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. 2022 Nov 17;2022(11):CD014963. doi: 10.1002/14651858.CD014963.pub2

Angus 2020.

Study characteristics
Methods Trial design: multicentre, open‐label, platform RCT
Type of publication: journal publication
Setting: inpatient
Recruitment dates: 9 March to 17 June 2020
Country: Australia, Canada, France, Ireland, the Netherlands, New Zealand, UK, USA
Language: English
Number of centres: 121 clinical sites
Trial registration number: NCT02735707
Date first posted: 13 April 2016
Participants Age: mean age of

  • 60.4 years (SD 11.6) in the fixed‐dose intervention group;

  • 59.5 years (SD 12.7) in the shock‐dependent intervention group;

  • 59.9 years (SD 14.6) in the control group.


Gender

  • 98 male (71.5%) and 39 female (28.5%) in the fixed‐dose intervention group;

  • 103 male (70.6%) and 43 female (29.5%) in the shock‐dependent intervention group;

  • 72 male (71.3%) and 29 female (28.7%) in the control group.


Proportion of confirmed infections

  • Positive: 81.3% fixed‐dose intervention arm 69.6%; shock‐dependent intervention; 79% in the control arm

  • Negative: not reported

  • Unclear: not reported


Ethnicity

  • White: 71.2% in fixed‐dose intervention group; 76.2% in the shock‐dependent intervention group; 57% in the control group

  • Asian: 16.2% in fixed‐dose intervention group; 10.5% in the shock‐dependent intervention group; 27.9% in the control group

  • Black: 3.6% in fixed‐dose intervention group; 6.7% in the shock‐dependent intervention group; 5.1% in the control group

  • Mixed: 3.6% in fixed‐dose intervention group; 0% in the shock‐dependent intervention group; 2.5% in the control group

  • Other: 5.4% in fixed‐dose intervention group; 6.7% in the shock‐dependent intervention group; 7.6% in the control group


Number of participants (recruited/allocated/evaluated)

  • Recruited: 614

  • Allocated: 143 fixed‐dose intervention group; 152 shock‐dependent intervention group; 108 control group

  • Evaluated: 137 fixed‐dose intervention group; 141 shock‐dependent group; 101 control group


Severity of condition according to study definition

  • Fixed‐dose intervention group

    • None/supplemental oxygen only: 0%

    • HFNC: 12.4%

    • IV only: 24.1%

    • IMV: 63.5%

    • ECMO: 0.7%

    • Vasopressor support: 40.9%

  • Shock‐dependent intervention group

    • None/supplemental oxygen only: 0.7%

    • HFNC: 15.8%

    • NIV only: 33.6%

    • IMV: 50%

    • ECMO: 0%

    • Vasopressor support: 32.2%

  • Control group

    • None/supplemental oxygen only: 0%

    • HFNC: 15.8%

    • NIV only: 31.7%

    • IMV: 52.5%

    • ECMO: 2.0%

    • Vasopressor support: 29.7%


Severity of condition according to WHO score: severe ≥ 6
Co‐morbidities: diabetes, respiratory disease, kidney disease, severe cardiovascular disease, immunosuppressive disease
Inclusion criteria

  • Adult patient admitted to hospital with acute illness due to suspected or proven pandemic (COVID‐19) infection

  • Severe disease state, defined by receiving respiratory or cardiovascular organ failure support in an ICU


Exclusion criteria

  • Death is deemed to be imminent and inevitable during the next 24 h AND one or more of the patient, substitute decision maker, or attending physician are not committed to full active treatment

  • Patient is expected to be discharged from hospital today or tomorrow

  • > 14 days have elapsed while admitted to hospital with symptoms of an acute illness due to suspected or proven pandemic infection

  • Previous participation in this REMAP within the last 90 days

  • Known hypersensitivity to hydrocortisone

  • Intention to prescribe systemic corticosteroids for a reason that is unrelated to the current episode of CAP/COVID‐19 (or direct complications of CAP/COVID‐19), such as chronic corticosteroid use before admission, acute severe asthma, or suspected or proven Pneumocystis jiroveci pneumonia

  • > 36 h have elapsed since ICU admission (noting that this may be operationalised as > 24 h has elapsed since commencement of sustained organ failure support)

  • Patient has been randomised in a trial evaluating corticosteroids, where the protocol of that trial requires ongoing administration of study drug

  • The treating clinician believes that participation in the domain would not be in the best interests of the patient

  • Previous treatments (e.g. experimental drug therapies, oxygen therapy, ventilation): yes
Interventions Treatment details of intervention group (e.g dose, route of administration, number of doses)

  • Type of corticosteroid: hydrocortisone

  • Dose:

    • Fixed‐dose: 50 mg every 6 h for 7 days

    • Shock‐dependent: 50 mg every 6 h for up to 28 days if in shock

  • Route of administration: IV


Treatment details of control group (e.g. dose, route of administration, number of doses)

  • No hydrocortisone

  • Concomitant therapy (e.g. description of standard care): not reported


Duration of follow‐up: follow‐up ended 12 August 2020
Treatment cross‐overs: no
Compliance with assigned treatment: yes
Outcomes Primary study outcome: respiratory and cardiovascular organ support‐free days up to day 21, with subcomponents in‐hospital deaths and organ support‐free days among survivors
Review outcomes: inpatient setting

  • Mortality: all‐cause mortality at day 14 or any longer observation period, in‐hospital all‐cause mortality: reported

  • Improvement of clinical status during the longest observation period available:

    • Ventilator‐free days (defined as days alive and free from mechanical ventilation): not reported

    • Participants discharged alive. Participants should be discharged without clinical deterioration or death: not reported

  • Deterioration of clinical status during the longest observation period available:

    • New need for invasive mechanical ventilation or death; that is, transition to WHO 7 to 9 if 6 or lower at baseline (see Figure 1): reported

  • Serious adverse events, defined as the number of participants with any event: reported

  • Adverse events (any grade), defined as the number of participants with any event: not reported

  • Specific adverse events: hospital‐acquired infections: not reported

  • Fungal infections: not reported

  • Quality of life, including fatigue and neurological status, assessed with standardised scales (e.g. WHOQOL‐100) during the longest period available: not reported

  • New need for dialysis during the longest period available: not reported

  • Viral clearance, assessed with reverse transcription polymerase chain reaction (RT‐PCR) test for SARS‐CoV‐2 at baseline, up to 3, 7, and 15 days: not reported


Additional study outcomes: time to death, cardiovascular organ support–free days, length of ICU stay, WHO scale at day 14
Identification  
Notes Date of publication: 2 September 2020
Sponsor/funding: Platform for European Preparedness Against (Re‐) emerging Epidemics (PREPARE) consortium by the European Union, FP7‐HEALTH‐2013‐INNOVATION‐1 (grant 602525), the Australian National Health and Medical Research Council (grant APP1101719), the New Zealand Health Research Council (grant 16/ 631), the Canadian Institute of Health Research Strategy for Patient‐Oriented Research Innovative Clinical Trials Program (grant 158584), the UK National Institute for Health Research (NIHR) and the NIHR Imperial Biomedical Research Centre, the Health Research Board of Ireland (grant CTN 2014‐012), the UPMC Learning While Doing Program, the Breast Cancer Research Foundation, the French Ministry of Health (grant PHRC‐20‐0147), and the Minderoo Foundation
Risk of bias table presents two entries for analysis 1.1 All‐cause mortality and analysis 1.5 Serious adverse events: one entry for fixed‐dose arm and one for shock‐dependent arm