Corona Virus Infection
Conditions
Brief summary
Treatment with glucocorticoids in COVID patients. Low-intervention, phase IV, open-label, randomised, low-intervention clinical trial comparing 2 active treatments.
Detailed description
The use of high-dose bolus glucocorticoids in the treatment of patients with COVID-19 infection will increase the anti-inflammatory effect without increasing side effects. This will allow a better patient outcome, reducing the number of deaths and the need for intubation or admission to the Intensive Care Unit.
Interventions
DRUGDexamethasone
6 mg/24h - 10 days
DRUGMethylprednisolone
250 mg/ 24h - 3 days
Sponsors
Instituto de Investigación Biomédica de Salamanca
Fundación Instituto de Estudios de Ciencias de la Salud de Castilla y León
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open-label, randomised clinical trial comparing 2 active treatments. Low-intervention clinical trial
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Over 18 years of age 2. Inpatient 3. Diagnosis of SARS-CoV-2 infection confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) or antigen 4. They present evidence in computerized axial tomography (CT) of pulmonary involvement attributed to the infection by COVID. Patients in whom CT scans are not performed must have suspected pulmonary involvement by clinical examination with simple compatible or suggestive radiology. 5. Requires supplementary oxygen due to basal saturation ≤ 93% (with ambient O2, 21%)
Exclusion criteria
1. The patient's situation is so serious that the doctor in charge thinks he could die within 24 hours. 2. At the time of randomisation, patients require one of the following 4 ventilatory supports: 1. high-flow oxygen devices. 2. non-invasive mechanical ventilation. 3. invasive mechanical ventilation. 4. Extracorporeal membrane oxygenation (ECMO). 3. The patient is or has been treated in the 2 weeks prior to randomisation with glucocorticoids or inflammation modifying drugs, both conventional (thiopurines, cyclophosphamide, cyclosporine, tacrolimus), leflunomide, methotrexate, mycophenolate mofetil/mycophenolic acid, sulfasalazine, hydroxychloroquine or chloroquine) as synthetics or biologics directed against therapeutic targets (abatacept, belimumab, CD-20, IL1, IL6, Il12. 23, IL-23, Il.17, TNF, integrin α4β7 or Janus kinase inhibitors JAK). Patients who are only on maintenance treatment with doses of steroids less than or equal to 7.5 mg of prednisone or equivalent per day will not be excluded. 4. The patient is pregnant or breastfeeding. 5. The patient has a chronic renal disease is stage 4 or 5 (CCr \<30 ml/min). 6. Moderate to severe dementia at the investigator's discretion. 7. Hypersensitivity to any of the active ingredients or to any of the excipients included in its formulation. 8. Untreated systemic infections not caused by COVID-19. 9. Active stomach or duodenal ulcer. 10. Recent vaccination with live vaccines. 11. Other infection or disease that explains the lung disorder. 12. Inability of the patient to understand the study or to sign the informed consent unless consent is delegated to a legal representative. 13. Active participation in another clinical study in the last 15 days.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mortality Rate | 28 days | Mortality rate (percentage) in COVID-19 patients after high-dose methylprednisolone bolus administration versus mortality rate intermediate-dose dexamethasone pattern (RECOVERY trial) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Evaluation of Respiratory Support Requirements | 28 days | * Proportion of patients (number of cases with respiratory support requirement / total number of patients) with non-invasive mechanical ventilation and/or high-flow oxygen requirements. * Proportion of patients (number of cases with respiratory support requirement / total number of patients) with invasive mechanical ventilation or intubation requirements. |
| Days in Hospital | 28 days | Number of days in hospital from the star of the treatment until discharge |
| Status According to the World Health Organization (WHO) 10-category Scale. | 90 days | Clinical evaluation of patient status according to the WHO 10-category scale. Minimum value: 1 and maximum value: 10, higher scores mean a worse outcome. |
| Evaluation of Other Immunosuppressors Requirements. | 28 days | Occurrence of use of other immunosuppressors, if applicable |
| Admission in Intensive Unit Care (ICU) | 28 days | Number of patients who have been admitted to the ICU. |
| Evaluation of Presence of Adverse Events Related With Use of High Dose of Glucocorticoids. | 28 days | Occurrence of infections, hyperglycaemia, psychotic states or other adverse effects, if applicable |
Countries
Spain
Participant flow
Recruitment details
The sample size estimation (295 patients) for the primary outcomes was based on data from the first waves of COVID-19. Changes in pandemia status triggered to our initial estimation for sample size calculation was outdated. In addition to the high percentage of people vaccinated in Spain, in the summer of 2021 was the end of the fifth wave of COVID-19, with a very small number of patients hospitalized, so the clinical trial was premature ended in August 2021.
Pre-assignment details
Randomisation was performed using a centralised, computer-generated allocation, stratified by trial site and by age under 70 years, in a 1:1 ratio. 158 patients were assessed for eligibility, and 128 were randomised: 64 to BOLUS group and 64 to RECOVERY group.
Participants by arm
| Arm | Count |
|---|---|
| BOLUS high-dose methylprednisolone bolus (250mg/24h - 3 days)
Methylprednisolone: 250 mg/24h - 3 days | 63 |
| RECOVERY intermediate-dose dexamethasone (6mg/24h - 10 days)
Dexamethasone: 6 mg/24h - 10 days | 62 |
| Total | 125 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Full Modified Intention-to-treat Anal. | Protocol Violation | 1 | 2 |
| Overall Study (90 Days) | Lost to Follow-up | 0 | 2 |
Baseline characteristics
| Characteristic | BOLUS | RECOVERY | Total |
|---|---|---|---|
| Age, Customized 18-69 years | 40 Participants | 42 Participants | 82 Participants |
| Age, Customized 70 years and over | 23 Participants | 20 Participants | 43 Participants |
| COVID-19 characteristics Arthralgia/Myalgia | 21 Participants | 19 Participants | 40 Participants |
| COVID-19 characteristics Cough | 47 Participants | 43 Participants | 90 Participants |
| COVID-19 characteristics Diarrhoea | 18 Participants | 16 Participants | 34 Participants |
| COVID-19 characteristics Fever | 47 Participants | 43 Participants | 90 Participants |
| COVID-19 characteristics Headache | 15 Participants | 9 Participants | 24 Participants |
| COVID-19 characteristics Hyposmia/hypogeusia | 10 Participants | 13 Participants | 23 Participants |
| COVID-19 characteristics Nausea | 13 Participants | 10 Participants | 23 Participants |
| COVID-19 characteristics Thoracic pain | 8 Participants | 7 Participants | 15 Participants |
| Diabetes | 13 Participants | 10 Participants | 23 Participants |
| Dyslipidaemia | 16 Participants | 22 Participants | 38 Participants |
| Hypertension | 31 Participants | 22 Participants | 53 Participants |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Sex: Female, Male Female | 20 Participants | 21 Participants | 41 Participants |
| Sex: Female, Male Male | 43 Participants | 41 Participants | 84 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 6 / 63 | 4 / 62 |
| other Total, other adverse events | 25 / 63 | 15 / 62 |
| serious Total, serious adverse events | 22 / 63 | 21 / 62 |
Outcome results
Primary
Mortality Rate
Mortality rate (percentage) in COVID-19 patients after high-dose methylprednisolone bolus administration versus mortality rate intermediate-dose dexamethasone pattern (RECOVERY trial)
Time frame: 28 days
Population: This outcome, mortality rate, was evaluated 28 days after treatment (63 participants in bolus arm vs. 62 participants in recovery arm).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BOLUS | Mortality Rate | 3 Participants |
| RECOVERY | Mortality Rate | 3 Participants |
Comparison: Null hypothesis of equal survival curves. Estimates of rate and risk ratios are shown with 95% confidence intervals. All the p-values are 2-sided and shown without adjustment for multiple testing, and p \< 0.05 was considered statistically significant. The analyses were performed using IBM SPSS Statistics for Windows, Version 26.0 (Armonk, NY, USA: IBM Corp.).p-value: 0.98495% CI: [0.2, 5.1]Log Rank
95% CI: [-8.8, 9.1]
Secondary
Admission in Intensive Unit Care (ICU)
Number of patients who have been admitted to the ICU.
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BOLUS | Admission in Intensive Unit Care (ICU) | 10 Participants |
| RECOVERY | Admission in Intensive Unit Care (ICU) | 9 Participants |
p-value: 0.83395% CI: [0.4, 3]Chi-squared
95% CI: [-14.2, 11.5]
Secondary
Days in Hospital
Number of days in hospital from the star of the treatment until discharge
Time frame: 28 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BOLUS | Days in Hospital | 13 Days | Standard Deviation 16 |
| RECOVERY | Days in Hospital | 13 Days | Standard Deviation 12 |
p-value: 0.90895% CI: [-5, 5]t-test, 1 sided
Secondary
Evaluation of Other Immunosuppressors Requirements.
Occurrence of use of other immunosuppressors, if applicable
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BOLUS | Evaluation of Other Immunosuppressors Requirements. | 14 Participants |
| RECOVERY | Evaluation of Other Immunosuppressors Requirements. | 14 Participants |
p-value: 0.96295% CI: [0.4, 2.3]Chi-squared
95% CI: [-14.2, 14.9]
Secondary
Evaluation of Presence of Adverse Events Related With Use of High Dose of Glucocorticoids.
Occurrence of infections, hyperglycaemia, psychotic states or other adverse effects, if applicable
Time frame: 28 days
Population: This adverse events related with use of high dose of glucocorticoids and were evaluated 28 days after treatment (63 participants in bolus arm vs. 62 participants in recovery arm).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BOLUS | Evaluation of Presence of Adverse Events Related With Use of High Dose of Glucocorticoids. | Secondary infections | 7 Events |
| BOLUS | Evaluation of Presence of Adverse Events Related With Use of High Dose of Glucocorticoids. | Hyperglycaemia | 17 Events |
| BOLUS | Evaluation of Presence of Adverse Events Related With Use of High Dose of Glucocorticoids. | Psychotic states | 1 Events |
| BOLUS | Evaluation of Presence of Adverse Events Related With Use of High Dose of Glucocorticoids. | Other adverse effects no related with use of high dose of glucocorticoids. | 77 Events |
| RECOVERY | Evaluation of Presence of Adverse Events Related With Use of High Dose of Glucocorticoids. | Other adverse effects no related with use of high dose of glucocorticoids. | 38 Events |
| RECOVERY | Evaluation of Presence of Adverse Events Related With Use of High Dose of Glucocorticoids. | Secondary infections | 8 Events |
| RECOVERY | Evaluation of Presence of Adverse Events Related With Use of High Dose of Glucocorticoids. | Psychotic states | 0 Events |
| RECOVERY | Evaluation of Presence of Adverse Events Related With Use of High Dose of Glucocorticoids. | Hyperglycaemia | 5 Events |
Comparison: Secondary infectionsp-value: 0.75895% CI: [0.3, 2.5]Chi-squared
Comparison: Secondary infections95% CI: [-10.1, 13.7]
Comparison: Hyperglycaemiap-value: 0.00795% CI: [1.4, 12.3]Chi-squared
Comparison: Hyperglycaemia95% CI: [-31.8, -5.6]
Comparison: Psychotic statesp-value: 0.31995% CI: [-8.5, 4.4]Chi-squared
Secondary
Evaluation of Respiratory Support Requirements
* Proportion of patients (number of cases with respiratory support requirement / total number of patients) with non-invasive mechanical ventilation and/or high-flow oxygen requirements. * Proportion of patients (number of cases with respiratory support requirement / total number of patients) with invasive mechanical ventilation or intubation requirements.
Time frame: 28 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BOLUS | Evaluation of Respiratory Support Requirements | invasive mechanical ventilation or intubation requirements | 0.13 proportion of participants |
| BOLUS | Evaluation of Respiratory Support Requirements | non-invasive mechanical ventilation | 0.05 proportion of participants |
| BOLUS | Evaluation of Respiratory Support Requirements | high-flow oxygen requirements. | 0.10 proportion of participants |
| RECOVERY | Evaluation of Respiratory Support Requirements | invasive mechanical ventilation or intubation requirements | 0.12 proportion of participants |
| RECOVERY | Evaluation of Respiratory Support Requirements | non-invasive mechanical ventilation | 0.03 proportion of participants |
| RECOVERY | Evaluation of Respiratory Support Requirements | high-flow oxygen requirements. | 0.13 proportion of participants |
Comparison: non-invasive mechanical ventilationp-value: 0.66195% CI: [0.2, 9.3]Chi-squared
Comparison: non-invasive mechanical ventilation95% CI: [-10.2, 6.9]
Comparison: high-flow oxygen requirementsp-value: 0.54995% CI: [0.2, 2.2]Chi-squared
Comparison: high-flow oxygen requirements95% CI: [-8.2, 15.1]
Comparison: Invasive mechanical ventilation or intubation requirements analysisp-value: 0.80995% CI: [0.4, 3.3]Chi-squared
Comparison: Invasive mechanical ventilation or intubation requirements analysis95% CI: [-13, 11.1]
Secondary
Status According to the World Health Organization (WHO) 10-category Scale.
Clinical evaluation of patient status according to the WHO 10-category scale. Minimum value: 1 and maximum value: 10, higher scores mean a worse outcome.
Time frame: 90 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BOLUS | Status According to the World Health Organization (WHO) 10-category Scale. | Dead (10) | 6 participants |
| BOLUS | Status According to the World Health Organization (WHO) 10-category Scale. | Intubation PaFi<150 plus vasopressors or ECMO or Dialysis (9) | 0 participants |
| BOLUS | Status According to the World Health Organization (WHO) 10-category Scale. | Intubation PaFi<150 or vasopressors (8) | 0 participants |
| BOLUS | Status According to the World Health Organization (WHO) 10-category Scale. | Intubation PaFi<150 (7) | 0 participants |
| BOLUS | Status According to the World Health Organization (WHO) 10-category Scale. | Hospitalized, NIV or high flow (6) | 0 participants |
| BOLUS | Status According to the World Health Organization (WHO) 10-category Scale. | Hospitalized, mask or nasal prongs (5) | 1 participants |
| BOLUS | Status According to the World Health Organization (WHO) 10-category Scale. | Hospitalized, no oxigen therapy (4) | 2 participants |
| BOLUS | Status According to the World Health Organization (WHO) 10-category Scale. | Symptomatic, assistance needed (3) | 0 participants |
| BOLUS | Status According to the World Health Organization (WHO) 10-category Scale. | Symptomatic, indeoendent (2) | 12 participants |
| BOLUS | Status According to the World Health Organization (WHO) 10-category Scale. | Asymptomatic (1) | 42 participants |
| RECOVERY | Status According to the World Health Organization (WHO) 10-category Scale. | Symptomatic, assistance needed (3) | 3 participants |
| RECOVERY | Status According to the World Health Organization (WHO) 10-category Scale. | Dead (10) | 4 participants |
| RECOVERY | Status According to the World Health Organization (WHO) 10-category Scale. | Hospitalized, mask or nasal prongs (5) | 0 participants |
| RECOVERY | Status According to the World Health Organization (WHO) 10-category Scale. | Intubation PaFi<150 plus vasopressors or ECMO or Dialysis (9) | 0 participants |
| RECOVERY | Status According to the World Health Organization (WHO) 10-category Scale. | Asymptomatic (1) | 38 participants |
| RECOVERY | Status According to the World Health Organization (WHO) 10-category Scale. | Intubation PaFi<150 or vasopressors (8) | 0 participants |
| RECOVERY | Status According to the World Health Organization (WHO) 10-category Scale. | Hospitalized, no oxigen therapy (4) | 0 participants |
| RECOVERY | Status According to the World Health Organization (WHO) 10-category Scale. | Intubation PaFi<150 (7) | 1 participants |
| RECOVERY | Status According to the World Health Organization (WHO) 10-category Scale. | Symptomatic, indeoendent (2) | 14 participants |
| RECOVERY | Status According to the World Health Organization (WHO) 10-category Scale. | Hospitalized, NIV or high flow (6) | 0 participants |