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

• ClinicalTrials.gov Identifier: NCT03852537
• Recruitment Status: Completed
• First Posted: February 25, 2019
• Results First Posted: September 16, 2021
• Last Update Posted: September 16, 2021
• Sponsor: Mayo Clinic
• Information provided by (Responsible Party): Hemang Yadav, Mayo Clinic

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 (Clinical Trial)
• 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: December 2, 2019
• Actual Primary Completion Date: November 17, 2020
• Actual Study Completion Date: November 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 Name: Biomarker guided steroid dosing

Outcome Measures

Primary Outcome Measures :

1. Timely Initiation of Corticosteroids and Implementation of Biomarker-titrated Corticosteroid Dosing [ Time Frame: 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 [ Time Frame: 90 days ]
   Number of subject deaths
2. Need for High Flow Nasal Cannula Oxygen [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Within hospitalization or 30 days of study enrollment (whichever is sooner) ]
    Number of subjects admitted to the ICU
13. Oxygen-free Days [ Time Frame: Within hospitalization or 30 days of study enrollment (whichever is sooner) ]
    Number of days subjects did not require oxygen assistance.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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).

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

United States, Minnesota

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)

Documents provided by Hemang Yadav, Mayo Clinic:

Study Protocol and Statistical Analysis Plan  [PDF] January 4, 2021

More Information

Additional Information:

Mayo Clinic Clinical Trials 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: 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.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)
• Time Frame: From 9 months to 36 months after article publication.

• 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, Mayo Clinic:

Pneumonia, steroid, COVID-19, SARS CoV-2

Additional relevant MeSH terms:

Pneumonia; Respiratory Tract Infections; Infections; Lung Diseases; Respiratory Tract Diseases; Methylprednisolone; Methylprednisolone Acetate; Methylprednisolone Hemisuccinate; Prednisolone; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuroprotective Agents; Protective Agents; Antineoplastic Agents, Hormonal; Antineoplastic Agents