Randomised Evaluation of COVID-19 Therapy

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Randomised Evaluation of COVID-19 Therapy

Conditions
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Severe Acute Respiratory Syndrome

Intervention / Treatment
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* Drug: Lopinavir-Ritonavir
* Drug: Corticosteroid
* Drug: Hydroxychloroquine
* Drug: Azithromycin
* Biological: Convalescent plasma
* Drug: Tocilizumab
* Biological: Immunoglobulin
* Drug: Synthetic neutralising antibodies
* Drug: Aspirin
* Drug: Colchicine
* Drug: Baricitinib
* Drug: Anakinra
* Drug: Dimethyl fumarate
* Drug: High Dose Corticosteroid
* Drug: Empagliflozin
* Drug: Sotrovimab
* Drug: Molnupiravir
* Drug: Paxlovid


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 0 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Standard Care<br>Patient receives usual hospital care | |
| Active Comparator: Low dose corticosteroids<br>First (main) randomisation part A [This arm is now closed to recruitment] | Drug: Corticosteroid<br>* 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)<br>|
| Active Comparator: Hydroxychloroquine<br>First (main) randomisation part A [This arm is now closed to recruitment] | Drug: Hydroxychloroquine<br>* Hydroxychloroquine by mouth for a total of 10 days (see Protocol for timing and dosage).<br>|
| Active Comparator: Lopinavir-Ritonavir<br>First (main) randomisation part A [This arm is now closed to recruitment] | Drug: Lopinavir-Ritonavir<br>* Lopinavir 400mg-Ritonavir 100mg by mouth (or nasogastric tube) every 12 hours for 10 days.<br>|
| Active Comparator: Azithromycin<br>First (main) randomisation part A [This arm is now closed to recruitment] | Drug: Azithromycin<br>* Azithromycin 500mg by mouth (or nasogastric tube) or intravenously once daily for 10 days.<br>|
| Active Comparator: Convalescent plasma<br>First (main) randomisation part B [This arm is now closed to recruitment] | Biological: Convalescent plasma<br>* 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).<br>|
| Active Comparator: Tocilizumab<br>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] | Drug: Tocilizumab<br>* Tocilizumab by intravenous infusion with the dose determined by body weight (see Protocol for dosage)<br>|
| Active Comparator: Intravenous Immunoglobulin<br>First (main) randomisation part A (children only) [This arm is now closed to recruitment] | Biological: Immunoglobulin<br>* Intravenous immunoglobulin (IVIg) for children >44 weeks gestational age and <18 years with PIMS-TS only (see Protocol for dosage)<br>|
| Active Comparator: Synthetic neutralising antibodies<br>First (main) randomisation part B. [This arm is now closed to recruitment] | Drug: Synthetic neutralising antibodies<br>* 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<br>* Other names: casirivimab and imdevimab;|
| Active Comparator: Aspirin<br>First (main) randomisation part C [This arm is now closed to recruitment] | Drug: Aspirin<br>* 150 mg by mouth (or nasogastric tube) or per rectum once daily until discharge, for adults ≥18 years old.<br>|
| Active Comparator: Colchicine<br>First (main) randomisation part A [This arm is now closed to recruitment] | Drug: Colchicine<br>* 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<br>|
| Active Comparator: Baricitinib<br>First (main) randomisation part D [This arm is now closed to recruitment] | Drug: Baricitinib<br>* 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.<br>|
| Active Comparator: Anakinra<br>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] | Drug: Anakinra<br>* 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.<br>|
| Active Comparator: Dimethyl fumarate<br>First (main) randomisation part A (UK adults only; early phase assessment) [This arm is now closed to recruitment] | Drug: Dimethyl fumarate<br>* 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).<br>|
| Active Comparator: High Dose Corticosteroids<br>First (main) randomisation part E | Drug: High Dose Corticosteroid<br>* 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.<br>|
| Active Comparator: Empagliflozin<br>First (main) randomisation part F | Drug: Empagliflozin<br>* Adults ≥18 years old only. 10 mg once daily by mouth for 28 days (or until discharge, if earlier).<br>|
| Active Comparator: Sotrovimab<br>First (main) randomisation part J | Drug: Sotrovimab<br>* 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.<br>|
| Active Comparator: Molnupiravir<br>First (main) randomisation part K | Drug: Molnupiravir<br>* Patients ≥18 years old. 800 mg twice daily for 5 days by mouth.<br>|
| Active Comparator: Paxlovid<br>First (main) randomisation part L | Drug: Paxlovid<br>* UK patients ≥18 years old. 300/100 mg twice daily for 5 days by mouth.<br>* Other names: nirmatrelvir/ritonavir;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-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. | Within 28 days after randomisation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of hospital stay | To assess the effects of study treatment on number of days stay in hospital | Within 28 days and up to 6 months after the main randomisation | 
| 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. | Within 28 days and up to 6 months after the main randomisation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, SARS-CoV-2, SARS coronavirus 2, SARS, Viral pneumonia syndrome