Clinical trial NCT04381936: Randomised Evaluation of COVID-19 Therapy
Official title: Randomised Evaluation of COVID-19 Therapy
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Severe Acute Respiratory Syndrome
Keywords: COVID-19
SARS-CoV-2
SARS coronavirus 2
SARS
Viral pneumonia syndrome
Community-acquired pneumonia
Bacterial pneumonia syndrome
Influenza A
Influenza B
Lead sponsor: University of Oxford
Sponsor class: OTHER
Collaborators: name: UK Research and Innovation
name: National Institute for Health Research, United Kingdom
name: Wellcome Trust
name: Bill and Melinda Gates Foundation
name: Department for International Development, United Kingdom
name: Health Data Research UK
name: Medical Research Council Population Health Research Unit
name: NIHR Clinical Trials Unit Support Funding
name: NIHR Health Protection Research Unit in Emerging and Zoonotic Infections
name: Flu Lab
First posted: 2020-05-11
Enrollment: 70000
Sex: ALL
Minimum age (years): 0
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention model description: RECOVERY participants are randomly allocated between one or more treatment arms. Not all treatments are available in all countries.

COVID-19:

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: discontinued

Part J: randomisation between no additional treatment vs sotrovimab

Part K: discontinued

Part L: discontinued

Influenza:

Part G: randomisation between no additional treatment vrs baloxavir marboxil

Part H: randomisation between no additional treatment vrs oseltamivir

Part I: randomisation between no additional treatment vrs Low-dose corticosteroids: Dexamethasone

Community-acquired pneumonia:

Part M: randomisation between no additional treatment vrs Low-dose corticosteroids: Dexamethasone
Primary purpose: TREATMENT

Brief summary: 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

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: All-cause mortality
timeFrame: Within 28 days after randomisation
measure: Influenza co-primary outcome: All-cause mortality (with subsidiary analysis of cause of death and death at various timepoints following discharge)
timeFrame: Within 28 days after randomisation
measure: Influenza co-primary outcome: Time to discharge alive from hospital
timeFrame: Within the first 28-days
Secondary outcomes:
measure: COVID-19 & community-acquired pneumonia: Duration of hospital stay
timeFrame: Within 28 days and up to 6 months after the main randomisation
measure: COVID-19 & community-acquired pneumonia: Composite endpoint of death or need for mechanical ventilation or ECMO
timeFrame: Within 28 days and up to 6 months after the main randomisation
measure: Influenza: Composite endpoint of death or need for mechanical ventilation or ECMO
timeFrame: Within 28 days and up to 6 months after the main randomisation
Other outcomes:
measure: Need for (and duration of) ventilation
timeFrame: Within 28 days and up to 6 months after the main randomisation
measure: Need for renal replacement
timeFrame: Within 28 days and up to 6 months after the main randomisation
measure: Number of patients who had thrombotic events
timeFrame: Within 28 days and up to 6 months after the main randomisation
Locations:
city: Kumasi
country: Ghana
facility: Kumasi Center for Collaborative Research in Tropical Medicine KNUST
city: New Delhi
country: India
facility: Indian Council of Medical Research, Division of Epidemiology and Communicable Diseases
city: Jakarta
country: Indonesia
facility: Eijkman Oxford Clinical Research Unit (EOCRU), Eijkman Institute for Molecular Biology
city: Kathmandu
country: Nepal
facility: Clinical Trial Unit, Oxford University Clinical Research Unit-Nepal, Patan Academy of Health Sciences
city: Johannesburg
country: South Africa
facility: Wits Health Consortium
city: Oxford
country: United Kingdom
facility: Nuffield Department of Population Health, University of Oxford
city: Ho Chi Minh City
country: Vietnam
facility: Oxford University Clinical Research Unit, Centre for Tropical Medicine
Study officials:
affiliation: University of Oxford
name: Peter W Horby
role: PRINCIPAL_INVESTIGATOR
References:
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