Clinicians should consider prescribing intravenous tocilizumab following the criteria defined below for patients in intensive care. Intravenous sarilumab could be considered as an alternative (if available).
Any provider organisation treating patients with this intervention will be required to assure itself that the internal governance arrangements have been completed before either medicine is prescribed.
These arrangements may be through the health board/hospital/trust’s drugs and therapeutics committee, or equivalent.
Anthony Gordon, professor of anaesthesia and critical care at Imperial College London and chief investigator of the study, told a Science Media Centre briefing: “If we treat 12 patients it would save one life. This is a very big effect and really exciting.”
The Department of Health and Social Care said that supplies of tocilizumab are already available in hospitals and that updated guidance would be issued to trusts across the UK encouraging its use. Either of the immune modulators could be used in addition to dexamethasone, which is already standard of care for patients in hospital with covid-19 receiving supplemental oxygen.
Promising interim results from the trial, involving 300 patients, were reported in November. The latest analysis of just over 800 patients is published as a preprint on medRxiv and has not yet been peer reviewed.
The study included 353 patients assigned to tocilizumab, 48 to sarilumab, and 402 to standard care. Over 90% of patients were also treated with corticosteroids. The drugs are given as an hour long infusion. Most patients received a single infusion, with around 30% needing a second dose.
The results were based on a combined outcome measure of survival and the length of time patients needed organ support. Compared with standard care, the odds ratios were 1.64 (95% confidence interval 1.25 to 2.14) for tocilizumab and 1.76 (1.17 to 2.91) for sarilumab. Hospital mortality was 28% for tocilizumab and 22.2% for sarilumab, compared with 35.8% for the control group.
Steroids such as dexamethasone act as general anti-inflammatory agents, whereas tocilizumab and sarilumab block one specific receptor on the inflammatory pathway—interleukin 6.
The cost of treatment with either of the drugs is £750-£1000 (€830-€1105; $1020-$1360) per patient, substantially more than 10 days of treatment with the steroid dexamethasone, which would cost around £50. But Gordon pointed out that a day in intensive care costs between £1800 and £2000. “These drugs save lives and reduce the time spent in [intensive care] so are cost effective,” he told the briefing.
Previous studies on tocilizumab have produced mixed results, although they have included patients that were less severely ill. Gordon said: “Previous trials using IL-6 receptor antagonists 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.” He added: “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.”
The RECOVERY trial, which is also looking at tocilizumab, includes patients who are less sick and has not yet published results. Its chief investigator Martin Landray, from the University of Oxford, said that the REMAP-CAP results were good news. “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?” He said the RECOVERY trial should answer some of those questions.
Peter Horby, professor of emerging infectious diseases at the University of Oxford, said that the results give doctors more tools to fight covid-19. “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,” he said.
Deputy chief medical officer 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.”
The REMAP-CAP study is led by Imperial College London and the Intensive Care National Audit and Research Centre in the UK and University Medical Center in Utrecht. It is funded by the National Institute for Health Research in the UK and by the EU funded PREPARE consortium.
The REMAP-CAP trial is also evaluating the use of convalescent plasma for covid-19. A small randomised trial published in the New England Journal of Medicine, indicates that early treatment with convalescent plasma reduces the risk of progression to severe covid-19 by 48%.
Emergent (as yet not peer-reviewed) data from the immune modulation arm of the REMAPCAP trial indicate sizeable positive benefits with the use of tocilizumab or sarilumab in patients admitted to an intensive care unit (ICU). In the REMAP-CAP trial, mortality was reported as 35.8% in the placebo group, compared to 27% in the treatment group, an overall
reduction in the risk of death of 24%. The treatment also reduced the time patients spent in ICU by more than a week on average. Most patients (over 80%) under evaluation in the REMAP-CAP trial were also treated with a corticosteroid (Corticosteroid CAS Alert), so the effect is thought to be supplementary to those from corticosteroids.
This Interim Position Statement provides further information to clinicians considering prescribing tocilizumab or sarilumab when the internal governance arrangements (described above) are in place.
The eligibility and exclusion criteria for this Interim Position Statement have been drawn from those used in the REMAP-CAP trial and the Summary of Product Characteristics (SmPC) for tocilizumab and sarilumab.
Clinicians are encouraged to check the appropriate SmPC carefully.
Patients must meet all of the eligibility criteria and none of the exclusion criteria. Patients are eligible to be considered for tocilizumab or sarilumab if:
• Admitted to ICU with severe pneumonia requiring respiratory support1
, such as highflow nasal oxygen, continuous positive airway pressure (CPAP) or non-invasive
ventilation, or invasive mechanical ventilation; and
• COVID-19 infection is confirmed by microbiological testing or where a multidisciplinary
team has a high level of confidence that the clinical and radiological features suggest
that COVID-19 is the most likely diagnosis
Exclusion criteria (drawn from REMAP-CAP and/or intervention SmPC)
Tocilizumab or sarilumab should not be administered in the following circumstances:
• Known hypersensitivity to tocilizumab or sarilumab [REMAP-CAP and SmPC
• Co-existing infection that might be worsened by tocilizumab or sarilumab [SmPC contraindication]
• More than 24 hours has elapsed since ICU admission or more than 24 hours after starting respiratory support (whichever is the greater) [REMAP-CAP]
• A baseline alanine aminotransferase (ALT) or aspartate aminotransferase (AST) more than 5 times the upper limit of normal (caution is recommended if hepatic enzymes are more than 1.5 times the upper limit of normal)[REMAP-CAP and SmPC special warning and precautions for use]
• A baseline platelet count of less than 50 x 109 /L [REMAP-CAP and SmPC special warning and precautions for use]
• A baseline absolute neutrophil count of less than 2 x 109 /L [SmPC special warning and precautions for use]
• A pre-existing condition or treatment resulting in ongoing immunosuppression [SmPC special warning and precautions for use]
Pregnancy and women of childbearing potential
The REMAP-CAP trial excluded pregnant women, whereas the RECOVERY trial has included pregnant women. Please check the relevant SmPC for either tocilizumab or sarilumab. The SmPC for sarilumab and tocilizumab currently states: “Women of childbearing potential must use effective contraception during and up to 3 months after treatment.”
In relation to use in pregnancy, the SmPC for tocilizumab states there is no
adequate data for the use in pregnant women. In relation to use in pregnancy, the SmPC for sarilumab states there is limited data for the use in pregnant women. A study in animals has shown an increased risk of spontaneous abortion/embryo-foetal death at a high dose with
tocilizumab. Tocilizumab or sarilumab should not be used during pregnancy unless clinically necessary.