BACC

Efficacy of Tocilizumab in Patients Hospitalized with COVID-19

Stone JH, for the BACC Bay Tocilizumab Trial Investigators. N Engl J Med 2020;383:2333-44. DOI: 10.1056/NEJMoa2028836

Clinical Question

  • In hospitalised patients with severe acute respiratory syndrome due to coronavirus 2 (SAR-CoV-2), does tocilizumab compared with placebo, reduce intubation rates or mortality?

Background

  • In December 2019 the Wuhan province in China became the epicentre of a devastating, highly contagious viral infection, SARS-CoV-2, a novel coronavirus that causes COVID-19 illness
  • By March 2020, the World Health Organisation announced they were deeply concerned by the alarming levels of spread and severity of the disease and characterised COVID-19 as a pandemic
  • To date, there are more than 74 million confirmed COVID-19 cases worldwide and 1.6 million deaths
  • There have been many trials conducted on patients with COVID-19, with the hope to find effective therapeutic options. To date, the treatments that have shown effectiveness are Dexamethasone, which reduces 28-day mortality and Remdesivir, which may reduce hospital length of stay.
  • Early observation in Chinese patients showed an association between high circulating levels of the pro-inflammatory cytokine IL-6 and progression to death and mechanical ventilation. Tocilizumab is an IL-6 receptor blocker
  • A retrospective, observational trial, STOP-COVID suggested a benefit to using tocilizumab, HR 0.71 for time to death. Several RCTs have not demonstrated a mortality benefit in patients receiving tocilizumab (EMPACTA, COVACTA, CORIMUNO-TOCI-1, RCT-TCZ-COVID-19)

Design

  • Randomised controlled trial
  • 2:1 randomisation to tocilizumab or placebo
  • Double-blinded
  • Random block size of 3 or 6
  • Stratification by site
  • Informed consent was obtained
  • With 243 patients the trial had a power of 80% to detect a reduction of death or the need for invasive mechanical ventilation from 30% to 15%
  • Modified intention to treat analysis – included all patients that were randomised and received either tocilizumab or placebo before intubation or death

Setting

  • 7 hospitals in Boston, MA, USA (Investigator initiated Boston Area COVID-19 Consortium: BACC)
  • The trial was funded by Genetech, who provided tocilizumab but had no role in the design or data analysis
  • Patients were enrolled between April 20 and June 15 2020: total number enrolled was 243 (161 received tocilizumab and 81 placebo)

Population

  • Inclusion: Age 19-85 AND confirmed SARS-CoV-2 AND 2 of: fever (>38C), pulmonary infiltrate, need for supplemental O2 to keep SaO2>92% AND 1 of CRP>50mg/L, Ferritin >500ng/ml, d-dimer>1000ng/ml or LDH > 250u/L
  • Exclusion: supplemental O2 >10L/min, recent treatment with biologic agents or immunosuppressive therapy, diverticulitis
  • Patients were well matched at baseline, except age > 65 years
    • Comparing tocilizumab vs placebo groups
      • Age >65 years: 37% vs. 27%
      • Nursed in non-intensive care ward and
        • not on oxygen: 14% vs. 18%
        • on oxygen: 83% vs. 74%
      • Receiving non-invasive ventilation of highflow oxygen: 3% vs. 6%
      • Mechanically ventilated: 0% vs. 1%
      • Received glucocorticoids: 11% vs. 6%

Intervention

  • Tocilizumab
    • A single dose of tocilizumab, 8mg/kg (not exceeding 800mg) and usual care

Control

  • Placebo

Management common to both groups

  • The trial was conducted after release of ACTT-1 trial, so some patients received remdesivir
  • The trial was conducted before the release of RECOVERY-dexamethasone, so no patients received dexamethasone

Outcome

  • Primary outcome: Hazard Ratio for intubation or death (time to event analysis) – no significant difference
    • Tocilizumab vs Placebo: HR 0.83 (95%CI 0.38-1.81) p=0.64
      • Rates of intubation or death by day 28: 10.6% vs. 12.5%
  • Secondary outcomes:
    • Comparing tocilizumab vs. placebo – no significant differences in
      • Clinical worsening at day 28
        • HR 1.11 (95%CI 0.59-2.10) p=0.73
      • Clinical improvement at Day 28 with discontinuation of supplemental O2
        • HR 0.94 (95%CI 0.67-1.3) p=0.69
      • Mortality at day 28
        • 5.6% vs. 3.8%, HR 1.52 (95% C.I. 0.41-5.61)
  • Safety:
    • Neutopenia more common in the Tocilizumab group (13.7% vs 1.2%)
    • Serious secondary infection more common in the placebo group (8.1% vs 17.1%)

Authors’ Conclusions

  • In this randomized, double-blind, placebo-controlled trial, we did not find any efficacy of IL-6 receptor blockade for the treatment of hospitalized patients with COVID-19

Strengths

  • Randomized, double-blinded
  • Allocation concealment
  • Complete follow-up
  • Ethnic diversity improves external validity

Weaknesses

  • Modified intention to treat analysis (although only 1 patient didn’t get analysed in the group they were allocated to and were included in the safety data
  • A small study that does not exclude benefit in all subgroups of patients with COVID-19 acute respiratory syndrome, eg severe COVID-19 pneumonitis
  • The primary event rate was much lower than the anticipated 30%. Despite this, there was still no signal to benefit for tocilizumab
  • The patients were not an ICU cohort at randomisation

The Bottom Line

  • The results of this small randomised trial are consistent with results of other small randomised trials of tocilizumab in patients with acute respiratory failure from SARS-CoV-2, that is, there is no benefit demonstrated
  • However, the patients in this trial were only moderately unwell and the wide confidence intervals do not exclude a treatment benefit in some patient groups, eg those with severe COVID-19 pneumonitis
  • I hold my judgement at this stage as to whether this trial’s results can be applied to ICU patients with severe COVID-19

External Links

Metadata

Summary author: Celia Bradford @celiabradford
Summary date: December 16 2020
Peer-review editor: @davidslessor

Image by Elliot Alderson from Pixabay

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