RECOVERY study reports that lopinavir/r fails to show benefit against COVID-19
22 July 2020. Related: COVID-19: investigational drugs, COVID-19.
Simon Collins, HIV i-Base
On 29 June 2020, the UK RECOVERY study announced by press release that lopinavir/r was not effective as a treatment for people hospitalised with COVID-19. [1]
RECOVERY is a large ongoing randomised study with multiple open-label experimental treatment arms and a shared control group receiving standard of care. The primary endpoint is all-cause mortality at day 28 with multiple secondary endpoints.
So far more than 11,800 participants have been enrolled from 176 hospitals across the UK.
The numbers of participants in this analysis included 1596 in the lopinavir/r arm and 3376 in the control arm. Although other baseline characteristics have not been released, on entry, most participants (70%) required oxygen alone and 26% did not need any respiratory intervention. The low percentage on mechanical ventilation (4%) was explained by the difficulty of administering lopinavir/r in this state.
The top-line results report no significant difference in 28-day mortality between arms, with 22.1% vs. 21.3% in investigational vs control group, respectively. The relative risk of mortality was 1.04 (95%CI: 0.91 to 1.18), p=0.58. The results were consistent in different subgroups of patients, but low use on mechanical ventilation technically prevented the study concluding on effect in this group.
The press statement summarises the results by saying the data “convincingly rule out any meaningful mortality benefit of lopinavir-ritonavir in the hospitalised COVID-19 patients we studied”.
COMMENT
RECOVERY was planned using an adaptive design to identify and continue effective treatments and similarly identify those that had no effect, enabling new strategies to then be added to the study.
This is same study that reported positive results for dexamethasone two weeks ago. [3]
However, this is the second time that the RECOVERY study has reported negative results from experimental treatment for COVID-19. [2]
The current lopinavir/r analysis, and decision to close the lopinavir/r arm, was based on a routine review of the DSMB on 25 June 2020 that recommended unblinding this arm of the study.
Although a different statistical analysis and DSMB review plan might have identified the lack of signal for potential benefit earlier, so far, the statistical analysis plan has not yet been posted online. [4]
It is unclear whether data from earlier studies reporting a lack of benefit with lopinavir/r were used to define likely expectations in this arm. [5, 6]
The three remaining active arms in RECOVERY use azithromycin, tocilizumab and convalescent plasma. Other papers have included more hopeful (though still uncertain) results with tocizumab and convalescent plasma.
References
- RECOVERY press statement. No clinical benefit from use of lopinavir-ritonavir in hospitalised COVID-19 patients studied in RECOVERY. (29 June 2020).
https://www.recoverytrial.net/files/lopinavir-ritonavir-recovery-statement-29062020_final.pdf (PDF) - UK RECOVERY study stops hydroxychloroquine (HCQ) for COVID-19: more than 1100 deaths question ethics and safety overall. HTB early access (6 June 2020).
https://i-base.info/htb/38188 - Dexamethasone significantly reduces mortality in subset of patients hospitalised with advanced COVID-19: UK RECOVERY study. HTB suppl(5), (17 June 2020).
https://i-base.info/htb/38241 - RECOVERY study website.
http://www.recoverytrial.net - Cao B et al. A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19. NEJM. DOI: 10.1056/NEJMoa2001282. (18 March 2020).
https://www.nejm.org/doi/full/10.1056/NEJMoa2001282 - Li Y et al. An exploratory randomized, controlled study on the efficacy and safety of lopinavir/ritonavir or arbidol treating adult patients hospitalized with mild/moderate COVID-19 (ELACOI). MedRxIV. 23 March 2020.
https://www.medrxiv.org/content/10.1101/2020.03.19.20038984v1
This report was first published on 2 July 2020.