Randomised Evaluation of COVID-19 Therapy (RECOVERY)

UK Research and Innovation, National Institute for Health Research, United Kingdom, Wellcome, Bill and Melinda Gates Foundation, Department for International Development, United Kingdom, Health Data Research UK, Medical Research Council Population Health Research Unit, NIHR Clinical Trials Unit Support Funding, NIHR Health Protection Research Unit in Emerging and Zoonotic Infections

RECOVERY is a randomised trial investigating whether treatment with Lopinavir-Ritonavir, Hydroxychloroquine, Corticosteroids, Azithromycin, Colchicine, IV Immunoglobulin (children only), Convalescent plasma, Casirivimab+Imdevimab, Tocilizumab, Aspirin, Baricitinib, Infliximab, Empagliflozin, Sotrovimab, Molnupiravir, Paxlovid or Anakinra (children only) prevents death in patients with COVID-19.

The RECOVERY trial has already shown that: Dexamethasone (a type of steroid) & tocilizumab reduce 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 or dimethyl fumarate 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. ELIGIBILITY AND RANDOMISATION: This protocol describes a randomised trial among patients hospitalised for COVID-19. All eligible patients are randomly allocated between several treatment arms, each to be given in addition to the usual standard of care in the participating hospital. 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: discontinued in Protocol v19.0, (children's recruitment to Part A discontinued in Protocol v17.1) Part B: discontinued in Protocol v16.0. Part C: discontinued in Protocol v15.0. Part D: discontinued in Protocol v20.0 Part E (adults ≥18 years old with hypoxia only): In a factorial design, high-dose corticosteroids vs no additional treatment. Part F (adults ≥18 years): In a factorial design, empagliflozin vs no additional treatment. Part J (UK patients ≥12 years old): In a factorial design, sotrovimab vs no additional treatment. Park K (patients ≥18 years old): In a factorial design, molnupiravir vs no additional treatment. Park L (UK patients ≥18 years old): In a factorial design, paxlovid 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.

RECOVERY includes multiple options for the Main Randomisation (Parts A to L), that can be undertaken simultaneously, as appropriate. Not all treatments are available in all countries. Parts A to D, and the arm for children with PIMS-TS, have been discontinued. Part E: randomisation between no additional treatment vs high dose corticosteroids Part F: randomisation between no additional treatment vs empagliflozin Part J: randomisation between no additional treatment vs sotrovimab Part K: randomisation between no additional treatment vs molnupiravir Part L: randomisation between no additional treatment vs paxlovid

Participants with progressive COVID-19 (as evidenced by hypoxia and an inflammatory state) may undergo randomisation between Tocilizumab and no additional treatment. (Children with COVID-19 pneumonia are not eligible for this comparison). [This arm is now closed to recruitment]

Randomisation for children only with PIMS-TS (Children with COVID-19 pneumonia are not eligible for this comparison). [This arm is now closed to recruitment]

First (main) randomisation part A (UK adults only; early phase assessment) [This arm is now closed to recruitment]

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)

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)

For participants ≥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.

UK Adults ≥18 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.

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.

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.

To assess the effects of study treatment on number of patients who needed any ventilation and (for invasive mechanical ventilation) the number of days it was required

To assess the effects of study treatment on number of patients who had thrombotic events, defined as either (i) acute pulmonary embolism; (ii) deep vein thrombosis; (iii) ischaemic stroke; (iv) myocardial infarction; or (v) systemic arterial embolism.

Inclusion Criteria: (i) Hospitalised (ii) Viral pneumonia syndrome In general, viral pneumonia should be suspected when a patient presents with: typical symptoms (e.g. influenza-like illness with fever and muscle pain, or respiratory illness with cough and shortness of breath); and compatible chest X-ray findings (consolidation or ground-glass shadowing); and alternative causes have been considered unlikely or excluded (e.g. heart failure, bacterial pneumonia). However, the diagnosis remains a clinical one based on the opinion of the managing doctor. (iii) SARS-CoV-2 infection (clinically suspected or laboratory confirmed) (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 Exclusion Criteria: 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.

Clinical Trial Unit, Oxford University Clinical Research Unit-Nepal, Patan Academy of Health Sciences

The data-sharing plans for this study have been provided in the Data Sharing Statement in RECOVERY publication: N Engl J Med. 2020 Jul 17;NEJMoa2021436. doi: 10.1056/NEJMoa2021436

Proposals for substudies must be approved by the Trial Steering Committee. Procedures for accessing the data for this study are available on https://www.ndph.ox.ac.uk/data-access

RECOVERY Collaborative Group; 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. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2021 Feb 25;384(8):693-704. doi: 10.1056/NEJMoa2021436. Epub 2020 Jul 17.

RECOVERY Collaborative Group. Lopinavir-ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2020 Oct 24;396(10259):1345-1352. doi: 10.1016/S0140-6736(20)32013-4. Epub 2020 Oct 5.

RECOVERY Collaborative Group; Horby P, Mafham M, Linsell L, Bell JL, Staplin N, Emberson JR, Wiselka M, Ustianowski A, Elmahi E, Prudon B, Whitehouse T, Felton T, Williams J, Faccenda J, Underwood J, Baillie JK, Chappell LC, Faust SN, Jaki T, Jeffery K, Lim WS, Montgomery A, Rowan K, Tarning J, Watson JA, White NJ, Juszczak E, Haynes R, Landray MJ. Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19. N Engl J Med. 2020 Nov 19;383(21):2030-2040. doi: 10.1056/NEJMoa2022926. Epub 2020 Oct 8.

RECOVERY Collaborative Group. Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2021 Feb 13;397(10274):605-612. doi: 10.1016/S0140-6736(21)00149-5. Epub 2021 Feb 2.

RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2021 May 1;397(10285):1637-1645. doi: 10.1016/S0140-6736(21)00676-0.

RECOVERY Collaborative Group. Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial. Lancet. 2021 May 29;397(10289):2049-2059. doi: 10.1016/S0140-6736(21)00897-7. Epub 2021 May 14.

RECOVERY Collaborative Group. Colchicine in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet Respir Med. 2021 Dec;9(12):1419-1426. doi: 10.1016/S2213-2600(21)00435-5. Epub 2021 Oct 18.

RECOVERY Collaborative Group. Aspirin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2022 Jan 8;399(10320):143-151. doi: 10.1016/S0140-6736(21)01825-0. Epub 2021 Nov 17.

RECOVERY Collaborative Group. Casirivimab and imdevimab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2022 Feb 12;399(10325):665-676. doi: 10.1016/S0140-6736(22)00163-5.

RECOVERY Collaborative Group. Baricitinib in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial and updated meta-analysis. Lancet. 2022 Jul 30;400(10349):359-368. doi: 10.1016/S0140-6736(22)01109-6. Erratum In: Lancet. 2022 Oct 1;400(10358):1102.

RECOVERY Collaborative Group. Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. medRxiv. 25 September 2022. doi.org/10.1101/2022.09.23.22280285

RECOVERY Collaborative Group. Higher dose corticosteroids in hospitalised COVID-19 patients with hypoxia but not requiring ventilatory support (RECOVERY): a randomised, controlled, open-label, platform trial. medRxiv. 17 December 2022. doi.org/10.1101/2022.12.16.22283578

Hirsch C, Park YS, Piechotta V, Chai KL, Estcourt LJ, Monsef I, Salomon S, Wood EM, So-Osman C, McQuilten Z, Spinner CD, Malin JJ, Stegemann M, Skoetz N, Kreuzberger N. SARS-CoV-2-neutralising monoclonal antibodies to prevent COVID-19. Cochrane Database Syst Rev. 2022 Jun 17;6(6):CD014945. doi: 10.1002/14651858.CD014945.pub2.

Kramer A, Prinz C, Fichtner F, Fischer AL, Thieme V, Grundeis F, Spagl M, Seeber C, Piechotta V, Metzendorf MI, Golinski M, Moerer O, Stephani C, Mikolajewska A, Kluge S, Stegemann M, Laudi S, Skoetz N. Janus kinase inhibitors for the treatment of COVID-19. Cochrane Database Syst Rev. 2022 Jun 13;6(6):CD015209. doi: 10.1002/14651858.CD015209.

Mikolajewska A, Fischer AL, Piechotta V, Mueller A, Metzendorf MI, Becker M, Dorando E, Pacheco RL, Martimbianco ALC, Riera R, Skoetz N, Stegemann M. Colchicine for the treatment of COVID-19. Cochrane Database Syst Rev. 2021 Oct 18;10(10):CD015045. doi: 10.1002/14651858.CD015045.

Kreuzberger N, Hirsch C, Chai KL, Tomlinson E, Khosravi Z, Popp M, Neidhardt M, Piechotta V, Salomon S, Valk SJ, Monsef I, Schmaderer C, Wood EM, So-Osman C, Roberts DJ, McQuilten Z, Estcourt LJ, Skoetz N. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19. Cochrane Database Syst Rev. 2021 Sep 2;9(9):CD013825. doi: 10.1002/14651858.CD013825.pub2.

Piechotta V, Iannizzi C, Chai KL, Valk SJ, Kimber C, Dorando E, Monsef I, Wood EM, Lamikanra AA, Roberts DJ, McQuilten Z, So-Osman C, Estcourt LJ, Skoetz N. Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a living systematic review. Cochrane Database Syst Rev. 2021 May 20;5(5):CD013600. doi: 10.1002/14651858.CD013600.pub4.

Tume LN, Menzies JC, Ray S, Scholefield BR; UK Paediatric Intensive Care Society Study Group. Research Priorities for U.K. Pediatric Critical Care in 2019: Healthcare Professionals' and Parents' Perspectives. Pediatr Crit Care Med. 2021 May 1;22(5):e294-e301. doi: 10.1097/PCC.0000000000002647.

RECOVERY Trial website (preliminary results, the Protocol, the Statistical Analysis Plan, and other trial documents can be downloaded from this website)