BACC

24 December 2020 Celia Bradford Intensive Care Medicine Leave a comment

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