Pneumonia
Conditions
Keywords
Pneumonia, steroid, COVID-19, SARS CoV-2
Brief summary
This research study is being done to determine the appropriate dose of steroids and the appropriate duration for steroid use to reduce inflammation in severe pneumonia needing a form of breathing support. This study seeks to compare usual care to a unique (individualized) dosing strategy. A marker of inflammation in the body will be measured in blood samples. This marker of inflammation is called C- reactive protein. The overall goal is to identify patients that will benefit most from steroid use and decrease use of steroids. The information collected from this study may provide information that may improve management of patients with severe pneumonia requiring a form of breathing support.
Detailed description
This is a two-arm single-center pilot phase II clinical trial. Patients will be screened at the time of hospital admission and will be required to be enrolled within the clinical trial within 48 hours of hospital admission. In the individualized, biomarker-concordant arm, all patients will receive steroids once at the time of admission, then a daily morning dose. In order to account for varying turnaround time at different laboratories, C-Reactive Protein (CRP) levels will be drawn with early morning labs, and used to determine the steroid dosing for the day. Patients will receive daily CRP measurements for the first 5 days of the hospitalization, or until hospital discharge. CRP measurements will be discontinued once the CRP is less than 50mmol/L. Steroid administration will be facilitated using standardized computerized physician order entry. The patients, treating physicians and outcome assessors will be blinded to the group assignment. Steroid order sets will include 6 hourly point of care glucose monitoring, and an insulin sliding scale for glucose levels to facilitate glucose management. The need for insulin drip will be determined by the treating physician. Additional testing including serum and urine ketones will be informed by the glucose level, serum anion gap and bicarbonate levels in routine basic metabolic panels and determined by the treating physician. In the usual care arm, patients will receive daily CRP measurements for the first 5 days of the hospitalization, or until hospital discharge.
Interventions
DRUGMethylprednisolone
Methylprednisolone will be administered based on CRP-guided protocol outlined under 'Biomarker-adjusted steroid dosing'.
OTHERUsual Care
Usual care as determined by the patients treatment team.
Sponsors
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
For the Pneumonia arm of the study: Inclusion Criteria: * Patients admitted to hospital with community acquired pneumonia. * Acute respiratory failure SpO2/FiO2 \< 315 (SpO2\<90% on room air or \<97% on 2L NC).
Exclusion criteria
* Contraindications or unwilling to use steroids by patient or provider * Refractory septic shock defined as a requirement of norepinephrine dose or equivalent above \>0.1 microgram/kilogram/minute or 2 or more vasopressors * Pre-admission chronic use of steroids or other immunosuppressive medications * Adrenal insufficiency * Comfort care * Leukopenia \<1000/mm or neutropenia \<500/mm (except if attributable to pneumonia) and HIV positive with a CD4 count \<100 * Recent or past history of bone marrow or solid organ transplantation * Hospital admission in the previous 30 days * Suspected flare of Interstitial lung disease (infectious and non-infectious) * Positive influenza testing or high suspicion for influenza For the COVID-19 arm of the study: Inclusion Criteria: * Patients admitted to hospital with COVID-19 pneumonia (high suspicion or confirmed by positive SARS CoV-2 testing). * Acute respiratory failure SpO2/FiO2 \< 315 (SpO2\<90% on room air or \<97% on 2L NC).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Timely Initiation of Corticosteroids and Implementation of Biomarker-titrated Corticosteroid Dosing | Within 30 days of enrollment in study. | Number of eligible subjects to adhered to the timely initiation and daily corticosteroid treatment according to ESICM/Society of Critical Care Medicine SCCM clinical practice guideline (control group) or biomarker concordance (intervention group) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Need for High Flow Nasal Cannula Oxygen | Within hospitalization or 30 days of study enrollment (whichever is sooner) | Number of subjects to need high flow nasal cannula oxygen |
| Need for Noninvasive Mechanical Ventilation | Within hospitalization or 30 days of study enrollment (whichever is sooner) | Assessed by the number of participants that required noninvasive mechanical ventilation. |
| Need for Invasive Mechanical Ventilation | Within hospitalization or 30 days of study enrollment (whichever is sooner) | Assessed by the number of participants that required invasive mechanical ventilation. |
| Organ Failure | Measured daily for approximately 5 days | Organ failures measured by Sequential Organ Failure Assessment (SOFA). The overall score is based on 6 sub-scores respiratory system, neurologic system, cardiovascular system, hepatic system, coagulation, and renal system using an overall scale of 0-24, which 0=no organ failure, 24=complete organ failure. |
| New Onset Cardiac Arrhythmias | Within hospitalization or 30 days of study enrollment (whichever is sooner) | Number of participants who develop arrhythmias identified by electrocardiogram or echocardiogram. |
| Myocardial Injury | Up to day +14 following study enrollment. | Number of participants with evidence of myocardial injury determined by daily troponin peak and /or new diagnosis of Left Ventricular (LV) dysfunction (LVEF \<40%) or new diagnosis of cor pulmonale |
| Mortality | 90 days | Number of subject deaths |
| Occurrence of Hyperglycemia | Up to day +5 following study enrollment. | Number of participants who have hyperglycemia while receiving corticosteroids. Hyperglycemia is defined as a consistently elevated blood sugar level requiring insulin administration. |
| Occurrence of Delirium | Up to day +5 following study enrollment. | Number of participants who develop delirium while receiving corticosteroids. Delirium will be assessed by Confusion Assessment Method for the ICU (CAM-ICU) measurement tool. The CAM-ICU is a binary (yes/no) scale for assessing the presence of delirium. |
| Occurrence of Secondary Infection | Up to day +14 following study enrollment. | Number of participants who develop secondary infections during and after steroid therapy. A secondary infection is defined as a new infection that develops after initiation of corticosteroid therapy, until 5 days after steroids are discontinued. |
| ICU Admission | Within hospitalization or 30 days of study enrollment (whichever is sooner) | Number of subjects admitted to the ICU |
| Oxygen-free Days | Within hospitalization or 30 days of study enrollment (whichever is sooner) | Number of days subjects did not require oxygen assistance. |
| Cardiovascular Dysfunction | Within hospitalization or 30 days of study enrollment (whichever is sooner) | Number of subjects with new and/or worsening right ventricle (RV)/left ventricle (LV) dysfunction |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Usual Care Corticosteroid use and dosing determined by the patient's primary team for standard of care.
Usual Care: Corticosteroid use and dosing determined by the patients treatment team for standard of care. | 23 |
| Biomarker-adjusted Steroid Dosing Individualized, biomarker concordant steroid use: dosing, titration and duration according to CRP level. This is a predetermined dosing table that adjusts dose of steroid by CRP level. Specifically: if CRP \< 50 mmol/L: discontinue steroid; if CRP is between 51-100 mmol/L: 0.5 mg methylprednisolone (or dose equivalent of oral prednisone); if CRP is between 101-150 mmol/L: 0.75 mg/kg methylprednisolone (or dose equivalent of oral prednisone); if CRP level is between 151-200 mmol/L: 1 mg/kg methylprednisolone (or dose equivalent of oral prednisone); if CRP level \> 200 mmol/L: 1.5 mg/kg methylprednisolone (or dose equivalent of oral prednisone).
Methylprednisolone: Methylprednisolone will be administered based on CRP-guided protocol outlined under 'Biomarker-adjusted steroid dosing'. | 21 |
| Total | 44 |
Baseline characteristics
| Characteristic | Usual Care | Total | Biomarker-adjusted Steroid Dosing |
|---|---|---|---|
| Age, Continuous | 60.0 years | 60.0 years | 59.0 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) White | 18 Participants | 35 Participants | 17 Participants |
| Region of Enrollment United States | 23 participants | 44 participants | 21 participants |
| Sex: Female, Male Female | 9 Participants | 18 Participants | 9 Participants |
| Sex: Female, Male Male | 14 Participants | 26 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 23 | 1 / 21 |
| other Total, other adverse events | 0 / 23 | 0 / 21 |
| serious Total, serious adverse events | 0 / 23 | 0 / 21 |
Outcome results
Primary
Timely Initiation of Corticosteroids and Implementation of Biomarker-titrated Corticosteroid Dosing
Number of eligible subjects to adhered to the timely initiation and daily corticosteroid treatment according to ESICM/Society of Critical Care Medicine SCCM clinical practice guideline (control group) or biomarker concordance (intervention group)
Time frame: Within 30 days of enrollment in study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Usual Care | Timely Initiation of Corticosteroids and Implementation of Biomarker-titrated Corticosteroid Dosing | 20 Participants |
| Biomarker-adjusted Steroid Dosing | Timely Initiation of Corticosteroids and Implementation of Biomarker-titrated Corticosteroid Dosing | 19 Participants |
Secondary
Cardiovascular Dysfunction
Number of subjects with new and/or worsening right ventricle (RV)/left ventricle (LV) dysfunction
Time frame: Within hospitalization or 30 days of study enrollment (whichever is sooner)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Usual Care | Cardiovascular Dysfunction | 1 Participants |
| Biomarker-adjusted Steroid Dosing | Cardiovascular Dysfunction | 1 Participants |
p-value: 1Fisher Exact
Secondary
ICU Admission
Number of subjects admitted to the ICU
Time frame: Within hospitalization or 30 days of study enrollment (whichever is sooner)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Usual Care | ICU Admission | 10 Participants |
| Biomarker-adjusted Steroid Dosing | ICU Admission | 5 Participants |
p-value: 0.213Chi-squared
Secondary
Mortality
Number of subject deaths
Time frame: 90 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Usual Care | Mortality | 1 Participants |
| Biomarker-adjusted Steroid Dosing | Mortality | 1 Participants |
Secondary
Myocardial Injury
Number of participants with evidence of myocardial injury determined by daily troponin peak and /or new diagnosis of Left Ventricular (LV) dysfunction (LVEF \<40%) or new diagnosis of cor pulmonale
Time frame: Up to day +14 following study enrollment.
Population: Data were missing for 8 subjects in the usual care arm and 4 subjects in the biomarker-adjusted steroid dosing arm.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Usual Care | Myocardial Injury | 8 Participants |
| Biomarker-adjusted Steroid Dosing | Myocardial Injury | 10 Participants |
p-value: 1Chi-squared
Secondary
Need for High Flow Nasal Cannula Oxygen
Number of subjects to need high flow nasal cannula oxygen
Time frame: Within hospitalization or 30 days of study enrollment (whichever is sooner)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Usual Care | Need for High Flow Nasal Cannula Oxygen | 7 Participants |
| Biomarker-adjusted Steroid Dosing | Need for High Flow Nasal Cannula Oxygen | 4 Participants |
p-value: 0.494Fisher Exact
Secondary
Need for Invasive Mechanical Ventilation
Assessed by the number of participants that required invasive mechanical ventilation.
Time frame: Within hospitalization or 30 days of study enrollment (whichever is sooner)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Usual Care | Need for Invasive Mechanical Ventilation | 3 Participants |
| Biomarker-adjusted Steroid Dosing | Need for Invasive Mechanical Ventilation | 2 Participants |
p-value: 1Fisher Exact
Secondary
Need for Noninvasive Mechanical Ventilation
Assessed by the number of participants that required noninvasive mechanical ventilation.
Time frame: Within hospitalization or 30 days of study enrollment (whichever is sooner)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Usual Care | Need for Noninvasive Mechanical Ventilation | 4 Participants |
| Biomarker-adjusted Steroid Dosing | Need for Noninvasive Mechanical Ventilation | 2 Participants |
p-value: 0.666Fisher Exact
Secondary
New Onset Cardiac Arrhythmias
Number of participants who develop arrhythmias identified by electrocardiogram or echocardiogram.
Time frame: Within hospitalization or 30 days of study enrollment (whichever is sooner)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Usual Care | New Onset Cardiac Arrhythmias | 0 Participants |
| Biomarker-adjusted Steroid Dosing | New Onset Cardiac Arrhythmias | 1 Participants |
p-value: 0.477Fisher Exact
Secondary
Occurrence of Delirium
Number of participants who develop delirium while receiving corticosteroids. Delirium will be assessed by Confusion Assessment Method for the ICU (CAM-ICU) measurement tool. The CAM-ICU is a binary (yes/no) scale for assessing the presence of delirium.
Time frame: Up to day +5 following study enrollment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Usual Care | Occurrence of Delirium | 5 Participants |
| Biomarker-adjusted Steroid Dosing | Occurrence of Delirium | 5 Participants |
p-value: 1Fisher Exact
Secondary
Occurrence of Hyperglycemia
Number of participants who have hyperglycemia while receiving corticosteroids. Hyperglycemia is defined as a consistently elevated blood sugar level requiring insulin administration.
Time frame: Up to day +5 following study enrollment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Usual Care | Occurrence of Hyperglycemia | 11 Participants |
| Biomarker-adjusted Steroid Dosing | Occurrence of Hyperglycemia | 18 Participants |
p-value: 0.011Fisher Exact
Secondary
Occurrence of Secondary Infection
Number of participants who develop secondary infections during and after steroid therapy. A secondary infection is defined as a new infection that develops after initiation of corticosteroid therapy, until 5 days after steroids are discontinued.
Time frame: Up to day +14 following study enrollment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Usual Care | Occurrence of Secondary Infection | 0 Participants |
| Biomarker-adjusted Steroid Dosing | Occurrence of Secondary Infection | 0 Participants |
Secondary
Organ Failure
Organ failures measured by Sequential Organ Failure Assessment (SOFA). The overall score is based on 6 sub-scores respiratory system, neurologic system, cardiovascular system, hepatic system, coagulation, and renal system using an overall scale of 0-24, which 0=no organ failure, 24=complete organ failure.
Time frame: Measured daily for approximately 5 days
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Usual Care | Organ Failure | Day 2 | 3.0 score on a scale |
| Usual Care | Organ Failure | Day 4 | 3.0 score on a scale |
| Usual Care | Organ Failure | Day 3 | 3.0 score on a scale |
| Usual Care | Organ Failure | Day 5 | 3.0 score on a scale |
| Usual Care | Organ Failure | Day 1 | 3.0 score on a scale |
| Biomarker-adjusted Steroid Dosing | Organ Failure | Day 5 | 5.5 score on a scale |
| Biomarker-adjusted Steroid Dosing | Organ Failure | Day 1 | 7.0 score on a scale |
| Biomarker-adjusted Steroid Dosing | Organ Failure | Day 2 | 3.0 score on a scale |
| Biomarker-adjusted Steroid Dosing | Organ Failure | Day 3 | 3.0 score on a scale |
| Biomarker-adjusted Steroid Dosing | Organ Failure | Day 4 | 3.0 score on a scale |
Secondary
Oxygen-free Days
Number of days subjects did not require oxygen assistance.
Time frame: Within hospitalization or 30 days of study enrollment (whichever is sooner)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Usual Care | Oxygen-free Days | 21.0 days |
| Biomarker-adjusted Steroid Dosing | Oxygen-free Days | 24.0 days |