Higher vs. Lower Doses of Dexamethasone for COVID-19 and Severe Hypoxia (COVIDSTEROID2)

Higher vs. Lower Doses of Dexamethasone in Patients With COVID-19 and Severe Hypoxia

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.

Study Overview

• Status: Completed
• Conditions: Hypoxia; Covid19
• Intervention / Treatment: Drug: Dexamethasone

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%.

• Study Type: Interventional
• Enrollment (Actual): 1000
• Phase: Phase 3

Contacts and Locations

Study Locations

• Denmark
  • Aalborg, Denmark
    • Dept. of Anaesthesia and Intensive Care, Aalborg University Hospital, Denmark.
  • Aarhus, Denmark
    • Dept. of Intensive care, Aarhus University Hospital
  • Copenhagen, Denmark, 2100
    • Dept. of Intensive Care, Copenhagen University Hospital, Rigshospitalet
  • Copenhagen, Denmark, 2100
    • Dept. of Neuroanaesthesiology
  • Copenhagen, Denmark, 2100
    • Dept. of Thoracic Anaesthesiology, Copenhagen University Hospital, Rigshospitalet
  • Copenhagen, Denmark
    • Dept of Infectious diseases, Copenhagen University Hospital, Rigshospitalet
  • Hellerup, Denmark, 2900
    • Dept. of Intensive Care, Gentofte Hospital
  • Herlev, Denmark, 2730
    • Dept. of Anaesthesia and Intensive Care, Herlev Hospital
  • Herning, Denmark, 7400
    • Dept. of Anaesthesia, Regional Hospital West Jutland, Herning
  • Hillerød, Denmark
    • Dept. of Intensive Care, Nordsjællands Hospital - Hillerød, Denmark.
  • 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
    • Dept. of Anaesthesia and Intensive Care, Lillebaelt Hospital
  • Køge, Denmark, 4600
    • Dept. of Intensive Care, Køge University Hospital
  • Odense, Denmark
    • Dept of intensive care, Odense University Hospital
  • Roskilde, Denmark
    • Dept. of Anaesthesia and Intensive Care, Zealand University Hospital Roskilde
  • Slagelse, Denmark, 4200
    • Dept. of Anaesthesia, Slagelse Hospital
  • Viborg, Denmark
    • Dept. of Anaesthesia and Intensive Care, Viborg Hospital
• India
  • Aligarh, India
    • Jawahar Lal Nehru Medical Collega, AMU
  • Chennai, India
    • Apollo Hospital
  • Kochi, India
    • Amrita Institute of Medical Sciences
  • Mumbai, India
    • Tata Memorial Hospital
  • Mumbai, India
    • Bombay Hospital & Medical Research Centre
  • Mumbai, India
    • K. J. Somaiya Super Specialty Hospital
  • Mumbai, India
    • P. D. Hinduja National Hospital & Medical Research Centre
  • Mumbai, India
    • S L Raheja Fortis Hospital
  • Mumbai, India
    • Wockhardt hospitals
  • New Delhi, India
    • Indraprastha Apollo Hospital
  • New Delhi, India
    • Max Super Specialty Hospital, Saket
  • Pune, India
    • Symbiosis University Hospital and Research Centre
  • Pune, India
    • Vishwaraj Hospital
  • Ranchi, India
    • Rajendra Institute of Medical Sciences
  • Vadodara, India
    • Gotri General Hospital
  • Vellore, India
    • Christian Medical College Vellore
• Sweden
  • Göteborg, Sweden
    • Dept. of Anaesthesia and Intensive Care, Sahlgranska Universitetssjukhuset
  • Göteborg, Sweden
    • Dept. of Infectious Diseases, Sahlgranska Universitetssjukhuset
  • Linköping, Sweden
    • Dept. of Anaesthesia and Intensive Care, Universitetssjukhuset i Linköping
  • Malmö, Sweden
    • Dept. of Anaesthesia and Intensive Care, Skånes Universitetssjukhus (SUS) Malmö
  • Malmö, Sweden
    • Dept. of Infectious Diseases, Skånes Universitetssjukhus (SUS) Malmö
  • Norrköping, Sweden
    • Dept. of Anaesthesia and Intensive Care, Vrinnevisjukhuset, Norrköping
  • Stockholm, Sweden
    • Södersjukhuset
  • Stockholm, Sweden
    • Dept. of Anaesthesia and Intensive Care, Capio St Görans Sjukhus
  • Stockholm, Sweden
    • Dept. of Anaesthesia and Intensive Care, Danderyds Sjukhuset
  • Stockholm, Sweden
    • Dept. of Anaesthesia and Intensive Care, Karolinska Universitetssjukhuset, Huddinge
  • Stockholm, Sweden
    • Dept. of Anaesthesia and Intensive Care, Karolinska Universitetssjukhuset, Solna
  • Stockholm, Sweden
    • Dept. of Cardiology, Södersjukhuset
  • Stockholm, Sweden
    • Dept. of Infectious Diseases, Danderyds Sjukhuset
  • Stockholm, Sweden
    • Dept. of Infectious Diseases, Karolinska Universitetssjukhuset, Solna
  • Stockholm, Sweden
    • Dept. of Infectious Diseases, Södersjukhuset
  • Stockholm, Sweden
    • Dept. of Internal Medicine, Danderyds Sjukhuset
  • Stockholm, Sweden
    • Dept. of Internal Medicine, Södersjukhuset
• Switzerland
  • Bern, Switzerland
    • Dept. of Intensive Care Medicine, Bern University Hospital (Inselspital)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

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: Dexamethasone 12 mg; Intravenous bolus injection of dexamethasone 12 mg once daily in addition to standard care for up to 10 days. We will allow the use of betamethasone 12 mg at sites, where dexamethasone is not available.	Drug: Dexamethasone; ATC code: H02AB02; Other Names: Dexavit
Active Comparator: Dexamethasone 6 mg; Intravenous bolus injection of dexamethasone 6 mg once daily in addition to standard care for up to 10 days. We will allow the use of betamethasone 6 mg at sites, where dexamethasone is not available.	Drug: Dexamethasone; ATC code: H02AB02; Other Names: Dexavit

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
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
Number of participants with one or more serious adverse reactions	Serious adverse reactions defined as new episodes of septic shock, invasive fungal infection, clinically important gastrointestinal bleeding or anaphylactic reaction	Day 28 after randomisation
All-cause mortality at day 180	Death from all causes	Day 180 after randomisation
Health-related quality of life at day 180	Assessed by EQ-5D-5L	Day 180 after randomisation
Health-related quality of life at day 180	Assessed by EQ-VAS	Day 180 after randomisation

Collaborators and Investigators

• Sponsor: Scandinavian Critical Care Trials Group
• Collaborators: Aarhus University Hospital; Rigshospitalet, Denmark; Aalborg University Hospital; The George Institute for Global Health, Australia; Copenhagen Trial Unit, Center for Clinical Intervention Research; Centre for Research in Intensive Care (CRIC)

Publications and helpful links

General Publications

• 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.
• 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.
• COVID STEROID 2 Trial Group, Munch MW, Myatra SN, Vijayaraghavan BKT, Saseedharan S, Benfield T, Wahlin RR, Rasmussen BS, Andreasen AS, Poulsen LM, Cioccari L, Khan MS, Kapadia F, Divatia JV, Brochner AC, Bestle MH, Helleberg M, Michelsen J, Padmanaban A, Bose N, Moller A, Borawake K, Kristiansen KT, Shukla U, Chew MS, Dixit S, Ulrik CS, Amin PR, Chawla R, Wamberg CA, Shah MS, Darfelt IS, Jorgensen VL, Smitt M, Granholm A, Kjaer MN, Moller MH, Meyhoff TS, Vesterlund GK, Hammond NE, Micallef S, Bassi A, John O, Jha A, Cronhjort M, Jakob SM, Gluud C, Lange T, Kadam V, Marcussen KV, Hollenberg J, Hedman A, Nielsen H, Schjorring OL, Jensen MQ, Leistner JW, Jonassen TB, Kristensen CM, Clapp EC, Hjortso CJS, Jensen TS, Halstad LS, Bak ERB, Zaabalawi R, Metcalf-Clausen M, Abdi S, Hatley EV, Aksnes TS, Gleipner-Andersen E, Alarcon AF, Yamin G, Heymowski A, Berggren A, La Cour K, Weihe S, Pind AH, Engstrom J, Jha V, Venkatesh B, Perner A. 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. JAMA. 2021 Nov 9;326(18):1807-1817. doi: 10.1001/jama.2021.18295. Erratum In: JAMA. 2021 Dec 14;326(22):2333. JAMA. 2022 Jan 18;327(3):286.
• 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.
• 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.

Helpful Links

• Trial website

Study record dates

Study Major Dates

• Study Start (Actual): August 27, 2020
• Primary Completion (Actual): June 17, 2021
• Study Completion (Actual): February 1, 2022

Study Registration Dates

• First Submitted: August 11, 2020
• First Submitted That Met QC Criteria: August 11, 2020
• First Posted (Actual): August 12, 2020

Study Record Updates

• Last Update Posted (Actual): February 24, 2022
• Last Update Submitted That Met QC Criteria: February 22, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Keywords: COVID-19; Hypoxia; Randomised clinical trial; Corticosteroids
• 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; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Dexamethasone
• Other Study ID Numbers: RH-ITA-009; 2020-003363-25 (EudraCT Number); 2020-07-16 (Other Identifier: Danish Medicines Agency); H-20051056 (Other Identifier: Ethic committee of the Capital Region, DK)

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