Steroid Dosing by bioMARker Guided Titration in Critically Ill Patients With Pneumonia

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT03852537
• Collaborator: (none)
• Enrollment: 44
• Location: 1
• Arms: 2
• Actual Duration (Months): 11.5
• Patients Per Site Per Month: 3.8

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Pneumonia	Drug: Methylprednisolone; Other: Usual Care	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 44 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Participant)
• Primary Purpose: Treatment
• Official Title: SMART Trial: Steroid Dosing by bioMARker Guided Titration in Critically Ill Patients With Pneumonia
• Actual Study Start Date: Dec 2, 2019
• Actual Primary Completion Date: Nov 17, 2020
• Actual Study Completion Date: Nov 17, 2020

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Usual Care Usual care as determined by the patient's primary team.	Other: Usual Care; Usual care as determined by the patients treatment team.
Experimental: 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).	Drug: Methylprednisolone; Methylprednisolone will be administered based on CRP-guided protocol outlined under 'Biomarker-adjusted steroid dosing'.; Other Names: Biomarker guided steroid dosing

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. Mortality [90 days]

   Number of subject deaths

2. 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

3. 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.

4. 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.

5. 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.

6. 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.

7. 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

8. 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

9. 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.

10. 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.

11. 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.

12. ICU Admission [Within hospitalization or 30 days of study enrollment (whichever is sooner)]

    Number of subjects admitted to the ICU

13. Oxygen-free Days [Within hospitalization or 30 days of study enrollment (whichever is sooner)]

    Number of days subjects did not require oxygen assistance.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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).

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

• Suspected flare of Interstitial lung disease (infectious and non-infectious)

• Positive influenza testing or high suspicion for influenza

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic in Rochester	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic

Investigators

• Principal Investigator: Hemang Yadav, Mayo Clinic

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 4, 2021

More Information

Additional Information:

• Mayo Clinic Clinical Trials

Publications

None provided.

• Responsible Party: Hemang Yadav, Principal Investigator, Mayo Clinic
• ClinicalTrials.gov Identifier: NCT03852537
• Other Study ID Numbers: 18-010925
• First Posted: Feb 25, 2019
• Last Update Posted: Sep 16, 2021
• Last Verified: Sep 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Hemang Yadav, Principal Investigator, Mayo Clinic: Pneumonia, steroid, COVID-19, SARS CoV-2
• Additional relevant MeSH terms: Pneumonia; Methylprednisolone; Methylprednisolone Acetate; Methylprednisolone Hemisuccinate; Prednisolone; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate

Study Results

Participant Flow

Arm/Group Title	Usual Care	Biomarker-adjusted Steroid Dosing
Arm/Group Description	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.	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'.
Period Title: Overall Study
STARTED	23	21
COMPLETED	23	21
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Usual Care	Biomarker-adjusted Steroid Dosing	Total
Arm/Group Description	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.	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'.	Total of all reporting groups
Overall Participants	23	21	44
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	60.0	59.0	60.0
Sex: Female, Male (Count of Participants)
Female	9 39.1%	9 42.9%	18 40.9%
Male	14 60.9%	12 57.1%	26 59.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	2 8.7%	0 0%	2 4.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	2 9.5%	2 4.5%
White	18 78.3%	17 81%	35 79.5%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	3 13%	2 9.5%	5 11.4%
Region of Enrollment (participants) [Number]
United States	23 100%	21 100%	44 100%

Outcome Measures

1. Primary Outcome

Title	Timely Initiation of Corticosteroids and Implementation of Biomarker-titrated Corticosteroid Dosing
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Usual Care	Biomarker-adjusted Steroid Dosing
Arm/Group Description	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.	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'.
Measure Participants	23	21
Count of Participants [Participants]	20 87%	19 90.5%

2. Secondary Outcome

Title	Mortality
Description	Number of subject deaths
Time Frame	90 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Usual Care	Biomarker-adjusted Steroid Dosing
Arm/Group Description	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.	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'.
Measure Participants	23	21
Count of Participants [Participants]	1 4.3%	1 4.8%

3. Secondary Outcome

Title	Need for High Flow Nasal Cannula Oxygen
Description	Number of subjects to need high flow nasal cannula oxygen
Time Frame	Within hospitalization or 30 days of study enrollment (whichever is sooner)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Usual Care	Biomarker-adjusted Steroid Dosing
Arm/Group Description	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.	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'.
Measure Participants	23	21
Count of Participants [Participants]	7 30.4%	4 19%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-adjusted Steroid Dosing
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.494
	Comments
	Method	Fisher Exact
	Comments

4. Secondary Outcome

Title	Need for Noninvasive Mechanical Ventilation
Description	Assessed by the number of participants that required noninvasive mechanical ventilation.
Time Frame	Within hospitalization or 30 days of study enrollment (whichever is sooner)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Usual Care	Biomarker-adjusted Steroid Dosing
Arm/Group Description	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.	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'.
Measure Participants	23	21
Count of Participants [Participants]	4 17.4%	2 9.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-adjusted Steroid Dosing
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.666
	Comments
	Method	Fisher Exact
	Comments

5. Secondary Outcome

Title	Need for Invasive Mechanical Ventilation
Description	Assessed by the number of participants that required invasive mechanical ventilation.
Time Frame	Within hospitalization or 30 days of study enrollment (whichever is sooner)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Usual Care	Biomarker-adjusted Steroid Dosing
Arm/Group Description	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.	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'.
Measure Participants	23	21
Count of Participants [Participants]	3 13%	2 9.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-adjusted Steroid Dosing
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Fisher Exact
	Comments

6. Secondary Outcome

Title	Organ Failure
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Usual Care	Biomarker-adjusted Steroid Dosing
Arm/Group Description	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.	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'.
Measure Participants	23	21
Day 1	3.0	7.0
Day 2	3.0	3.0
Day 3	3.0	3.0
Day 4	3.0	3.0
Day 5	3.0	5.5

7. Secondary Outcome

Title	New Onset Cardiac Arrhythmias
Description	Number of participants who develop arrhythmias identified by electrocardiogram or echocardiogram.
Time Frame	Within hospitalization or 30 days of study enrollment (whichever is sooner)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Usual Care	Biomarker-adjusted Steroid Dosing
Arm/Group Description	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.	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'.
Measure Participants	23	21
Count of Participants [Participants]	0 0%	1 4.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-adjusted Steroid Dosing
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.477
	Comments
	Method	Fisher Exact
	Comments

8. Secondary Outcome

Title	Myocardial Injury
Description	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.

Outcome Measure Data

Analysis Population Description

Data were missing for 8 subjects in the usual care arm and 4 subjects in the biomarker-adjusted steroid dosing arm.

Arm/Group Title	Usual Care	Biomarker-adjusted Steroid Dosing
Arm/Group Description	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.	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'.
Measure Participants	15	17
Count of Participants [Participants]	8 34.8%	10 47.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-adjusted Steroid Dosing
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Chi-squared
	Comments

9. Secondary Outcome

Title	Cardiovascular Dysfunction
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Usual Care	Biomarker-adjusted Steroid Dosing
Arm/Group Description	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.	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'.
Measure Participants	23	21
Count of Participants [Participants]	1 4.3%	1 4.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-adjusted Steroid Dosing
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Fisher Exact
	Comments

10. Secondary Outcome

Title	Occurrence of Hyperglycemia
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Usual Care	Biomarker-adjusted Steroid Dosing
Arm/Group Description	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.	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'.
Measure Participants	23	21
Count of Participants [Participants]	11 47.8%	18 85.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-adjusted Steroid Dosing
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.011
	Comments
	Method	Fisher Exact
	Comments

11. Secondary Outcome

Title	Occurrence of Delirium
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Usual Care	Biomarker-adjusted Steroid Dosing
Arm/Group Description	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.	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'.
Measure Participants	23	21
Count of Participants [Participants]	5 21.7%	5 23.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-adjusted Steroid Dosing
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Fisher Exact
	Comments

12. Secondary Outcome

Title	Occurrence of Secondary Infection
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Usual Care	Biomarker-adjusted Steroid Dosing
Arm/Group Description	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.	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'.
Measure Participants	23	21
Count of Participants [Participants]	0 0%	0 0%

13. Secondary Outcome

Title	ICU Admission
Description	Number of subjects admitted to the ICU
Time Frame	Within hospitalization or 30 days of study enrollment (whichever is sooner)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Usual Care	Biomarker-adjusted Steroid Dosing
Arm/Group Description	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.	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'.
Measure Participants	23	21
Count of Participants [Participants]	10 43.5%	5 23.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-adjusted Steroid Dosing
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.213
	Comments
	Method	Chi-squared
	Comments

14. Secondary Outcome

Title	Oxygen-free Days
Description	Number of days subjects did not require oxygen assistance.
Time Frame	Within hospitalization or 30 days of study enrollment (whichever is sooner)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Usual Care	Biomarker-adjusted Steroid Dosing
Arm/Group Description	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.	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'.
Measure Participants	23	21
Median (Inter-Quartile Range) [days]	21.0	24.0

Adverse Events

Time Frame	Adverse events were collected from baseline to end of study for a total of approximately 90 days on all participants.
Arm/Group Title	Usual Care		Biomarker-adjusted Steroid Dosing
Arm/Group Description	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.		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'.
All Cause Mortality
	Usual Care		Biomarker-adjusted Steroid Dosing
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/23 (4.3%)		1/21 (4.8%)
Serious Adverse Events
	Usual Care		Biomarker-adjusted Steroid Dosing
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/23 (0%)		0/21 (0%)
Other (Not Including Serious) Adverse Events
	Usual Care		Biomarker-adjusted Steroid Dosing
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/23 (0%)		0/21 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.