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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Usual Care | Active Comparator | Usual care as determined by the patient's primary team. |
|
| Biomarker-adjusted Steroid Dosing | Experimental | 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). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Methylprednisolone | Drug | Methylprednisolone will be administered based on CRP-guided protocol outlined under 'Biomarker-adjusted steroid dosing'. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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) | Within 30 days of enrollment in study. |
| Measure | Description | Time Frame |
|---|---|---|
| Mortality | Number of subject deaths | 90 days |
| Need for High Flow Nasal Cannula Oxygen | Number of subjects to need high flow nasal cannula oxygen |
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For the Pneumonia arm of the study:
Inclusion Criteria:
Exclusion Criteria:
For the COVID-19 arm of the study:
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Hemang Yadav | Mayo Clinic | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Mayo Clinic in Rochester | Rochester | Minnesota | 55905 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 34983600 | Derived | Odeyemi YE, Chalmers SJ, Barreto EF, Jentzer JC, Gajic O, Yadav H. Early, biomarker-guided steroid dosing in COVID-19 Pneumonia: a pilot randomized controlled trial. Crit Care. 2022 Jan 4;26(1):9. doi: 10.1186/s13054-021-03873-2. |
| Label | URL |
|---|---|
| Mayo Clinic Clinical Trials | View source |
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Individual participant data that underlie the results reported in any manuscript resulting from this research, after deidentification (text, tables, figures, and appendices) and the study protocol will be shared beginning 9 months and ending 36 months following article publication, to anyone who wishes to access the data. Proposals should be directed to yadav.hemang@mayo.edu. To gain access, data requestors will need to sign a data access agreement.
From 9 months to 36 months after article publication.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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'. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | Biomarker-adjusted Steroid Dosing |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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) | Posted | Count of Participants | Participants | Within 30 days of enrollment in study. |
|
Adverse events were collected from baseline to end of study for a total of approximately 90 days on all participants.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Hemang Yadav, MBBS, MS | Mayo Clinic | 507-266-3958 | Yadav.Hemang@mayo.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jan 4, 2021 | Jun 29, 2021 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D011014 | Pneumonia |
| D000086382 | COVID-19 |
| ID | Term |
|---|---|
| D012141 | Respiratory Tract Infections |
| D007239 | Infections |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
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| ID | Term |
|---|---|
| D008775 | Methylprednisolone |
| ID | Term |
|---|---|
| D011239 | Prednisolone |
| D011246 | Pregnadienetriols |
| D011245 | Pregnadienes |
| D011278 | Pregnanes |
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|
| Usual Care | Other | Usual care as determined by the patients treatment team. |
|
| Within hospitalization or 30 days of study enrollment (whichever is sooner) |
| Need for Noninvasive Mechanical Ventilation | Assessed by the number of participants that required noninvasive mechanical ventilation. | Within hospitalization or 30 days of study enrollment (whichever is sooner) |
| Need for Invasive Mechanical Ventilation | Assessed by the number of participants that required invasive mechanical ventilation. | Within hospitalization or 30 days of study enrollment (whichever is sooner) |
| 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. | Measured daily for approximately 5 days |
| New Onset Cardiac Arrhythmias | Number of participants who develop arrhythmias identified by electrocardiogram or echocardiogram. | Within hospitalization or 30 days of study enrollment (whichever is sooner) |
| 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 | Up to day +14 following study enrollment. |
| Cardiovascular Dysfunction | Number of subjects with new and/or worsening right ventricle (RV)/left ventricle (LV) dysfunction | Within hospitalization or 30 days of study enrollment (whichever is sooner) |
| 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. | Up to day +5 following study enrollment. |
| 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. | Up to day +5 following study enrollment. |
| 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. | Up to day +14 following study enrollment. |
| ICU Admission | Number of subjects admitted to the ICU | Within hospitalization or 30 days of study enrollment (whichever is sooner) |
| Oxygen-free Days | Number of days subjects did not require oxygen assistance. | Within hospitalization or 30 days of study enrollment (whichever is sooner) |
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'. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
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'.
|
|
| Secondary | Mortality | Number of subject deaths | Posted | Count of Participants | Participants | 90 days |
|
|
|
| Secondary | Need for High Flow Nasal Cannula Oxygen | Number of subjects to need high flow nasal cannula oxygen | Posted | Count of Participants | Participants | Within hospitalization or 30 days of study enrollment (whichever is sooner) |
|
|
|
|
| Secondary | Need for Noninvasive Mechanical Ventilation | Assessed by the number of participants that required noninvasive mechanical ventilation. | Posted | Count of Participants | Participants | Within hospitalization or 30 days of study enrollment (whichever is sooner) |
|
|
|
|
| Secondary | Need for Invasive Mechanical Ventilation | Assessed by the number of participants that required invasive mechanical ventilation. | Posted | Count of Participants | Participants | Within hospitalization or 30 days of study enrollment (whichever is sooner) |
|
|
|
|
| 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. | Posted | Median | Inter-Quartile Range | score on a scale | Measured daily for approximately 5 days |
|
|
|
| Secondary | New Onset Cardiac Arrhythmias | Number of participants who develop arrhythmias identified by electrocardiogram or echocardiogram. | Posted | Count of Participants | Participants | Within hospitalization or 30 days of study enrollment (whichever is sooner) |
|
|
|
|
| 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 | Data were missing for 8 subjects in the usual care arm and 4 subjects in the biomarker-adjusted steroid dosing arm. | Posted | Count of Participants | Participants | Up to day +14 following study enrollment. |
|
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|
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| Secondary | Cardiovascular Dysfunction | Number of subjects with new and/or worsening right ventricle (RV)/left ventricle (LV) dysfunction | Posted | Count of Participants | Participants | Within hospitalization or 30 days of study enrollment (whichever is sooner) |
|
|
|
|
| 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. | Posted | Count of Participants | Participants | Up to day +5 following study enrollment. |
|
|
|
|
| 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. | Posted | Count of Participants | Participants | Up to day +5 following study enrollment. |
|
|
|
|
| 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. | Posted | Count of Participants | Participants | Up to day +14 following study enrollment. |
|
|
|
| Secondary | ICU Admission | Number of subjects admitted to the ICU | Posted | Count of Participants | Participants | Within hospitalization or 30 days of study enrollment (whichever is sooner) |
|
|
|
|
| Secondary | Oxygen-free Days | Number of days subjects did not require oxygen assistance. | Posted | Median | Inter-Quartile Range | days | Within hospitalization or 30 days of study enrollment (whichever is sooner) |
|
|
|
| 1 |
| 23 |
| 0 |
| 23 |
| 0 |
| 23 |
| EG001 | 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'. | 1 | 21 | 0 | 21 | 0 | 21 |
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| D011024 |
| Pneumonia, Viral |
| D014777 | Virus Diseases |
| D018352 | Coronavirus Infections |
| D003333 | Coronaviridae Infections |
| D030341 | Nidovirales Infections |
| D012327 | RNA Virus Infections |
| D013256 |
| Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
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| Day 4 |
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| Day 5 |
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