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{{short description| Test of existing medicines on COVID-19}}
{{Short description| Test of existing medicines on COVID-19}}
{{Distinguish|RECOVER Initiative}}
{{more medical citations needed|date=May 2021}}
{{more medical citations needed|date=May 2021}}
{{Use British English|date=June 2021}}
[[File:Recovery-logo-chosen-mar-2020.jpg|right]]
{{Use dmy dates|date=June 2021}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
[[File:Recovery-logo-chosen-mar-2020.jpg|alt=RECOVERY: Randomized Evaluation of COVID-19 Therapy|thumb|RECOVERY Trial logo]]
{{COVID-19 pandemic sidebar}}
{{COVID-19 pandemic sidebar}}

The '''Randomised Evaluation of COVID-19 Therapy''' ('''RECOVERY Trial''')<ref>{{Cite web|url=http://www.isrctn.com/ISRCTN50189673|title=ISRCTN - ISRCTN50189673: A randomised trial of treatments to prevent death in patients hospitalised with COVID-19 (coronavirus)|website=www.isrctn.com}}</ref> is a large-enrollment [[clinical trial]] of possible treatments for people in the [[United Kingdom]] admitted to hospital with severe [[COVID-19]] infection.<ref name="RECOVERY Home">{{cite web |title=RECOVERY Trial |url=https://www.recoverytrial.net/ |access-date=17 June 2020}}</ref><ref name="BBC17June20">{{cite web |title=Coronavirus: Dexamethasone being used to treat NHS patients today |url=https://www.bbc.co.uk/news/health-53077893 |access-date=17 June 2020}}</ref><ref name="NatBio 11May20" /> The trial was later expanded to [[Indonesia]], [[Nepal]] and [[Vietnam]].<ref>{{Cite web|title=International sites — RECOVERY Trial|url=https://www.recoverytrial.net/international|access-date=2021-05-17|website=www.recoverytrial.net}}</ref> The trial has tested ten interventions on adults: eight [[COVID-19 drug repurposing research|repurposed drugs]], one [[COVID-19 drug development|newly developed drug]] and [[antiserum|convalescent plasma]].<ref name="RECOVERY Home" />
The '''Randomised Evaluation of COVID-19 Therapy''' ('''RECOVERY Trial''')<ref>{{Cite web|url=http://www.isrctn.com/ISRCTN50189673|title=ISRCTN - ISRCTN50189673: A randomised trial of treatments to prevent death in patients hospitalised with COVID-19 (coronavirus)|website=www.isrctn.com}}</ref> is a large-enrollment [[clinical trial]] of possible treatments for people in the [[United Kingdom]] admitted to hospital with severe [[COVID-19]] infection.<ref name="RECOVERY Home">{{cite web |title=RECOVERY Trial |url=https://www.recoverytrial.net/ |access-date=17 June 2020}}</ref><ref name="BBC17June20">{{cite news |title=Coronavirus: Dexamethasone being used to treat NHS patients today |work=BBC News |date=17 June 2020 |url=https://www.bbc.co.uk/news/health-53077893 |access-date=17 June 2020}}</ref><ref name="NatBio 11May20">{{cite journal|date=11 May 2020|title=Biggest COVID-19 trial tests repurposed drugs first|journal=Nature Biotechnology|volume=38|issue=5|page=510|doi=10.1038/s41587-020-0528-x|pmid=32393915|doi-access=free|s2cid=218593584}}</ref> The trial was later expanded to [[Indonesia]], [[Nepal]] and [[Vietnam]].<ref>{{Cite web|title=International sites — RECOVERY Trial|url=https://www.recoverytrial.net/international|access-date=2021-05-17|website=www.recoverytrial.net}}</ref> The trial has tested ten interventions on adults: eight [[COVID-19 drug repurposing research|repurposed drugs]], one [[COVID-19 drug development|newly developed drug]] and [[antiserum|convalescent plasma]].<ref name="RECOVERY Home" />

=={{Anchor|Design}}Overview==
The RECOVERY Trial is a large-scale, [[randomized controlled trial]].<ref name="RECOVERY Home" /><ref name="rec-04381936">{{ClinicalTrialsGov|NCT04381936|Randomised Evaluation of COVID-19 Therapy (RECOVERY)}}. 2 March 2021; page is updated from time to time.</ref> It is an "[[Open-label trial|open label]]" study: people receiving the treatment and the attending clinicians both know which treatment is being administered.<ref name="RECOVERY Home" /> It is a multi-arm [[adaptive clinical trial]], meaning that new treatments can be added into the trial as it progresses, and other treatment "arms" closed to new enrolment when results have been produced.<ref name="NatBio 11May20" />

The very fast setting up of the trial was crucial for the fast-developing COVID-19 pandemic.
Martin Landray, one of the trial's creators, said in March 2021 "I think it has set a new standard for what can be delivered and not just for pandemics. It would be a travesty if we went back to a situation where it takes years sometimes to get a trial off the ground."<ref name="gallagher">{{Cite news|last=Gallagher|first=James|date=25 March 2021|title=Covid: The London bus trip that saved maybe a million lives|website=BBC News|url=https://www.bbc.co.uk/news/health-56508369}}</ref>

=== Enrollment ===
When people who have been hospitalised with COVID-19 are enrolled in the trial, they are automatically randomized to receive trial treatments. If any treatment is contra-indicated (or positively indicated) for that patient, or is not available, then that treatment is not included in the randomization process. The main randomization stage has three parts, so that patients might be allocated none, one, two or three of the trial treatments. If their disease progresses, there may also be a second randomization.<ref name="Protocol">{{cite web|date=21 Nov 2020|title=Randomised evaluation of COVID-19 therapy (RECOVERY) – Trial protocol v11|url=https://www.recoverytrial.net/files/recovery-protocol-v11-1-2020-11-21.pdf|access-date=14 Dec 2020|publisher=RECOVERY Trial}}</ref>

=== Goals ===
The primary objective of the trial is to "provide reliable estimates of the effect of study treatments on all-cause mortality at 28 days after first randomization".<ref name="RECOVERY Home" /><ref name="rec-04381936" />

The trial protocol was developed in March 2020. The design minimizes the administrative load on hospital staff, who at the time were facing the prospect of overwhelming numbers of COVID-19 admissions.<ref name="BBC 20Jun20">{{cite web|author1=Fergus Walsh|date=20 June 2020|title=At last some good news about coronavirus|url=https://www.bbc.co.uk/news/health-53096736|access-date=20 June 2020|website=BBC News}}</ref><ref name="Protocol" />


==Treatments==
==Treatments==
As of 25th June 2021, the following treatments are allocated at random to hospitalized people with severe COVID-19 infection:<ref>{{cite web |title=RECOVERY Trial |url=https://www.recoverytrial.net/ |access-date=25 June 2021}}</ref>
As of 25 June 2021, the following treatments are allocated at random to hospitalized people with severe COVID-19 infection:<ref name="RECOVERY Home"/>
* [[Baricitinib]] (an immunomodulatory drug used in rheumatoid arthritis)
* [[Baricitinib]] (an immunomodulatory drug used in rheumatoid arthritis)
*[[Dimethyl fumarate]] (adults only, early phase assessment)
* [[Dimethyl fumarate]] (adults only, early phase assessment)
*[[Infliximab]] (adults only)
* [[Infliximab]] (adults only)
*High-dose [[dexamethasone]] (adults with [[Hypoxia (medical)|hypoxia]] only)
* High-dose [[dexamethasone]] (adults with [[Hypoxia (medical)|hypoxia]] only)


Children with [[Multisystem inflammatory syndrome in children|PIMS-TS]] may also be allocated the following:<ref name="Recovery Protocol">{{cite web|title=Recovery Trial Protocol v15|url=https://www.recoverytrial.net/files/recovery-protocol-v15-0-2021-04-12.pdf|url-status=live|access-date=4 Feb 2021|website=Recovery Trial}}</ref>
Children with [[Multisystem inflammatory syndrome in children|PIMS-TS]] may also be allocated the following:<ref name="Recovery Protocol">{{cite web|title=Recovery Trial Protocol v15|url=https://www.recoverytrial.net/files/recovery-protocol-v15-0-2021-04-12.pdf|access-date=4 Feb 2021|website=Recovery Trial}}</ref>
* Low-dose [[dexamethasone]] (a [[steroid]], which reduces [[inflammation]])
* Low-dose [[dexamethasone]] (a [[steroid]], which reduces [[inflammation]])
* Intravenous [[immunoglobulin]]
* Intravenous [[immunoglobulin]]
* [[Tocilizumab]] (an anti-inflammatory)
* [[Tocilizumab]] (an anti-inflammatory)
* [[Anakinra]] (a drug used to treat rheumatoid arthritis)
* [[Anakinra]] (an anti-inflammatory)


The following treatments have previously been included in the trial:
The following treatments have previously been included in the trial and obtained positive results:
* Low-dose [[dexamethasone]]
* [[Tocilizumab]]
* [[REGN-COV2]] (a cocktail of two anti-viral monoclonal antibodies)
* [[Baricitinib#COVID-19|Baricitinib]]


The following treatments have previously been included in the trial and were closed to new entrants after being shown to be ineffective.:<ref name="lop-rit" /><ref name="rec-nobenefit">{{Cite web|title=No clinical benefit from use of hydroxychloroquine in hospitalised patients with COVID-19|publisher=Recovery Trial, Nuffield Department of Population Health, University of Oxford, UK|url=https://www.recoverytrial.net/news/statement-from-the-chief-investigators-of-the-randomised-evaluation-of-covid-19-therapy-recovery-trial-on-hydroxychloroquine-5-june-2020-no-clinical-benefit-from-use-of-hydroxychloroquine-in-hospitalised-patients-with-covid-19|access-date=2020-06-07|date=2020-06-05}}</ref><ref name="Azithromycin-20201214" /><ref name="Plasma-20210115" />
* [[Lopinavir]]-[[Ritonavir]] (an [[HIV]] medication)
* [[Lopinavir]]-[[Ritonavir]] (an [[HIV]] medication)
* [[Hydroxychloroquine]] (used to treat malaria and rheumatism)
* [[Hydroxychloroquine]] (used to treat malaria and rheumatism)
* [[Azithromycin]] (an [[antibiotic]])
* [[Azithromycin]] (an [[antibiotic]])
* [[Convalescent plasma]] ([[blood plasma]] from people who have recovered from COVID-19 and which may contain [[antibodies]] against the [[SARS-CoV-2]] virus)
* [[Convalescent plasma]] ([[blood plasma]] from people who have recovered from COVID-19 and which may contain [[antibodies]] against the [[SARS-CoV-2]] virus)
* [[REGN-COV2]] (a cocktail of two anti-viral monoclonal antibodies)
* [[Aspirin]] (a commonly used blood thinner)
* [[Aspirin]] (a commonly used blood thinner)
* [[Colchicine]] (a drug used for gout)
* [[Colchicine]] (a drug used for gout)

The latter seven arms were closed to new entrants after being shown to be ineffective.<ref name="lop-rit" /><ref name="rec-nobenefit">{{Cite web|title=No clinical benefit from use of hydroxychloroquine in hospitalised patients with COVID-19|publisher=Recovery Trial, Nuffield Department of Population Health, University of Oxford, UK|url=https://www.recoverytrial.net/news/statement-from-the-chief-investigators-of-the-randomised-evaluation-of-covid-19-therapy-recovery-trial-on-hydroxychloroquine-5-june-2020-no-clinical-benefit-from-use-of-hydroxychloroquine-in-hospitalised-patients-with-covid-19|access-date=2020-06-07|date=2020-06-05}}</ref><ref name="Azithromycin-20201214" /><ref name="Plasma-20210115" />

Dexamethasone and Tocilizumab were closed to new adult entries after positive results.

==Design==
The RECOVERY Trial is a large-scale, [[randomized controlled trial]].<ref name="RECOVERY Home"/><ref name="rec-04381936">{{ClinicalTrialsGov|NCT04381936|Randomised Evaluation of COVID-19 Therapy (RECOVERY)}}. 2 March 2021; page is updated from time to time.</ref> The primary objective of the trial is to "provide reliable estimates of the effect of study treatments on all-cause mortality at 28 days after first randomisation".<ref name="RECOVERY Home"/><ref name=rec-04381936/>

It is an "[[Open-label trial|open label]]" study: people receiving the treatment and the attending clinicians both know which treatment is being administered.<ref name="RECOVERY Home"/> It is a multi-arm [[adaptive clinical trial]], meaning that new treatments can be added into the trial as it progresses, and other treatment "arms" closed to new enrolment when results have been produced.<ref name="NatBio 11May20">{{cite journal |title=Biggest COVID-19 trial tests repurposed drugs first |url=https://www.nature.com/articles/s41587-020-0528-x |journal=Nature Biotechnology |access-date=26 June 2020 |doi=10.1038/s41587-020-0528-x |date=11 May 2020|volume=38 |issue=5 |page=510 |pmid=32393915 |s2cid=218593584 |doi-access=free }}</ref>

The trial protocol was developed in March 2020. The design minimizes the administrative load on hospital staff, who at the time were facing the prospect of overwhelming numbers of COVID-19 admissions.<ref name="BBC 20Jun20">{{cite web |author1=Fergus Walsh |title=At last some good news about coronavirus |url=https://www.bbc.co.uk/news/health-53096736 |website=BBC News |access-date=20 June 2020 |date=20 June 2020}}</ref><ref name="Protocol">{{cite web |title=Randomised evaluation of COVID-19 therapy (RECOVERY) - Trial protocol v11 |url=https://www.recoverytrial.net/files/recovery-protocol-v11-1-2020-11-21.pdf |publisher=RECOVERY Trial |access-date=14 Dec 2020 |date=21 Nov 2020}}</ref>

When people who have been hospitalised with COVID-19 are enrolled in the trial, they are automatically randomized to receive trial treatments. If any treatment is contra-indicated (or positively indicated) for that patient, or is not available, then that treatment is not included in the randomization process. The main randomization stage has three parts, so that patients might be allocated none, one, two or three of the trial treatments. If their disease progresses, there may also be a second randomization.<ref name="Protocol" />

The very fast setting up of the trial was crucial for the fast-developing COVID-19 pandemic.
Martin Landray, one of the trial's creators, said in March 2021 "I think it has set a new standard for what can be delivered and not just for pandemics. It would be a travesty if we went back to a situation where it takes years sometimes to get a trial off the ground."<ref name=gallagher>{{Cite news |title=Covid: The London bus trip that saved maybe a million lives |last=Gallagher |first=James |website=BBC News |date=25 March 2021 |url= https://www.bbc.co.uk/news/health-56508369}}</ref>


==Operations==
==Operations==
The trial is run by the Nuffield Departments of Population Health and of Medicine at the [[University of Oxford]].<ref name=rec-nobenefit/><ref name="BBC 20Jun20" /> The study is led by [[Peter Horby]] and [[Martin Landray]] who serve as Co-Chief Investigators of the trial.<ref>{{cite web |title=Preliminary trial results find dexamethasone reduces death in hospitalised patients with severe respiratory complications of COVID-19 - UK Research and Innovation |url=https://www.ukri.org/news/preliminary-trial-results-dexamethasone/ |website=www.ukri.org |publisher=UK Research and Innovation |access-date=19 October 2020 |language=en}}</ref><ref>{{cite news |last1=editor |first1=Sarah Boseley Health |title=Dexamethasone: low-cost drug helps prevent deaths of sickest coronavirus patients |url=https://www.theguardian.com/world/2020/jun/16/steroid-found-to-help-prevent-deaths-of-sickest-coronavirus-patients |work=The Guardian |date=17 June 2020}}</ref> By July 2020, the trial was in progress at 176 [[NHS]] hospitals in the UK, involving many thousands of health professionals.<ref>{{cite news |last1=KupferschmidtJul. 2 |first1=Kai |title=One U.K. trial is transforming COVID-19 treatment. Why haven't others delivered more results? |url=https://www.sciencemag.org/news/2020/07/one-uk-trial-transforming-covid-19-treatment-why-haven-t-others-delivered-more-results |access-date=19 October 2020 |work=Science |date=2 July 2020 |language=en}}</ref>
The trial is run by the Nuffield Departments of Population Health and of Medicine at the [[University of Oxford]]<ref name=rec-nobenefit/><ref name="BBC 20Jun20" /> and supported by the [[National Institute for Health Research]] (NIHR). The study is led by [[Peter Horby]] and [[Martin Landray]] who serve as Co-Chief Investigators of the trial.<ref>{{cite web |title=Preliminary trial results find dexamethasone reduces death in hospitalised patients with severe respiratory complications of COVID-19 - UK Research and Innovation |url=https://www.ukri.org/news/preliminary-trial-results-dexamethasone/ |website=www.ukri.org |publisher=UK Research and Innovation |access-date=19 October 2020 |language=en |archive-date=24 October 2020 |archive-url=https://web.archive.org/web/20201024030908/https://www.ukri.org/news/preliminary-trial-results-dexamethasone/ }}</ref><ref>{{cite news |last1=Boseley |first1=Sarah |title=Dexamethasone: low-cost drug helps prevent deaths of sickest coronavirus patients |url=https://www.theguardian.com/world/2020/jun/16/steroid-found-to-help-prevent-deaths-of-sickest-coronavirus-patients |work=The Guardian |date=17 June 2020}}</ref> By July 2020, the trial was in progress at 176 [[NHS]] hospitals in the UK, involving many thousands of health professionals.<ref>{{cite news |last1=Kupferschmidt |first1=Kai |title=One U.K. trial is transforming COVID-19 treatment. Why haven't others delivered more results? |url=https://www.science.org/content/article/one-uk-trial-transforming-covid-19-treatment-why-haven-t-others-delivered-more-results |access-date=19 October 2020 |work=Science |date=2 July 2020 }}</ref>


The trial began in March 2020. As of March 2021 the trial had enrolled more than 40,000 COVID-19 participants admitted to hospitals in the UK;<ref name=gallagher/> the estimated primary completion date was December 2021, and the estimated study completion date was December 2031.<ref name=rec-04381936/><ref name="Azithromycin-20201214" />
The trial began in March 2020. As of March 2021 the trial had enrolled more than 40,000 COVID-19 participants admitted to hospitals in the UK;<ref name=gallagher/> the estimated primary completion date was December 2021, and the estimated study completion date was December 2031.<ref name=rec-04381936/><ref name="Azithromycin-20201214" />
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{{see also|COVID-19 drug repurposing research#Dexamethasone}}
{{see also|COVID-19 drug repurposing research#Dexamethasone}}


[[File:RECOVERY Trial Dexamethasone ventilated.jpg|thumb|right|Mortality over 28 days for 1007 COVID-19 patients on [[mechanical ventilation]] at time of randomisation: 324 patients who received [[dexamethasone]] (red) compared to 683 who received standard hospital care (black)<ref name="Paper 22June2020" />]]
[[File:RECOVERY Trial Dexamethasone ventilated.jpg|thumb|Mortality over 28 days for 1007 COVID-19 patients on [[mechanical ventilation]] at time of randomisation: 324 patients who received [[dexamethasone]] (red) compared to 683 who received standard hospital care (black)<ref name="Paper 22June2020" />]]


On 22 June 2020, preliminary results were published in a preprint showing that low-dose [[dexamethasone]] treatment reduced the death rate by one third in hospitalized people needing [[ventilator]]s due to severe COVID-19 infection, and by one fifth in people treated with [[oxygen therapy]]. There was no benefit (and the possibility of harm) among people who did not require oxygen.<ref name="Paper 22June2020">{{cite journal |author1=RECOVERY Collaborative Group |title=Effect of Dexamethasone in Hospitalized Patients with COVID-19 – Preliminary Report |url=https://www.medrxiv.org/content/10.1101/2020.06.22.20137273v1 |website=MedRXiv |year=2020 |doi=10.1101/2020.06.22.20137273 |s2cid=219965377 |access-date=23 June 2020|doi-access=free }}</ref> The preliminary report was subsequently published in ''[[The New England Journal of Medicine]]''.<ref name="NEJM-17July20">{{cite journal |vauthors=Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, Staplin N, Brightling C, Ustianowski A, Elmahi E, Prudon B, Green C, Felton T, Chadwick D, Rege K, Fegan C, Chappell LC, Faust SN, Jaki T, Jeffery K, Montgomery A, Rowan K, Juszczak E, Baillie JK, Haynes R, Landray MJ | display-authors=6 |title=Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report |journal=New England Journal of Medicine |date=July 2020 | volume=384 | issue=8 | pages=693–704 |doi=10.1056/NEJMoa2021436 | pmid=32678530 | pmc=7383595 |doi-access=free }}</ref>
In June 2020, preliminary results were published in a preprint showing that low-dose [[dexamethasone]] treatment reduced the death rate by one third in hospitalized people needing [[ventilator]]s due to severe COVID-19 infection, and by one fifth in people treated with [[oxygen therapy]]. There was no benefit (and the possibility of harm) among people who did not require oxygen.<ref name="Paper 22June2020">{{Cite medRxiv |author1=RECOVERY Collaborative Group |title=Effect of Dexamethasone in Hospitalized Patients with COVID-19 – Preliminary Report |year=2020 |medrxiv=10.1101/2020.06.22.20137273v1}}</ref> The preliminary report was subsequently published in ''[[The New England Journal of Medicine]]''.<ref name="NEJM-17July20">{{cite journal |vauthors=Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, Staplin N, Brightling C, Ustianowski A, Elmahi E, Prudon B, Green C, Felton T, Chadwick D, Rege K, Fegan C, Chappell LC, Faust SN, Jaki T, Jeffery K, Montgomery A, Rowan K, Juszczak E, Baillie JK, Haynes R, Landray MJ |title=Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report |journal=New England Journal of Medicine |date=July 2020 | volume=384 | issue=8 | pages=693–704 |doi=10.1056/NEJMoa2021436 | pmid=32678530 | pmc=7383595 |doi-access=free }}</ref>


====Impacts====
====Impacts====
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{{cite web |title=The National Institutes of Health COVID-19 Treatment Guidelines Panel Provides Recommendations for Dexamethasone in Patients with COVID-19 |url=https://www.covid19treatmentguidelines.nih.gov/dexamethasone/ |website=NIH COVID-19 Treatment Guidelines |publisher=National Institutes of Health |access-date=26 June 2020 |date=25 June 2020}}</ref>
{{cite web |title=The National Institutes of Health COVID-19 Treatment Guidelines Panel Provides Recommendations for Dexamethasone in Patients with COVID-19 |url=https://www.covid19treatmentguidelines.nih.gov/dexamethasone/ |website=NIH COVID-19 Treatment Guidelines |publisher=National Institutes of Health |access-date=26 June 2020 |date=25 June 2020}}</ref>


Other countries granted specific approval for the drug as part of standard medical care, among them Japan,<ref>{{Cite web|last=hermesauto|date=2020-07-22|title=Japan approves dexamethasone as coronavirus treatment|url=https://www.straitstimes.com/asia/east-asia/japan-approves-dexamethasone-as-coronavirus-treatment|access-date=2020-09-06|website=The Straits Times|language=en}}</ref> Taiwan<ref>{{Cite news|date=2020-08-04|title=Taiwan provisionally approves dexamethasone as coronavirus treatment|language=en|work=Reuters|url=https://www.reuters.com/article/us-health-coronavirus-taiwan-dexamethaso-idUSKCN250106|access-date=2020-09-06}}</ref> and South Africa.<ref>{{Cite web|title=South Africa approves dexamethasone to treat COVID-19|url=https://www.aa.com.tr/en/africa/south-africa-approves-dexamethasone-to-treat-covid-19/1883532}}</ref>
Other countries granted specific approval for the drug as part of standard medical care, among them Japan,<ref>{{Cite web|last=hermesauto|date=2020-07-22|title=Japan approves dexamethasone as coronavirus treatment|url=https://www.straitstimes.com/asia/east-asia/japan-approves-dexamethasone-as-coronavirus-treatment|access-date=2020-09-06|website=The Straits Times|language=en}}</ref> Taiwan<ref>{{Cite news|date=2020-08-04|title=Taiwan provisionally approves dexamethasone as coronavirus treatment|language=en|work=Reuters|url=https://www.reuters.com/article/us-health-coronavirus-taiwan-dexamethaso-idUSKCN250106|access-date=2020-09-06}}</ref> and South Africa.<ref>{{Cite web|url=https://www.aa.com.tr/en/africa/south-africa-approves-dexamethasone-to-treat-covid-19/1883532|title=South Africa approves dexamethasone to treat COVID-19|website=www.aa.com.tr}}</ref>


A pre-print study, which was awarded Health Data Research UK Open Access Publication of the Month for August 2020, found that the discovery would save approximately 650,000 lives globally over the course of six months.<ref>{{Cite web|title=The potential health and economic impact of dexamethasone treatment for patients with COVID-19|url=https://www.hdruk.ac.uk/case-studies/131977/|access-date=2020-09-06|website=HDR UK|language=en-GB}}</ref><ref>{{Cite journal|last1=Aguas|first1=Ricardo|last2=Mahdi|first2=Adam|last3=Shretta|first3=Rima|last4=Horby|first4=Peter|last5=Landray|first5=Martin|last6=White|first6=Lisa J.|date=2020-07-30|title=The potential health and economic impact of dexamethasone treatment for patients with COVID-19|url=https://www.medrxiv.org/content/10.1101/2020.07.29.20164269v1|journal=MedRxiv|language=en|pages=2020.07.29.20164269|doi=10.1101/2020.07.29.20164269|s2cid=220846974}}</ref>
A pre-print study, which was awarded Health Data Research UK Open Access Publication of the Month for August 2020, found that the discovery would save approximately 650,000 lives globally over the course of six months.<ref>{{Cite web|title=The potential health and economic impact of dexamethasone treatment for patients with COVID-19|url=https://www.hdruk.ac.uk/case-studies/131977/|access-date=2020-09-06|website=HDR UK|language=en-GB}}</ref><ref>{{Cite medRxiv |last1=Aguas |first1=Ricardo |last2=Mahdi |first2=Adam |last3=Shretta |first3=Rima |last4=Horby |first4=Peter |last5=Landray |first5=Martin |last6=White |first6=Lisa J. |date=2020-07-30 |title=The potential health and economic impact of dexamethasone treatment for patients with COVID-19 |language=en |medrxiv=10.1101/2020.07.29.20164269v1}}</ref>


====Limitations of dexamethasone result====
====Limitations of dexamethasone result====
[[File:RECOVERY Trial Dexamethasone Unassisted.jpg|thumb|right|Mortality over 28 days for 1535 COVID-19 patients not receiving oxygen at time of randomisation: 501 patients who received [[dexamethasone]] (red) compared to 1034 who received standard hospital care (black)<ref name="Paper 22June2020" />]]
[[File:RECOVERY Trial Dexamethasone Unassisted.jpg|thumb|right|Mortality over 28 days for 1535 COVID-19 patients not receiving oxygen at time of randomisation: 501 patients who received [[dexamethasone]] (red) compared to 1034 who received standard hospital care (black)<ref name="Paper 22June2020" />]]
* John Fletcher, research editor at the ''[[BMJ]]'', noted that there were "limitations and causes of concern" in the dexamethasone results.<ref name="BMJ 23Jun20" />
John Fletcher, research editor at the ''[[BMJ]]'', noted that there were "limitations and causes of concern" in the dexamethasone results.<ref name="BMJ 23Jun20" />
* Around a third of patients in the trial were still in hospital at the end of the 28-day trial period, so their final outcomes were not known.<ref name="BMJ 23Jun20" />
* Around a third of patients in the trial were still in hospital at the end of the 28-day trial period, so their final outcomes were not known.<ref name="BMJ 23Jun20" />
* As an [[immunosuppressive drug]], there are fears that dexamethasone could make the illness worse, and prolong the infection in patients where the immune system has not yet overreacted and caused inflammation.<ref name="BBC 20Jun20" /><ref name="NYT 24Jun20">{{cite web |author1=Roni Caryn Rabin |title=Breakthrough Drug for Covid-19 May Be Risky for Mild Cases |url=https://www.nytimes.com/2020/06/24/health/coronavirus-dexamethasone.html |work=New York Times |access-date=25 June 2020 |date=24 June 2020}}</ref>
* As an [[immunosuppressive drug]], there are fears that dexamethasone could make the illness worse, and prolong the infection in patients where the immune system has not yet overreacted and caused inflammation.<ref name="BBC 20Jun20" /><ref name="NYT 24Jun20">{{cite web |author1=Roni Caryn Rabin |title=Breakthrough Drug for Covid-19 May Be Risky for Mild Cases |url=https://www.nytimes.com/2020/06/24/health/coronavirus-dexamethasone.html |work=New York Times |access-date=25 June 2020 |date=24 June 2020}}</ref>
* The preprint authors themselves warned that "the results are consistent with possible harm" in patients who did not require oxygen at the time of enrolment.<ref name="Paper 22June2020" /> The trial observed a 22% ''increase'' in mortality in these patients (rate ratio 1.22 [95% Confidence Interval 0.93 to 1.61]; p=0.14), though this observation may still be due to chance.<ref name="Paper 22June2020" />
* The preprint authors themselves warned that "the results are consistent with possible harm" in patients who did not require oxygen at the time of enrolment.<ref name="Paper 22June2020" /> The trial observed a 22% ''increase'' in mortality in these patients (rate ratio 1.22 [95% Confidence Interval 0.93 to 1.61]; p=0.14), though this observation may still be due to chance.<ref name="Paper 22June2020" />
* Responding to the publication, the [[WHO]] emphasized that dexamethasone should only be used for patients with severe or critical disease, under close clinical supervision, stating that "There is no evidence this drug works for patients with mild disease or as a preventative measure, and it could cause harm."<ref name="WHO 22Jun20">{{cite web |title=WHO Director-General's opening remarks at the media briefing on COVID-19 - 22 June 2020 |url=https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---22-june-2020 |publisher=World Health Organization |access-date=25 June 2020}}</ref>
* Responding to the publication, the [[WHO]] emphasized that dexamethasone should only be used for patients with severe or critical disease, under close clinical supervision, stating that "There is no evidence this drug works for patients with mild disease or as a preventative measure, and it could cause harm."<ref name="WHO 22Jun20">{{cite web |title=WHO Director-General's opening remarks at the media briefing on COVID-19 - 22 June 2020 |url=https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---22-june-2020 |publisher=World Health Organization |access-date=25 June 2020}}</ref>


====Confirmation of dexamethasone result====
====Confirmation of dexamethasone result====
The results of this initial finding have now been replicated in a systematic review by the [[World Health Organization]]'s ''Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group''.<ref>{{Cite journal|last1=Group|first1=The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working|last2=Sterne|first2=Jonathan A. C.|last3=Murthy|first3=Srinivas|last4=Diaz|first4=Janet V.|last5=Slutsky|first5=Arthur S.|last6=Villar|first6=Jesús|last7=Angus|first7=Derek C.|last8=Annane|first8=Djillali|last9=Azevedo|first9=Luciano Cesar Pontes|last10=Berwanger|first10=Otavio|last11=Cavalcanti|first11=Alexandre B.|date=2020-09-02|title=Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis|url= |journal=JAMA|volume=324|issue=13|pages=1330–1341|language=en|doi=10.1001/jama.2020.17023|pmid=32876694|pmc=7489434}}</ref>
The results of this initial finding were replicated in a systematic review published in September 2020 by the WHO's ''Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group''.<ref>{{Cite journal|last1=The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group|last2=Sterne|first2=Jonathan A. C.|last3=Murthy|first3=Srinivas|last4=Diaz|first4=Janet V.|last5=Slutsky|first5=Arthur S.|last6=Villar|first6=Jesús|last7=Angus|first7=Derek C.|last8=Annane|first8=Djillali|last9=Azevedo|first9=Luciano Cesar Pontes|last10=Berwanger|first10=Otavio|last11=Cavalcanti|first11=Alexandre B.|date=2020-09-02|title=Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis|url=|journal=JAMA|language=en|volume=324|issue=13|pages=1330–1341|doi=10.1001/jama.2020.17023|pmc=7489434|pmid=32876694}}</ref>


===Hydroxychloroquine===
===Hydroxychloroquine===
{{main|Chloroquine and hydroxychloroquine during the COVID-19 pandemic}}
{{main|Chloroquine and hydroxychloroquine during the COVID-19 pandemic}}


On 5 June 2020, the trial determined that there was no clinical benefit from use of [[hydroxychloroquine]] in people hospitalized with COVID-19.<ref name=rec-nobenefit/>
In June 2020, the trial determined that there was no clinical benefit from use of [[hydroxychloroquine]] in people hospitalized with COVID-19.<ref name=rec-nobenefit/>


===Lopinavir-ritonavir===
===Lopinavir-ritonavir===
On 29 June 2020, chief investigators of the trial reported there was no clinical benefit from use of lopinavir-ritonavir in 1,596 people hospitalized with severe COVID-19 infection over 28 days of treatment.<ref name="lop-rit">{{Cite web|date=29 June 2020|title=No clinical benefit from use of lopinavir-ritonavir in hospitalised COVID-19 patients studied in RECOVERY|url=https://www.recoverytrial.net/files/lopinavir-ritonavir-recovery-statement-29062020_final.pdf|publisher=RECOVERY Trial: Statement from the Chief Investigators|access-date=30 June 2020}}</ref> These results were published in ''The Lancet'' on 5 October 2020.<ref name="Lancet-20201005">
In June 2020, chief investigators of the trial reported there was no clinical benefit from use of lopinavir-ritonavir in 1,596 people hospitalized with severe COVID-19 infection over 28 days of treatment.<ref name="lop-rit">{{Cite web|date=29 June 2020|title=No clinical benefit from use of lopinavir-ritonavir in hospitalised COVID-19 patients studied in RECOVERY|url=https://www.recoverytrial.net/files/lopinavir-ritonavir-recovery-statement-29062020_final.pdf|publisher=RECOVERY Trial: Statement from the Chief Investigators|access-date=30 June 2020}}</ref> These results were published in ''The Lancet'' on 5 October 2020.<ref name="Lancet-20201005">
{{cite journal |journal=The Lancet
{{cite journal |journal=The Lancet
|title=Lopinavir–ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial |date=5 October 2020
|title=Lopinavir–ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial |date=5 October 2020
|doi=10.1016/S0140-6736(20)32013-4
|doi=10.1016/S0140-6736(20)32013-4
|url= |last1=Horby |first1=Peter W. |last2=Mafham |first2=Marion |last3=Bell |first3=Jennifer L. |last4=Linsell |first4=Louise |last5=Staplin |first5=Natalie |last6=Emberson |first6=Jonathan |last7=Palfreeman |first7=Adrian |last8=Raw |first8=Jason |last9=Elmahi |first9=Einas |last10=Prudon |first10=Benjamin |last11=Green |first11=Christopher |last12=Carley |first12=Simon |last13=Chadwick |first13=David |last14=Davies |first14=Matthew |last15=Wise |first15=Matthew P. |last16=Baillie |first16=J Kenneth |last17=Chappell |first17=Lucy C. |last18=Faust |first18=Saul N. |last19=Jaki |first19=Thomas |last20=Jefferey |first20=Katie |last21=Lim |first21=Wei Shen |last22=Montgomery |first22=Alan |last23=Rowan |first23=Kathryn |last24=Juszczak |first24=Edmund |last25=Haynes |first25=Richard |last26=Landray |first26=Martin J. |volume=396 |issue=10259 |pages=1345–1352 |pmid=33031764 |pmc=7535623 }}</ref>
|url= |last1=Horby |first1=Peter W. |last2=Mafham |first2=Marion |last3=Bell |first3=Jennifer L. |last4=Linsell |first4=Louise |last5=Staplin |first5=Natalie |last6=Emberson |first6=Jonathan |last7=Palfreeman |first7=Adrian |last8=Raw |first8=Jason |last9=Elmahi |first9=Einas |last10=Prudon |first10=Benjamin |last11=Green |first11=Christopher |last12=Carley |first12=Simon |last13=Chadwick |first13=David |last14=Davies |first14=Matthew |last15=Wise |first15=Matthew P. |last16=Baillie |first16=J Kenneth |last17=Chappell |first17=Lucy C. |last18=Faust |first18=Saul N. |last19=Jaki |first19=Thomas |last20=Jefferey |first20=Katie |last21=Lim |first21=Wei Shen |last22=Montgomery |first22=Alan |last23=Rowan |first23=Kathryn |last24=Juszczak |first24=Edmund |last25=Haynes |first25=Richard |last26=Landray |first26=Martin J. |volume=396 |issue=10259 |pages=1345–1352 |pmid=33031764 |pmc=7535623 }}</ref>


===Azithromycin===
===Azithromycin===
In a news release on 14 December 2020, the chief investigators announced that they had found no benefit from azithromycin in patients hospitalised with COVID-19. 2582 patients had received azithromycin, and 5182 were randomised to usual care alone. 28-day mortality in both cohorts was 19%.<ref name="Azithromycin-20201214">{{cite web |author1=Peter Horby |author2=Martin Landray |title=RECOVERY trial finds no benefit from azithromycin in patients hospitalised with COVID-19 |url=https://www.recoverytrial.net/news/recovery-trial-finds-no-benefit-from-azithromycin-in-patients-hospitalised-with-covid-19 |publisher=RECOVERY Trial |date=14 December 2020}}</ref> These preliminary results were released as a preprint on the same day.<ref name="medRxiv-20201214">
In December 2020, the chief investigators announced that they had found no benefit from azithromycin in patients hospitalised with COVID-19. 2582 patients had received azithromycin, and 5182 were randomised to usual care alone. 28-day mortality in both cohorts was 19%.<ref name="Azithromycin-20201214">{{cite web |author1=Peter Horby |author2=Martin Landray |title=RECOVERY trial finds no benefit from azithromycin in patients hospitalised with COVID-19 |url=https://www.recoverytrial.net/news/recovery-trial-finds-no-benefit-from-azithromycin-in-patients-hospitalised-with-covid-19 |publisher=RECOVERY Trial |date=14 December 2020}}</ref> These preliminary results were released as a preprint on the same day.<ref name="medRxiv-20201214">
{{Cite medRxiv |title=Azithromycin in Hospitalised Patients with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial |date=14 December 2020 |last1=Horby |first1=Peter W. |last2=Roddick |first2=Alistair |last3=Spata |first3=Enti |last4=Staplin |first4=Natalie |last5=Emberson |first5=Jonathan R. |last6=Pessoa-Amorim |first6=Guilherme |last7=Peto |first7=Leon |last8=Campbell |first8=Mark |last9=Brightling |first9=Christopher |last10=Prudon |first10=Ben |last11=Chadwick |first11=David |last12=Ustianowski |first12=Andrew |last13=Ashish |first13=Abdul |last14=Todd |first14=Stacy |last15=Yates |first15=Bryan |last16=Buttery |first16=Robert |last17=Scott |first17=Stephen |last18=Maseda |first18=Diego |last19=Baillie |first19=J Kenneth |last20=Buch |first20=Maya H. |last21=Chappell |first21=Lucy C. |last22=Day |first22=Jeremy N. |last23=Faust |first23=Saul N. |last24=Jaki |first24=Thomas |last25=Jeffery |first25=Katie |last26=Juszczak |first26=Edmund |last27=Lim |first27=Wei Shen |last28=Montgomery |first28=Alan |last29=Mumford |first29=Andrew |last30=Rowan |first30=Kathryn |medrxiv=10.1101/2020.12.10.20245944v1}}
{{cite document
|title=Azithromycin in Hospitalised Patients with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial
</ref><ref>{{cite journal |author=RECOVERY Collaborative Group |title=Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. |journal=Lancet |date=2021-02-13 |volume=397 |issue=10274 |pages=605–612 |doi=10.1016/S0140-6736(21)00149-5 |pmid=33545096 |pmc=7884931 |hdl=10044/1/86993 |hdl-access=free }}</ref>
|url=https://www.medrxiv.org/content/10.1101/2020.12.10.20245944v1
|access-date=14 December 2020
|doi=10.1101/2020.12.10.20245944
|date=14 December 2020|last1=Horby
|first1=Peter W.
|last2=Roddick
|first2=Alistair
|last3=Spata
|first3=Enti
|last4=Staplin
|first4=Natalie
|last5=Emberson
|first5=Jonathan R.
|last6=Pessoa-Amorim
|first6=Guilherme
|last7=Peto
|first7=Leon
|last8=Campbell
|first8=Mark
|last9=Brightling
|first9=Christopher
|last10=Prudon
|first10=Ben
|last11=Chadwick
|first11=David
|last12=Ustianowski
|first12=Andrew
|last13=Ashish
|first13=Abdul
|last14=Todd
|first14=Stacy
|last15=Yates
|first15=Bryan
|last16=Buttery
|first16=Robert
|last17=Scott
|first17=Stephen
|last18=Maseda
|first18=Diego
|last19=Baillie
|first19=J Kenneth
|last20=Buch
|first20=Maya H.
|last21=Chappell
|first21=Lucy C.
|last22=Day
|first22=Jeremy N.
|last23=Faust
|first23=Saul N.
|last24=Jaki
|first24=Thomas
|last25=Jeffery
|first25=Katie
|last26=Juszczak
|first26=Edmund
|last27=Lim
|first27=Wei Shen
|last28=Montgomery
|first28=Alan
|last29=Mumford
|first29=Andrew
|last30=Rowan
|first30=Kathryn
|display-authors=1
}}
</ref>
<ref>{{cite journal |last1=RECOVERY Collaborative |first1=Group. |title=Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. |journal=Lancet (London, England) |date=2021-02-13 |volume=397 |issue=10274 |pages=605-612 |doi=10.1016/S0140-6736(21)00149-5 |pmid=33545096 |url=https://pubmed.ncbi.nlm.nih.gov/33545096/ |access-date=25 June 2021}}</ref>


===Convalescent plasma===
===Convalescent plasma===
In a news release on 15 January 2021, the chief investigators announced the closure of the convalescent plasma arm of the trial. Among 1873 reported deaths from 10,405 patients, the trial reported "no significant difference in the primary endpoint of 28-day mortality (18% convalescent plasma vs. 18% usual care alone; risk ratio 1.04 [95% confidence interval 0.95-1.14]; p=0.34)".<ref name="Plasma-20210115">{{cite web|last1=RECOVERY trial chief investigators|date=15 January 2021|title=Recovery trial closes recruitment for convalescent plasma treatment for patients hospitalised with COVID-19|url=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|url-status=live|archive-url=|archive-date=|access-date=15 January 2021|website=}}</ref> The article with full results was published on 14 May 2021.<ref>{{Cite journal|date=2021-05-14|title=Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial|url=https://linkinghub.elsevier.com/retrieve/pii/S0140673621008977|journal=The Lancet|language=en|pages=2049–2059|doi=10.1016/S0140-6736(21)00897-7|pmc=8121538|authors=RECOVERY Collaborative Group|volume=397|issue=10289|pmid=34000257}}</ref>
In January 2021, the chief investigators announced the closure of the convalescent plasma arm of the trial. Among 1873 reported deaths from 10,405 patients, the trial reported "no significant difference in the primary endpoint of 28-day mortality (18% convalescent plasma vs. 18% usual care alone; risk ratio 1.04 [95% confidence interval 0.95-1.14]; p=0.34)".<ref name="Plasma-20210115">{{cite web|last1=RECOVERY trial chief investigators|date=15 January 2021|title=Recovery trial closes recruitment for convalescent plasma treatment for patients hospitalised with COVID-19|url=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|access-date=15 January 2021|website=}}</ref> The article with full results was published on 14 May 2021.<ref>{{Cite journal|date=2021-05-14|title=Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial|journal=The Lancet|language=en|pages=2049–2059|doi=10.1016/S0140-6736(21)00897-7 |issn=0140-6736|pmc=8121538|author=RECOVERY Collaborative Group|volume=397|issue=10289|pmid=34000257}}</ref>


===Tocilizumab===
===Tocilizumab===
Tocilizumab significantly reduces the risk of death when given to hospitalised patients with severe COVID-19. 2022 patients allocated to Tocilizumab were compared to 2094 who received standard hospital care. "''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%.''" Receiving tocilizumab also increased the chance of discharge from hospital within 28 days.<ref name="Tocilizumab-20210211">{{cite web |title=Tocilizumab reduces deaths in patients hospitalised with COVID-19 |url=https://www.recoverytrial.net/news/tocilizumab-reduces-deaths-in-patients-hospitalised-with-covid-19 |website=Recovery Trial |access-date=11 February 2021 |date=11 February 2021}}</ref><ref name="BBC-20210211">{{cite web |author1=Michelle Roberts |title=Arthritis drug tocilizumab cuts deaths from Covid |url=https://www.bbc.co.uk/news/health-56024772 |website=BBC News Online |publisher=BBC |access-date=11 February 2021 |date=11 February 2021}}</ref><ref name="pmid33933194">{{cite journal | vauthors = Gupta S, Leaf DE | title = Tocilizumab in COVID-19: some clarity amid controversy | journal = Lancet | volume = 397 | issue = 10285 | pages = 1599–1601 | date = May 2021 | pmid = 33933194 | doi = 10.1016/S0140-6736(21)00712-1 | pmc = 8084409 | url = | doi-access = free }}</ref>
Tocilizumab significantly reduces the risk of death when given to hospitalised patients with severe COVID-19. 2022 patients allocated to Tocilizumab were compared to 2094 who received standard hospital care. "''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%.''" Receiving tocilizumab also increased the chance of discharge from hospital within 28 days.<ref name="Tocilizumab-20210211">{{cite web |title=Tocilizumab reduces deaths in patients hospitalised with COVID-19 |url=https://www.recoverytrial.net/news/tocilizumab-reduces-deaths-in-patients-hospitalised-with-covid-19 |website=Recovery Trial |access-date=11 February 2021 |date=11 February 2021}}</ref><ref name="BBC-20210211">{{cite web |author1=Michelle Roberts |title=Arthritis drug tocilizumab cuts deaths from Covid |url=https://www.bbc.co.uk/news/health-56024772 |website=BBC News Online |publisher=BBC |access-date=11 February 2021 |date=11 February 2021}}</ref><ref name="pmid33933194">{{cite journal | vauthors = Gupta S, Leaf DE | title = Tocilizumab in COVID-19: some clarity amid controversy | journal = Lancet | volume = 397 | issue = 10285 | pages = 1599–1601 | date = May 2021 | pmid = 33933194 | doi = 10.1016/S0140-6736(21)00712-1 | pmc = 8084409 | url = | doi-access = free }}</ref><ref>{{cite journal | author=RECOVERY Collaborative Group |title=Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. |journal=Lancet |date=2021-05-01 |volume=397 |issue=10285 |pages=1637–1645 |doi=10.1016/S0140-6736(21)00676-0 |pmid=33933206 |pmc=8084355 |hdl=2164/16630 |hdl-access=free }}</ref>
<ref>{{cite journal |last1=RECOVERY Collaborative |first1=Group. |title=Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. |journal=Lancet (London, England) |date=2021-05-01 |volume=397 |issue=10285 |pages=1637-1645 |doi=10.1016/S0140-6736(21)00676-0 |pmid=33933206 |url=https://pubmed.ncbi.nlm.nih.gov/33933206/ |access-date=25 June 2021}}</ref>


This result supports the earlier findings of the Remap-Cap trial on the effectiveness of Tocilizumab for patients in intensive care, and extends those findings to a wider group of patients.<ref name="Guardian-20210211">{{cite web |author1=Nicola Davis |title=Arthritis drug that helps Covid ICU patients has wider benefits, trial finds |url=https://www.theguardian.com/world/2021/feb/11/arthritis-drug-tocilizumab-found-to-help-covid-icu-patients-has-wider-benefits-trial-finds |website=Guardian News |publisher=The Guardian |access-date=11 February 2021 |date=11 February 2021}}</ref>
This result supports the earlier findings of the Remap-Cap trial on the effectiveness of Tocilizumab for patients in intensive care, and extends those findings to a wider group of patients.<ref name="Guardian-20210211">{{cite web |author1=Nicola Davis |title=Arthritis drug that helps Covid ICU patients has wider benefits, trial finds |url=https://www.theguardian.com/world/2021/feb/11/arthritis-drug-tocilizumab-found-to-help-covid-icu-patients-has-wider-benefits-trial-finds |website=The Guardian |access-date=11 February 2021 |date=11 February 2021}}</ref>

===Dimethyl fumarate===
A study published in January 2024 by the trial's chief investigators found that dimethyl fumarate did not significantly improve clinical outcomes in hospitalized COVID-19 patients.<ref name="pmid38296965">{{cite journal |vauthors=Horby PW, Peto L, Staplin N, Campbell M, Pessoa-Amorim G, Mafham M, Emberson JR, Stewart R, Prudon B, Uriel A, Green CA, Dhasmana DJ, Malein F, Majumdar J, Collini P, Shurmer J, Yates B, Baillie JK, Buch MH, Day J, Faust SN, Jaki T, Jeffery K, Juszczak E, Knight M, Lim WS, Montgomery A, Mumford A, Rowan K, Thwaites G, Haynes R, Landray MJ |title=Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial |journal=[[Nature Communications]] |volume=15 |issue=1 |pages=924 |date=January 2024 |pmid=38296965 |pmc=10831058 |doi=10.1038/s41467-023-43644-x}}</ref>


==See also==
==See also==
*[[Solidarity trial]]
* [[Solidarity trial]]
* [[PANORAMIC|PANORAMIC trial]]
*[[COVID-19 drug development]]
* [[AGILE|AGILE trial]]
* [[COVID-19 drug development]]


==References==
==References==
Line 181: Line 125:


==External links==
==External links==
* {{Official website}}
*[https://www.recoverytrial.net/ RECOVERY Trial website]
*[https://www.recoverytrial.net/files/recovery-protocol-v12-1-2020-12-16.pdf Trial Protocol (v12.1) dated 2020-12-16]
* [https://www.recoverytrial.net/files/recovery-protocol-v12-1-2020-12-16.pdf Trial Protocol (v12.1) dated 2020-12-16]
*[https://www.bbc.co.uk/news/health-53096736 BBC Article: How breakthrough coronavirus drug dexamethasone was found]
*[https://www.medrxiv.org/content/10.1101/2020.06.22.20137273v1 (BMJ preprint, 22 June 2020) Effect of Dexamethasone in Hospitalized Patients with COVID-19: Preliminary Report]


{{COVID-19 pandemic in the United Kingdom, Crown Dependencies and British Overseas Territories}}
{{Portal bar | Medicine | Viruses | COVID-19}}
{{Portal bar | Medicine | Viruses | COVID-19}}


{{COVID-19 pandemic in the United Kingdom, Crown Dependencies and British Overseas Territories}}
[[Category:COVID-19 pandemic in the United Kingdom]]
[[Category:Clinical trials related to COVID-19]]

[[Category:Clinical trials]]
[[Category:Medical responses to the COVID-19 pandemic]]
[[Category:Medical responses to the COVID-19 pandemic]]
[[Category:United Kingdom responses to the COVID-19 pandemic]]

Latest revision as of 19:12, 22 November 2024

Not to be confused with RECOVER Initiative.

RECOVERY: Randomized Evaluation of COVID-19 Therapy
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Part of a series on the
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The Randomised Evaluation of COVID-19 Therapy (RECOVERY Trial)[1] is a large-enrollment clinical trial of possible treatments for people in the United Kingdom admitted to hospital with severe COVID-19 infection.[2][3][4] The trial was later expanded to Indonesia, Nepal and Vietnam.[5] The trial has tested ten interventions on adults: eight repurposed drugs, one newly developed drug and convalescent plasma.[2]

Overview

[edit]

The RECOVERY Trial is a large-scale, randomized controlled trial.[2][6] It is an "open label" study: people receiving the treatment and the attending clinicians both know which treatment is being administered.[2] It is a multi-arm adaptive clinical trial, meaning that new treatments can be added into the trial as it progresses, and other treatment "arms" closed to new enrolment when results have been produced.[4]

The very fast setting up of the trial was crucial for the fast-developing COVID-19 pandemic. Martin Landray, one of the trial's creators, said in March 2021 "I think it has set a new standard for what can be delivered and not just for pandemics. It would be a travesty if we went back to a situation where it takes years sometimes to get a trial off the ground."[7]

Enrollment

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When people who have been hospitalised with COVID-19 are enrolled in the trial, they are automatically randomized to receive trial treatments. If any treatment is contra-indicated (or positively indicated) for that patient, or is not available, then that treatment is not included in the randomization process. The main randomization stage has three parts, so that patients might be allocated none, one, two or three of the trial treatments. If their disease progresses, there may also be a second randomization.[8]

Goals

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The primary objective of the trial is to "provide reliable estimates of the effect of study treatments on all-cause mortality at 28 days after first randomization".[2][6]

The trial protocol was developed in March 2020. The design minimizes the administrative load on hospital staff, who at the time were facing the prospect of overwhelming numbers of COVID-19 admissions.[9][8]

Treatments

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As of 25 June 2021, the following treatments are allocated at random to hospitalized people with severe COVID-19 infection:[2]

Children with PIMS-TS may also be allocated the following:[10]

The following treatments have previously been included in the trial and obtained positive results:

The following treatments have previously been included in the trial and were closed to new entrants after being shown to be ineffective.:[11][12][13][14]

Operations

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The trial is run by the Nuffield Departments of Population Health and of Medicine at the University of Oxford[12][9] and supported by the National Institute for Health Research (NIHR). The study is led by Peter Horby and Martin Landray who serve as Co-Chief Investigators of the trial.[15][16] By July 2020, the trial was in progress at 176 NHS hospitals in the UK, involving many thousands of health professionals.[17]

The trial began in March 2020. As of March 2021 the trial had enrolled more than 40,000 COVID-19 participants admitted to hospitals in the UK;[7] the estimated primary completion date was December 2021, and the estimated study completion date was December 2031.[6][13]

Results

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Dexamethasone

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See also: COVID-19 drug repurposing research § Dexamethasone
Mortality over 28 days for 1007 COVID-19 patients on mechanical ventilation at time of randomisation: 324 patients who received dexamethasone (red) compared to 683 who received standard hospital care (black)[18]

In June 2020, preliminary results were published in a preprint showing that low-dose dexamethasone treatment reduced the death rate by one third in hospitalized people needing ventilators due to severe COVID-19 infection, and by one fifth in people treated with oxygen therapy. There was no benefit (and the possibility of harm) among people who did not require oxygen.[18] The preliminary report was subsequently published in The New England Journal of Medicine.[19]

Impacts

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Six days before the pre-print, these results had been announced in a news release.[20] A UK Therapeutic Alert was issued the same day, and all the Chief Medical Officers in the United Kingdom exceptionally recommended an immediate change of UK-wide clinical practice, in advance of publication of any final paper.[21]

Demand for dexamethasone surged after publication of the preprint.[22]

Based on the preliminary, unpublished results of the RECOVERY trial, the US National Institutes of Health COVID-19 Treatment Guidelines Panel recommended dexamethasone in patients with COVID-19 who are on mechanical ventilation or those who require supplemental oxygen, and recommended against dexamethasone for those not requiring supplemental oxygen.[23]

Other countries granted specific approval for the drug as part of standard medical care, among them Japan,[24] Taiwan[25] and South Africa.[26]

A pre-print study, which was awarded Health Data Research UK Open Access Publication of the Month for August 2020, found that the discovery would save approximately 650,000 lives globally over the course of six months.[27][28]

Limitations of dexamethasone result

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Mortality over 28 days for 1535 COVID-19 patients not receiving oxygen at time of randomisation: 501 patients who received dexamethasone (red) compared to 1034 who received standard hospital care (black)[18]

John Fletcher, research editor at the BMJ, noted that there were "limitations and causes of concern" in the dexamethasone results.[22]

  • Around a third of patients in the trial were still in hospital at the end of the 28-day trial period, so their final outcomes were not known.[22]
  • As an immunosuppressive drug, there are fears that dexamethasone could make the illness worse, and prolong the infection in patients where the immune system has not yet overreacted and caused inflammation.[9][29]
  • The preprint authors themselves warned that "the results are consistent with possible harm" in patients who did not require oxygen at the time of enrolment.[18] The trial observed a 22% increase in mortality in these patients (rate ratio 1.22 [95% Confidence Interval 0.93 to 1.61]; p=0.14), though this observation may still be due to chance.[18]
  • Responding to the publication, the WHO emphasized that dexamethasone should only be used for patients with severe or critical disease, under close clinical supervision, stating that "There is no evidence this drug works for patients with mild disease or as a preventative measure, and it could cause harm."[30]

Confirmation of dexamethasone result

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The results of this initial finding were replicated in a systematic review published in September 2020 by the WHO's Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group.[31]

Hydroxychloroquine

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Main article: Chloroquine and hydroxychloroquine during the COVID-19 pandemic

In June 2020, the trial determined that there was no clinical benefit from use of hydroxychloroquine in people hospitalized with COVID-19.[12]

Lopinavir-ritonavir

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In June 2020, chief investigators of the trial reported there was no clinical benefit from use of lopinavir-ritonavir in 1,596 people hospitalized with severe COVID-19 infection over 28 days of treatment.[11] These results were published in The Lancet on 5 October 2020.[32]

Azithromycin

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In December 2020, the chief investigators announced that they had found no benefit from azithromycin in patients hospitalised with COVID-19. 2582 patients had received azithromycin, and 5182 were randomised to usual care alone. 28-day mortality in both cohorts was 19%.[13] These preliminary results were released as a preprint on the same day.[33][34]

Convalescent plasma

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In January 2021, the chief investigators announced the closure of the convalescent plasma arm of the trial. Among 1873 reported deaths from 10,405 patients, the trial reported "no significant difference in the primary endpoint of 28-day mortality (18% convalescent plasma vs. 18% usual care alone; risk ratio 1.04 [95% confidence interval 0.95-1.14]; p=0.34)".[14] The article with full results was published on 14 May 2021.[35]

Tocilizumab

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Tocilizumab significantly reduces the risk of death when given to hospitalised patients with severe COVID-19. 2022 patients allocated to Tocilizumab were compared to 2094 who received standard hospital care. "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%." Receiving tocilizumab also increased the chance of discharge from hospital within 28 days.[36][37][38][39]

This result supports the earlier findings of the Remap-Cap trial on the effectiveness of Tocilizumab for patients in intensive care, and extends those findings to a wider group of patients.[40]

Dimethyl fumarate

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A study published in January 2024 by the trial's chief investigators found that dimethyl fumarate did not significantly improve clinical outcomes in hospitalized COVID-19 patients.[41]

See also

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References

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  1. ^ "ISRCTN - ISRCTN50189673: A randomised trial of treatments to prevent death in patients hospitalised with COVID-19 (coronavirus)". www.isrctn.com.
  2. ^ a b c d e f "RECOVERY Trial". Retrieved 17 June 2020.
  3. ^ "Coronavirus: Dexamethasone being used to treat NHS patients today". BBC News. 17 June 2020. Retrieved 17 June 2020.
  4. ^ a b "Biggest COVID-19 trial tests repurposed drugs first". Nature Biotechnology. 38 (5): 510. 11 May 2020. doi:10.1038/s41587-020-0528-x. PMID 32393915. S2CID 218593584.
  5. ^ "International sites — RECOVERY Trial". www.recoverytrial.net. Retrieved 17 May 2021.
  6. ^ a b c Clinical trial number NCT04381936 for "Randomised Evaluation of COVID-19 Therapy (RECOVERY)" at ClinicalTrials.gov. 2 March 2021; page is updated from time to time.
  7. ^ a b Gallagher J (25 March 2021). "Covid: The London bus trip that saved maybe a million lives". BBC News.
  8. ^ a b "Randomised evaluation of COVID-19 therapy (RECOVERY) – Trial protocol v11" (PDF). RECOVERY Trial. 21 November 2020. Retrieved 14 December 2020.
  9. ^ a b c Fergus Walsh (20 June 2020). "At last some good news about coronavirus". BBC News. Retrieved 20 June 2020.
  10. ^ "Recovery Trial Protocol v15" (PDF). Recovery Trial. Retrieved 4 February 2021.
  11. ^ a b "No clinical benefit from use of lopinavir-ritonavir in hospitalised COVID-19 patients studied in RECOVERY" (PDF). RECOVERY Trial: Statement from the Chief Investigators. 29 June 2020. Retrieved 30 June 2020.
  12. ^ a b c "No clinical benefit from use of hydroxychloroquine in hospitalised patients with COVID-19". Recovery Trial, Nuffield Department of Population Health, University of Oxford, UK. 5 June 2020. Retrieved 7 June 2020.
  13. ^ a b c Peter Horby, Martin Landray (14 December 2020). "RECOVERY trial finds no benefit from azithromycin in patients hospitalised with COVID-19". RECOVERY Trial.
  14. ^ a b RECOVERY trial chief investigators (15 January 2021). "Recovery trial closes recruitment for convalescent plasma treatment for patients hospitalised with COVID-19". Retrieved 15 January 2021.
  15. ^ "Preliminary trial results find dexamethasone reduces death in hospitalised patients with severe respiratory complications of COVID-19 - UK Research and Innovation". www.ukri.org. UK Research and Innovation. Archived from the original on 24 October 2020. Retrieved 19 October 2020.
  16. ^ Boseley S (17 June 2020). "Dexamethasone: low-cost drug helps prevent deaths of sickest coronavirus patients". The Guardian.
  17. ^ Kupferschmidt K (2 July 2020). "One U.K. trial is transforming COVID-19 treatment. Why haven't others delivered more results?". Science. Retrieved 19 October 2020.
  18. ^ a b c d e RECOVERY Collaborative Group (2020). "Effect of Dexamethasone in Hospitalized Patients with COVID-19 – Preliminary Report". medRxiv 10.1101/2020.06.22.20137273v1.
  19. ^ Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, et al. (July 2020). "Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report". New England Journal of Medicine. 384 (8): 693–704. doi:10.1056/NEJMoa2021436. PMC 7383595. PMID 32678530.
  20. ^ "Dexamethasone reduces death in hospitalised patients with severe respiratory complications of COVID-19". University of Oxford. 16 June 2020. Retrieved 16 June 2020.
  21. ^ "Dexamethasone in COVID-19" (PDF). 16 June 2020. Retrieved 23 June 2020.
  22. ^ a b c Mahase E (June 2020). "Covid-19: Demand for dexamethasone surges as RECOVERY trial publishes preprint". BMJ. 369: m2512. doi:10.1136/bmj.m2512. PMID 32576548.
  23. ^ "The National Institutes of Health COVID-19 Treatment Guidelines Panel Provides Recommendations for Dexamethasone in Patients with COVID-19". NIH COVID-19 Treatment Guidelines. National Institutes of Health. 25 June 2020. Retrieved 26 June 2020.
  24. ^ hermesauto (22 July 2020). "Japan approves dexamethasone as coronavirus treatment". The Straits Times. Retrieved 6 September 2020.
  25. ^ "Taiwan provisionally approves dexamethasone as coronavirus treatment". Reuters. 4 August 2020. Retrieved 6 September 2020.
  26. ^ "South Africa approves dexamethasone to treat COVID-19". www.aa.com.tr.
  27. ^ "The potential health and economic impact of dexamethasone treatment for patients with COVID-19". HDR UK. Retrieved 6 September 2020.
  28. ^ Aguas R, Mahdi A, Shretta R, Horby P, Landray M, White LJ (30 July 2020). "The potential health and economic impact of dexamethasone treatment for patients with COVID-19". medRxiv 10.1101/2020.07.29.20164269v1.
  29. ^ Roni Caryn Rabin (24 June 2020). "Breakthrough Drug for Covid-19 May Be Risky for Mild Cases". New York Times. Retrieved 25 June 2020.
  30. ^ "WHO Director-General's opening remarks at the media briefing on COVID-19 - 22 June 2020". World Health Organization. Retrieved 25 June 2020.
  31. ^ The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Sterne JA, Murthy S, Diaz JV, Slutsky AS, Villar J, et al. (2 September 2020). "Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis". JAMA. 324 (13): 1330–1341. doi:10.1001/jama.2020.17023. PMC 7489434. PMID 32876694.{{cite journal}}: CS1 maint: numeric names: authors list (link)
  32. ^ Horby PW, Mafham M, Bell JL, Linsell L, Staplin N, Emberson J, et al. (5 October 2020). "Lopinavir–ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial". The Lancet. 396 (10259): 1345–1352. doi:10.1016/S0140-6736(20)32013-4. PMC 7535623. PMID 33031764.
  33. ^ Horby PW, Roddick A, Spata E, Staplin N, Emberson JR, Pessoa-Amorim G, et al. (14 December 2020). "Azithromycin in Hospitalised Patients with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial". medRxiv 10.1101/2020.12.10.20245944v1.
  34. ^ RECOVERY Collaborative Group (13 February 2021). "Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial". Lancet. 397 (10274): 605–612. doi:10.1016/S0140-6736(21)00149-5. hdl:10044/1/86993. PMC 7884931. PMID 33545096.
  35. ^ RECOVERY Collaborative Group (14 May 2021). "Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial". The Lancet. 397 (10289): 2049–2059. doi:10.1016/S0140-6736(21)00897-7. ISSN 0140-6736. PMC 8121538. PMID 34000257.
  36. ^ "Tocilizumab reduces deaths in patients hospitalised with COVID-19". Recovery Trial. 11 February 2021. Retrieved 11 February 2021.
  37. ^ Michelle Roberts (11 February 2021). "Arthritis drug tocilizumab cuts deaths from Covid". BBC News Online. BBC. Retrieved 11 February 2021.
  38. ^ Gupta S, Leaf DE (May 2021). "Tocilizumab in COVID-19: some clarity amid controversy". Lancet. 397 (10285): 1599–1601. doi:10.1016/S0140-6736(21)00712-1. PMC 8084409. PMID 33933194.
  39. ^ RECOVERY Collaborative Group (1 May 2021). "Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial". Lancet. 397 (10285): 1637–1645. doi:10.1016/S0140-6736(21)00676-0. hdl:2164/16630. PMC 8084355. PMID 33933206.
  40. ^ Nicola Davis (11 February 2021). "Arthritis drug that helps Covid ICU patients has wider benefits, trial finds". The Guardian. Retrieved 11 February 2021.
  41. ^ Horby PW, Peto L, Staplin N, Campbell M, Pessoa-Amorim G, Mafham M, et al. (January 2024). "Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial". Nature Communications. 15 (1): 924. doi:10.1038/s41467-023-43644-x. PMC 10831058. PMID 38296965.
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