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Randomised Evaluation of COVID-19 Therapy (RECOVERY)

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ClinicalTrials.gov Identifier: NCT04381936
Recruitment Status : Recruiting
First Posted : May 11, 2020
Last Update Posted : March 2, 2021
Sponsor:
Collaborators:
UK Research and Innovation
National Institute for Health Research, United Kingdom
Wellcome
Bill and Melinda Gates Foundation
Department for International Development, United Kingdom
Health Data Research UK
Medical Research Council Population Health Research Unit
NIHR Clinical Trials Unit Support Funding
NIHR Health Protection Research Unit in Emerging and Zoonotic Infections
Information provided by (Responsible Party):
University of Oxford

Tracking Information
First Submitted Date  ICMJE May 7, 2020
First Posted Date  ICMJE May 11, 2020
Last Update Posted Date March 2, 2021
Actual Study Start Date  ICMJE March 19, 2020
Estimated Primary Completion Date December 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 7, 2020)
All-cause mortality [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 25, 2020)
  • Duration of hospital stay [ Time Frame: 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
  • Composite endpoint of death or need for mechanical ventilation or ECMO [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 7, 2020)
  • Duration of hospital stay [ Time Frame: Within 28 days after randomisation ]
    To assess the effects of study treatment on number of days stay in hospital
  • Need for (and duration of) ventilation [ Time Frame: Within 28 days after randomisation ]
    To assess the effects of study treatment on number of patients who needed ventilation and the number of days it was required
  • Need for renal replacement [ Time Frame: Within 28 days after randomisation ]
    To assess the effects of study treatment on number of patients who needed renal replacement therapy
Current Other Pre-specified Outcome Measures
 (submitted: February 5, 2021)
  • Need for (and duration of) ventilation [ Time Frame: Within 28 days and up to 6 months after the main randomisation ]
    To assess the effects of study treatment on number of patients who needed any ventilation and (for invasive mechanical ventilation) the number of days it was required
  • Need for renal replacement [ Time Frame: Within 28 days and up to 6 months after the main randomisation ]
    To assess the effects of study treatment on number of patients who needed renal replacement therapy
  • Number of patients who had thrombotic events [ Time Frame: Within 28 days and up to 6 months after the main randomisation ]
    To assess the effects of study treatment on number of patients who had thrombotic events, defined as either (i) acute pulmonary embolism; (ii) deep vein thrombosis; (iii) ischaemic stroke; (iv) myocardial infarction; or (v) systemic arterial embolism.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Randomised Evaluation of COVID-19 Therapy
Official Title  ICMJE Randomised Evaluation of COVID-19 Therapy
Brief 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.
Detailed 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Factorial Assignment
Intervention Model Description:

Main randomisation (part A): Simultaneously with part B, C or D (if appropriate), patients are randomly allocated between no additional treatment, colchicine, dimethyl fumarate (UK adults only; early phase assessment), corticosteroids (children only) or intravenous immunoglobulin (children only).

Main randomisation (part B): Simultaneously with part A, C or D (if appropriate), patients are randomly allocated between no additional treatment or synthetic neutralizing antibodies (REGN-COV2) .

Main Randomisation (part C): Simultaneously with part A, B or D (if appropriate), patients are randomly allocated between no additional treatment or aspirin

Main randomisation (part D): Simultaneously with part A, B or C (if appropriate), patients are randomly allocated between no additional treatment or baricitinib.

Subsequent randomisation: Children with PIMS-TS (hyper-inflammatory state associated with COVID-19) can be randomised to no additional treatment vs tocilizumab vs anakinra.

Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Severe Acute Respiratory Syndrome
Intervention  ICMJE
  • Drug: Lopinavir-Ritonavir
    Lopinavir 400mg-Ritonavir 100mg by mouth (or nasogastric tube) every 12 hours for 10 days.
  • Drug: Corticosteroid
    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)
  • Drug: Hydroxychloroquine
    Hydroxychloroquine by mouth for a total of 10 days (see Protocol for timing and dosage).
  • Drug: Azithromycin
    Azithromycin 500mg by mouth (or nasogastric tube) or intravenously once daily for 10 days.
  • Biological: Convalescent plasma
    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).
  • Drug: Tocilizumab
    Tocilizumab by intravenous infusion with the dose determined by body weight (see Protocol for dosage)
  • Biological: Immunoglobulin
    Intravenous immunoglobulin (IVIg) for children >44 weeks gestational age and <18 years with PIMS-TS only (see Protocol for dosage)
  • Drug: Synthetic neutralising antibodies
    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
    Other Name: REGN-COV2
  • Drug: Aspirin
    150 mg by mouth (or nasogastric tube) or per rectum once daily until discharge, for adults ≥18 years old.
  • Drug: Colchicine
    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
  • Drug: Baricitinib
    4 mg once daily by mouth or nasogastric tube for 10 days in total
  • Drug: Anakinra
    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.
  • Drug: Dimethyl fumarate
    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).
Study Arms  ICMJE
  • No Intervention: Standard Care
    Patient receives usual hospital care
  • Active Comparator: Low dose corticosteroids

    First (main) randomisation part A

    [This arm is now closed to adult recruitment]

    Intervention: Drug: Corticosteroid
  • Active Comparator: Hydroxychloroquine

    First (main) randomisation part A

    [This arm is now closed to recruitment]

    Intervention: Drug: Hydroxychloroquine
  • Active Comparator: Lopinavir-Ritonavir

    First (main) randomisation part A

    [This arm is now closed to recruitment]

    Intervention: Drug: Lopinavir-Ritonavir
  • Active Comparator: Azithromycin

    First (main) randomisation part A

    [This arm is now closed to recruitment]

    Intervention: Drug: Azithromycin
  • Active Comparator: Convalescent plasma

    First (main) randomisation part B

    [This arm is now closed to recruitment]

    Intervention: Biological: Convalescent plasma
  • Active Comparator: Tocilizumab

    Subsequent randomisation.

    Participants with progressive COVID-19 (as evidenced by hypoxia and an inflammatory state) may undergo an optional subsequent randomisation between Tocilizumab and no additional treatment.

    [This arm is now closed to adult recruitment]

    Intervention: Drug: Tocilizumab
  • Active Comparator: Intravenous Immunoglobulin
    First (main) randomisation part A (open to children only)
    Intervention: Biological: Immunoglobulin
  • Active Comparator: Synthetic neutralising antibodies
    First (main) randomisation part B
    Intervention: Drug: Synthetic neutralising antibodies
  • Active Comparator: Aspirin
    First (main) randomisation part C
    Intervention: Drug: Aspirin
  • Active Comparator: Colchicine
    First (main) randomisation part A
    Intervention: Drug: Colchicine
  • Active Comparator: Baricitinib
    First (main) randomisation part D
    Intervention: Drug: Baricitinib
  • Active Comparator: Anakinra
    Subsequent randomisation for children only with PIMS-TS
    Intervention: Drug: Anakinra
  • Active Comparator: Dimethyl fumarate
    First (main) randomisation part A (UK adults only; early phase assessment)
    Intervention: Drug: Dimethyl fumarate
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 5, 2021)
40000
Original Estimated Enrollment  ICMJE
 (submitted: May 7, 2020)
12000
Estimated Study Completion Date  ICMJE December 2031
Estimated Primary Completion Date December 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • (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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE Child, Adult, Older Adult
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Richard Haynes +44 (0)1865 743743 recoverytrial@ndph.ox.ac.uk
Listed Location Countries  ICMJE Indonesia,   Nepal,   United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04381936
Other Study ID Numbers  ICMJE NDPHRECOVERY
2020-001113-21 ( EudraCT Number )
ISRCTN50189673 ( Registry Identifier: ISRCTN )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: The data-sharing plans for this study have been provided in the Data Sharing Statement in RECOVERY publication: N Engl J Med. 2020 Jul 17;NEJMoa2021436. doi: 10.1056/NEJMoa2021436
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Access Criteria: Proposals for substudies must be approved by the Trial Steering Committee. Procedures for accessing the data for this study are available on https://www.ndph.ox.ac.uk/data-access
URL: https://www.ndph.ox.ac.uk/data-access
Responsible Party University of Oxford
Study Sponsor  ICMJE University of Oxford
Collaborators  ICMJE
  • UK Research and Innovation
  • National Institute for Health Research, United Kingdom
  • Wellcome
  • Bill and Melinda Gates Foundation
  • Department for International Development, United Kingdom
  • Health Data Research UK
  • Medical Research Council Population Health Research Unit
  • NIHR Clinical Trials Unit Support Funding
  • NIHR Health Protection Research Unit in Emerging and Zoonotic Infections
Investigators  ICMJE
Principal Investigator: Peter W Horby University of Oxford
PRS Account University of Oxford
Verification Date February 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP