Clinical Trial Results:
Higher vs. Lower Doses of Dexamethasone in Patients with COVID-19 and Severe Hypoxia: the COVID STEROID 2 trial
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Summary
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EudraCT number |
2020-003363-25 |
Trial protocol |
DK |
Global end of trial date |
16 Nov 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
22 Jul 2022
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First version publication date |
22 Jul 2022
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
v. 1.9, date 27.01.2021
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04509973 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Department of Intensive Care, Rigshospitalet
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Sponsor organisation address |
Blegdamsvej 9, Copenhagen, Denmark, 2100
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Public contact |
Anders Perner, Department of Intensive Care, Copenhagen University Hospital - Rigshospitalet, Denmark, +45 35458333, anders.perner@regionh.dk
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Scientific contact |
Anders Perner, Department of Intensive Care, Copenhagen University Hospital - Rigshospitalet, Denmark, +45 35458333, anders.perner@regionh.dk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
01 Feb 2022
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
16 Nov 2021
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
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.
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Protection of trial subjects |
The RECOVERY trial (doi: 10.1056/NEJMoa2021436) reported a reduction in 28-day mortality with low-dose dexamethasone (6 mg) for hospitalised patients with suspected or confirmed COVID-19. Yet, higher doses were used in the other trials of corticosteroids in COVID-19 (median dose 12 mg).
We surveyed 278 doctors at COVID STEROID 2 trial sites on their clinical preferences for corticosteroid use in patients with COVID-19. The dose preference varied with 56% of 240 responders preferring a dose of 6 mg of dexamethasone or equivalent, and 36% of 240 responders preferring doses higher than 6 mg of dexamethasone or equivalent (doi: 10.1111/aas.13941). Most would enrol patients in a future trial comparing a higher vs lower dose of dexamethasone, primarily into one comparing 12 mg vs 6 mg of dexamethasone (55% of 237 responders) (doi: 10.1111/aas.13941).
Taken together, it was unclear which dose of dexamethasone was most beneficial to COVID-19, and clinical equipoise existed among clinicians and researchers.
The trial was conducted to the highest of methodological standards with ongoing assessment of the known serious adverse reactions to corticosteroid, including a planned interim analysis. Any serious
adverse reactions for single participants and the group of participants receiving higher vs. lower dose of dexamethasone was assessed and handled.
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Background therapy |
All other treatments than the trial drug were at the discretion of the treating clinicians. | ||
Evidence for comparator |
The control group received the exact same protocol as in the RECOVERY trial (i.e., 6 mg of dexamethasone daily for 10 days) in addition to usual clinical care. | ||
Actual start date of recruitment |
27 Aug 2020
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety, Efficacy | ||
Long term follow-up duration |
6 Months | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Sweden: 79
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Country: Number of subjects enrolled |
Denmark: 485
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Country: Number of subjects enrolled |
India: 369
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Country: Number of subjects enrolled |
Switzerland: 49
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Worldwide total number of subjects |
982
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EEA total number of subjects |
564
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
491
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From 65 to 84 years |
471
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85 years and over |
20
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Recruitment
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Recruitment details |
We recruited patients from 27 August 2020 to 20 May 2021. | |||||||||||||||
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Pre-assignment
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Screening details |
We screened adult patients (18 years or above) with confirmed SARS-CoV-2 and severe hypoxia (i.e., use of invasive mechanical ventilation, NIV, or continuous use of CPAP for hypoxia, or oxygen supplementation with an oxygen flow of at least 10 L/min). We screened 1414, excluded 414, randomised 1000, and included 982 patients in the analyses. | |||||||||||||||
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Period 1
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Period 1 title |
Intervention period (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Carer, Assessor | |||||||||||||||
Blinding implementation details |
The Management Committee, investigators, trial site staff registering outcome data, trial statistician, clinical staff, relatives, and patients were all blinded to the allocation. Trial medication was prepared daily using shelf-medication by unblinded staff (medical students and/or research nurses and doctors). The unblinded staff were not involved in the care of patients, outcome data entry, or statistical analyses.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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12 mg of dexamethasone | |||||||||||||||
Arm description |
12 mg of dexamethasone (14.4 mg dexamethasone phosphate) suspended in sodium chloride 0.9% and administered as a masked bolus injection (5 mL) intravenously once daily for up to 10 days from randomisation. | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
Dexamethasone
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Investigational medicinal product code |
H02AB02
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Other name |
Dexavit
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
12 mg per day as bolus injection once daily for up to 10 days after randomisation. Used at all sites but one Swedish site that used betamethasone instead.
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Investigational medicinal product name |
Betamethasone
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Investigational medicinal product code |
H02AB02
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Other name |
Betapred
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
12 mg of betamethasone as bolus injection once daily for up to 10 days after randomisation. Only used at one Swedish site, where dexamethasone was not available.
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Arm title
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6 mg of dexamethasone | |||||||||||||||
Arm description |
6 mg of dexamethasone (7.2 mg dexamethasone phosphate) suspended in sodium chloride 0.9% and administered as a masked bolus injection (5 mL) intravenously once daily for up to 10 days from randomisation. | |||||||||||||||
Arm type |
Active comparator | |||||||||||||||
Investigational medicinal product name |
Dexamethasone
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Investigational medicinal product code |
H02AB02
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Other name |
Dexavit
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
6 mg per day as bolus injection once daily for up to 10 days after randomisation. Used at all sites but one Swedish site that used betamethasone instead.
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Investigational medicinal product name |
Betamethasone
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Investigational medicinal product code |
H02AB02
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Other name |
Betapred
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
6 mg of betamethasone as bolus injection once daily for up to 10 days after randomisation. Only used at one Swedish site, where dexamethasone was not available.
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Baseline characteristics reporting groups
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Reporting group title |
12 mg of dexamethasone
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Reporting group description |
12 mg of dexamethasone (14.4 mg dexamethasone phosphate) suspended in sodium chloride 0.9% and administered as a masked bolus injection (5 mL) intravenously once daily for up to 10 days from randomisation. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
6 mg of dexamethasone
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Reporting group description |
6 mg of dexamethasone (7.2 mg dexamethasone phosphate) suspended in sodium chloride 0.9% and administered as a masked bolus injection (5 mL) intravenously once daily for up to 10 days from randomisation. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
12 mg of dexamethasone
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Reporting group description |
12 mg of dexamethasone (14.4 mg dexamethasone phosphate) suspended in sodium chloride 0.9% and administered as a masked bolus injection (5 mL) intravenously once daily for up to 10 days from randomisation. | ||
Reporting group title |
6 mg of dexamethasone
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Reporting group description |
6 mg of dexamethasone (7.2 mg dexamethasone phosphate) suspended in sodium chloride 0.9% and administered as a masked bolus injection (5 mL) intravenously once daily for up to 10 days from randomisation. | ||
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End point title |
Days alive without life support at day 28 | ||||||||||||
End point description |
Days alive without the use of life support (i.e., invasive mechanical ventilation, circulatory support, or renal replacement therapy, including days in between intermittent renal replacement therapy).
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End point type |
Primary
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End point timeframe |
From randomisation to day 28.
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Statistical analysis title |
Primary analysis | ||||||||||||
Statistical analysis description |
P-value calculated using the Kryger Jensen and Lange test adjusted for stratification variables (site, age younger than 70 years, and use of invasive mechanical ventilation).
The mean difference and confidence interval were calculated using an adjusted linear regression and bootstrapping with 50,000 resamples.
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Comparison groups |
12 mg of dexamethasone v 6 mg of dexamethasone
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Number of subjects included in analysis |
971
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.07 | ||||||||||||
Method |
Kryger Jensen and Lange test | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
1.3
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0 | ||||||||||||
upper limit |
2.6 | ||||||||||||
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End point title |
Days alive without life support at day 90 | ||||||||||||
End point description |
Days alive without the use of life support (i.e., invasive mechanical ventilation, circulatory support, or renal replacement therapy, including days in between intermittent renal replacement therapy).
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End point type |
Secondary
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End point timeframe |
From randomisation to day 90.
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Statistical analysis title |
Primary analysis | ||||||||||||
Statistical analysis description |
P-value calculated using the Kryger Jensen and Lange test adjusted for stratification variables (site, age younger than 70 years, and use of invasive mechanical ventilation).
The mean difference and confidence interval were calculated using an adjusted linear regression and bootstrapping with 50,000 resamples.
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Comparison groups |
12 mg of dexamethasone v 6 mg of dexamethasone
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Number of subjects included in analysis |
967
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.15 | ||||||||||||
Method |
Kryger Jensen and Lange test | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
4.4
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Confidence interval |
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level |
99% | ||||||||||||
sides |
2-sided
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lower limit |
-1.6 | ||||||||||||
upper limit |
10.4 | ||||||||||||
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End point title |
Days alive and out of hospital at day 90 | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
From randomisation to day 90.
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Statistical analysis title |
Primary analysis | ||||||||||||
Statistical analysis description |
P-value calculated using the Kryger Jensen and Lange test adjusted for stratification variables (site, age younger than 70 years, and use of invasive mechanical ventilation).
The mean difference and confidence interval were calculated using an adjusted linear regression and bootstrapping with 50,000 resamples.
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Comparison groups |
12 mg of dexamethasone v 6 mg of dexamethasone
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Number of subjects included in analysis |
968
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.09 | ||||||||||||
Method |
Kryger Jensen and Lange test | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
4.1
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Confidence interval |
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level |
99% | ||||||||||||
sides |
2-sided
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lower limit |
-1.3 | ||||||||||||
upper limit |
9.5 | ||||||||||||
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End point title |
Mortality at day 28 | |||||||||
End point description |
All-cause mortality.
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End point type |
Secondary
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End point timeframe |
From randomisation to day 28.
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Statistical analysis title |
Primary analysis | |||||||||
Statistical analysis description |
Logistic regression adjusted for the stratification variables and g-computation.
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Comparison groups |
12 mg of dexamethasone v 6 mg of dexamethasone
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Number of subjects included in analysis |
971
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Analysis specification |
Post-hoc
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Analysis type |
superiority | |||||||||
P-value |
= 0.1 | |||||||||
Method |
Regression, Logistic | |||||||||
Parameter type |
Risk ratio (RR) | |||||||||
Point estimate |
0.86
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Confidence interval |
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level |
99% | |||||||||
sides |
2-sided
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lower limit |
0.68 | |||||||||
upper limit |
1.08 | |||||||||
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End point title |
Mortality at day 90 | |||||||||
End point description |
All-cause mortality.
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End point type |
Secondary
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End point timeframe |
From randomisation to day 90
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Statistical analysis title |
Primary analysis | |||||||||
Statistical analysis description |
Logistic regression adjusted for the stratification variables and g-computation.
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Comparison groups |
12 mg of dexamethasone v 6 mg of dexamethasone
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Number of subjects included in analysis |
968
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Analysis specification |
Post-hoc
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Analysis type |
superiority | |||||||||
P-value |
= 0.09 | |||||||||
Method |
Regression, Logistic | |||||||||
Parameter type |
Risk ratio (RR) | |||||||||
Point estimate |
0.87
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Confidence interval |
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level |
99% | |||||||||
sides |
2-sided
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lower limit |
0.7 | |||||||||
upper limit |
1.07 | |||||||||
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End point title |
Number of patients with one or more serious adverse reactions | |||||||||
End point description |
The number of patients with 1 or more serious adverse reactions (i.e., new episodes of septic shock, invasive fungal infection, clinically important gastrointestinal bleeding, or anaphylactic reaction to dexamethasone).
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End point type |
Secondary
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End point timeframe |
From randomisation to day 28
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Statistical analysis title |
Primary analysis | |||||||||
Statistical analysis description |
Logistic regression adjusted for the stratification variables and g-computation.
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Comparison groups |
12 mg of dexamethasone v 6 mg of dexamethasone
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Number of subjects included in analysis |
982
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Analysis specification |
Post-hoc
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Analysis type |
superiority | |||||||||
P-value |
= 0.27 | |||||||||
Method |
Regression, Logistic | |||||||||
Parameter type |
Risk ratio (RR) | |||||||||
Point estimate |
0.83
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Confidence interval |
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level |
99% | |||||||||
sides |
2-sided
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lower limit |
0.54 | |||||||||
upper limit |
1.29 | |||||||||
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End point title |
Mortality at day 180 | |||||||||
End point description |
All-cause mortality
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End point type |
Secondary
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End point timeframe |
From randomisation to day 180.
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Statistical analysis title |
Primary analysis | |||||||||
Statistical analysis description |
Logistic regression adjusted for the stratification variables and g-computation.
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Comparison groups |
12 mg of dexamethasone v 6 mg of dexamethasone
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Number of subjects included in analysis |
963
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Analysis specification |
Post-hoc
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Analysis type |
superiority | |||||||||
P-value |
= 0.13 | |||||||||
Method |
Regression, Logistic | |||||||||
Parameter type |
Risk ratio (RR) | |||||||||
Point estimate |
0.89
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Confidence interval |
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level |
99% | |||||||||
sides |
2-sided
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lower limit |
0.72 | |||||||||
upper limit |
1.09 | |||||||||
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End point title |
EQ-VAS | ||||||||||||
End point description |
Health-related quality of life assessed by EQ-VAS
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End point type |
Secondary
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End point timeframe |
At day 180.
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Statistical analysis title |
Primary analysis | ||||||||||||
Statistical analysis description |
P-value calculated using the Kryger Jensen and Lange test adjusted for stratification variables (site, age younger than 70 years, and use of invasive mechanical ventilation).
The mean difference and confidence interval were calculated using an adjusted linear regression and bootstrapping with 50,000 resamples.
Non-survivors were assigned the worst possible value (i.e., 0 mm). Data from non-responders were multiply imputed (n = 58).
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Comparison groups |
12 mg of dexamethasone v 6 mg of dexamethasone
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Number of subjects included in analysis |
982
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.22 | ||||||||||||
Method |
Kryger Jensen and Lange test | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
4
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Confidence interval |
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level |
99% | ||||||||||||
sides |
2-sided
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lower limit |
-3 | ||||||||||||
upper limit |
10 | ||||||||||||
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End point title |
EQ-5D-5L index value | ||||||||||||
End point description |
Health-related quality of life assessed by the EQ-5D-5L index values.
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End point type |
Secondary
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End point timeframe |
At day 180.
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Statistical analysis title |
Primary analysis | ||||||||||||
Statistical analysis description |
P-value calculated using the Kryger Jensen and Lange test adjusted for stratification variables (site, age younger than 70 years, and use of invasive mechanical ventilation).
The mean difference and confidence interval were calculated using an adjusted linear regression and bootstrapping with 50,000 resamples.
Non-survivors were assigned scores of zero corresponding to a health state equivalent to death for EQ-5D-5L index values. Data from non-responders were multiply imputed (n = 60).
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Comparison groups |
12 mg of dexamethasone v 6 mg of dexamethasone
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Number of subjects included in analysis |
982
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.1 | ||||||||||||
Method |
Kryger Jensen and Lange test | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.06
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Confidence interval |
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level |
99% | ||||||||||||
sides |
2-sided
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lower limit |
-4 | ||||||||||||
upper limit |
4 | ||||||||||||
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Adverse events information [1]
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Timeframe for reporting adverse events |
From randomisation to day 28.
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Adverse event reporting additional description |
For SARs and SAEs, refer to Table 2 and Supplement 2, eTable 10.
Link: https://jamanetwork.com/journals/jama/fullarticle/2785529?utm_campaign=articlePDF&utm_medium=articlePDFlink&utm_source=articlePDF&utm_content=jama.2021.18295
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Assessment type |
Systematic | ||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||
Dictionary version |
1
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| Frequency threshold for reporting non-serious adverse events: 0% | |||
| Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: We only recorded serious adverse reactions and serious adverse events in the trial. No non-serious adverse events were recorded, but the patient charts contain daily registrations of clinical data, which can be obtained on request from the medical authorities. |
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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09 Jan 2021 |
We generally recommended against the use of other immunosuppresive agents during the intervention period. However, after 9 January 2021, we allowed the use of interleukin 6 (IL-6) inhibitors after the publications of the results from the IL-6 inhibitor domain of the REMAP-CAP trial (doi: 10.1056/NEJMoa2100433). |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| Changes in the treatment of COVID-19 during the course of the trial. Intervention period varied from 6-10 days according to the number of days of steroid treatment before randomisation (max 4 days allowed). Both may have influenced the trial results. | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/34673895 |
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