Randomised Evaluation of COVID-19 Therapy

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.
• Sotrovimab reduces the risk of death in some patients (specifically those with higher levels of the virus in their blood) hospitalised with COVID-19.
• In patients hospitalised with COVID-19, dexamethasone (at a dose of 6mg daily in hypoxic patients), tocilizumab (in hypoxic patients with CRP ≥75 mg/L), baricitinib, casirivimab-imdevimab (in seronegative patients), and sotrovimab (in high antigen patients) reduced 6-month mortality. Dexamethasone at a dose of 6mg daily was associated with an increase in major non-COVID infection but there was no evidence of other later emerging harms. Other treatments tested in RECOVERY did not reduce 6-month mortality.

The trial also concluded that there is no beneficial effect of hydroxychloroquine, lopinavir-ritonavir, azithromycin, convalescent plasma, colchicine, aspirin, dimethyl fumarate, empagliflozin, molnupiravir, or paxlovid in patients hospitalised with COVID-19, and these arms have been closed to recruitment with results reported.

BACKGROUND: In early 2020, as the RECOVERY Trial was being set-up, there were no approved treatments for COVID-19, a disease induced by the novel coronavirus SARSCoV-2 that emerged in China in late 2019. Opening in March 2020, RECOVERY evaluated twenty SARS-CoV-2 therapies, providing reliable evidence about their efficacy and safety that has informed the treatment of patients worldwide.

Since then, the 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 (version 28.0) includes treatment comparisons for influenza and community-acquired pneumonia. No COVID-19 comparisons are currently open in the trial. Eligible patients are randomly allocated between one or more treatment arms, each to be given in addition to the usual standard of care in the participating hospital. The study is dynamic, and treatments are added and removed as results and suitable treatments become available, or as new infectious respiratory threats emerge. For patients for whom not all the trial arms are appropriate or at locations where not all are available, randomisation will be between fewer comparisons.

All COVID-19 arms of the protocol (Part A to F, and J to L) have now been discontinued with results reported.

The arms currently open to recruitment are as follows:

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 any age (≥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 corticosteroids (dexamethasone) vrs no additional treatment.

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 corticosteroids (dexamethasone) vs no additional treatment.

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 England 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, illness 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.

Other information to be recorded relevant to safety will include acute kidney or liver injury, cardiac arrhythmia, infection, thrombosis, bleeding, metabolic disturbances, and seizures.

Reminders will be sent if outcome data have not been recorded by 28 days after randomisation. Suspected Serious Adverse Reactions (SSARs) to one of the study medications (eg, Stevens-Johnson syndrome, anaphylaxis, aplastic anaemia) will be collected and unexpected SSARs (SUSARs) will be 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 the epidemiology of the relevant infections over the next few years. 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 viral or bacterial pneumonia.

ADD-ON STUDIES: Particular countries or groups of hospitals, may well want to collaborate in adding further measurements or observations, such as serial blood gases or chemistry, 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 (as per Protocol v28.0):

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:

• 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
• objective evidence of acute lung disease (e.g. consolidation or ground-glass shadowing on X-ray or CT, hypoxia, or compatible clinical examination); and
• 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:

• Confirmed influenza A or B infection (including patients with SARS-CoV-2 co-infection)
• Community-acquired pneumonia (CAP) with planned antibiotic treatment (excluding patients with suspected or confirmed SARS-CoV-2, influenza, active pulmonary tuberculosis or Pneumocystis jirovecii pneumonia)

(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

Patients with suspected or confirmed active pulmonary tuberculosis or Pneumocystis jirovecii pneumonia (also known as PCP or PJP) are excluded from the CAP comparison, as these infections are caused by specific organisms with distinct pathologies, and so are not usually categorised as CAP. Eligibility for the CAP comparison also requires planned antibiotic treatment, so patients being treated solely for fungal or viral pneumonia are not eligible.

Patients with SARS-CoV-2 and influenza co-infection are eligible, but would be excluded from certain comparisons if the attending clinician believes that there is a specific contra-indication to one of the active drug treatment arms (see Protocol Appendix 2, Appendix 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.

Patients who have been previously recruited into RECOVERY are eligible to be recruited again as long as their previous randomisation was >6 months ago. Patients will not be recruited into the same randomised comparison (e.g. sotrovimab vs. usual care) on more than one occasion, regardless of how far apart they occur.

In some locations, children (aged <18 years) will not be recruited, to comply with local and national regulatory approvals (see Appendix 6).

Note: the eligibility criteria has changed from COVID-19 to pneumonia (Influenza & CAP). For detailed information about previous eligibility criteria please see the previous Protocol's on the study website: https://www.recoverytrial.net/uk/for-site-staff/site-set-up-1/regulatory-documents