Tocilizimab effectively reduces COVID-19 related deaths and hospitalisation time: additive benefit with dexamethasone

Simon Collins, HIV i-Base

On 11 February 2021, the latest results from the UK RECOVERY study reported significant benefits from the IL-6 antagonist tocilizumab. These were in addition to those provided by dexamethasone showing the importance of combination therapy as a principal in the effective management of COVID-19. [1, 2]

Tocilizumab, a monoclonal antibody commonly used to treat arthritis, significantly reduced mortality in people hospitalised with severe COVID-19. Other benefits included significantly reduced the time in hospital before discharge and the need for oxygen.

The RECOVERY study is a randomised, open-label multi-arm platform study that has now enrolled more than 36,000 participants at 178 active sites. Since March 2020 various treatment arms have been stopped and added with some participants having dual randomisations. The initial randomisation originally included dexamethasone, hydroxychloroquine, lopinavir/r or azithromycin (with later options including colchicine or aspirin). However, participants with clinical progression up to 21 days after the initial randomisation (including oxygen saturation <92% or receiving oxygen therapy, and CRP >75 mg/L), were able to undergo a second randomisation that included to options that included tocilizumab (or convalescent plasma or REGN-COV2) – or to standard of care. All randomised options also depended on availability at the study site. [3]

Between 23 April 2020 and 24 January 2021, 4116 adults were randomised to tocilizumab (n=2022) or standard of care (n=2094). This represented 19% of the 21,550 participants in the 131 sites taking part in the tocilizumb study. Tocilizumab IV infusion varied by body weight (from 400 mg to 800 mg) with the option of a second infusion within 12-24 hours if there was no immediate improvement.

At baseline, 14% participants were receiving invasive mechanical ventilation, 41% receiving non-invasive respiratory support, and 45% only received oxygen. Dexamethasone or another systemic steroid was widely used by 82% (and 97% since announcement of dexamethasone benefit).

For the primary endpoint of all-cause mortality within 28 days of randomisation (to tocilizumab), available for 92% of participants, there were 596 (29%) vs 694 (33%) deaths in the tocilizumab vs standard of care groups respectively. The absolute difference of 4% produced a rate ratio of 0.86 (95%CI: 0.77 to 0.96), p=0.007 and NNT of 25 (Number Needed to Treat to prevent one death).

Among those not receiving invasive mechanical ventilation at baseline, tocilizumab significantly reduced the composite endpoint of progression to ventilation or death: 33% vs 38%: RR 0.85 (95%CI: 0.78 to 0.93), p=0·0005.

The three serious tocilizumab-related AEs (otitis externa, Staphylococcus aureus bacteraemia and lung abscess) all resolved with standard treatment.

The discussion notes the benefits of tocilizumab in the recent REMAP-CAP study but also that contradictory results were reported in smaller studies.  Overall mortality from eight studies, including RECOVERY, results in a 13% proportional reduction in 28-day mortality (death rate ratio 0.87, 95% CI: 0.79 to 0.96), p=0·005. These benefits are in addition to those from dexamethasone which for most participants in RECOVERY was standard of care when requiring oxygen.

Benefits were seen in all patient subgroups, including by COVID-19 severity at baseline.

However, in a prespecified analysis, tocilizumab had no impact on future use of non-invasive or mechanical oxygen, or in stopping invasive oxygen in those using this at baseline.

Although this analysis was not directly addressed in the paper, the press release from RECOVERY stated that in participants with significant inflammation, the additive benefits of tocilizumab plus dexamethasone reduced mortality by one-third for those using simple oxygen and by half for those on mechanical ventilation.

These dramatic reductions are in a subset of the most severely ill participants and are not reflected in the overall mortality which was 29% vs 33% in the tocilizumab vs standard of care groups respectively.

Full results are expected in early March after >99% of participants will have reached the 28-day endpoint.

comment

Positive results are always good news and the size of RECOVERY and it’s randomised design supports the immediate access to tocilizumab in the UK that was announced last month after the results of the REMAP-CAP study. REMAP-CAP was able to report significant benefits from a much smaller study.

Although the benefits from these results will have a huge impact on future standards of care, this is thanks to the many thousands of participants in the RECOVERY who were not lucky enough to be randomised to an active arm. So far, direct interventions in the this study have only reduced mortality for about several hundred participants, questioning whether closer monitoring and/or more sensitive stop/go thresholds might stop non-performing arms earlier.

Last month the convalescent plasma arm of RECOVERY was stopped due to lack of benefit. The limited results in the press release reported 1873 deaths among 10,406 randomised participants: 18% in both the active and control arms, with a risk ratio of 1.04 (95%CI: 0.95 to 1.14), p=0.34. [4]

The pre-review paper has not yet been posted for this arm of RECOVERY so it is also unclear whether high-titre plasma might have produced more positive results. [5]

Reference

1. RECOVERY Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): preliminary results of a randomised, controlled, open-label, platform trial. MedRxiv pre-review. doi: 10.1101/2021.02.11.21249258. (11 February 2021).
   https://www.medrxiv.org/content/10.1101/2021.02.11.21249258v1 (html)
   https://www.medrxiv.org/content/10.1101/2021.02.11.21249258v1.full.pdf (PDF)
2. RECOVERY press release. Tocilizumab reduces deaths in patients hospitalised with COVID-19. (11 February 2021).
   https://www.recoverytrial.net/news/tocilizumab-reduces-deaths-in-patients-hospitalised-with-covid-19
3. Randomised Evaluation of COVID-19 Therapy (RECOVERY) study. clinicaltrials.gov (NCT04381936).
   https://www.recoverytrial.net
4. RECOVERY press release. RECOVERY trial closes recruitment to convalescent plasma treatment for patients hospitalised with COVID-19. (15 January 2021).
   https://www.recoverytrial.net/news/statement-from-the-recovery-trial-chief-investigators-15-january-2021-recovery-trial-closes-recruitment-to-convalescent-plasma-treatment-for-patients-hospitalised-with-covid-19
5. US FDA specifies high antibody titre for convalescent plasma and to only use in early COVID-19. HTB (6 February 2021).
   https://i-base.info/htb/39892

This report was first published on 14 February 2021.