Randomised Evaluation of COVID-19 Therapy

  • STATUS
    Recruiting
  • End date
    Dec 11, 2031
  • participants needed
    40000
  • sponsor
    University of Oxford
Updated on 11 March 2021
pneumonia
azithromycin
corticosteroids
lopinavir
ritonavir
covid-19
hydroxychloroquine

Summary

RECOVERY is a randomised trial investigating whether treatment with Lopinavir-Ritonavir, Hydroxychloroquine, Corticosteroids, Azithromycin, Colchicine, IV Immunoglobulin (children only), Convalescent plasma, Synthetic neutralizing antibodies (REGN-COV2), Tocilizumab, Aspirin, Baricitinib or Anakinra (children only) prevents death in patients with COVID-19.

Description

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. The trial also concluded that there is no beneficial effect of hydroxychloroquine, lopinavir-ritonavir or azithromycin 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: No additional treatment vs colchicine vs corticosteroids (children only) vs intravenous immunoglobulin (children only) (main randomisation part A). In a factorial design (in the UK alone), eligible patients are allocated simultaneously to no additional treatment vs synthetic neutralising antibodies (REGN-COV2) (part B). Separately, all participants aged 18 years or older will be allocated to either aspirin vs control (part C), and in a further factorial, baricitinib vs no additional treatment (part D, UK only). The study allows a subsequent randomisation for children with PIMS-TS (hyper-inflammatory state associated with COVID-19): No additional treatment vs tocilizumab vs anakinra. 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.

RECOVERY will also assess interventions for which additional information is required to determine whether they are considered for large-scale assessment as their potential to improve outcomes in COVID-19 is uncertain. Hence, for some patients the main randomisation part A will include an Early Phase Assessment arm in which patients may be randomised to receive dimethyl fumarate and additional information on efficacy and safety collected.

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. 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.

Details
Condition Upper respiratory infection, Severe Acute Respiratory Syndrome, Throat and Tonsil Infections, sars, severe acute respiratory syndrome (sars)
Treatment Azithromycin, Aspirin, Tocilizumab, Anakinra, colchicine, hydroxychloroquine, dimethyl fumarate, lopinavir-ritonavir, Corticosteroid, Baricitinib, immunoglobulin, Convalescent plasma, Synthetic neutralising antibodies
Clinical Study IdentifierNCT04381936
SponsorUniversity of Oxford
Last Modified on11 March 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Gender: Male or Female
Do you have any of these conditions: Throat and Tonsil Infections or Severe Acute Respiratory Syndrome or Upper respiratory infection?
Do you have any of these conditions: sars or Severe Acute Respiratory Syndrome or severe acute respiratory syndrome (sars) or Throat and Tonsil Infections or Upper respiratory infection?
Do you have any of these conditions: Throat and Tonsil Infections or sars or severe acute respiratory syndrome (sars) or Severe Acute Respiratory Syndrome or Upper respiratory infection?
Do you have any of these conditions: severe acute respiratory syndrome (sars) or Throat and Tonsil Infections or Severe Acute Respiratory Syndrome or Upper respiratory infection or sars?
Do you have any of these conditions: Throat and Tonsil Infections or severe acute respiratory syndrome (sars) or Upper respiratory infection or Severe Acute Respiratory Syndrome or sars?
Do you have any of these conditions: sars or severe acute respiratory syndrome (sars) or Throat and Tonsil Infections or Severe Acute Respiratory Syndrome or Upper respiratory infection?
Do you have any of these conditions: sars or Upper respiratory infection or Throat and Tonsil Infections or severe acute respiratory syndrome (sars) or Severe Acute Respiratory Syndrome?
Do you have any of these conditions: Throat and Tonsil Infections or Severe Acute Respiratory Syndrome or severe acute respiratory syndrome (sars) or sars or Upper respiratory infection?
Do you have any of these conditions: Throat and Tonsil Infections or Severe Acute Respiratory Syndrome or Upper respiratory infection or sars or severe acute respiratory syndrome (sars)?
Do you have any of these conditions: Upper respiratory infection or Throat and Tonsil Infections or Severe Acute Respiratory Syndrome or severe acute respiratory syndrome (sars) or sars?
(i) Hospitalised
(ii) SARS-CoV-2 infection (clinically suspected or laboratory confirmed)
(iii) 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
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