Hot on the heels of a terrific pun and blog post about the use of Tocilizumab, capturing all the intrigue, hope and caution with the potential use of this novel therapeutic agent for patients with severe COVID-19 requiring critical care admission, comes this feebly entitled blog post. Maybe I am post nights. Maybe I have peaked pun wise. Either way, this one is less about the pun and more about the science……
We saw back in December that the REMAP-CAP investigators had seen a positive signal with this IL-6 antagonist in the sickest patients with COVID-19, when prescribed within a trial setting and strict inclusion criteria. This was great news, but the team rightly urged caution; several hundred other patients had also been recruited and were awaiting analysis. The RECOVERY trial was ongoing. Continued recruitment to REMAP was recommended and we all held on to our hats.
Our hats were then blown away on Friday when the REMAP-CAP team and the UK government fired an evidence-based carpet bomb in our direction. We saw a trial press release, a preprint article, an alert letter from the MHRA/DHSC, national media coverage and a government press release all within 24h of each other.1-4 We were delighted about the first 2 in rapid sequence – here at St Emlyns we have advocated for data transparency and information sharing throughout the pandemic and it was great to see the authors release the full preprint manuscript on this at the same time as the press release.4
We were less pleased about the latter 2 – this is a drug with a serious side effect profile and very strict prescribing conditions within the context of the research. There is a very real impact on families, patient conversations and individualised/autonomous prescribing from a government press release describing a new wonder drug, with no mention of adverse events. This is often difficult to unravel on the unit at 2am.
However, this is about the evidence, rather than our angst about knowledge dissemination. Let’s take a look at it.
What did they do?
This preprint reports results from the immune modulation therapy intervention domain of the international adaptive platform trial, REMAP-CAP. We have talked about this before -Bayesian adaptive trials appear to be all the rage at present and the REMAP-CAP website is excellent for giving a generalised overview as needed. This paper reports on the use of 2 open label interventions within this domain, tocilizumab and sarilumab, compared against control.
General inclusion criteria included adult patients >18 with suspected or confirmed COVID-19, admitted to a critical care environment and receiving respiratory or cardiovascular organ support. Domain specific exclusion criteria are interesting and included the following: >24h from ICU admission; known condition or treatment resulting in ongoing immune suppression including neutropenia; hypersensitivity; already received or already on immune modulatory therapy; pregnancy; liver enzymes more than 5* ULN; Platelet count <50; Treating clinician believes that participation in the domain would not be in the patients best interests. This last point is of particular relevance in regard to concomitant infections, which we will talk about shortly.
When eligible to participate and meeting appropriate consent procedures, patients were randomised via centralised computer system in a balanced ratio for those interventions available. Tocilizumab was given open label over 1 hour as an IV infusion at a dose of 8mg/kg ABW up to a max of 800mg. A second dose could be repeated at 12-24h at clinical discretion. Sarilumab was given as a once only 400mg infusion over 1 hour.
What were they looking for?
The primary outcome was a composite ordinal outcome focussed on respiratory and cardiovascular organ support-free days up to day 21. All deaths within hospital were assigned the worst outcome (-1). The higher the number, the more days without organ support, the better. It’s a little unclear how this reflects speed to step down or discharge home. The authors considered 1.5 days to be a minimal clinically important difference.
Secondary outcomes included the following: 90 day survival; respiratory support-free days; cardiovascular support-free days; Time to ICU discharge; time to hospital discharge; WHO scale at day 14; Progression to IMV, ECMO or death, restricted to those not intubated at baseline
The Bayesian design removes the need for a specific sample size and focuses more on regular interim analyses with predefined statistical triggers for superiority, equivalence and futility
What did they find?
895 patients were randomised within this domain overall, in 113 sites across 6 countries. 69 patients were randomised to other interventions, leaving 803 patients included within this final analysis, following 30 patients withdrawing consent and 11 patients having missing primary data.
Patients were well balanced on baseline characteristics and evenly spread regarding respiratory support, using HFNO (28.8%) NIV (41.5%) and invasive mechanical ventilation (29.4%). The majority of patients recruited received steroids in some form (690/803). The median duration of time in hospital prior to inclusion was 1.2 days (IQR 0.8 to 2.8). The median P/F ratio was 115mmHg (IQR 89 to 162). Extrapolating these figures from the available data, it would suggest an average FiO2 requirement >0.5 in order to maintain nationally recommended target saturations.
Vasopressor use was seen in <20% patients at baseline, median CRP was 150 (IQR 85 to 221) and median neutrophil count 8 (5.8 to 10.7). These figures potentially reflect a subgroup of COVID-19 patients with moderate to severe hypoxaemia who are free of additional infective complications (such as bacteraemia) at the point of CCU admission.
Compared with control, median adjusted odds ratios for increased organ support free days were 1.64 (95% CrI 1.25 to 2.14 for tocilizumab and 1.76 (95% CrI 1.17 to 2.91) for sarilumab. A pretty decent increase in odds with either IL-6 antagonist. Even more impressive, median adjusted odds ratios for hospital survival were 1.64 (95% CrI 1.14 to 2.35 for tocilizumab and 2.01 (95% CrI 1.18 to 4.71) for sarilumab. In old money, this data would equate to a 7.8% ARR and an NNT of 13 for tocilizumab, which would (we think) be statistically significant using Fishers exact test with a 2 tailed p value of 0.0278 (<0.05). Primitive, I know….
The IL-6 antagonists were effective across all secondary outcomes. In addition, there was no difference in reported adverse events between tocilizumab and control. Only 29% of patients received a second dose of tocilizumab and there is no data reporting on this group separately.
Are these results conclusive?
Well they are certainly alluring. This is a well conducted study in the right cohort and the authors have worked hard to ensure this agent is given to those they perceive are most likely to benefit. The results are clinically and statistically significant, whatever maths you use, and the adverse event profile appears negligible over short term follow up. This latter finding is mirrored by other studies looking at this agent.5-7
However, when you put everything together in a meta-analysis (as the RECOVERY team have done), you are left with this trial as a significant outlier and an estimate of clinical effectiveness that is still uncertain. In addition, the continuation of randomisation within the RECOVERY trial suggests that their recent DSMB review of almost 3000 patients (more than twice those recruited in any other study) did not see a clear signal of benefit.
Optimists will likely propose the reason for this as earlier recruitment of sicker patients in REMAP-CAP. Pessimists will say that science is about reproducible results and that any trial suggesting a large mortality benefit in critically ill patients is often too good to be true. Indeed, we have been burned by this before.8
Are there any concerns with this particular study?
I suppose the big one is that these data have not been peer reviewed at present. Pending this, my main challenge with the preprint and press release is assurance regarding the population studied. This was an open label trial and the subjective exclusion criteria allowed clinicians a degree of control over who was recruited. Both these issues introduce the possibility of selection bias, through the potential to exclude higher risk patients (those with suspected bacterial superinfection) and also through influence on clinical management decisions. In addition, other weaknesses of the trial have already been highlighted by others; we have no long term data on outcomes or recurrent infection and many of the trial participants remain in hospital at the time of reporting; almost 5% patients were lost to follow up or withdrew consent; very few patients received sarilumab (48) which makes it challenging to generalise results to this agent; finally, the number of organ support free days in survivors don’t actually seem to differ much between tocilizumab and control arms of the study, at 14 (IQR 7 to 17) and 13 (IQR 4 to 17) respectively. This makes the claims regarding significantly reduced ICU stay challenging to interpret in a real-world context
What should I do now?
Although the government press release and central alert has put clinicians in a challenging situation with regard to this medicine, the Intensive Care Society in the UK (via the recent rapid update) would suggest it is still reasonable to do one of 2 things;
- Offer patients ongoing research opportunity within the context of the RECOVERY trial, or the immune modulation domain of REMAP-CAP, on the basis of continuing uncertainty.
- Offer tocilizumab within the strict trial inclusion/exclusion criteria of REMAP-CAP on the basis that you and your colleagues have lost equipoise in this population. Ensure that patients and relatives are made aware that prescribing is off label and explain/document your rationale for use, in line with GMC guidance.
I agree and would add that personally, I think it will become increasingly hard to sit on your hands and wait for more evidence, if you are not randomising to one of the above. Patients and their relatives are very likely to start asking difficult questions.
Any other questions?
There are loads. What about patients on respiratory support units? What if someone has been on high flow nasal oxygen for a few days before ICU referral? Who should get a second dose and why? What blood tests and microbiological screens should we send prior to commencement of this drug? How long should we follow people up? What about pregnancy and patients of childbearing age? Is it safe to give this medication outside of ICU, such as in the ED? The number of outstanding questions I suspect may push some on the fence to more of a pessimistic position. However, we should acknowledge that there are always lots of questions following a positive trial result. This one is no different. The positive news here is that lots of further research has already been conducted, and we are simply awaiting publication.
And if I am still not sure?
Read the preprint. Watch the webinar. Read the central alert letter. Have a look at the summary of product characteristics for tocilizumab and acknowledge the issues that have been identified through use of this agent for other conditions. And then chat to your colleagues, pharmacists and general MDT about what you all think. A departmental consensus is always more defensible than a personal opinion, and unfortunately this is an area where we can all be asked difficult questions.
Although these are challenging times, these results are an excellent example of how the knowledge translation window is being absolutely stripped back. This can be a hugely positive thing, provided we continue to engage with the process and make rational decisions based on the evidence. Rather than what’s on the news. Even if it is the BBC.
Best wishes everyone
1. Bodkin H. Arthritis drugs that reduce risk of Covid death by 24 per cent to be given to ICU patients. The Telegraph 2021.
2. CMO. COVID-19 Therapeutic Alert: Interleukin-6 inhibitors (tocilizumab or sarilumab) for patients admitted to ICU with COVID-19 pneumonia (adults), 2021. https://www.cas.mhra.gov.uk/ViewandAcknowledgment/ViewAlert.aspx?AlertID=103134
3. DHSC. NHS patients to receive life-saving COVID-19 treatments that could cut hospital time by 10 days. Gov.uk, 2021.
4. Investigators TR-C. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19 – Preliminary report. medRxiv, 2021. https://www.medrxiv.org/content/10.1101/2021.01.07.21249390v1
5. Hermine O, Mariette X, Tharaux PL, et al. Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia: A Randomized Clinical Trial. JAMA Intern Med2021;181(1):32-40. doi: 10.1001/jamainternmed.2020.6820 [published Online First: 2020/10/21]
6. Salama C, Han J, Yau L, et al. Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia. N Engl J Med2021;384(1):20-30. doi: 10.1056/NEJMoa2030340 [published Online First: 2020/12/18]
7. Stone JH, Frigault MJ, Serling-Boyd NJ, et al. Efficacy of Tocilizumab in Patients Hospitalized with Covid-19. N Engl J Med 2020;383(24):2333-44. doi: 10.1056/NEJMoa2028836 [published Online First: 2020/10/22]
8. Ioannidis J. Why most published research findings are false. PLOS Medicine 2005 doi: https://doi.org/10.1371/journal.pmed.0020124
9. Dan Horner, “Tocilizumaybe? Immune modulation in COVID-19 @StEmlyns,” in St.Emlyn’s, December 4, 2020, https://www.stemlynsblog.org/tocilizumaybe-immune-modulation-in-covid-19-stemlyns/.