Efficacy of Early Administration of Tocilizumab in COVID-19 Patients - RCT-TCZ-COVID-19

Contribution To Literature:

Among patients with COVID-19 pneumonia not requiring ICU care in the RCT-TCZ-COVID-19 trial, early administration of intravenous tocilizumab did not improve clinical outcomes by day 14.

Description:

The goal of the trial was to assess the safety and efficacy of tocilizumab given early to patients with coronavirus disease 2019 (COVID-19) pneumonia. 

Study Design

Patients were randomized in a 1:1 fashion to either tocilizumab (n = 60) or usual care (n = 66). Usual care (antibiotic agents, antiviral agents, corticosteroids, vasopressor support, anticoagulants) was provided at the discretion of the clinicians. Tocilizumab was administered intravenously (IV) within 8 hours from randomization at a dose of 8 mg/kg up to a maximum of 800 mg, followed by a second dose after 12 hours. Patients in the control arm received supportive care following the treatment protocols of each center.

  • Total number of enrollees: 126
  • Duration of follow-up: 14 days
  • Median patient age: 60 years
  • Percentage female: 39%

Inclusion criteria:

  • Confirmed severe acute respiratory syndrome coronavirus 2 infection
  • Age ≥18 years
  • Presence of acute respiratory failure with a partial pressure of arterial oxygen to fraction of inspired oxygen (PaO2/FiO2) ratio between 200 and 300 mm Hg
  • An inflammatory phenotype defined by a temperature >38°C (>100.4°F) during the last 2 days, and/or serum C-reactive protein (CRP) levels of  ≥10 mg/dl and/or CRP level increased to at least twice the admission measurement

Exclusion criteria:

  • Intensive care unit (ICU) admission
  • Known hypersensitivity to tocilizumab
  • Any condition preventing future admission to ICU

Other salient features/characteristics:

  • Time from symptom onset to randomization: 8 days
  • CRP 5.2 mg/dl
  • PaO2/FiO2 ratio: 264.5
  • Hydroxychloroquine: 91.3%

Principal Findings:

The primary outcome, clinical worsening (admission to ICU with mechanical ventilation, all-cause mortality, PaO2/FIO2 ratio <150 mm Hg) within 14 days, for tocilizumab vs. control, was 28.3% vs. 27.0%, rate ratio 1.05, 95% confidence interval 0.59-1.86 (p = 0.87). Admission to ICU was 10% for tocilizumab vs. 7.9% for control.

Secondary outcomes for tocilizumab vs. control:

  • All-cause mortality: 3.3% vs. 1.6%
  • Any adverse events:  23.3% vs. 11.1%
  • Infections and infestations: 1.7% vs. 6.3%

Interpretation:

The results of this trial indicate that among patients with COVID-19 pneumonia not requiring ICU care, early administration of IV tocilizumab did not improve clinical outcomes by day 14. No difference on mortality at 30 days was noted either. Rates of secondary infections were not higher in the tocilizumab arm.

Longer-term data are awaited. This trial is small but adds to the overall literature on therapeutic options for COVID-19 management. Tocilizumab is an anti–human interleukin-6 receptor (IL-6R) mono-clonal antibody that inhibits IL-6 signaling by binding soluble IL-6R and membrane IL-6R and is approved for rheumatoid arthritis, juvenile inflammatory arthritis, and refractory giant cell arteritis.

References:

Salvarani C, Dolci G, Massari M, et al., on behalf of the RCT-TCZ-COVID-19 Study Group. Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial. JAMA Intern Med 2020;Oct 20:[Epub ahead of print].

Clinical Topics: Anticoagulation Management, Prevention, Novel Agents, Statins

Keywords: Anti-Bacterial Agents, Anticoagulants, Antiviral Agents, Coronavirus, COVID-19, C-Reactive Protein, Hydroxychloroquine, Pneumonia, Primary Prevention, Receptors, Interleukin-6, Respiration, Artificial, severe acute respiratory syndrome coronavirus 2, Vasoconstrictor Agents


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