The RECOVERY Trial – Blog Post #346 by Asrar Qureshi
The RECOVERY Trial – Blog Post #346 by Asrar Qureshi
Dear Colleagues! This is Pharma Veterans Blog Post #346. Pharma Veterans welcomes sharing of knowledge and wisdom by Veterans for the benefit of Community at large. Pharma Veterans Blog is published by Asrar Qureshi on WordPress, the top blog site. Please email to asrar@asrarqureshi.com for publishing your contributions here.
Randomised Evaluation of COVID-19 Therapy (RECOVERY) is the current hot topic under discussion. In this blog, we look at the basic facts of the trial, its outcomes and the news surrounding it.
There is no doubt that RECOVERY Trial has produced exciting and encouraging results. However, the results and context must be understood more clearly. Any rush to take Dexamethasone on your own must be avoided. Even physician-advised improper use should be questioned and discouraged.
1. I have given below the summary for those who are not familiar with clinical trials and terms.
2. I have given a more detailed description for technically oriented readers. Further reading may be done by following the links at the end of this post.
3. I have given the Abstract of the publication prepared by the investigators.
4. The readers may choose accordingly.
The University of Oxford in UK is acting as the trial Sponsor. The trial is being coordinated by a Central Coordinating Office within the Nuffield Department of Population Health. This study is supported by a grant to the University of Oxford from UK Research and Innovation/National Institute for Health Research (NIHR) and by core funding provided by NIHR Oxford Biomedical Research Centre, the Wellcome Trust, the Bill and Melinda Gates Foundation, Health Data Research UK, and the Medical Research Council Population Health Research Unit, and NIHR Clinical Trials Unit Support Funding.
SUMMARY
The RECOVERY trial is a large, randomised controlled trial of possible treatments for patients admitted to hospital with COVID-19. Over 11,500 patients have been randomised (enrolled) to the following treatment arms, or no additional treatment:
· Lopinavir-Ritonavir (commonly used to treat HIV)
· Low-dose Dexamethasone (a type of steroid, which typically used to reduce inflammation)
· Hydroxychloroquine (which has now been stopped due to lack of efficacy)
· Azithromycin (a commonly used antibiotic)
· Tocilizumab - ACTEMRA (an anti-inflammatory treatment given by injection)
· Convalescent plasma (collected from donors who have recovered from COVID-19 and contains antibodies against the SARS-CoV-2 virus).
Overall dexamethasone reduced the 28-day mortality rate by 17% (0.83 [0.74 to 0.92]; P=0.0007) with a highly significant trend showing greatest benefit among those patients requiring ventilation (test for trend p<0.001).
But it is important to recognise that we found no evidence of benefit for patients who did not require oxygen and we did not study patients outside the hospital setting. Follow-up is complete for over 94% of participants.
DETAILED DESCRIPTION
Background: In early 2020, as this protocol was being developed, there were no approved treatments for COVID-19, a disease induced by the novel coronavirus SARS- CoV-2 that emerged in China in late 2019. The UK New and Emerging Respiratory Virus Threats Advisory Group (NERVTAG) advised that several possible treatments should be evaluated…
Eligibility and randomisation: This protocol describes a randomised trial among patients hospitalised for COVID-19. All eligible patients are randomly allocated between several treatment arms, each to be given in addition to the usual standard of care in the participating hospital
Numbers to be randomised: The larger the number randomised the more accurate the results will be, but the numbers that can be randomised will depend critically on how large the epidemic becomes. If substantial numbers are hospitalised in the participating centres then it may be possible to randomise several thousand with mild disease and a few thousand with severe disease, but realistic, appropriate sample sizes could not be estimated at the start of the trial.
From version 6.0 of the protocol, a factorial design will be used such that eligible and consenting participants may be randomised to one of the treatment arms in Randomisation A and, simultaneously, to one of the treatment arms in Randomisation B.
Randomisation part A: Eligible patients will be randomly allocated between the following treatment arms (although not all arms may be available at any one time):
· No additional treatment: There are currently no approved anti-viral or host- directed treatments for COVID-19.
· Lopinavir-ritonavir: Lopinavir is a human immunodeficiency virus 1 (HIV-1) protease inhibitor, which is combined with ritonavir to increase lopinavir’s plasma half-life. Lopinavir-Ritonavir has shown activity against SARS and MERS CoVs.
· Low dose corticosteroids: Favourable immune response modulation by low-dose corticosteroids might help treat severe acute respiratory coronavirus infections, including COVID-19, SARS and MERS.
· Hydroxychloroquine: Hydroxychloroquine, a derivative of chloroquine, has been used for many decades to treat malaria and rheumatological diseases. It has antiviral activity against SARS-CoV-2 in cell culture.
· Azithromycin: Azithromycin is a macrolide antibiotic with immunomodulatory properties that has shown benefit in inflammatory lung disease.
Randomisation part B: Simultaneously, eligible patients will be randomly allocated between the following treatment arms (provided there are no contraindications and the appropriate consent has been given):
· No additional treatment: There are currently no approved anti-viral or host- directed treatments for COVID-19.
· Convalescent plasma: Plasma from patients who have recovered from SARS- CoV-2 infection may contain antibodies that can bind to and neutralise the virus. Infusion of convalescent plasma containing high concentrations of neutralising antibody may accelerate clearance of the virus and clinical improvement.
1.2.2 Second randomisation for patients with progressive COVID-19
· No additional treatment: There are currently no approved immunomodulatory or other host-directed treatments to prevent the progression of COVID-19.
· Tocilizumab (ACTEMRA): Tocilizumab is an interleukin-6 (IL-6) receptor antibody, which blocks a component of the immune response that may drive progression to ARDS.
Outcomes: The main outcomes will be death, discharge, need for ventilation and need for renal replacement therapy. For the main analyses, follow-up will be censored at 28 days after randomisation. Additional information on longer term outcomes may be collected through review of medical records or linkage to medical databases such as those managed by NHS Digital and equivalent organisations in the devolved nations.
PUBLISHED INFORMATION
Peter Horby Lim Jonathan Emberson Marion Mafham Jennifer Bell Louise Linsell Natalie Staplin Christopher Brightling Andrew Ustianowski Einas Elmahi Benjamin Prudon Christopher Green Timothy Felton David Chadwick Kanchan Rege Christopher Fegan Lucy C Chappell Saul N Faust Thomas Jaki Katie Jeffery Alan Montgomery Kathryn Rowan Edmund Juszczak J Kenneth Baillie Richard Haynes Martin J Landray RECOVERY Collaborative Group
doi:
Abstract
Background: Coronavirus disease 2019 (COVID-19) is associated with diffuse lung damage. Corticosteroids may modulate immune-mediated lung injury and reducing progression to respiratory failure and death.
Methods: The Randomised Evaluation of COVID-19 therapy (RECOVERY) trial is a randomized, controlled, open-label, adaptive, platform trial comparing a range of possible treatments with usual care in patients hospitalized with COVID-19.
We report the preliminary results for the comparison of dexamethasone 6 mg given once daily for up to ten days vs. usual care alone. The primary outcome was 28-day mortality.
Results: 2104 patients randomly allocated to receive dexamethasone were compared with 4321 patients concurrently allocated to usual care. Overall, 454 (21.6%) patients allocated dexamethasone and 1065 (24.6%) patients allocated usual care died within 28 days (age-adjusted rate ratio [RR] 0.83; 95% confidence interval [CI] 0.74 to 0.92; P<0.001). The proportional and absolute mortality rate reductions varied significantly depending on level of respiratory support at randomization (test for trend p<0.001): Dexamethasone reduced deaths by one-third in patients receiving invasive mechanical ventilation (29.0% vs. 40.7%, RR 0.65 [95% CI 0.51 to 0.82]; p<0.001), by one-fifth in patients receiving oxygen without invasive mechanical ventilation (21.5% vs. 25.0%, RR 0.80 [95% CI 0.70 to 0.92]; p=0.002), but did not reduce mortality in patients not receiving respiratory support at randomization (17.0% vs. 13.2%, RR 1.22 [95% CI 0.93 to 1.61]; p=0.14).
Conclusions: In patients hospitalized with COVID-19, dexamethasone reduced 28-day mortality among those receiving invasive mechanical ventilation or oxygen at randomization, but not among patients not receiving respiratory support.
Concluded.
https://www.recoverytrial.net/files/recovery-protocol-v6-0-2020-05-14.pdf
https://www.recoverytrial.net/files/recovery_dexamethasone_statement_160620_v2final.pdf
https://www.medrxiv.org/content/10.1101/2020.06.22.20137273v1
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