COVID therapy: Interleukin-6 receptor antagonists (tocilizumab or sarilumab)

This is part of the ongoing series of articles updating the evidence on current COVID-19 therapies. The rest of the series can be found here, and there is more to come. This article will cover the evidence for Interleukin-6 receptor antagonists (tocilizumab or sarilumab) in COVID-19.

This is a group of drugs that block the actions of interleukin-6 and therefore inflammatory pathways that rely on IL-6. Prior to COVID, tocilizumab was primarily used to treat cytokine release syndrome that occurs after CAR-T therapy for some lymphomas and leukemias. It has also been used to treat refractory rheumatoid arthritis. 

A philosophical interlude

If this is the first post in this series that you are reading, it might be worth reading the philosophical interlude from part 1 of the series which explains why my conclusions sometimes differ from those of the Ontario Science Table.

The Ontario Science Table recommendation

• Tocilizumab is recommended for critically ill patients with 14 days of hospital admission and receiving systemic steroids. (In cases of drug shortage, a second dose should not be given).
• Tocilizumab is recommended for moderately ill patients within 14 days of hospital admission, with CRP 75 or higher, and evidence of disease progression despite 24-48 hours of systemic corticosteroids.
• Sarilumab is an alternative option to tocilizumab lists in cases of drug shortages.

(Science table recommendations available here)

The WHO also gives a strong recommendation for IL-6 receptor blockers in severe or critically ill patients with COVID-19.

The evidence for monoclonal antibodies

There are at least 9 RCTs of tocilizumab, including about 6,000 patients. (Hermine 2020; Horby 2021; REMAP-CAP-2021; Rosas 2021; Salama 2021; Salvarani 2021; Stone 2020; Veiga 2021; Wang 2020) Unlike some of the other reviews, I am not going to go into detail on every study. This is mostly because I am not the one making decisions about tocilizumab where I work, and I imagine the situation is similar for most emergency physicians.Therefore, I don’t feel as compelled to spend my limited time doing a deep dive into all these papers. I am just going to highlight the key details of the most important studies.

The RECOVERY trial was an open label RCT. (RECOVERY 2021) The tocilizumab portion required patients to have hypoxia and a CRP >74. The comparison was standard of care. They enrolled 4116 patients. The primary outcome of all cause mortality was significantly lower with tocilizumab (31% vs 35%, RR 0.85, 95% CI 0.76-0.94). Obviously unblinded trials are problematic, but the primary outcome of all cause mortality limits the impacts of bias to some extent.

The REMAP-CAP study is another ongoing open label adaptive platform trial, which compared tocilizumab or sarilumab to standard care in 895 ICU patients. (REMAP-CAP 2021) The primary outcome was an ordinal scale assessing respiratory and cardiovascular organ support-free days, which is somewhat subjective and more problematic in an open label trial. Both tocilizumab and sarilumab were positive for the primary outcome, with about 10 ‘organ support free days’ compared to 0 in the control group. Mortality, ICU length of stay, and hospital length of stay were all also better with treatment.

The EMPACTA trial was a placebo controlled trial of 389 patients hospitalized but not receiving mechanical ventilation, comparing tocilizumab to placebo. (Salama 2021) The primary composite outcome of mechanical ventilation or death was significantly lower with tocilizumab (12% vs 19.3%, HR 0.56, 05% CI 0.33 to 0.97). However, this was entirely due to the mechanical ventilation part of the outcome. Mortality was actually a little higher with tocilizumab (10.4% vs 8.6%). 

The BACC Bay trial is a placebo controlled RCT in 243 moderately ill hospitalized patients with laboratory signs of inflammation, but excluding anyone requiring 10l/min or more of oxygen. (Stone 2020) The primary outcome of intubation (or death) was not statistically significant, but a little lower with tocilizumab (11% vs 13%). None of the secondary outcomes were statistically significant.

The COVACTA trial is a placebo controlled RCTof tocilizumab in hospitalized hypoxic COVID-19 patients. The primary outcome was an ordinal scale of ‘clinical status’ at 28 days. 

(Rosas 2021) The trial was not significantly significant for this outcome, nor were there significant changes in death or mechanical ventilation.

Meta-analysis

I will use some numbers from the Ontario Science Table meta-analysis to summarize this data.

• Tocilizumab reduces overall mortality (risk ratio is 0.90 95% CI 0.83 to 0.97)
• Tocilizumab decreases the progression to mechanical ventilation (RR 0.78 95% CI 0.68 to 0.90)

However, both of these outcomes are based almost entirely on the RECOVERY trial.

Comments

This data is stronger than for other agents, such as remdesivir. It is still not perfect, but there is a fairly consistent trend towards benefit, even though a number of trials were probably too small for definitive results. More of these trials were blinded than for other experimental COVID therapies. However, the meta-analysis is dominated by a single study (given about a 75% weight in most analyses), and that was the unblinded RECOVERY trial. So your confidence in the meta-analysis should really only be as good as your confidence in the RECOVERY trial (which really can’t be too high, given the unblinded design).

One key potential confounder in this data is the variance in concomitant treatment. In the earlier trials, in which patients were not routinely given steroids, the results look worse. In the later positive trials, patients were almost universally on systemic steroids. It is only a subgroup analysis, and so needs to be taken with a grain of salt, but it seems like a reasonable criterion for tocilizumab use for the time being.

A lot of these adaptive platform trials don’t have a set sample size, but instead check the data intermittently and stop at predefined statistical end points. When I was learning methodology, a very similar practice was called ‘p-hacking’. Checking data repeatedly increases the chance of false positives. These trials use some statistical tools to account for this intermittent checking, but it is not always well described, (and I may just not fully understand it). For a discussion on this topic by a statistician, see this twitter thread.

If COVID does become endemic, morbidity and mortality will likely (but but definitely) be different from what we have seen during the pandemic. Novel strains will probably also alter the efficacy of these drugs. We will need to study all COVID therapies again in the future to determine whether the efficacy is maintained as the face of the disease changes with time.

Bottom line

The evidence for interleukin-6 receptor antagonists is strong enough to warrant their use in sick inpatients. However, the unblinded nature of the biggest trials still leaves uncertainty, and follow-up blinded RCTs should be performed. 

Other FOAMed

Other First10EM COVID therapeutics updates can be found here

Ontario Science Table Recommendations

PulmCrit – RECOVERY confirms benefit of toci combined with dexamethasone

References

Hermine O, Mariette X, Tharaux P-L, 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 Med. 2020;181(1):32. https://doi.org/10.1001/jamainternmed.2020.6820

RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2021 May 1;397(10285):1637-1645. doi: 10.1016/S0140-6736(21)00676-0. PMID: 33933206

REMAP-CAP Investigators, Gordon AC, Mouncey PR, et al. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19. N Engl J Med. 2021. Published online February 25, 2021. https://doi.org/10.1056/NEJMoa2100433

Rosas IO, Brau N, Waters M, et al. Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia. N Engl J Med. 2021. Published online February 25, 2021. https://doi.org/10.1056/NEJMoa2028700

Salama C, Han J, Yau L, et al. Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia. N Engl J Med. 2021;384(1):20-30. https://doi.org/10.1056/NEJMoa2030340

Salvarani C, Dolci G, Massari M, et al. Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial. JAMA Intern Med. 2021;181(1):24. https://doi.org/10.1001/jamainternmed.2020.6615

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):2333-2344. https://doi.org/10.1056/NEJMoa2028836

Veiga VC, Prats JAGG, Farias DLC, et al. Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial. BMJ. 2021;372:n84. https://doi.org/10.1136/bmj.n84

Wang D, Fu B, Peng Z, et al. Tocilizumab Ameliorates the Hypoxia in COVID-19 Moderate Patients with Bilateral Pulmonary Lesions: A Randomized, Controlled, Open-Label, Multicenter Trial. Social Science Research Network; 2020. https://doi.org/10.2139/ssrn.3667681

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