Tocilizumab Flashcards
Findings in Recovery Trial
The Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial has demonstrated that an anti-inflammatory treatment, tocilizumab, reduces the risk of death when given to hospitalised patients with severe COVID-19. The study also showed that tocilizumab shortens the time until patients are successfully discharged from hospital and reduces the need for a mechanical ventilator. The RECOVERY trial has been testing a range of potential treatments for COVID-19 since March 2020. Tocilizumab, an intravenous drug used to treat rheumatoid arthritis, was added to the trial in April 2020 for patients with COVID-19 who required oxygen and had evidence of inflammation. Recruitment to the tocilizumab arm stopped on 24 January 2021 since, in the view of the trial Steering Committee, sufficient patients had been enrolled to establish whether or not the drug had a meaningful benefit. A total of 2022 patients were randomly allocated to receive tocilizumab by intravenous infusion and were compared with 2094 patients randomly allocated to usual care alone. 82% of patients were taking a systemic steroid such as dexamethasone. Treatment with tocilizumab significantly reduced deaths: 596 (29%) of the patients in the tocilizumab group died within 28 days compared with 694 (33%) patients in the usual care group (rate ratio 0·86; [95% confidence interval [CI] 0·77 to 0·96]; p=0·007), an absolute difference of 4%. This means that for every 25 patients treated with tocilizumab, one additional life would be saved. Tocilizumab also increased the probability of discharge alive within 28 days from 47% to 54% (rate ratio 1·23, [95% CI 1·12 to 1·34], p<0·0001). These benefits were seen in all patient subgroups, including those requiring oxygen via a simple face mask through to those requiring mechanical ventilators in an intensive care unit. Among patients not on invasive mechanical ventilation when entered into the trial, tocilizumab significantly reduced the chance of progressing to invasive mechanical ventilation or death from 38% to 33% (risk ratio 0·85, [95% CI 0·78 to 0·93], p=0·0005). However, there was no evidence that tocilizumab had any effect on the chance of successful cessation of invasive mechanical ventilation.
Study methods
Oxygen saturations less than 92% or on oxygen CRP > 74 400mg or 800 mg depending on weight A second dose at 12 to 24 hours later if not improved Primary endpoint was mortality at 28 days using ITT population
Australian Commentary
Consider using tocilizumab for the treatment of COVID-19 in adults who require supplemental oxygen, particularly where there is evidence of systemic inflammation. In patients hospitalised with COVID-19 who require supplemental oxygen, tocilizumab probably reduces the risk of death. Because of this, the Taskforce gives a conditional recommendation for tocilizumab both within and outside the context of a randomised trial unless contraindicated (e.g. patients with other active, severe infections). In accordance with the RECOVERY trial, tocilizumab should be administered as a single intravenous infusion over 60 minutes, with the potential for a second dose to be administered either 12 or 24 hours later if the patient’s condition has not improved. The suggested dose is dependent on body weight: Patients > 90 kg: 800 mg tocilizumab Patients 66–90 kg: 600 mg tocilizumab Patients 41–65 kg: 400 mg tocilizumab Patients ≤ 40 kg: 8 mg/kg tocilizumab In addition, the RECOVERY and REMAP-CAP trials have demonstrated a significant benefit when using corticosteroids in conjunction with tocilizumab. Use of combined tocilizumab and corticosteroids should be considered in patients hospitalised with COVID-19 who require oxygen, however the optimal sequencing of tocilizumab and corticosteroid use is unclear. As tocilizumab inhibits the production of C-reactive protein (CRP), a reduction in CRP should not be used as a marker of clinical improvement.
Lancet Volume 397, ISSUE 10285, P1637-1645, May 01, 2021 Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
Summary
Background
In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation.
Methods
This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient’s condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936).
Findings
Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001).
Interpretation
In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids.
