patients had been assigned to tocilizumab, 48 to sarilumab and 402 to control. The majority of patients were also treated with corticosteroids and were receiving respiratory support.

The trial data yielded an odds ratio of 1.64 for a better outcome with tocilizumab, and 1.76 for sarilumab, compared to no immune modulation, with a high degree of statistical certainty (>99.5% probability that both treatments are superior to no immune modulation).

Hospital mortality was reported as 27.3% among patients receiving IL-6 receptor agonists (28.0% for tocilizumab, 22.2% for sarilumab) compared with 35.8% for control group.

Gordon added: “Previous trials using IL-6 receptor agonists have showed no clear benefit on either disease progression or survival in COVID-19 patients, but those studies included less severely ill patients and started treatment at different stages in the disease course.

“A crucial difference may be that in our study, critically ill patients were enrolled within 24 hours of starting organ support. This highlights a potential early window for treatment where the sickest patients may gain the most benefit from immune modulation treatment.”

REMAP-CAP study is led by Imperial College London and the Intensive Care National Audit & Research Centre (ICNARC) in the UK and University Medical Centre Utrecht in Europe. It began investigating treatments for COVID-19 in March 2020, enrolling hospitalised patients with either moderate or severe (requiring ICU care) COVID-19 disease.

The study design randomises patients to multiple combinations of treatments, enabling researchers to evaluate different treatments for COVID-19, including antivirals, drugs which modulate the immune response, and therapies that modulate or support other vital aspects of the body’s response to the virus.

In total, over 3,900 patients in 15 countries have been enrolled at more than 290 hospitals worldwide and randomised to multiple treatment combinations. The effects of interventions are assessed separately for moderate and severely ill patients.

The latest findings on tocilizumab and sarilumab add to REMAP-CAP findings from earlier this year, which found that hydrocortisone steroid treatment improved recovery among critically ill COVID-19 patients.

The study is supported in the UK by the National Institute for Health Research (NIHR) and Imperial College London & ICNARC are partners in the EU funded PREPARE consortium.

 

Study details
Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19 – Preliminary report

The REMAP-CAP Investigators, Anthony C. Gordon, Paul R Mouncey, Farah Al-Beidh, Kathryn M Rowan, Alistair D Nichol, Yaseen M Arabi, Djillali Annane, Abi Beane, Wilma van Bentum-Puijk, Lindsay R Berry, Zahra Bhimani, Marc J.M. Bonten, Charlotte A Bradbury, Frank M Brunkhorst, Adrian Buzgau, Allen C Cheng, Michelle A Detry, Eamon J Duffy, Lise J Estcourt, Mark Fitzgerald, Herman Goossens, Rashan Haniffa, Alisa M Higgins, Thomas E Hills, Christopher M Horvat, Francois Lamontagne, Patrick R Lawler, Helen L Leavis, Kelsey M Linstrum, Edward Litton, Elizabeth Lorenzi, John C Marshall, Florian B Mayr, Danny McAuley, Anna McGlothlin, Shay P McGuinness, Bryan J McVerry, Stephanie K Montgomery, Susan C Morpeth, Srinivas Murthy, Katrina Orr, Rachael L Parke, Jane C Parker, Asad E Patanwala, Ville Pettilä, Emma Rademaker, Marlene S Santos, Christina T Saunders, Christopher W Seymour, Manu Shankar-Hari, Wendy I Sligl, Alexis F Turgeon, Anne M Turner, Frank L van de Veerdonk, Ryan Zarychanski, Cameron Green, Roger J Lewis, Derek C Angus, Colin J McArthur, Scott Berry, Steve A Webb, Lennie PG Derde

Published in MedRxiv on 7 January 2021

Abstract

Background
The efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear.

Methods
We evaluated tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial. Adult patients with Covid-19, within 24 hours of commencing organ support in an intensive care unit, were randomized to receive either tocilizumab (8mg/kg) or sarilumab (400mg) or standard care (control). The primary outcome was an ordinal scale combining in-hospital mortality (assigned −1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with pre-defined triggers to declare superiority, efficacy, equivalence or futility.

Results
Tocilizumab and sarilumab both met the pre-defined triggers for efficacy. At the time of full analysis 353 patients had been assigned to tocilizumab, 48 to sarilumab and 402 to control. Median organ support-free days were 10 (interquartile range [IQR] −1, 16), 11 (IQR 0, 16) and 0 (IQR −1, 15) for tocilizumab, sarilumab and control, respectively. Relative to control, median adjusted odds ratios were 1.64 (95% credible intervals [CrI] 1.25, 2.14) for tocilizumab and 1.76 (95%CrI 1.17, 2.91) for sarilumab, yielding >99.9% and 99.5% posterior probabilities of superiority compared with control. Hospital mortality was 28.0% (98/350) for tocilizumab, 22.2% (10/45) for sarilumab and 35.8% (142/397) for control. All secondary outcomes and analyses supported efficacy of these IL-6 receptor antagonists.

Conclusions
In critically ill patients with Covid-19 receiving organ support in intensive care, treatment with the IL-6 receptor antagonists, tocilizumab and sarilumab, improved outcome, including survival.

 

 

National Institute for Health Research UK material

 

Imperial College London material

 

MedRxiv study (not peer reviewed)

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