Critical Care, Critical Care Alert, COVID-19

Critical Care Alert: Tocilizumab in Patients Admitted to Hospital with COVID-19 (RECOVERY)

Critical Care Alert

ARTICLE
RECOVERY Collaborative Group, Horby PW, Pessoa-Amorim G, et al. Tocilizumab in Patients Admitted to Hospital with COVID-19 (RECOVERY): Preliminary Results of a Randomised, Controlled, Open-label, Platform Trial. Online ahead of print. Pending peer review.

OBJECTIVE
To evaluate the efficacy and safety of Tocilizumab in COVID-19 patients with both hypoxia and evidence of systemic inflammation

BACKGROUND
In 2020 the RECOVERY trial group in the United Kingdom found that the steroid dexamethasone reduces mortality in select patients with COVID-19 infection. To date, this remains the only regimen that demonstrates reduced mortality in a subset of COVID patients. Knowing the immunomodulatory effects steroids have on the immune system has led scientists to believe that other immunomodulators could be beneficial for patients infected with COVID-19

One such immunomodulator is tocilizumab. Tocilizumab is a monoclonal antibody that targets the interleukin-6 (IL-6) receptor and blocks IL-6 binding, resulting in a reduction of the systemic inflammatory response. Originally designed for use in rheumatoid arthritis, tocilizumab is being considered as a potential therapeutic agent to treat COVID-19. Data from the COVID-19 pandemic highlight the elevated levels of IL-6, and some scientists postulate that regulation of IL-6 activity will have positive downstream effects on the inflammatory cascade in this patient population. Numerous small trials of tocilizumab have shown mixed results, and a larger trial is needed to find a clear answer to its efficacy.

This paper reports the results of the largest study yet of tocilizumab and has been released pre-print. It has not gone through peer review and does not report full follow-up results of the study. Its results should be interpreted with caution.

DESIGN
Randomized, controlled, open-label trial of the drug Tocilizumab in patients across 131 hospitals in the UK.

The RECOVERY trial is a large platform trial organized in the UK to evaluate efficacy of various treatments against the COVID-19 pandemic and has conducted numerous studies of potential treatments over the past year.

POPULATION

Inclusion Criteria

  • Patients > 18 years old
  • Clinically suspected or laboratory-confirmed SARS-CoV-19 infection
  • Hypoxia (SpO2 <92% on room air)
  • Evidence of inflammatory response (CRP >75) within 21 days of enrolling in the RECOVERY trial

Exclusion Criteria

  • Hypersensitivity to Tocilizumab
  • Active TB, other fungal, viral, or bacterial infection
  • Other medical history the treating clinician thought would be harmed by Tocilizumab administration
  • Some RECOVERY hospitals did not have access to Tocilizumab and patients treated at those hospitals were excluded as well

INTERVENTION
It should be noted that the RECOVERY trial platform is evaluating multiple treatments at once. Randomization into the usual care vs. tocilizumab group was performed in patients who had already been randomized into another arm of the RECOVERY trial's initial randomization process, but who have demonstrated progressive disease. (Please see Figure 1 in the pending paper.)

A single infusion of Tocilizumab, dose determined by body weight:

  • >90 kg: 800 mg
  • 65-90 kg: 600 mg
  • 40-65 kg: 400 mg
  • <40 kg: 8 mg/kg

The dose could be repeated in 12-24 hours if the treating physician determined clinical condition had not improved.

CONTROL
Usual care

OUTCOMES
Primary outcome

  • 28 day all cause mortality

Secondary outcomes

  • Time to discharge alive from hospital
  • Progression to mechanical ventilation (including ECMO) or death, among those not yet receiving mechanical ventilation at randomization

KEY RESULTS
This paper reports the preliminary results of the study, with data up to February 8, 2021. At this time, 92% of randomized patients have primary outcome results available. A total of 4116 patients were randomized for the study.  At randomization, 45% of patients required only oxygen therapy, 41% required non-invasive ventilation, and 14% of patients required mechanical ventilation. Steroids had been administered to 82% of total patients at randomization and 97% of patients randomized after the results of the dexamethasone study were released.

Among patients with complete data available, 1333 (83%) of patients randomized to the treatment group and 44 (3%) of those randomized to control received tocilizumab. The primary outcome, 28-day mortality, occurred in 596 (29%) of tocilizumab patients and 694 (33%) of control patients (RR 0.86; 95% CI: 0.77-0.96, p=0.007), via an intention-to-treat analysis. Results were similar in an analysis of patients with laboratory-confirmed SARS-CoV-19. The secondary outcomes of discharge from the hospital alive in 28 days (54% vs 47%, RR 1.22, 95% CI: 1.12-1.34, p<0.0001) and reduction in progression to mechanical ventilation (33% vs 38%, RR 0.85, 95% CI: 0.78-0.93, p=0.0005) were also significant. The study found a larger effect of tocilizumab in patients who were also receiving steroids, but this was one of many secondary analyses. These results may be due to chance. (Please see Figure 2 in the pending paper.)

There were three serious adverse effects associated with Tocilizumab: one episode of otitis externa, one episode of Staph aureus bacteremia, and one lung abscess.

STRENGTHS

  • The RECOVERY trial group is well respected and rigorous in its methodology.
  • This is the largest trial to date of Tocilizumab, and includes three times the number of deaths as all the prior studies combined.
  • This study was conducted across a broad spectrum of hospitals in the UK.
  • The trial sponsor, Roche, supplied the drugs for the trial but had no input in analysis.

LIMITATIONS

  • This is a preprint, and has not yet undergone peer review.
  • This paper only reports preliminary results of the study and does not include full follow-up results.
  • This was an open label study.
  • Primary outcome data only available for 92% of patients
  • 17% of patients randomized to the treatment arm did not receive tocilizumab therapy (reasons for this were not recorded)
  • Hospital course for patients often is >28 days and therefore we do not yet have long-term outcomes

EM TAKE-AWAYS
This is the biggest trial to date on tocilizumab and is the first since the RECOVERY dexamethasone trial to show a treatment for COVID-19 that reduces mortality. The addition of a second mortality-reducing drug to our treatment regimen is an exciting prospect. Their secondary analysis (which must be interpreted with caution) suggests that the combination of steroids and Tocilizumab may reduce mortality in COVID-19 patients receiving oxygen by one-third and those receiving mechanical ventilation by one-half.

Only 83% of patients in the treatment arm received the drug, which the authors suggest underestimates the effect in an intention-to-treat analysis. This is true only if there is no bias in which patients randomized to the tocilizumab arm ended up receiving the drug. Due to the study's open-label nature, the drug may have been withheld from patients if their physicians were concerned it could be harmful to them. The combination of poor adherence to the randomization and the study's open-label design introduces a clear chance of bias that may have produced overly optimistic results. Overall, this paper does demonstrate a mortality benefit in patients who have hypoxia <<92% and a CRP 75mg/L.

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