Condition category
Infections and Infestations
Date applied
30/03/2020
Date assigned
02/04/2020
Last edited
06/10/2020
Prospective/Retrospective
Retrospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
In early 2020, as this study was being developed, there were no approved treatments for COVID-19, a disease caused 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, including lopinavir + ritonavir, low-dose corticosteroids and hydroxychloroquine. These groups also advised that other treatments will soon emerge that require evaluation. A World Health Organization (WHO) expert group issued broadly similar advice.
This study aims to compare several different treatments that may be useful for patients with COVID-19. Some are tablets and some are injections. Although these treatments show promise, nobody knows if any of them will turn out to be more effective in helping patients recover than the usual hospital standard of care (which all patients will receive). However, the side-effects are well-known from other uses and doctors will be able to monitor patients appropriately.

Who can participate?
Patients may be included in this study if they have COVID-19 (clinically suspected or laboratory-confirmed), and are in hospital. Patients will not be included if the attending doctor thinks there is a particular reason why none of the study treatments are suitable.

What does the study involve?
If a patient decides to join, they will be asked to sign the consent form (for children, their parent/guardian will sign the consent form). Next, brief details identifying them and answering a few questions about their health and medical conditions will be entered into a computer. The computer will then allocate them at random (like rolling a dice) to one of the possible treatment options. The treatments are: corticosteroids for children only (a type of steroid used in a range of conditions typically to reduce inflammation); or azithromycin (a commonly used antibiotic); or intravenous immunoglobulin (which is commonly used to treat a similar but different inflammatory condition called Kawasaki disease) (children only).
Simultaneously, eligible patients are allocated to no additional treatment; or convalescent plasma (which has been collected from individuals who have recovered from COVID-19 infection and contains antibodies to the virus that may help fight the virus); or synthetic neutralising antibodies (synthetic human monoclonal antibodies have been developed to bind to and neutralise the virus. Such antibodies may accelerate clearance of the virus and clinical improvement).
The researchers will also collect a sample of serum from these participants to measure coronavirus and antibodies against it. For patients whose condition is more severe, tocilizumab (a treatment for rheumatoid arthritis) is also an option. The additional treatment might be given by mouth or injection. Neither patients nor their doctors can choose which of these options will be allocated. In all cases, treatment will include the usual standard of care for the hospital.

What are the possible benefits and risks of participating?
The study treatment may or may not help patients personally, but this study should help future patients. Apart from the known side effects of these treatments (which may include tummy upset, ‘flu-like symptoms, and blood test abnormalities), there is the unlikely possibility of a severe reaction to a study drug. Although tocilizumab has been very rarely associated with liver damage in prolonged use this is not expected to be a problem with the short-term administration in this study. The potential side effects of plasma transfusions include allergic reactions (rash, fever, chills) and increased difficulty breathing and are easily treated. The plasma will undergo all the usual testing for the presence of other infections, but a very small risk of infection transmission does remain. Patients should ask their hospital doctor if they would like more information. Once a participant has been included in the study, they and their doctors will know which treatment the computer has allocated. Doctors will be aware of whether there are any particular side effects that they should look out for.
Women who are pregnant may be included, however, the effect of some of the treatments on unborn babies is uncertain - although all the treatments have previously been used in pregnancy for other medical conditions without safety concerns being raised. If a patient receives treatment and is not already pregnant, as a precaution, the researchers advise that they should not get pregnant within 3 months of the completion of the trial treatment(s).

Where is the study run from?
The study is being conducted by researchers at the University of Oxford, which acts as the sponsor for the research, working with doctors at many hospitals across the UK.

When is the study starting and how long is it expected to run for?
The study started in March 2020. It is not yet known how long this study will run for but we anticipate it will be at least the duration of the current COVID-19 epidemic.

Who is funding the study?
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, the Department for International Development (DfID), Health Data Research UK, the NIHR Health Protection Research Unit in Emerging and Zoonotic Infections and the Medical Research Council Population Health Research Unit, and NIHR Clinical Trials Unit Support Funding.

Who is the main contact?
Prof. Peter Horby (Chief Investigator)
recoverytrial@ndph.ox.ac.uk


Trial website

https://www.recoverytrial.net/

Contact information

Type

Scientific

Primary contact

Prof Peter Horby

ORCID ID

http://orcid.org/0000-0002-9822-1586

Contact details

University of Oxford
New Richards Building
Old Road Campus
Headington
Oxford
OX3 7LG
United Kingdom
-
recoverytrial@ndph.ox.ac.uk

Type

Public

Additional contact

Ms Michelle Nunn

ORCID ID

Contact details

CTSU
Nuffield Department of Population Health
University of Oxford
Richard Doll Building
Old Road Campus
Oxford
OX3 7LF
United Kingdom
-
recoverytrial@ndph.ox.ac.uk

Additional identifiers

EudraCT number

2020-001113-21

ClinicalTrials.gov number

NCT04381936

Protocol/serial number

NDPHRECOVERY, CPMS 45388, IRAS 281712

Study information

Scientific title

Randomized evaluation of COVID-19 therapy

Acronym

RECOVERY

Study hypothesis

Current study hypothesis as of 25/09/2020:
Does treatment with lopinavir + ritonavir, hydroxychloroquine, corticosteroids, azithromycin, intravenous immunoglobulin (children only), convalescent plasma, synthetic neutralising antibodies or tocilizumab prevent death in hospitalised patients with COVID-19?

Previous study hypothesis as of 21/08/2020:
Does treatment with either lopinavir + ritonavir, hydroxychloroquine, corticosteroids, azithromycin, intravenous immunoglobulin (children only), convalescent plasma or tocilizumab prevent death in hospitalised patients with COVID-19?

Previous study hypothesis as of 27/05/2020:
Does treatment with either lopinavir + ritonavir, hydroxychloroquine, corticosteroids, azithromycin, convalescent plasma or tocilizumab prevent death in hospitalised patients with COVID-19?

Previous study hypothesis as of 07/05/2020:
Does treatment with either lopinavir + ritonavir, hydroxychloroquine, corticosteroids, azithromycin or tocilizumab prevent death in hospitalised patients with COVID-19?

Original study hypothesis:
Does treatment with either lopinavir + ritonavir, inhaled interferon β1a, hydroxychloroquine or low-dose corticosteroids prevent death in hospitalised patients with COVID-19?

Ethics approval

Approved 17/03/2020, East of England - Cambridge East Research Ethics Committee (The Old Chapel, Royal Standard Place, Nottingham, NG1 6FS, UK; +44 (0)207 972 2503; CambridgeEast.REC@hra.nhs.uk), REC ref: 20/EE/0101

Study design

Randomised adaptive trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

https://www.recoverytrial.net/

Condition

Severe Acute Respiratory Syndrome, COVID-19 (SARS coronavirus 2 [SARS-CoV-2] infection)

Intervention

Current intervention as of 25/09/2020:

RECOVERY is a randomised trial among people hospitalised for COVID-19. 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: No additional treatment vs corticosteroids (for children only) vs azithromycin vs intravenous immunoglobulin (children only). In a factorial design, eligible patients are allocated simultaneously to no additional treatment vs convalescent plasma vs synthetic neutralising antibodies. The study allows a subsequent randomisation for patients with progressive COVID-19 (evidence of hypoxia [or in children a hyper-inflammatory state] and raised inflammatory markers): No additional treatment vs tocilizumab. For patients for whom not all the trial arms are appropriate or at locations where not all are available, randomisation will be between fewer arms.

RECOVERY has an adaptive trial design. The interim trial results will be monitored by an independent Data Monitoring Committee (DMC). The DMC will assess whether the randomised comparisons in the study have provided evidence on mortality that is strong enough (with a range of uncertainty around the results that is narrow enough) to affect national and global treatment strategies. In such a circumstance, the DMC will inform the Trial Steering Committee who will make the results available to the public and amend the trial arms accordingly. New trial arms can be added as evidence emerges that other candidate therapeutics should be evaluated.

Drug dosage and duration
Main randomisation part A:
1. Lopinavir 400 mg + ritonavir 100 mg: by mouth (or nasogastric tube) every 12 h for 10 days or until discharge (treatment arm closed, preliminary results reported)
2. Corticosteroid in the form of dexamethasone: administered as an oral (liquid or tablets) or intravenous preparation 6 mg once daily for 10 days. In pregnancy or breastfeeding women, prednisolone 40 mg administered by mouth (or intravenous hydrocortisone 80 mg twice daily) should be used instead of dexamethasone. (Note: It is permitted to switch between the two routes of administration according to clinical circumstances) (treatment arm closed to adults, preliminary results reported)
Corticosteroid (in children ≤44 weeks gestational age, or >44 weeks gestational age with PIMS-TS only) in the form of hydrocortisone or methylprednisolone sodium succinate (see protocol for dose and duration)
3. Hydroxychloroquine: by mouth for a total of 10 days (see protocol for timing and dosing) (treatment arm closed, preliminary results reported)
4. Azithromycin 500 mg: by mouth (or nasogastric tube) or intravenously once daily for 10 days
5. Intravenous immunoglobulin (IVIg) for children >44 weeks gestational age and <18 years with PIMS-TS only (see protocol for dose)

Main randomisation part B:
1. Convalescent plasma: Single unit of ABO compatible convalescent plasma (275 ml +/- 75 ml) intravenous per day on study days 1 (as soon as possible after randomisation) and 2 (with a minimum of 12-h interval between 1st and 2nd units).
2. Synthetic neutralising antibodies for participants aged ≥12 years only: A single dose of REGN10933 + REGN10987 8 g (4 g of each monoclonal antibody) in 250 ml 0.9% saline infused intravenously over 60 min +/- 15 min as soon as possible after randomisation

Second randomisation for patients with progressive COVID-19:
Tocilizumab by intravenous infusion with the dose determined by body weight (see protocol for dosing).

Dosing for children provided in the protocol.

All randomised participants are to be followed up until death, discharge from hospital or 28 days after randomisation (whichever is sooner).

Longer-term (up to 10 years) follow-up will be sought through linkage to electronic healthcare records and medical databases including those held by NHS Digital and equivalent bodies, and to relevant research databases (e.g. UK Biobank, Genomics England, ISARIC-4C and PHOSP-COVID).

_____

Previous intervention as of 21/08/2020:

RECOVERY is a randomised trial among people hospitalised for COVID-19. 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: No additional treatment vs corticosteroids (for children only) vs azithromycin vs intravenous immunoglobulin (children only). In a factorial design, eligible patients are allocated simultaneously to no additional treatment vs convalescent plasma. The study allows a subsequent randomisation for patients with progressive COVID-19 (evidence of hypoxia [or in children a hyper-inflammatory state] and raised inflammatory markers): No additional treatment vs tocilizumab. For patients for whom not all the trial arms are appropriate or at locations where not all are available, randomisation will be between fewer arms.

RECOVERY has an adaptive trial design. The interim trial results will be monitored by an independent Data Monitoring Committee (DMC). The DMC will assess whether the randomised comparisons in the study have provided evidence on mortality that is strong enough (with a range of uncertainty around the results that is narrow enough) to affect national and global treatment strategies. In such a circumstance, the DMC will inform the Trial Steering Committee who will make the results available to the public and amend the trial arms accordingly. New trial arms can be added as evidence emerges that other candidate therapeutics should be evaluated.

Drug dosage and duration
Main randomisation part A:
1. Lopinavir 400 mg + ritonavir 100 mg: by mouth (or nasogastric tube) every 12 hours for 10 days or until discharge (treatment arm closed, preliminary results reported)
2. Corticosteroid in the form of dexamethasone: administered as an oral (liquid or tablets) or intravenous preparation 6 mg once daily for 10 days. In pregnancy or breastfeeding women, prednisolone 40 mg administered by mouth (or intravenous hydrocortisone 80 mg twice daily) should be used instead of dexamethasone. (Note: It is permitted to switch between the two routes of administration according to clinical circumstances) (treatment arm closed to adults, preliminary results reported)
Corticosteroid (in children ≤44 weeks gestational age, or >44 weeks gestational age with PIMS-TS only) in the form of hydrocortisone or methylprednisolone sodium succinate (see protocol for dose and duration)
3. Hydroxychloroquine: by mouth for a total of 10 days (see protocol for timing and dosing) (treatment arm closed, preliminary results reported)
4. Azithromycin 500mg: by mouth (or nasogastric tube) or intravenously once daily for 10 days
5. Intravenous immunoglobulin (IVIg) for children >44 weeks gestational age and <18 years with PIMS-TS only (see protocol for dose)

Main randomisation part B:
Convalescent plasma: Single unit of ABO compatible convalescent plasma (275 ml +/- 75 ml) intravenous per day on study days 1 (as soon as possible after randomisation) and 2 (with a minimum of 12-hour interval between 1st and 2nd units).

Second randomisation for patients with progressive COVID-19:
Tocilizumab by intravenous infusion with the dose determined by body weight (see protocol for dosing).

Dosing for children provided in the protocol.

All randomised participants are to be followed up until death, discharge from hospital or 28 days after randomisation (whichever is sooner).

Longer-term (up to 10 years) follow-up will be sought through linkage to electronic healthcare records and medical databases including those held by NHS Digital, Public Health England and equivalent bodies, and to relevant research databases (e.g. UK Biobank, Genomics England).

______

Previous intervention as of 02/07/2020:

RECOVERY is a randomised trial among people hospitalised for COVID-19. 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: No additional treatment vs corticosteroids (for children only) vs azithromycin. In a factorial design, eligible patients are allocated simultaneously to no additional treatment vs convalescent plasma. The study allows a subsequent randomisation for patients with progressive COVID-19 (evidence of hypoxia [or in children a hyper-inflammatory state] and raised inflammatory markers): No additional treatment vs Tocilizumab. For patients for whom not all the trial arms are appropriate or at locations where not all are available, randomisation will be between fewer arms.

RECOVERY has an adaptive trial design. The interim trial results will be monitored by an independent Data Monitoring Committee (DMC). The DMC will assess whether the randomised comparisons in the study have provided evidence on mortality that is strong enough (with a range of uncertainty around the results that is narrow enough) to affect national and global treatment strategies. In such a circumstance, the DMC will inform the Trial Steering Committee who will make the results available to the public and amend the trial arms accordingly. New trial arms can be added as evidence emerges that other candidate therapeutics should be evaluated.

Drug dosage and duration
Main randomisation part A:
1. Lopinavir 400 mg + ritonavir 100 mg: by mouth (or nasogastric tube) every 12 hours for 10 days or until discharge (treatment arm closed, preliminary results reported)
2. Corticosteroid in the form of dexamethasone: administered as an oral (liquid or tablets) or intravenous preparation 6 mg once daily for 10 days. In pregnancy or breastfeeding women, prednisolone 40 mg administered by mouth (or intravenous hydrocortisone 80 mg twice daily) should be used instead of dexamethasone. (Note: It is permitted to switch between the two routes of administration according to clinical circumstances) (treatment arm closed to adults, preliminary results reported)
3. Hydroxychloroquine: by mouth for a total of 10 days (see protocol for timing and dosing) (treatment arm closed, preliminary results reported)
4. Azithromycin 500mg: by mouth (or nasogastric tube) or intravenously once daily for 10 days

Main randomisation part B:
Convalescent plasma: Single unit of ABO compatible convalescent plasma (275 ml +/- 75 ml) intravenous per day on study days 1 (as soon as possible after randomisation) and 2 (with a minimum of 12-hour interval between 1st and 2nd units).

Second randomisation for patients with progressive COVID-19:
Tocilizumab by intravenous infusion with the dose determined by body weight (see protocol for dosing).

Dosing for children provided in the protocol.

All randomised participants are to be followed up until death, discharge from hospital or 28 days after randomisation (whichever is sooner).

Longer-term (up to 10 years) follow-up will be sought through linkage to electronic healthcare records and medical databases including those held by NHS Digital, Public Health England and equivalent bodies, and to relevant research databases (e.g. UK Biobank, Genomics England).

______

Previous intervention as of 27/05/2020:

RECOVERY is a randomised trial among people hospitalised for COVID-19. 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: No additional treatment vs lopinavir + ritonavir vs corticosteroids vs hydroxychloroquine vs azithromycin. In a factorial design, eligible patients are allocated simultaneously to no additional treatment vs convalescent plasma. The study allows a subsequent randomisation for patients with progressive COVID-19 (evidence of hypoxia [or in children a hyper-inflammatory state] and raised inflammatory markers): No additional treatment vs Tocilizumab. For patients for whom not all the trial arms are appropriate or at locations where not all are available, randomisation will be between fewer arms.

RECOVERY has an adaptive trial design. The interim trial results will be monitored by an independent Data Monitoring Committee (DMC). The DMC will assess whether the randomised comparisons in the study have provided evidence on mortality that is strong enough (with a range of uncertainty around the results that is narrow enough) to affect national and global treatment strategies. In such a circumstance, the DMC will inform the Trial Steering Committee who will make the results available to the public and amend the trial arms accordingly. New trial arms can be added as evidence emerges that other candidate therapeutics should be evaluated.

Drug dosage and duration
Main randomisation part A:
1. Lopinavir 400 mg + ritonavir 100 mg: by mouth (or nasogastric tube) every 12 hours for 10 days or until discharge
2. Corticosteroid in the form of dexamethasone: administered as an oral (liquid or tablets) or intravenous preparation 6 mg once daily for 10 days. In pregnancy or breastfeeding women, prednisolone 40 mg administered by mouth (or intravenous hydrocortisone 80 mg twice daily) should be used instead of dexamethasone. (Note: It is permitted to switch between the two routes of administration according to clinical circumstances)
3. Hydroxychloroquine: by mouth for a total of 10 days (see protocol for timing and dosing)
4. Azithromycin 500mg: by mouth (or nasogastric tube) or intravenously once daily for 10 days

Main randomisation part B:
Convalescent plasma: Single unit of ABO compatible convalescent plasma (275 ml +/- 75 ml) intravenous per day on study days 1 (as soon as possible after randomisation) and 2 (with a minimum of 12-hour interval between 1st and 2nd units).

Second randomisation for patients with progressive COVID-19:
Tocilizumab by intravenous infusion with the dose determined by body weight (see protocol for dosing).

Dosing for children provided in the protocol.

All randomised participants are to be followed up until death, discharge from hospital or 28 days after randomisation (whichever is sooner).

Longer-term (up to 10 years) follow-up will be sought through linkage to electronic healthcare records and medical databases including those held by NHS Digital, Public Health England and equivalent bodies, and to relevant research databases (e.g. UK Biobank, Genomics England).

______

Previous intervention as of 07/05/2020:

RECOVERY is a randomised trial among people hospitalised for COVID-19. 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: No additional treatment vs lopinavir + ritonavir vs corticosteroids vs hydroxychloroquine vs azithromycin. The study allows a second randomisation for patients with progressive COVID-19 (evidence of hypoxia and a hyper-inflammatory state): No additional treatment vs Tocilizumab. For patients for whom not all the trial arms are appropriate or at locations where not all are available, randomisation will be between fewer arms.

RECOVERY has an adaptive trial design. The interim trial results will be monitored by an independent Data Monitoring Committee (DMC). The DMC will assess whether the randomised comparisons in the study have provided evidence on mortality that is strong enough (with a range of uncertainty around the results that is narrow enough) to affect national and global treatment strategies. In such a circumstance, the DMC will inform the Trial Steering Committee who will make the results available to the public and amend the trial arms accordingly. New trial arms can be added as evidence emerges that other candidate therapeutics should be evaluated.

Drug dosage and duration
First (main) randomisation:
1. Lopinavir 400 mg + ritonavir 100 mg: by mouth (or nasogastric tube) every 12 hours for 10 days or until discharge
2. Corticosteroid in the form of dexamethasone: administered as an oral (liquid or tablets) or intravenous preparation 6 mg once daily for 10 days. In pregnancy or breastfeeding women, prednisolone 40 mg administered by mouth (or intravenous hydrocortisone 80 mg twice daily) should be used instead of dexamethasone. (Note: It is permitted to switch between the two routes of administration according to clinical circumstances)
3. Hydroxychloroquine: by mouth for a total of 10 days (see protocol for timing and dosing)
4. Azithromycin 500mg: by mouth (or nasogastric tube) or intravenously once daily for 10 days

Second randomisation for patients with progressive COVID-19:
Tocilizumab by intravenous infusion with the dose determined by body weight (see protocol for dosing).

Dosing for children provided in the protocol.

All randomised participants are to be followed up until death, discharge from hospital or 28 days after randomisation (whichever is sooner).

Longer-term (up to 10 years) follow-up will be sought through linkage to electronic healthcare records and medical databases including those held by NHS Digital, Public Health England and equivalent bodies, and to relevant research databases (e.g. UK Biobank, Genomics England).

______

Original intervention:

RECOVERY is a randomised trial among adults hospitalised for COVID-19. 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: No additional treatment vs lopinavir + ritonavir vs interferon 1β vs low-dose corticosteroids vs hydroxychloroquine. For patients for whom not all the trial arms are appropriate or at locations where not all are available, randomisation will be between fewer arms.

RECOVERY has an adaptive trial design. The interim trial results will be monitored by an independent Data Monitoring Committee (DMC). The DMC will assess whether the randomised comparisons in the study have provided evidence on mortality that is strong enough (with a range of uncertainty around the results that is narrow enough) to affect national and global treatment strategies. In such a circumstance, the DMC will inform the Trial Steering Committee who will make the results available to the public and amend the trial arms accordingly. New trial arms can be added as evidence emerges that other candidate therapeutics should be evaluated.

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: No additional treatment vs Lopinavir-Ritonavir vs Interferon 1β vs Low-dose Corticosteroids vs Hydroxychloroquine.
For patients for whom not all the trial arms are appropriate or at locations where not all are available, randomisation will be between fewer arms.

Drug dosage and duration:
Lopinavir 400 mg + ritonavir 100 mg: by mouth (or nasogastric tube) every 12 hours for 10 days or until discharge.
Interferon-β1a: Nebulized solution of IFN-β1a 6 MIU (0.5ml of a solution containing 12 MIU/ml) once daily for 10 days or until discharge.
Corticosteroid in the form of dexamethasone: administered as an oral (liquid or tablets) or intravenous preparation 6 mg once daily for 10 days or until discharge (Note: It is permitted to switch between the two routes of administration according to clinical circumstances).
Hydroxychloroquine: by mouth for a total of 10 days (see protocol for timing and dosing)

All randomised participants are to be followed up until death, discharge from hospital or 28 days after randomisation (whichever is sooner). Data from routine healthcare records (including linkage to medical databases held by organisations such as NHS Digital) will allow subsidiary analyses of the effect of the study treatments on particular non-fatal events, the influence of pre-existing major co-morbidity (e.g. diabetes, heart disease, lung disease), and longer-term outcomes (e.g. 6-month survival) as well as in particular sub-categories of patient.

Intervention type

Drug

Phase

Phase II/III

Drug names

Current drug names as of 25/09/2020:
Corticosteroids (for children only), azithromycin, intravenous immunoglobulin (IVIg) (for children only), tocilizumab, convalescent plasma, synthetic neutralising antibodies (REGN-COV2, comprising REGN-10933 + REGN-10987)

Previous drug names as of 21/08/2020:
Corticosteroids (for children only), azithromycin, intravenous immunoglobulin (IVIg)(for children only), tocilizumab, convalescent plasma

Previous drug names as of 02/07/2020:
Corticosteroids (for children only), azithromycin, tocilizumab, convalescent plasma

Previous drug names as of 27/05/2020:
Lopinavir + ritonavir, corticosteroids, hydroxychloroquine, azithromycin, tocilizumab, convalescent plasma

Previous drug names as of 07/05/2020:
Lopinavir + ritonavir, corticosteroids, hydroxychloroquine, azithromycin, tocilizumab

Original drug names:
Lopinavir + ritonavir, interferon-β1a, dexamethasone, hydroxychloroquine

Primary outcome measure

Current primary outcome measure as of 07/05/2020:
All-cause mortality at 28 days after randomisation. Data collected via a secure web-based case report form wherever possible, or otherwise via linkage to electronic health records.

Previous primary outcome measure:
Number of hospitalised patients who died within 28 days of randomisation, data collected via a secure web-based case report form

Secondary outcome measures

Current secondary outcome measures as of 25/09/2020:
1. Number of days stay in hospital
2. Among patients not on invasive mechanical ventilation at baseline, the number of patients with a composite endpoint of death or need for invasive mechanical ventilation or ECMO

Other outcome measures:
3. Number of patients who needed ventilation and the number of days it was required
4. Number of patients who needed renal replacement therapy
5. Number of patients developing new major cardiac arrhythmias

Data collected via a secure web-based case report form wherever possible, or otherwise via linkage to electronic health records. Study outcomes will be assessed based on data recorded up to 28 days and up to 6 months after the main randomisation.

_____

Current secondary outcome measures as of 02/07/2020:
1. Number of days stay in hospital
2. Among patients not on mechanical ventilation at baseline, the number of patients with a composite endpoint of death or need for mechanical ventilation or ECMO

Other outcome measures:
3. Number of patients who needed ventilation and the number of days it was required
4. Number of patients who needed renal replacement therapy
5. Number of patients developing new major cardiac arrhythmias

Data collected via a secure web-based case report form wherever possible, or otherwise via linkage to electronic health records. Study outcomes will be assessed based on data recorded up to 28 days and up to 6 months after the main randomisation.

_____

Previous secondary outcome measures as of 27/05/2020:
1. Number of days stay in hospital
2. Number of patients who needed ventilation and the number of days it was required
3. Among patients not on ventilation at baseline, the number of patients with a composite endpoint of death or need for mechanical ventilation or ECMO

Other outcome measures:
4. Number of patients who needed renal replacement therapy
5. Number of patients developing new major cardiac arrhythmias

Data collected via a secure web-based case report form wherever possible, or otherwise via linkage to electronic health records. Study outcomes will be assessed based on data recorded up to 28 days and up to 6 months after the main randomisation.

Original secondary outcome measures:
1. Number of days stay in hospital
2. Number of patients who needed ventilation and the number of days it was required, within 28 days of randomisation
3. Number of patients who needed renal replacement therapy, within 28 days of randomisation

Data collected via a secure web-based case report form. All randomised participants are to be followed up until death, discharge from hospital or 28 days after randomisation (whichever is sooner).

Overall trial start date

09/03/2020

Overall trial end date

31/12/2031

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

Current inclusion criteria as of 07/05/2020:

1. Hospitalised
2. SARS-CoV-2 infection (clinically suspected or laboratory-confirmed)
3. 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 the trial

______

Previous inclusion criteria:

1. Aged at least 18 years
2. Hospitalised
3. SARS-CoV-2 infection

Participant type

Patient

Age group

All

Gender

Both

Target number of participants

15,000 (estimated, depending on extent of epidemic). 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.

Participant exclusion criteria

Current inclusion criteria as of 07/05/2020:

Participants will be excluded if the attending clinician believes that there is a specific contra-indication to one of the active drug treatment arms (see Protocol Appendix 2; section 8.2 and Appendix 3; section 8.3 for children), or that the patient should definitely be receiving one of the active drug treatment arms then that arm will not be available for randomisation for that patient. For patients who lack capacity, an advanced directive or behaviour that clearly indicates that they would not wish to participate in the trial would be considered sufficient reason to exclude them from the trial.

______

Previous exclusion criteria:

1. Patients will be excluded if they have a medical history that might, in the opinion of the attending clinician, put the patient at significant risk if he/she were to participate in the trial
2. In addition, if the attending clinician believes that there is a specific contra-indication to one of the active drug treatment arms, then the patient will be excluded from randomisation to that arm

Recruitment start date

19/03/2020

Recruitment end date

31/12/2021

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Nuffield Department of Population Health
University of Oxford Richard Doll Building Old Road Campus Roosevelt Drive
Oxford
OX3 7LF
United Kingdom

Sponsor information

Organisation

University of Oxford

Sponsor details

Clinical Trials & Research Governance
University of Oxford
Joint Research Office
Churchill Hospital
Oxford
OX3 7LE
United Kingdom
+44 (0)1865 289885
ctrg@admin.ox.ac.uk

Sponsor type

University/education

Website

http://www.ox.ac.uk/

Funders

Funder type

Government

Funder name

UK Research and Innovation

Alternative name(s)

UKRI

Funding Body Type

private sector organisation

Funding Body Subtype

Other non-profit organizations

Location

United Kingdom

Funder name

National Institute for Health Research

Alternative name(s)

NIHR

Funding Body Type

government organisation

Funding Body Subtype

National government

Location

United Kingdom

Funder name

NIHR Oxford Biomedical Research Centre

Alternative name(s)

NIHR Biomedical Research Centre, Oxford, OxBRC

Funding Body Type

private sector organisation

Funding Body Subtype

Research institutes and centers

Location

United Kingdom

Funder name

Wellcome Trust

Alternative name(s)

Funding Body Type

private sector organisation

Funding Body Subtype

International organizations

Location

United Kingdom

Funder name

Bill and Melinda Gates Foundation

Alternative name(s)

बिल एंड मिलिंडा गेट्स फाउंडेशन, Bill & Melinda Gates Foundation, Gates Foundation, 比尔及梅琳达·盖茨基金会, BMGF, B&MGF

Funding Body Type

private sector organisation

Funding Body Subtype

Trusts, charities, foundations (both public and private)

Location

United States of America

Funder name

Department for International Development

Alternative name(s)

DFID

Funding Body Type

government organisation

Funding Body Subtype

National government

Location

United Kingdom

Funder name

Health Data Research UK

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

Medical Research Council Population Health Research Unit

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

NIHR Clinical Trials Unit Support Funding

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

NIHR Health Protection Research Unit in Emerging and Zoonotic Infections

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Results will be published in health or scientific journals and be discussed at major conferences. All study documentation (including the protocol and participant information sheet) is freely available at https://www.recoverytrial.net

Added 02/07/2020:
Preliminary results are available at https://www.recoverytrial.net/results

IPD sharing statement
The data-sharing plans for the current study are unknown and will be made available at a later date.

Intention to publish date

31/12/2020

Participant level data

To be made available at a later date

Basic results (scientific)

Publication list

2020 preliminary dexamethasone results in https://pubmed.ncbi.nlm.nih.gov/32678530/ (added 20/07/2020)
2020 lopinavir–ritonavir results in https://doi.org/10.1016/S0140-6736(20)32013-4 (added 06/10/2020)

Publication citations

Additional files

Editorial Notes

06/10/2020: Publication reference added. 25/09/2020: The following changes have been made: 1. The study hypothesis has been updated. 2. The intervention has been changed. 3. The drug names have been changed. 4. The secondary outcome measures have been changed. 5. The NIHR Health Protection Research Unit in Emerging and Zoonotic Infections has been added to the funders. 6. The plain English summary has been updsated to reflect the above changes. 21/08/2020: The plain English summary, hypothesis, interventions and drug names were updated. 20/07/2020: Publication reference added. 02/07/2020: The following changes were made to the trial record: 1. The interventions, drug names, secondary outcome measures, publication and dissemination plan and plain English summary were updated. 2. The recruitment end date was changed from 31/12/2020 to 31/12/2021. 3. The overall trial end date was changed from 30/06/2021 to 31/12/2031. 4. The target number of participants was changed from 12,000 to 15,000. 27/05/2020: The following changes were made to the trial record: 1. The plain English summary, hypothesis, interventions, drug names, and secondary outcome measures were updated. 2. ClinicalTrials.gov number added. 07/05/2020: The following changes were made to the trial record: 1. The plain English summary, hypothesis, interventions, drug names, inclusion and exclusion criteria, and primary outcome measure were updated. 2. The target number of participants was changed from 5000 to 12,000. 30/03/2020: Trial's existence confirmed by the NIHR.