Clinical Trial Results:
Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia: The COVID STEROID randomised, placebo-controlled trial
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Summary
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EudraCT number |
2020-001395-15 |
Trial protocol |
DK |
Global end of trial date |
12 Jun 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. 2.1, date 12.05.2020
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04348305 | ||
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 |
Prof. Anders Perner, Department of Intensive Care, Copenhagen University Hospital - Rigshospitalet, Denmark, +45 35458333, contact@cric.nu
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Scientific contact |
Prof. Anders Perner, Department of Intensive Care, Copenhagen University Hospital - Rigshospitalet, Denmark, +45 35458333, contact@cric.nu
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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 |
14 Oct 2021
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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 |
12 Jun 2021
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
To assess benefits and harms of low dose IV hydrocortisone versus placebo on patient-important outcome measures in adult patients with COVID-19 and severe hypoxia.
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Protection of trial subjects |
Patients with COVID-19 and severe hypoxia are at high risk of death. When this trial was initiated, there was no proven treatment for COVID-19; the care was only supportive, including respiratory and circulatory support. For other patient groups with similar critical illnesses, lower dose corticosteroids were used because they mitigate critical illness and potentially also mortality without serious adverse reactions. Therefore, there was reason to believe that similar positive effects could be obtained in patients with COVID-19 and severe hypoxia without serious adverse reactions.
The trial was conducted to the highest of methodological standards with ongoing assessment of the known serious adverse reactions to corticosteroid and three planned interim analyses. The control group received placebo and best clinical care without corticosteroids as was recommended for these patients in Denmark at that time.
The trial was ended prematurely due to the results from a WHO-initiated prospective meta-analysis of ongoing or recently completed trials demonstrating benefit from systemic corticosteroids on 28-day mortality in critically ill patients with COVID-19, which in turn led to an update in the guideline from the WHO strongly recommending the use of systemic corticosteroids for patients with severe
or critical COVID-19.
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Background therapy |
All other treatments than the trial drug were at the discretion of the treating clinicians. | ||
Evidence for comparator |
Placebo | ||
Actual start date of recruitment |
15 Apr 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 |
1 Years | ||
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 |
Denmark: 30
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Worldwide total number of subjects |
30
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EEA total number of subjects |
30
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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) |
19
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From 65 to 84 years |
8
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85 years and over |
3
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Recruitment
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Recruitment details |
We recruited patients from 15 April 2020 to 16 June 2020. | ||||||||||||||||||
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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 infection 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 67, excluded 37, and randomised 30 patients. | ||||||||||||||||||
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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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Hydrocortisone | ||||||||||||||||||
Arm description |
Intravenous hydrocortisone 200 mg per day for 7 days | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Hydrocortisone
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Investigational medicinal product code |
H02AB09
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Other name |
Solu-Cortef
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Pharmaceutical forms |
Powder and solvent for solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
200 mg/day given as continuous infusion over 24 hours or bolus injection (50 mg per bolus) every 6 hours.
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Arm title
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Placebo | ||||||||||||||||||
Arm description |
Isotonic saline for 7 days | ||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||
Investigational medicinal product name |
Sodium Chloride
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Investigational medicinal product code |
B05BB01
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Continuous infusion over 24 hours or as bolus injections every 6 hours for 7 days.
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Baseline characteristics reporting groups
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Reporting group title |
Hydrocortisone
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Reporting group description |
Intravenous hydrocortisone 200 mg per day for 7 days | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Isotonic saline for 7 days | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Hydrocortisone
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Reporting group description |
Intravenous hydrocortisone 200 mg per day for 7 days | ||
Reporting group title |
Placebo
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Reporting group description |
Isotonic saline for 7 days | ||
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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 replacementtherapy)
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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 |
Linear regression adjusted for invasive mechanical ventilation and age below 70 years. We were unable to adjust for site due to the reduced sample size.
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Comparison groups |
Hydrocortisone v Placebo
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Number of subjects included in analysis |
30
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Analysis specification |
Post-hoc
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Analysis type |
superiority [1] | ||||||||||||
P-value |
= 0.79 | ||||||||||||
Method |
Regression, Linear | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-1.1
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-9.5 | ||||||||||||
upper limit |
7.3 | ||||||||||||
| Notes [1] - We had to conduct another statistical analysis than the pre-planned due to the reduced sample size. |
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End point title |
Number of patients with one or more serious adverse reactions at day 14 | |||||||||
End point description |
Number of patients with one or more serious adverse reactions (i.e., new episodes of septic shock, invasive fungal infection, clinically important gastrointestinal bleeding, or anaphylactic reaction).
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End point type |
Secondary
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End point timeframe |
From randomisation to day 14
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Statistical analysis title |
Primary analysis | |||||||||
Comparison groups |
Hydrocortisone v Placebo
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Number of subjects included in analysis |
30
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
= 1 | |||||||||
Method |
Fisher exact | |||||||||
Confidence interval |
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End point title |
All-cause 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 |
Unadjusted generalised linear model with log link and binomial error distribution
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Comparison groups |
Placebo v Hydrocortisone
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Number of subjects included in analysis |
30
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Analysis specification |
Pre-specified
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Analysis type |
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P-value |
= 0.19 | |||||||||
Method |
GLM log link/binomial error distrib. | |||||||||
Parameter type |
Risk ratio (RR) | |||||||||
Point estimate |
2.63
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.74 | |||||||||
upper limit |
16.03 | |||||||||
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End point title |
All-cause 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 |
Unadjusted generalised linear model with log link and binomial error distribution.
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Comparison groups |
Hydrocortisone v Placebo
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Number of subjects included in analysis |
30
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
= 0.22 | |||||||||
Method |
GLM log link/binomial error distrib. | |||||||||
Parameter type |
Risk ratio (RR) | |||||||||
Point estimate |
2.04
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.71 | |||||||||
upper limit |
8.16 | |||||||||
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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 |
Linear regression adjusted for invasive mechanical ventilation (y/n) and age below 70 (y/n).
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Comparison groups |
Hydrocortisone v Placebo
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Number of subjects included in analysis |
30
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Analysis specification |
Post-hoc
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.25 | ||||||||||||
Method |
Regression, Linear | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-14.7
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-40.4 | ||||||||||||
upper limit |
10.9 | ||||||||||||
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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 |
Linear regression adjusted for invasive mechanical ventilation (y/n) and age below 70 (y/n).
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Comparison groups |
Placebo v Hydrocortisone
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Number of subjects included in analysis |
30
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Analysis specification |
Post-hoc
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.57 | ||||||||||||
Method |
Regression, Linear | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-6.5
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-29.6 | ||||||||||||
upper limit |
16.7 | ||||||||||||
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End point title |
All-cause mortality at 1 year | |||||||||
End point description |
All-cause mortality
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End point type |
Secondary
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End point timeframe |
From randomisation to 1 year.
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Statistical analysis title |
Primary analysis | |||||||||
Statistical analysis description |
Unadjusted generalised linear model with log link and binomial error distribution.
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Comparison groups |
Hydrocortisone v Placebo
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Number of subjects included in analysis |
30
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
= 0.14 | |||||||||
Method |
GLM log link/binomial error distrib. | |||||||||
Parameter type |
Risk ratio (RR) | |||||||||
Point estimate |
2.33
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.86 | |||||||||
upper limit |
9.17 | |||||||||
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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 1 year
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Statistical analysis title |
Primary analysis | ||||||||||||
Statistical analysis description |
EQ-VAS ranges from 0-100 mm. Analysed using a linear regression adjusted for invasive mechanical ventilation (y/n) and age below 70 years (y/n).
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Comparison groups |
Hydrocortisone v Placebo
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Number of subjects included in analysis |
27
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Analysis specification |
Post-hoc
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.61 | ||||||||||||
Method |
Regression, Linear | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-7.8
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-38.5 | ||||||||||||
upper limit |
23 | ||||||||||||
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End point title |
EQ-5D-5L index value | ||||||||||||
End point description |
EQ-5D-5L index value are anchored at 1 (perfect health) and 0 (health state as bad as being dead) with negative values representing health states worse than death.
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End point type |
Secondary
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End point timeframe |
At 1 year.
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Statistical analysis title |
Primary analysis | ||||||||||||
Statistical analysis description |
Analysed using a linear regression adjusted for invasive mechanical ventilation (y/n) and age below 70 years (y/n).
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Comparison groups |
Hydrocortisone v Placebo
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Number of subjects included in analysis |
27
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Analysis specification |
Post-hoc
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.61 | ||||||||||||
Method |
Regression, Linear | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-0.09
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.43 | ||||||||||||
upper limit |
0.25 | ||||||||||||
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Adverse events information [1]
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Timeframe for reporting adverse events |
From randomisation to day 14.
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Adverse event reporting additional description |
Serious adverse reactions were a predefined outcome in the trial. The following SARs occured in the two reporting groups:
Hydrocortisone: septic shock 1/16
Placebo: septic shock 0/14
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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? No | ||||||||||
Interruptions (globally) |
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| Were there any global interruptions to the trial? Yes | ||||||||||
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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. | ||||||||||
| Highly uncertain results due to the reduced sample size (3% of the planned sample size). | ||||||||||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/34138478 http://www.ncbi.nlm.nih.gov/pubmed/35067914 |
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