Randomised Evaluation of COVID-19 Therapy

Phase 3

Recruiting

Conditions: Severe Acute Respiratory Syndrome

Interventions: Drug: Lopinavir-Ritonavir
Biological: Convalescent plasma
Biological: Immunoglobulin
Drug: Corticosteroid
Drug: Synthetic neutralising antibodies
Drug: Empagliflozin
Drug: Anakinra
Drug: High Dose Corticosteroid
Drug: Sotrovimab
Drug: Paxlovid
Drug: Baloxavir Marboxil
Drug: Hydroxychloroquine
Drug: Azithromycin
Drug: Tocilizumab
Drug: Aspirin
Drug: Dimethyl fumarate
Drug: Colchicine
Drug: Baricitinib
Drug: Oseltamivir
Drug: Molnupiravir

Registration Number: NCT04381936

Lead Sponsor: University of Oxford

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.

Recruitment & Eligibility

Status: RECRUITING

Sex: All

Target Recruitment: 70000

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:

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 SARS-CoV-2 infection (including patients with influenza co-infection)
Confirmed influenza A or B infection (including patients with SARS-CoV-2 co-infection)
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.

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: FACTORIAL

Arm && Interventions

Group	Intervention	Description
Lopinavir-Ritonavir	Lopinavir-Ritonavir	First (main) randomisation part A \[This arm is now closed to recruitment\]
Convalescent plasma	Convalescent plasma	First (main) randomisation part B \[This arm is now closed to recruitment\]
Intravenous Immunoglobulin	Immunoglobulin	First (main) randomisation part A (children only) \[This arm is now closed to recruitment\]
Low dose corticosteroids	Corticosteroid	First (main) randomisation part A \[This arm is now closed to recruitment\]
Synthetic neutralising antibodies	Synthetic neutralising antibodies	First (main) randomisation part B. \[This arm is now closed to recruitment\]
Empagliflozin	Empagliflozin	First (main) randomisation part F \[This arm is now closed to recruitment\]
Anakinra	Anakinra	Randomisation for children only with PIMS-TS (Children with COVID-19 pneumonia are not eligible for this comparison). \[This arm is now closed to recruitment\]
High Dose Corticosteroids	High Dose Corticosteroid	First (main) randomisation part E
Sotrovimab	Sotrovimab	First (main) randomisation part J
Paxlovid	Paxlovid	First (main) randomisation part L \[This arm is now closed to recruitment\]
Baloxavir marboxil	Baloxavir Marboxil	Randomisation part G (influenza)
Hydroxychloroquine	Hydroxychloroquine	First (main) randomisation part A \[This arm is now closed to recruitment\]
Azithromycin	Azithromycin	First (main) randomisation part A \[This arm is now closed to recruitment\]
Tocilizumab	Tocilizumab	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). \[This arm is now closed to recruitment\]
Aspirin	Aspirin	First (main) randomisation part C \[This arm is now closed to recruitment\]
Dimethyl fumarate	Dimethyl fumarate	First (main) randomisation part A (UK adults only; early phase assessment) \[This arm is now closed to recruitment\]
Colchicine	Colchicine	First (main) randomisation part A \[This arm is now closed to recruitment\]
Baricitinib	Baricitinib	First (main) randomisation part D \[This arm is now closed to recruitment\]
Oseltamivir	Oseltamivir	Randomisation part H (influenza)
Molnupiravir	Molnupiravir	First (main) randomisation part K \[This arm is now closed to recruitment\]

Primary Outcome Measures

Name	Time	Method
All-cause mortality	Within 28 days 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.
Influenza co-primary outcome: All-cause mortality (with subsidiary analysis of cause of death and death at various timepoints following discharge)	Within 28 days after randomisation
Influenza co-primary outcome: Time to discharge alive from hospital	Within the first 28-days

Secondary Outcome Measures

Name	Time	Method
COVID-19 & community-acquired pneumonia: Duration of hospital stay	Within 28 days and up to 6 months after the main randomisation	To assess the effects of study treatment on number of days stay in hospital
COVID-19 & community-acquired pneumonia: Composite endpoint of death or need for mechanical ventilation or ECMO	Within 28 days and up to 6 months after the main randomisation	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.
Influenza: Composite endpoint of death or need for mechanical ventilation or ECMO	Within 28 days and up to 6 months after the main randomisation	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.

Trial Locations

Locations (7): Oxford University Clinical Research Unit, Centre for Tropical Medicine
🇻🇳
Ho Chi Minh City, Vietnam
Kumasi Center for Collaborative Research in Tropical Medicine KNUST
🇬🇭
Kumasi, Ghana
Indian Council of Medical Research, Division of Epidemiology and Communicable Diseases
🇮🇳
New Delhi, India
Clinical Trial Unit, Oxford University Clinical Research Unit-Nepal, Patan Academy of Health Sciences
🇳🇵
Kathmandu, Nepal
Eijkman Oxford Clinical Research Unit (EOCRU), Eijkman Institute for Molecular Biology
🇮🇩
Jakarta, Indonesia
Nuffield Department of Population Health, University of Oxford
🇬🇧
Oxford, United Kingdom
Wits Health Consortium
🇿🇦
Johannesburg, South Africa

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