Clinical trial NCT04509973: Higher vs. Lower Doses of Dexamethasone for COVID-19 and Severe Hypoxia
Official title: Higher vs. Lower Doses of Dexamethasone in Patients With COVID-19 and Severe Hypoxia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Covid19
Hypoxia
Keywords: Randomised clinical trial
COVID-19
Hypoxia
Corticosteroids
Lead sponsor: Scandinavian Critical Care Trials Group
Sponsor class: OTHER
Collaborators: name: Copenhagen Trial Unit, Center for Clinical Intervention Research
name: Centre for Research in Intensive Care (CRIC)
name: Aarhus University Hospital
name: Aalborg University Hospital
name: Rigshospitalet, Denmark
name: The George Institute for Global Health, Australia
First posted: 2020-08-12
Enrollment: 1000
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 higher (12 mg) vs lower doses (6 mg) of dexamethasone on patient-centered outcomes in patients with COVID-19 and severe hypoxia.

Detailed description: Background: Preliminary results from the Randomised Evaluation of COVid-19 thERapY (RECOVERY) trial have reported a reduction in 28-day mortality with low-dose dexamethasone (6 mg) once daily versus no intervention in hospitalised patients with COVID-19; an effect that may have been more pronounced in patients with increasing hypoxia. Yet, higher doses of dexamethasone may be beneficial in patients with non-COVID-19 acute respiratory distress syndrome. At present, it is unclear what dose of dexamethasone is most beneficial in patients with COVID-19 and severe hypoxia, and clinical equipoise exists.

Objective: We aim to assess the effects of higher (12 mg) vs lower doses (6 mg) of intravenous dexamethasone on the number of days alive without life-support in adult patients with COVID-19 and severe hypoxia.

Design: International, 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: Dexamethasone 12 mg once daily for up to 10 days in addition to standard care.

Control intervention: Dexamethasone 6 mg once daily for up to 10 days in addition to standard care.

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) at day 28; days alive without life support at day 90; days alive and out of hospital at day 90; all-cause mortality at day 28, 90 and 180; and health-related quality of life at day 180.

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 of the following 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 other indications than COVID-19 in doses higher than 6 mg dexamethasone equivalents
* Use of systemic corticosteroids for COVID-19 for 5 days consecutive days or more
* Invasive fungal infection
* Active tuberculosis
* Fertile woman (\<60 years of age) with positive urine human gonadotropin (hCG) or plasma-hCG
* Known hypersensitivity to dexamethasone
* Previously randomised into the COVID STEROID 2 trial
* Informed consent not obtainable

Primary outcomes:
measure: Days alive without life support at day 28
timeFrame: Day 28 after randomisation
Secondary outcomes:
measure: Number of participants with one or more serious adverse reactions
timeFrame: Day 28 after randomisation
measure: All-cause mortality at day 28
timeFrame: Day 28 after randomisation
measure: All-cause mortality at day 90
timeFrame: Day 90 after randomisation
measure: Days alive without life support at day 90
timeFrame: Day 90 after randomisation
measure: Days alive and out of hospital at day 90
timeFrame: Day 90 after randomisation
measure: All-cause mortality at day 180
timeFrame: Day 180 after randomisation
measure: Health-related quality of life at day 180
timeFrame: Day 180 after randomisation
measure: Health-related quality of life at day 180
timeFrame: Day 180 after randomisation
Other outcomes:
Locations:
city: Aalborg
country: Denmark
facility: Dept. of Anaesthesia and Intensive Care, Aalborg University Hospital, Denmark.
city: Aarhus
country: Denmark
facility: Dept. of Intensive care, Aarhus University Hospital
city: Copenhagen
country: Denmark
facility: Dept. of Intensive Care, Copenhagen University Hospital, Rigshospitalet
city: Copenhagen
country: Denmark
facility: Dept. of Neuroanaesthesiology
city: Copenhagen
country: Denmark
facility: Dept. of Thoracic Anaesthesiology, Copenhagen University Hospital, Rigshospitalet
city: Copenhagen
country: Denmark
facility: Dept of Infectious diseases, Copenhagen University Hospital, Rigshospitalet
city: Hellerup
country: Denmark
facility: Dept. of Intensive Care, Gentofte Hospital
city: Herlev
country: Denmark
facility: Dept. of Anaesthesia and Intensive Care, Herlev Hospital
city: Herning
country: Denmark
facility: Dept. of Anaesthesia, Regional Hospital West Jutland, Herning
city: Hillerød
country: Denmark
facility: Dept. of Intensive Care, Nordsjællands Hospital - Hillerød, Denmark.
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: Dept. of Anaesthesia and Intensive Care, Lillebaelt Hospital
city: Køge
country: Denmark
facility: Dept. of Intensive Care, Køge University Hospital
city: Odense
country: Denmark
facility: Dept of Intensive Care, Odense University Hospital
city: Roskilde
country: Denmark
facility: Dept. of Anaesthesia and Intensive Care, Zealand University Hospital Roskilde
city: Slagelse
country: Denmark
facility: Dept. of Anaesthesia, Slagelse Hospital
city: Viborg
country: Denmark
facility: Dept. of Anaesthesia and Intensive Care, Viborg Hospital
city: Aligarh
country: India
facility: Jawahar Lal Nehru Medical Collega, AMU
city: Chennai
country: India
facility: Apollo Hospital
city: Kochi
country: India
facility: Amrita Institute of Medical Sciences
city: Mumbai
country: India
facility: Bombay Hospital & Medical Research Centre
city: Mumbai
country: India
facility: K. J. Somaiya Super Specialty Hospital
city: Mumbai
country: India
facility: P. D. Hinduja National Hospital & Medical Research Centre
city: Mumbai
country: India
facility: S L Raheja Fortis Hospital
city: Mumbai
country: India
facility: Tata Memorial Hospital
city: Mumbai
country: India
facility: Wockhardt hospitals
city: New Delhi
country: India
facility: Indraprastha Apollo Hospital
city: New Delhi
country: India
facility: Max Super Specialty Hospital, Saket
city: Pune
country: India
facility: Symbiosis University Hospital and Research Centre
city: Pune
country: India
facility: Vishwaraj Hospital
city: Ranchi
country: India
facility: Rajendra Institute of Medical Sciences
city: Vadodara
country: India
facility: Gotri General Hospital
city: Vellore
country: India
facility: Christian Medical College Vellore
city: Göteborg
country: Sweden
facility: Dept. of Anaesthesia and Intensive Care, Sahlgranska Universitetssjukhuset
city: Göteborg
country: Sweden
facility: Dept. of Infectious Diseases, Sahlgranska Universitetssjukhuset
city: Linköping
country: Sweden
facility: Dept. of Anaesthesia and Intensive Care, Universitetssjukhuset i Linköping
city: Malmö
country: Sweden
facility: Dept. of Anaesthesia and Intensive Care, Skånes Universitetssjukhus (SUS) Malmö
city: Malmö
country: Sweden
facility: Dept. of Infectious Diseases, Skånes Universitetssjukhus (SUS) Malmö
city: Norrköping
country: Sweden
facility: Dept. of Anaesthesia and Intensive Care, Vrinnevisjukhuset, Norrköping
city: Stockholm
country: Sweden
facility: Dept. of Anaesthesia and Intensive Care, Capio St Görans Sjukhus
city: Stockholm
country: Sweden
facility: Dept. of Anaesthesia and Intensive Care, Danderyds Sjukhuset
city: Stockholm
country: Sweden
facility: Dept. of Anaesthesia and Intensive Care, Karolinska Universitetssjukhuset, Huddinge
city: Stockholm
country: Sweden
facility: Dept. of Anaesthesia and Intensive Care, Karolinska Universitetssjukhuset, Solna
city: Stockholm
country: Sweden
facility: Dept. of Cardiology, Södersjukhuset
city: Stockholm
country: Sweden
facility: Dept. of Infectious Diseases, Danderyds Sjukhuset
city: Stockholm
country: Sweden
facility: Dept. of Infectious Diseases, Karolinska Universitetssjukhuset, Solna
city: Stockholm
country: Sweden
facility: Dept. of Infectious Diseases, Södersjukhuset
city: Stockholm
country: Sweden
facility: Dept. of Internal Medicine, Danderyds Sjukhuset
city: Stockholm
country: Sweden
facility: Dept. of Internal Medicine, Södersjukhuset
city: Stockholm
country: Sweden
facility: Södersjukhuset
city: Bern
country: Switzerland
facility: Dept. of Intensive Care Medicine, Bern University Hospital (Inselspital)
Study officials:
References:
citation: Granholm A, Kjaer MN, Munch MW, Myatra SN, Vijayaraghavan BKT, Cronhjort M, Wahlin RR, Jakob SM, Cioccari L, Vesterlund GK, Meyhoff TS, Helleberg M, Moller MH, Benfield T, Venkatesh B, Hammond NE, Micallef S, Bassi A, John O, Jha V, Kristiansen KT, Ulrik CS, Jorgensen VL, Smitt M, Bestle MH, Andreasen AS, Poulsen LM, Rasmussen BS, Brochner AC, Strom T, Moller A, Khan MS, Padmanaban A, Divatia JV, Saseedharan S, Borawake K, Kapadia F, Dixit S, Chawla R, Shukla U, Amin P, Chew MS, Wamberg CA, Bose N, Shah MS, Darfelt IS, Gluud C, Lange T, Perner A. Long-term outcomes of dexamethasone 12 mg versus 6 mg in patients with COVID-19 and severe hypoxaemia. Intensive Care Med. 2022 May;48(5):580-589. doi: 10.1007/s00134-022-06677-2. Epub 2022 Mar 31.
citation: Durr KM, Hendin A, Perry JJ. Effect of 12 mg vs 6 mg of dexamethasone on the number of days alive without life support in adults with COVID-19 and severe hypoxemia: the COVID STEROID 2 randomized trial. CJEM. 2022 Apr;24(3):266-267. doi: 10.1007/s43678-022-00293-1. Epub 2022 Mar 29. No abstract available.
citation: Granholm A, Munch MW, Myatra SN, Vijayaraghavan BKT, Cronhjort M, Wahlin RR, Jakob SM, Cioccari L, Kjaer MN, Vesterlund GK, Meyhoff TS, Helleberg M, Moller MH, Benfield T, Venkatesh B, Hammond NE, Micallef S, Bassi A, John O, Jha V, Kristiansen KT, Ulrik CS, Jorgensen VL, Smitt M, Bestle MH, Andreasen AS, Poulsen LM, Rasmussen BS, Brochner AC, Strom T, Moller A, Khan MS, Padmanaban A, Divatia JV, Saseedharan S, Borawake K, Kapadia F, Dixit S, Chawla R, Shukla U, Amin P, Chew MS, Wamberg CA, Gluud C, Lange T, Perner A. Dexamethasone 12 mg versus 6 mg for patients with COVID-19 and severe hypoxaemia: a pre-planned, secondary Bayesian analysis of the COVID STEROID 2 trial. Intensive Care Med. 2022 Jan;48(1):45-55. doi: 10.1007/s00134-021-06573-1. Epub 2021 Nov 10.
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citation: Granholm A, Munch MW, Myatra SN, Vijayaraghavan BKT, Cronhjort M, Wahlin RR, Jakob SM, Cioccari L, Kjaer MN, Vesterlund GK, Meyhoff TS, Helleberg M, Moller MH, Benfield T, Venkatesh B, Hammond N, Micallef S, Bassi A, John O, Jha V, Kristiansen KT, Ulrik CS, Jorgensen VL, Smitt M, Bestle MH, Andreasen AS, Poulsen LM, Rasmussen BS, Brochner AC, Strom T, Moller A, Khan MS, Padmanaban A, Divatia JV, Saseedharan S, Borawake K, Kapadia F, Dixit S, Chawla R, Shukla U, Amin P, Chew MS, Gluud C, Lange T, Perner A. Higher vs Lower Doses of Dexamethasone in Patients with COVID-19 and Severe Hypoxia (COVID STEROID 2) trial: Protocol for a secondary Bayesian analysis. Acta Anaesthesiol Scand. 2021 May;65(5):702-710. doi: 10.1111/aas.13793. Epub 2021 Feb 25.