In arguably the most important therapeutic news of the pandemic since Dexamethasone, the RECOVERY trial investigators have revealed the initial results on the Tocilizumab arm of the trial showing a significant benefit. This short blog is just the headlines. We will follow up with a more in depth analysis in the next few days/weeks (with Dan Horner).
The press release was announced today, followed shortly after by the preprint version. We await the full peer reviewed article.
We have covered RECOVERY several times already. As you may know it has already shown the following.
- Dexamethasone saves lives in patients requiring oxygen or ventilatory support
- Hydroxychloroquine does not work in hospitalised patients
- Azithromycin does not work in hospitalised patients
- Lopinavir/Ritonavir does not work in hospitalised patients
- Convalescent plasma does not work in hospitalised patients
The trial is still recruiting to the following arms of the trial
- Monoclonal antibodies
What are the latest results?
Tocilizumab recruitment stopped a few weeks ago as we had reached the target number of participants. In the RECOVERY trial patients were eligible for a second randomisation to the Tocilizumab arm if they met the following criteria.
- Hospitalised patient with proven or highly likely COVID disease
- Randomised into the RECOVERY trial no more than 21 days ago
- Clinical evidence of progressive COVID-19:
- a. oxygen saturation <92% on room air or requiring oxygen; and
- b. C-reactiveprotein≥75mg/L
- No medical history that might, in the opinion of the attending clinician, put the patient at significant risk if he/she were to participate in this aspect of the RECOVERY trial. (Note: Pregnancy and breastfeeding are not specific exclusion criterion.)
Participants could undergo this second randomisation at any point after being first randomised, provided they meet the above criteria, and thus may receive up to two study treatments. For some participants the second randomisation may be immediately after the first but for others it may occur a few hours or days later, if and when they deteriorate.
The verbatim results via press release today are as follows.
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.
In June 2020, the RECOVERY trial found that the inexpensive and widely available steroid dexamethasone reduces death for patients with severe COVID-19. This rapidly became part of standard-of-care given to all such patients. The benefits of tocilizumab were clearly seen to be in addition to those of steroids.
The data suggest that in COVID-19 patients with hypoxia (requiring oxygen) and significant inflammation, treatment with the combination of a systemic corticosteroid (such as dexamethasone) plus tocilizumab reduces mortality by about one third for patients requiring simple oxygen and nearly one half for those requiring invasive mechanical ventilation.
At the moment we don’t have the full paper, or even a pre-print and so we must be very cautious about interpreting the press release. However, we do know the trial well as we have seen the methods already and there are already several publications from the study in the public domain.
This result fits with how many of us see the disease process. RECOVERY has shown that anti-virals seem to have little or no effect in hospitalised patients. What matters and what seems to kill patients is the immune response and so immune modulation has potential to save lives. This is what we have seen with Dexamethasone and now with Tocilizumab. It should also be noted that following the REMAP-CAP results, Tocilizumab has become a common treatement for ICU patients within 24 hours of admission. This result will no doubt extend that indication.
Also important to note the benefits of Tocilizumab are describe as being on top of those we see from Dexamethasone.
Going forward it will be fascinating to see how clinicians cope with using this quite powerful IL-6 inhibitor together with its associated complications. In addition we are now randomising to Baricitinib (a JAK-2 inhibitor) and thus we have the potential for patients to receive multiple immunosuppressives. The consequences of this cannot be assumed and we will need more data to see how these might interact (Tocilizumab use is currently a contraindication for randomising to Baricitinib). Anecdotally my ICU colleagues tell me that they are seeing some pretty nasty bacterial infections in COVID patients who have received immunosuppressives.
This is incredibly welcome news. Tocilizumab is only the second drug to show a mortality benefit in this terrible disease. It’s fantastic scientific progress but there is still much work to do, so please do keep recruiting to RECOVERY.
A huge thanks to every patient, doctor, nurse, pharmacist, triallist, family member and more who have supported recruitment to clinical trials for COVID19. You’ve all helped make a difference.
Simon Carley and Dan Horner
@EMManchester and @RCEMProf
- Horby et al. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): preliminary results of a randomised, controlled, open-label, platform trial https://www.medrxiv.org/content/10.1101/2021.02.11.21249258v1
- The NIHR-supported RECOVERY trial has found no clinical benefit from the antibiotic azithromycin for hospitalised patients with severe COVID-19. https://www.nihr.ac.uk/news/recovery-trial-shows-no-clinical-benefit-from-azithromycin-for-hospitalised-patients/26401
- Dexamethasone, COVID-19 and the RECOVERY trial. St Emlyn’s https://www.stemlynsblog.org/dexamethasone-covid-19-and-the-recovery-trial-st-emlyns/
- The RECOVERY platform trial: No benefit to Hydroxychloroquine in Covid-19. St Emlyn’s https://www.stemlynsblog.org/the-recovery-platform-trial-no-benefit-to-hydroxychloroquine-in-covid-19-st-emlyns/
- RECOVERY trial https://www.recoverytrial.net/
- thomas shanahan, “JC: Azithromycin in patients hospitalised with COVID-19,” in St.Emlyn’s, December 20, 2020, https://www.stemlynsblog.org/jc-azithromycin-in-patients-hospitalised-with-covid-19/.
- Simon Carley, “JC: Convalescent plasma in COVID 19 patients.,” in St.Emlyn’s, November 21, 2020, https://www.stemlynsblog.org/jc-convalescent-plasma-in-covid-19-patients/.
- Simon Carley, “JC: Hydroxychloroquine in the the treatment of hospitalised COVID19 patients.,” in St.Emlyn’s, October 10, 2020, https://www.stemlynsblog.org/jc-hydroxychloroquine-in-the-the-treatment-of-hospitalised-covid19-patients/.