RECOVERY is a randomised trial of treatments to prevent death in patients hospitalised with 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 - Dexamethasone Community-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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
70,000
Lopinavir 400mg-Ritonavir 100mg by mouth (or nasogastric tube) every 12 hours for 10 days.
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)
Hydroxychloroquine by mouth for a total of 10 days (see Protocol for timing and dosage).
Azithromycin 500mg by mouth (or nasogastric tube) or intravenously once daily for 10 days.
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).
Tocilizumab by intravenous infusion with the dose determined by body weight (see Protocol for dosage)
Intravenous immunoglobulin (IVIg) for children \>44 weeks gestational age and \<18 years with PIMS-TS only (see Protocol for dosage)
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
150 mg by mouth (or nasogastric tube) or per rectum once daily until discharge, for adults ≥18 years old.
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
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.
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.
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).
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.
Adults ≥18 years old only. 10 mg once daily by mouth for 28 days (or until discharge, if earlier).
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.
Patients ≥18 years old. 800 mg twice daily for 5 days by mouth.
UK patients ≥18 years old. 300/100 mg twice daily for 5 days by mouth.
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.
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)
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)
≥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)
Kumasi Center for Collaborative Research in Tropical Medicine KNUST
Kumasi, Ghana
RECRUITINGIndian Council of Medical Research, Division of Epidemiology and Communicable Diseases
New Delhi, India
RECRUITINGEijkman Oxford Clinical Research Unit (EOCRU), Eijkman Institute for Molecular Biology
Jakarta, Indonesia
RECRUITINGClinical Trial Unit, Oxford University Clinical Research Unit-Nepal, Patan Academy of Health Sciences
Kathmandu, Nepal
RECRUITINGWits Health Consortium
Johannesburg, South Africa
RECRUITINGNuffield Department of Population Health, University of Oxford
Oxford, United Kingdom
RECRUITINGOxford University Clinical Research Unit, Centre for Tropical Medicine
Ho Chi Minh City, Vietnam
RECRUITINGAll-cause mortality
For each pairwise comparison with the 'no additional treatment' arm, the primary objective is to provide reliable estimates of the effect of study treatments on all-cause mortality.
Time frame: Within 28 days after randomisation
Influenza co-primary outcome: All-cause mortality (with subsidiary analysis of cause of death and death at various timepoints following discharge)
Time frame: Within 28 days after randomisation
Influenza co-primary outcome: Time to discharge alive from hospital
Time frame: Within the first 28-days
COVID-19 & community-acquired pneumonia: Duration of hospital stay
To assess the effects of study treatment on number of days stay in hospital
Time frame: Within 28 days and up to 6 months after the main randomisation
COVID-19 & community-acquired pneumonia: Composite endpoint of death or need for mechanical ventilation or ECMO
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.
Time frame: Within 28 days and up to 6 months after the main randomisation
Influenza: Composite endpoint of death or need for mechanical ventilation or ECMO
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.
Time frame: Within 28 days and up to 6 months after the main randomisation
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