We’ve reported on the RECOVERY trial several times already on the blog. It stands out as the most important trial of therapeutics in hospitalised patients with COVID19. In the last month the RECOVERY trial has released the result that monoclonal REGN antibodies are effective for a subgroup of hospitalised patients with COVID-19 . We await the peer reviewed paper, but we are already very familiar with the trial and it’s processes having reported the results on the blog already. We are therefore pretty confident about the methodology.
To briefly summarise the trial so far
Eligibility: Hospitalised patients with COVID19.
Principle Outcome: 28 day mortality
- Drugs shown to work
- Dexamethasone
- Tocilizumab
- REGN monoclonal antibodies in patients with low levels of their own antibodies at admission.
- Drugs shown to have no benefit
- Drugs still being randomised
- Baricitinib
- Dimethyl Fumarate
- High-dose corticosteroids and infliximab
In the REGN arm of the trial there were 9785 patients randomised between REGN and usual care with 4839 randomised to the REGN arm
To quote the RECOVERY team
Between 18 September 2020 and 22 May 2021, 9785 patients hospitalised with COVID-19 were randomly allocated to receive usual care plus the antibody combination treatment (casirivimab 4g with imdevimab 4g by intravenous infusion) or usual care alone as part of the RECOVERY trial. Of these, about one-third were seronegative at baseline (ie they had not mounted a natural antibody response of their own), one-half were seropositive (ie they had already developed natural antibodies), and one-sixth had unknown serostatus. Among patients who received usual care alone, 28-day mortality was twice as high in those who were seronegative (30%) vs. those who were seropositive (15%) at study entry.
RECOVERY TRIAL TEAM
In terms of the results then the trial has reported the following through press release on the main trial website. As always we need to be cautious about interpreting data based on a press release, but as we have previously seen the trial methodology in a number of previous publications we are confident that the trial is well designed and delivered.
Among patients who were seronegative at baseline (the primary analysis population for this comparison), the (REGN) antibody combination significantly reduced the primary outcome of 28-day mortality by one-fifth compared with usual care alone (24% of patients in the antibody combination group died vs 30% of patients in the usual care group; rate ratio 0·80; 95% confidence interval 0·70–0·91; p=0·001). Thus, for every 100 such patients treated with the antibody combination, there would be six fewer deaths.
There was clear evidence that the effect of treatment in seronegative patients differed from that in seropositive patients (test for heterogeneity p=0·001). When combining the larger seropositive group (as well as those with unknown status) with the seronegative patients, there was no longer a significant effect on 28-day mortality (overall 20% of patients in the antibody combination group died vs 21% of patients in the usual care group; rate ratio 0·96; 95% confidence interval 0·86–1·03; p=0·17).
For the seronegative patients, the duration of hospital stay was four days shorter (median 13 days vs. 17 days) among those allocated to the antibody combination than the usual care group, and the proportion of patients discharged alive by day 28 was greater (64% vs. 58%; rate ratio 1·19, 95% confidence interval 1·08 to 1·30). Among the seronegative patients not on invasive mechanical ventilation at baseline, the risk of progressing to the composite endpoint of invasive mechanical ventilation or death was lower among those allocated to the antibody combination than the usual care group (30% vs. 37%; risk ratio 0·83, 95% confidence interval 0·75 to 0·92). No such benefits were seen in the overall study population (combining patients with negative, positive, or unknown serostatus).
RECOVERY TRIAL TEAM
So the findings suggest a significant benefit from REGN in terms of the primary outcome of mortality for patients who have low levels of their own antibodies at the time of admission. This was an unexpected result for me as I’ve usually considered the REGN antibodies to be an antiviral action as opposed to immunomodulatory and thus far it is the immunomodulatory drugs that have shown mortality benefit, whereas the large number of antiviral drugs tested has shown little impact (Remdesivir changes illness duration but not mortality).
The finding that a lack of the patient’s own antibodies at the time of randomisation was associated with adverse outcomes was seen back in March (see tweet below) in the results of the convalescent plasma arm of RECOVERY. I’m not sure I understand the mechanism of why this would then be more likely to lead to higher death rates, but it is clear that the host response/infection interaction is complex and at the heart of why people go on to develop the pneumonitis and other life threatening complications (though most patients in the trial will have pneumonitis at the point of randomisation).
As ever there are a few caveats. We must remember that RECOVERY is an open label trial and at the moment we only have results up to the 28-day point (further analyses at 6 months will eventually be available). However, the margins seen in this trial result make the likelihood of any meaningful difference very unlikely indeed.
The pre-print of the paper has gone up here on the MedRxiv server.
Where next?
We are well into another wave of cases in the UK as we predicted in previous posts. I’m still seeing horrible looking chest X-rays on a daily basis and our critical care and ward beds are filling up. This disease is with us for some time to come.
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References
- Aspirin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. https://www.medrxiv.org/content/10.1101/2021.06.08.21258132v1.full.pdf
- RECOVERY trial closes recruitment to colchicine treatment for patients hospitalised with COVID-19 https://www.recoverytrial.net/news/recovery-trial-closes-recruitment-to-colchicine-treatment-for-patients-hospitalised-with-covid-19
- Simon Carley, “JC: RECOVERY trial shows Tocilizumab effective for COVID19. St Emlyn’s,” in St.Emlyn’s, February 11, 2021, https://www.stemlynsblog.org/jc-recovery-trial-shows-tocilizumab-effective-for-covid19-st-emlyns/.
- Simon Carley, “The RECOVERY platform trial: No benefit to Hydroxychloroquine in Covid-19. St Emlyn’s,” in St.Emlyn’s, June 6, 2020, https://www.stemlynsblog.org/the-recovery-platform-trial-no-benefit-to-hydroxychloroquine-in-covid-19-st-emlyns/.
- Simon Carley, “Dexamethasone, COVID-19 and the RECOVERY trial. St Emlyn’s,” in St.Emlyn’s, June 28, 2020, https://www.stemlynsblog.org/dexamethasone-covid-19-and-the-recovery-trial-st-emlyns/.
- Simon Carley, “JC: Lopinavir/Ritonavir in the treatment of COVID-19,” in St.Emlyn’s, December 23, 2020, https://www.stemlynsblog.org/jc-lopinavir-ritonavir-in-the-treatment-of-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, “The RECOVERY platform trial: No benefit to Hydroxychloroquine in Covid-19. St Emlyn’s,” in St.Emlyn’s, June 6, 2020, https://www.stemlynsblog.org/the-recovery-platform-trial-no-benefit-to-hydroxychloroquine-in-covid-19-st-emlyns/.
- Simon Carley, “JC: Aspirin is not effective for hospitalised COVID19 patients. St Emlyn’s,” in St.Emlyn’s, June 8, 2021, https://www.stemlynsblog.org/jc-aspirin-does-not-work-in-hospitalised-covid19-patients-st-emlyns/.
