I am sure many of you saw the breaking news on the BBC the other week, about a new wonderdrug to strengthen our defences against the tidal wave that is COVID19. This follows a press release from an international adaptive platform trial (REMAP-CAP) which reports a favourable outcome with Tocilizumab in severe cases. Good news? Maybe. However, before we celebrate in earnest we should probably practice what we preach and take a good look at this new evidence, the implications, ramifications and considerations. (1) We wouldn’t want to start a riot over an expensive placebo…
What the hell is Tocilizumab?
I asked myself the same question 9 months ago…. TCZ is a humanised monoclonal antibody which antagonises IL-6. What is IL-6? Well, it’s a cytokine which acts in a variety of ways (pleiotropic) on T cells, B cells, monocytes and fibroblasts to produce a pro-inflammatory state. It is also responsible for perhaps the highest quality academic pun I have seen to date as yet, although I am sure others will have their own personal favourites.
Tocilizumab has been licensed for use in rheumatoid arthritis and other conditions since 2010 so we already have some insight into side effects and extended use. It is also off patent of course, and therefore not outlandishly expensive, but not particularly cheap either (£500-1000).
Yes, but hear us out. There is a potential rationale for using Tocilizumab in acute illness, which appears to be mainly based on the prevention of cytokine storm. (2) More here from this excellent recent review of cytokine storm in the NEJM. (3) However, there is debate about the contribution of this to severe illness in COVID19 and also whether IL-6 represents a therapeutic target or part of a functioning adaptive immune response. For instance, some authors have recently reported an immune signature involving IL-6 which can potentially anticipate disease progression. (4) Others caution that IL-6 levels are not actually that high in COVID-19 compared to other oncological cytokine storm conditions, and raise concerns about secondary infections from immunomodulation. (5) Either way, the drug is of interest and has joined others in rapid progression to the clinical trial domain
Does it work in COVID-19?
Well, I am not sure we have the answer yet. The most positive evidence to date comes in the form of the aforementioned press release from the REMAP-CAP team. They report an interim analysis on 303 patients conducted by their DSMB stating that TCZ met the trigger for efficacy (when compared to no immune modulation) with an Odds ratio of 1.87 and a poster probability of superiority at 99.75% (see our previous post for some discussions of prior/posterior probability and Baysian analysis). What does this mean? It means that an early look at the data suggests the odds of a favourable composite outcome (including survival and duration of organ support) on an ordinal scale in patients on the ICU with COVID19 were significantly improved if they got Tocilizumab, compared to no immune modulation. In context, this is a bigger OR than that seen within the same study looking at the effect of steroids (OR 1.43). Interesting stuff.
Of note, REMAP-CAP only recruits COVID-19 patients who require intensive care and organ support, so these findings (if confirmed) may not be generalizable outside the ICU. In addition, it is unclear how many of these patients received dexamethasone, with the investigators reporting that patients were recruited into this study prior to routine use of steroids, and afterwards. We also don’t know anything yet about adverse events, protocol deviations or the individual components of the composite outcome.
What about other evidence?
There is a fair bit on this topic giving fairly conflicting results, which is always interesting. A paper published in the Lancet Rheumatology in October reported on 210 patients receiving Tocilizumab, within an observational cohort of 764 patients with severe COVID 19 requiring ICU care. (6) This was not a randomised trial and only reports off label use of Tocilizumab, but a cox regression analysis with propensity score matching suggested a reduced risk of hospital related mortality with Tocilizumab (HR 0.64, 95% CI 0.47 to 0.87, p=0.0040). Around this time, we also saw a press release regarding the commercial EMPACTA trial conducted by Roche, suggesting that Tocilizumab could significantly reduce the risk of mechanical ventilation or death in patients with COVID-19 pneumonia (HR 0.56, 95% CI 0.32 to 0.97). Hold the phone.
These findings were followed up by the BACC study, a randomised controlled trial of 243 patients published in the NEJM and reporting no benefit from Tocilizumab in moderately ill (any 2 of fever, pulmonary infiltrates or oxygen use, with biochemical evidence of inflammatory response) hospitalised patients with COVID -19. (7) No ICU patients in this one (exclusions included oxygen use >10L/min) but interesting to see none the less. Another press release from Roche, and the COVACTA results rained on the parade as well; no improvement in clinical status in patients with COVID-19 associated pneumonia who were randomised to Tocilizumab within this double blind placebo controlled trial.
All of this (with a little more besides) is collated beautifully in a forest plot produced by the RECOVERY chief investigators, which highlights that the published data so far actually crosses the line of no significance overall and trends towards harm.
What about side effects/adverse events?
There are a fair few with this immune modulation agent, which perhaps raise the bar of the evidence we would need to see prior to routinely prescribing. Neutropenia, thrombocytopenia, drug induced hepatitis, infections, hypersensitivity reactions. There are also some issues around reduced utility of biomarkers following administration – CRP and procalcitonin may be less helpful to detect superadded infection for example.
Right then. Should I be offering this to my patients?
Not routinely, I would suggest. This is a viewpoint shared by the RECOVERY trial team as above and the chief investigator for the UK, who cautioned against adoption into practice too early during a very good recent webinar. Others have urged caution also, including the UK Faculty of Intensive Care Medicine. Hundreds of additional patients have been randomised within REMAP and RECOVERY since this interim analysis and it is important to look at all the evidence within this project, including follow up data. For now, I think most of us will keep offering the opportunity to participate in trials which include immune modulators and try to avoid jumping the gun based on a single press release regarding an interim analysis, no matter how tempting. ‘Don’t do a Donald’, as we are starting to say within the scientific world….
What should I say if families ask why their relative is not on it?
You should say what you have always said when asked about an experimental therapy by a family member.
All drugs have side effects, interactions and opportunity costs. This drug is a potent immunosuppressant; as such if we give it to your relative there are risks it could worsen things, rather than improve them. We also don’t have enough evidence to be sure that it helps, despite the promising early data. All our patients have access to new drugs through participation in the research studies we are conducting. These studies have clear safety protocols about when we should give it, how we should monitor things and when we should stop it. As such, the safest way to have access to this drug is within a research context. We will continue to offer research opportunity to your relative whenever they meet the criteria for inclusion in a study and when we can safely deliver this.
Not really. Good to have some good news, but let’s be sensible and hopeful about it. Pandemics are not solved by press releases.
Happy December everyone I hope your trees are up and your lights are glowing .
- Carley S, Horner D, Body R, et al. Evidence-based medicine and COVID-19: what to believe and when to change. Emergency Medicine Journal 2020;37:572-575.
- Cortegiani et al. Rationale and evidence of the use of tocilizumab in COVID-19: a systematic review. Pulmonology 2020; article in press
- Fajgenbaum and June. Cytokine Storm. N Engl J Med 2020; 383:2255-2273
- Laing, A.G., Lorenc, A., del Molino del Barrio, I. et al. A dynamic COVID-19 immune signature includes associations with poor prognosis. Nat Med 2020 26, 1623–1635
- Hedrick et al. COVID-19: Clean up on IL-6. American Journal of Respiratory Cell and Molecular Biology 2020; 63(4): 541-3
- Biran et al. Tocilizumab among patients with COVID-19 in the intensive care unit: a multicentre observational study. Lancet Rheumatology 2020; 2(10):E603-E612
- Stone et al. Efficacy of Tocilizumab in Patients Hospitalized with Covid-19. N Engl J Med 2020; Online first
- Simon Carley, “Covid19: Why we need Evidence Based Medicine (EBM) more than ever during a pandemic. St Emlyn’s,” in St.Emlyn’s, April 11, 2020, https://www.stemlynsblog.org/covid19-why-we-need-evidence-based-medicine-ebm-more-than-ever-in-a-pandemic-st-emlyns/.
- REMAP-CAP https://www.remapcap.org/
- Covid-19: Critically ill patients treated with arthritis drug tocilizumab show improved outcomes, researchers report BMJ 2020;371:m4530
- Tocilizumab in the RECOVERY trial https://www.recoverytrial.net/files/recovery_lettertoinvestigators_tocilizumab_2020-11-27_final.pdf
- expert reaction to REMAP-CAP trial reporting that critically ill COVID-19 patients treated with tocilizumab are more likely to have improved outcomes https://www.sciencemediacentre.org/expert-reaction-to-remap-cap-trial-reporting-that-critically-ill-covid-19-patients-treated-with-tocilizumab-are-more-likely-to-have-improved-outcomes/
- Clarification on the use of Tociluzimab for critically ill patients with COVID-19 https://www.ficm.ac.uk/news-events-education/news/clarification-use-tociluzimab-critically-ill-patients-covid-19