RECOVERY is a randomised trial of treatments to prevent death in patients hospitalisedwith pneumonia.The treatments being investigated are:COVID-19: Lopinavir-Ritonavir, Hydroxychloroquine, Corticosteroids, Azithromycin,Colchicine, IV Immunoglobulin (children only), Convalescent plasma,Casirivimab+Imdevimab, Tocilizumab, Aspirin, Baricitinib, Empagliflozin, Sotrovimab,Molnupiravir, Paxlovid or Anakinra (children only)Influenza: Baloxavir marboxil, Oseltamivir, Low-dose corticosteroids - DexamethasoneCommunity-acquired pneumonia: Low-dose corticosteroids - Dexamethasone
The RECOVERY trial has already shown that:
- Dexamethasone (a type of steroid) reduces the risk of dying for patients
hospitalised with COVID-19 receiving oxygen,
- Regeneron's monoclonal antibody combination reduces deaths for hospitalised COVID-19
patients who have not mounted their own immune response,
- Tocilizumab reduces the risk of death when given to hospitalised patients with
severe COVID-19. It also shortens the time until patients are successfully
discharged from hospital and reduces the need for a mechanical ventilator.
- Baricitinib reduces the risk of death when given to hospitalised patients with
severe COVID-19.
- In patients hospitalised for COVID-19 with clinical hypoxia but requiring either no
oxygen or simple oxygen only, higher dose corticosteroids significantly increased
the risk of death compared to usual care, which included low dose corticosteroids.
The trial also concluded that there is no beneficial effect of hydroxychloroquine,
lopinavir-ritonavir, azithromycin, convalescent plasma, colchicine, aspirin, dimethyl
fumarate or empagliflozin in patients hospitalised with COVID-19, and these arms have
been closed to recruitment.
BACKGROUND: In early 2020, as this protocol was being developed, there were no approved
treatments for COVID-19, a disease induced by the novel coronavirus SARSCoV-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 (which has now been
done). A World Health Organization (WHO) expert group issued broadly similar advice.
These groups also advised that other treatments will soon emerge that require evaluation.
Since then, progress in COVID-19 treatment has highlighted the need for better evidence
for the treatment of pneumonia caused by other pathogens, such as influenza and bacteria,
for which therapies are widely used without good evidence of benefit or safety.
ELIGIBILITY AND RANDOMISATION: This protocol (v27.0 as of Dec 2023) describes a
randomised trial among patients hospitalised with pneumonia caused by COVID-19,
influennza or other organisms. All eligible patients are randomly allocated between
several treatment arms, each to be given in addition to the usual standard of care in the
participating hospital. The study is subdivided into several parts, according to whether
participants are children or adults, and by geographic area. The study is dynamic, and
treatments are added and removed as results and suitable treatments become available. The
parts in the current version of the protocol are as follows:
Part A (COVID-19): discontinued in Protocol v19.0, (children's recruitment to Part A
discontinued in Protocol v17.1)
Part B (COVID-19): discontinued in Protocol v16.0.
Part C (COVID-19): discontinued in Protocol v15.0.
Part D (COVID-19): discontinued in Protocol v20.0
Part E (COVID-19): Adults ≥18 years old with hypoxia only, randomised to high-dose
corticosteroids vs no additional treatment.
Part F (COVID-19): discontinued in Protocol v26.0
Part G (Influenza): UK patients ≥12 years old (≥18 years old in other countries), with or
without SARS-CoV-2 co-infection, randomised to baloxavir marboxil vrs no additional
treatment
Part H (Influenza): UK patients ≥12 years old (≥18 years old in other countries), with or
without SARS-CoV-2 co-infection, randomised to oseltamivir vrs no additional treatment
Part I (Influenza): UK patients any age (≥18 years old in other countries), without
suspected or confirmed SARS-CoV-2 infection, and with clinical evidence of hypoxia (i.e.
receiving oxygen or with oxygen saturations <92% on room air), randomised to Low-dose
corticosteroids: Dexamethasone vrs no additional treatment.
Part J (COVID-19): UK patients ≥12 years old, randomised to sotrovimab vs no additional
treatment.
Park K (COVID-19): discontinued in Protocol v26.0
Park L (COVID-19): discontinued in Protocol v26.0
Part M (Community-acquired pneumonia with planned antibiotic treatment and without
suspected or confirmed SARS-CoV-2, influenza, active pulmonary tuberculosis, or
Pneumocystis pneumonia): Patients ≥18 years old randomised to Low-dose corticosteroids:
Dexamethasone vs no additional treatment.
Children with PIMS-TS: Tocilizumab vs anakinra vs no additional treatment (UK only)
(discontinued in Protocol v23.1).
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.
ADAPTIVE DESIGN: The interim trial results will be monitored by an independent Data
Monitoring Committee (DMC). The most important task for the DMC will be to 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.
OUTCOMES: The main outcomes will be death, discharge, need for ventilation and need for
renal replacement therapy. For the main analyses, follow-up will be censored at 28 days
after randomisation. Additional information on longer term outcomes may be collected
through review of medical records or linkage to medical databases where available (such
as those managed by NHS Digital and equivalent organisations in the devolved nations).
SIMPLICITY OF PROCEDURES: To facilitate collaboration, even in hospitals that suddenly
become overloaded, patient enrolment (via the internet) and all other trial procedures
are greatly streamlined. Informed consent is simple and data entry is minimal.
Randomisation via the internet is simple and quick, at the end of which the allocated
treatment is displayed on the screen and can be printed or downloaded. Key follow-up
information is recorded at a single timepoint and may be ascertained by contacting
participants in person, by phone or electronically, or by review of medical records and
databases.
DATA TO BE RECORDED: At randomisation, information will be collected on the identity of
the randomising clinician and of the patient, age, sex, major co-morbidity, pregnancy,
COVID-19 onset date and severity, and any contraindications to the study treatments. The
main outcomes will be death (with date and probable cause), discharge (with date), need
for ventilation (with number of days recorded) and need for renal replacement therapy.
Reminders will be sent if outcome data have not been recorded by 28 days after
randomisation. Suspected Unexpected Serious Adverse Reactions (SUSARs) to one of the
study medication (eg, Stevens-Johnson syndrome, anaphylaxis, aplastic anaemia) will be
collected and reported in an expedited fashion. Other adverse events will not be recorded
but may be available through linkage to medical databases.
NUMBERS TO BE RANDOMISED: The larger the number randomised the more accurate the results
will be, but the numbers that can be randomised will depend critically on how large the
epidemic becomes. If substantial numbers are hospitalised in the participating centres
then it may be possible to randomise several thousand with mild disease and a few
thousand with severe disease, but realistic, appropriate sample sizes could not be
estimated at the start of the trial.
HETEROGENEITY BETWEEN POPULATIONS: If sufficient numbers are studied, it may be possible
to generate reliable evidence in certain patient groups (e.g. those with major
comorbidity or who are older). To this end, data from this study may be combined with
data from other trials of treatments for COVID-19, such as those being planned by the
WHO.
ADD-ON STUDIES: Particular countries or groups of hospitals, may well want to collaborate
in adding further measurements or observations, such as serial virology, serial blood
gases or chemistry, serial lung imaging, or serial documentation of other aspects of
disease status. While well-organised additional research studies of the natural history
of the disease or of the effects of the trial treatments could well be valuable (although
the lack of placebo control may bias the assessment of subjective side-effects, such as
gastrointestinal problems), they are not core requirements.
Drug: Lopinavir-Ritonavir
Lopinavir 400mg-Ritonavir 100mg by mouth (or nasogastric tube) every 12 hours for 10
days.
Drug: Corticosteroid
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. 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 timing and
dosage)
Drug: Hydroxychloroquine
Hydroxychloroquine by mouth for a total of 10 days (see Protocol for timing and dosage).
Drug: Azithromycin
Azithromycin 500mg by mouth (or nasogastric tube) or intravenously once daily for 10
days.
Biological: Convalescent plasma
Single unit of ABO compatible convalescent plasma (275mls +/- 75 mls) 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).
Drug: Tocilizumab
Tocilizumab by intravenous infusion with the dose determined by body weight (see Protocol
for dosage)
Biological: Immunoglobulin
Intravenous immunoglobulin (IVIg) for children >44 weeks gestational age and <18 years
with PIMS-TS only (see Protocol for dosage)
Drug: Synthetic neutralising antibodies
Patients ≥12 years only with COVID-19 pneumonia: A single dose of REGN10933 + REGN10987 8
g (4 g of each monoclonal antibody) in 250ml 0.9% saline infused intravenously over 60
minutes +/- 15 minutes as soon as possible after randomisation
Other Name: REGEN-COV,casirivimab and imdevimab
Drug: Aspirin
150 mg by mouth (or nasogastric tube) or per rectum once daily until discharge, for
adults ≥18 years old.
Drug: Colchicine
1 mg after randomisation followed by 500mcg 12 hours later and then 500 mcg twice daily
by mouth or nasogastric tube for 10 days in total, for men ≥18 years old and women ≥55
years old only
Drug: Baricitinib
UK [age ≥2 years with COVID pneumonia] and India [age ≥18 years with COVID-19 pneumonia]:
4 mg once daily by mouth or nasogastric tube for 10 days in total.
Drug: Anakinra
For children ≥1 <18 years old only: subcutaneously or intravenously once daily for 7 days
or discharge (if sooner). NB Anakinra will be excluded from the randomisation of children
<10 kg in weight.
Drug: Dimethyl fumarate
Early phase assessment. UK adults ≥18 years old only (excluding those on ECMO). 120 mg
every 12 hours for 4 doses followed by 240 mg every 12 hours by mouth for 8 days (10 days
in total).
Drug: High Dose Corticosteroid
Adults ≥18 years old with hypoxia only. Dexamethasone 20 mg (base) once daily by mouth,
nasogastric tube or intravenous infusion for 5 days follow by dexamethasone 10 mg (base)
once daily by mouth, nasogastric tube or intravenous infusion for 5 days.
Drug: Empagliflozin
Adults ≥18 years old only. 10 mg once daily by mouth for 28 days (or until discharge, if
earlier).
Drug: Sotrovimab
UK patients ≥12 years old. 1000 mg in 100 mL 0.9% sodium chloride or 5% dextrose by
intravenous infusion over 1 hour as soon as possible after randomisation.
Drug: Molnupiravir
Patients ≥18 years old. 800 mg twice daily for 5 days by mouth.
Drug: Paxlovid
UK patients ≥18 years old. 300/100 mg twice daily for 5 days by mouth.
Other Name: nirmatrelvir/ritonavir
Drug: Baloxavir Marboxil
Patients ≥12 years old in the UK (or ≥18 years old in other countries), with or without
SARS-CoV-2 co-infection.
40mg (or 80mg if weight ≥80kg) once daily by mouth or nasogastic tube to be given on day
1 and day 4.
Other Name: Xofluza
Drug: Oseltamivir
Any age in the UK (or ≥18 years old in other countries), with or without SARS-CoV-2
co-infection.
75mg twice daily by mouth or nasogastric tube for five days. (See Protocol for detailed
dosage information)
Other Name: Tamiflu
Drug: Low-dose corticosteroids: Dexamethasone
Any age in the UK (or ≥18 years old in other countries), without suspected or confirmed
SARS-CoV-2 infection, and with clinical evidence of hypoxia (i.e. receiving oxygen or
with oxygen saturations <92% on room air) 6mg once daily given orally or intravenously
for ten days or until discharge (whichever happens earliest)
Drug: Low-dose corticosteroids: Dexamethasone
≥18 years old) with a diagnosis of community-acquired pneumonia (with planned antibiotic
use and without suspected or confirmed SARS-CoV-2, influenza, active pulmonary
tuberculosis, or Pneumocystis jirovecii infection) 6mg once daily given orally or
intravenously for ten days or until discharge (whichever happens earliest)
Inclusion Criteria:
Patients are eligible for the study if all of the following are true:
(i) Hospitalised
(ii) Pneumonia syndrome
In general, pneumonia should be suspected when a patient presents with:
1. typical symptoms of a new respiratory tract infection (e.g. influenza-like illness
with fever and muscle pain, or respiratory illness with cough and shortness of
breath); and
2. objective evidence of acute lung disease (e.g. consolidation or ground-glass
shadowing on X-ray or CT, hypoxia, or compatible clinical examination); and
3. alternative causes have been considered unlikely or excluded (e.g. heart failure).
However, the diagnosis remains a clinical one based on the opinion of the managing doctor
(the above criteria are just a guide).
(iii) One of the following diagnoses:
1. Confirmed SARS-CoV-2 infection (including patients with influenza co-infection)
2. Confirmed influenza A or B infection (including patients with SARS-CoV-2
co-infection)
3. Community-acquired pneumonia with planned antibiotic treatment (excluding patients
with suspected or confirmed SARS-CoV-2, influenza, active pulmonary tuberculosis or
Pneumocystis jirovecii pneumonia)
Exclusion criteria:
(iv) 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
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, and Appendix 4 for
pregnant and breastfeeding women), 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.
Kumasi Center for Collaborative Research in Tropical Medicine KNUST
Kumasi, Ghana
Indian Council of Medical Research, Division of Epidemiology and Communicable Diseases
New Delhi, India
Eijkman Oxford Clinical Research Unit (EOCRU), Eijkman Institute for Molecular Biology
Jakarta, Indonesia
Clinical Trial Unit, Oxford University Clinical Research Unit-Nepal, Patan Academy of Health Sciences
Kathmandu, Nepal
Wits Health Consortium
Johannesburg, South Africa
Nuffield Department of Population Health, University of Oxford
Oxford, United Kingdom
Oxford University Clinical Research Unit, Centre for Tropical Medicine
Ho Chi Minh City, Vietnam
Richard Haynes
+44 (0)1865 743743
recoverytrial@ndph.ox.ac.uk
Peter W Horby, Principal Investigator
University of Oxford