Clinical trial NCT04348305: Hydrocortisone for COVID-19 and Severe Hypoxia
Official title: Low-dose Hydrocortisone in Patients With COVID-19 and Severe Hypoxia - the COVID STEROID Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Covid-19
Hypoxia
Lead sponsor: Scandinavian Critical Care Trials Group
Sponsor class: OTHER
Collaborators: name: Rigshospitalet, Denmark
name: Copenhagen Trial Unit, Center for Clinical Intervention Research
name: University of Copenhagen
name: Aarhus University Hospital
First posted: 2020-04-16
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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%.

Eligibility criteria: 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

Primary outcomes:
measure: Days alive without life support at day 28
timeFrame: Day 28 after randomisation
Secondary outcomes:
measure: All-cause mortality at day 28
timeFrame: Day 28 after randomisation
measure: Days alive without life support at day 90
timeFrame: Day 90 after randomisation
measure: All-cause mortality at day 90
timeFrame: Day 90 after randomisation
measure: Number of participants with one or more serious adverse reactions
timeFrame: Day 14 after randomisation
measure: Days alive and out of hospital at day 90
timeFrame: Day 90 after randomisation
measure: All-cause mortality at 1 year after randomisation
timeFrame: 1 year after randomisation
measure: Health-related quality of life at 1 year
timeFrame: 1 year after randomisation
measure: Health-related quality of life at 1 year
timeFrame: 1 year after randomisation
Other outcomes:
Locations:
city: Aarhus
country: Denmark
facility: Aarhus University Hospital - Dept of Intensive care
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Copenhagen
country: Denmark
facility: Dept of Infectious diseases, Rigshospitalet
city: Herlev
country: Denmark
facility: Herlev Hospital - Dept. of Intensive Care
city: Hillerød
country: Denmark
facility: North Zealand Hospital
city: Hvidovre
country: Denmark
facility: Hvidovre Hospital - Dept of Infectious diseases
city: Hvidovre
country: Denmark
facility: Hvidovre Hospital - Dept of Intensive Care
city: Hvidovre
country: Denmark
facility: Hvidovre Hospital - Dept of Pulmonary Medicine
city: Kolding
country: Denmark
facility: Kolding Hospital
city: Køge
country: Denmark
facility: Køge Hospital
city: Odense
country: Denmark
facility: Dept of Intensive Care, Odense University Hospital
city: Roskilde
country: Denmark
facility: Roskilde Hospital
city: Slagelse
country: Denmark
facility: Slagelse Hospital
city: Viborg
country: Denmark
facility: Viborg Hospital
Study officials:
affiliation: Rigshospitalet, Denmark
name: Anders Perner, MD, PhD
role: STUDY_CHAIR
References:
citation: 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.
citation: Munch MW, Meyhoff TS, Helleberg M, Kjaer MN, Granholm A, Hjortso CJS, Jensen TS, Moller MH, Hjortrup PB, Wetterslev M, Vesterlund GK, Russell L, Jorgensen VL, Kristiansen KT, Benfield T, Ulrik CS, Andreasen AS, Bestle MH, Poulsen LM, Hildebrandt T, Knudsen LS, Moller A, Solling CG, Brochner AC, Rasmussen BS, Nielsen H, Christensen S, Strom 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, Osterby 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, Arnerlov E, Lykke M, Holst-Hansen MZB, Tostesen 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.