Hydrocortisone for COVID-19 and Severe Hypoxia (COVID STEROID)

Low-dose Hydrocortisone in Patients With COVID-19 and Severe Hypoxia - the COVID STEROID Trial

We aim to assess the benefits and harms of low-dose hydrocortisone in patients with COVID-19 and severe hypoxia.

Study Overview

• Status: Completed
• Conditions: Covid-19; Hypoxia
• Intervention / Treatment: Drug: Hydrocortisone; Drug: Sodium Chloride 9mg/mL

Detailed Description

Background: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused a pandemic of coronavirus disease (COVID-19) with many patients developing severe hypoxic respiratory failure. Many patients have died, and healthcare systems in several countries have been or will be overwhelmed because of a surge of patients needing hospitalisation and intensive care. There is no proven treatment for COVID-19; the care is supportive, including respiratory and circulatory support. For other patient groups with similar critical illness (acute respiratory disease syndrome and septic shock), corticosteroids are used because they reduce the duration of mechanical ventilation, length of stay in the intensive care unit, and potentially also mortality. Corticosteroids have been used in some patients with COVID-19, but the recommendations in clinical guidelines differ; some suggest their use, others against.

Objectives: We aim to assess the effects of low-dose intravenous hydrocortisone on the number of days alive without life-support in adult patients with COVID-19 and severe hypoxia.

Design: Multicentre, parallel-group, centrally randomised, stratified, blinded, clinical trial.

Population: Adult patients with documented COVID-19 receiving at least 10 L/min of oxygen independent of delivery system OR mechanical ventilation.

Experimental intervention: Continuous IV infusion of hydrocortisone 200 mg daily will be given for 7 days in addition to standard care.

Control intervention: Continuous IV infusion of matching placebo (0.9% saline) will be given in addition to standard care (no corticosteroids).

Outcomes: The primary outcome is days alive without life support (i.e. mechanical ventilation, circulatory support, or renal replacement therapy) at day 28. Secondary outcomes are serious adverse reactions (i.e. anaphylactic reaction to hydrocortisone, new episode of septic shock, invasive fungal infection or clinically important gastrointestinal bleeding); days alive without life support at day 90; days alive and out of hospital at day 90; all-cause mortality at day 28, day 90 and 1 year; and health-related quality of life at 1 year.

Sample size: A total of 1000 participants will be randomised in order to detect a 15% relative reduction in 28-day mortality combined with a 10% reduction in time on life support among the survivors with a power of 85%.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 3

Contacts and Locations

Study Locations

• Denmark
  • Aarhus, Denmark
    • Aarhus University Hospital - Dept of Intensive care
  • Copenhagen, Denmark, DK-2100
    • Rigshospitalet
  • Copenhagen, Denmark
    • Dept of Infectious diseases, Rigshospitalet
  • Herlev, Denmark
    • Herlev Hospital - Dept. of Intensive Care
  • Hillerød, Denmark
    • North Zealand Hospital
  • Hvidovre, Denmark
    • Hvidovre Hospital - Dept of Infectious diseases
  • Hvidovre, Denmark
    • Hvidovre Hospital - Dept of Intensive Care
  • Hvidovre, Denmark
    • Hvidovre Hospital - Dept of Pulmonary Medicine
  • Kolding, Denmark
    • Kolding Hospital
  • Køge, Denmark
    • Køge Hospital
  • Odense, Denmark
    • Dept of intensive care, Odense University Hospital
  • Roskilde, Denmark
    • Roskilde Hospital
  • Slagelse, Denmark
    • Slagelse Hospital
  • Viborg, Denmark
    • Viborg Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

All the following criteria must be fulfilled:

• Aged 18 years or above AND
• Confirmed SARS-CoV-2 (COVID-19) requiring hospitalisation AND

• Use of one of the following:

  • Invasive mechanical ventilation OR
  • Non-invasive ventilation or continuous use of continuous positive airway pressure (CPAP) for hypoxia OR
  • Oxygen supplementation with an oxygen flow of at least 10 L/min independent of delivery system

Exclusion Criteria:

We will exclude patients who fulfil any of the following criteria:

• Use of systemic corticosteroids for any other indication than COVID-19
• Invasive mechanical ventilation for more than 48 hours
• Invasive fungal infection
• Fertile woman (< 60 years of age) with positive urine human gonadotropin (hCG) or plasma-hCG
• Known hypersensitivity to hydrocortisone
• A patient for whom the clinical team has decided not to use invasive mechanical ventilation
• Previously randomised into the COVID STEROID trial
• Informed consent not obtainable

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Hydrocortisone; Continuous intravenous infusion of hydrocortisone 200 mg over 24 hours (total 104 ml). The trial intervention will be given in addition to standard care. If continuous intravenous infusion is not possible, we will allow the use of bolus injection of the trial medication (50 mg (10 ml) every 6 hours).	Drug: Hydrocortisone; Continuous infusion: 200 mg (104 ml) every 24 hours, Bolus injections: 50 mg (10 ml) every 6 hours, Total treatment duration: 7 days; Other Names: Solu-cortef
Placebo Comparator: Isotonic Saline; Continuous intravenous infusion of matching isotonic saline (0.9%) placebo at a dose volume of 104 ml over 24 hours in addition to standard care (no corticosteroid treatment). If continuous intravenous infusion is not possible, we will allow the use of bolus injection of matching saline placebo (10 ml every 6 hours).	Drug: Sodium Chloride 9mg/mL; Continuous infusion: 104 ml every 24 hours, Bolus injections: 10 ml every 6 hours, Total treatment duration: 7 days; Other Names: Isotonic saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Days alive without life support at day 28	Days alive without life support (i.e. invasive mechanical ventilation, circulatory support or renal replacement therapy) from randomisation to day 28	Day 28 after randomisation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause mortality at day 28	Death from all causes	Day 28 after randomisation
Days alive without life support at day 90	Days alive without life support (i.e. invasive mechanical ventilation, circulatory support or renal replacement therapy) from randomisation to day 90	Day 90 after randomisation
All-cause mortality at day 90	Death from all causes	Day 90 after randomisation
Number of participants with one or more serious adverse reactions	Defined as new episodes of septic shock, invasive fungal infection, clinically important GI bleeding or anaphylactic reaction	Day 14 after randomisation
Days alive and out of hospital at day 90	Number of days alive and out of hospital not limited to the index admission	Day 90 after randomisation
All-cause mortality at 1 year after randomisation	Death from all causes	1 year after randomisation
Health-related quality of life at 1 year	Assessed by EQ-5D-5L	1 year after randomisation
Health-related quality of life at 1 year	Assessed by EQ-VAS	1 year after randomisation

Collaborators and Investigators

• Sponsor: Scandinavian Critical Care Trials Group
• Collaborators: Aarhus University Hospital; Rigshospitalet, Denmark; University of Copenhagen; Copenhagen Trial Unit, Center for Clinical Intervention Research
• Investigators: Study Chair: Anders Perner, MD, PhD, Rigshospitalet, Denmark

Publications and helpful links

General Publications

• Munch MW, Granholm A, Kjaer MN, Aksnes TS, Solling CG, Christensen S, Perner A. Long-term mortality and health-related quality of life in the COVID STEROID trial. Acta Anaesthesiol Scand. 2022 Apr;66(4):543-545. doi: 10.1111/aas.14029. Epub 2022 Feb 3. No abstract available.
• Munch MW, Meyhoff TS, Helleberg M, Kjaer MN, Granholm A, Hjortsø CJS, Jensen TS, Møller MH, Hjortrup PB, Wetterslev M, Vesterlund GK, Russell L, Jørgensen VL, Kristiansen KT, Benfield T, Ulrik CS, Andreasen AS, Bestle MH, Poulsen LM, Hildebrandt T, Knudsen LS, Møller A, Sølling CG, Brøchner AC, Rasmussen BS, Nielsen H, Christensen S, Strøm T, Cronhjort M, Wahlin RR, Jakob SM, Cioccari L, Venkatesh B, Hammond N, Jha V, Myatra SN, Jensen MQ, Leistner JW, Mikkelsen VS, Svenningsen JS, Laursen SB, Hatley EV, Kristensen CM, Al-Alak A, Clapp E, Jonassen TB, Bjerregaard CL, Østerby NCH, Jespersen MM, Abou-Kassem D, Lassen ML, Zaabalawi R, Daoud MM, Abdi S, Meier N, la Cour K, Derby CB, Damlund BR, Laigaard J, Andersen LL, Mikkelsen J, Jensen JLS, Rasmussen AH, Arnerlöv E, Lykke M, Holst-Hansen MZB, Tøstesen BW, Schwab J, Madsen EK, Gluud C, Lange T, Perner A. Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia: The COVID STEROID randomised, placebo-controlled trial. Acta Anaesthesiol Scand. 2021 Nov;65(10):1421-1430. doi: 10.1111/aas.13941. Epub 2021 Sep 20.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): April 17, 2020
• Primary Completion (Actual): September 10, 2020
• Study Completion (Actual): September 8, 2021

Study Registration Dates

• First Submitted: April 11, 2020
• First Submitted That Met QC Criteria: April 14, 2020
• First Posted (Actual): April 16, 2020

Study Record Updates

• Last Update Posted (Actual): September 21, 2021
• Last Update Submitted That Met QC Criteria: September 20, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; Signs and Symptoms, Respiratory; COVID-19; Hypoxia; Anti-Inflammatory Agents; Hydrocortisone; Hydrocortisone hemisuccinate
• Other Study ID Numbers: RH-ITA-008; 2020-001395-15 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Fully de-identified IPD will be shared after the approval by the the trial management committee
• IPD Sharing Time Frame: Immediate sharing of protocol, SAP and ICF. CSR will be shared no later than 6 months after last-patient-last-visit
• IPD Sharing Access Criteria: Contact to the trial management committee
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No