Conditions: Pneumonia
Keywords: Pneumonia, steroid, COVID-19, SARS CoV-2
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 44
Healthy volunteers: no

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.

Arms:
arm 1: Usual care as determined by the patient's primary team. arm 2: 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).

Interventions: intervention 1: Methylprednisolone intervention 2: Usual Care
Intervention descriptions: intervention 1: Methylprednisolone will be administered based on CRP-guided protocol outlined under 'Biomarker-adjusted steroid dosing'. intervention 2: Usual care as determined by the patients treatment team.

Protocol document:
Prot_SAP_000.pdf: 
 
 
SMART Trial: Steroid Dosing by bioMARker 
Guided Titration in Critically Ill Patients 
With Pneumonia 
 
 
NCT03852537 
 
January 4, 2021 


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SMART trial: Steroid dosing by bioMARker guided Titration in critically ill patients with Pneumonia. 
IRB number:-18-010925 
 
Principal Investigator:   Hemang Yadav M.D 
Co-Principal Investigator:   Ognjen Gajic M.D. 
Co-investigators: Yewande Odeyemi M.D, Svetlana Herasevich M.D, Erin Barreto Pharm.D. 
Statistician: Ryan Frank M.S 
Protocol Version: 8; 1/4/2021 
 
Abstract  
Pneumonia is the most common cause of acute hypoxemic respiratory failure. The limited and 
variable use of corticosteroids in critically ill patients with pneumonia is largely due to an 
inability to identify patients that will benefit from the use of anti-inflammatory medications. 
Increased levels of pro-inflammatory mediators are a prominent feature of pneumonia and 
previous studies have tracked the effect of steroids on inflammatory biomarkers or, more 
recently, used biomarkers (i.e. C Reactive Protein -CRP) to enroll patients in to clinical trials.  
The objective of this prospective, single-center pilot trial is to compare individualized, biomarker 
concordant vs usual care in patients with pneumonia and acute hypoxemic respiratory failure 
identified in the emergency department whose bedside physicians intend to provide adjunctive 
corticosteroid treatment.  These data will be used to assess feasibility, refine the protocol, and 
calculate the sample size in preparation for a larger pragmatic clinical trial comparing the two 
strategies.   
 
 
 
 
 
 


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Research Plan 
I. 
Specific Aims 
 
Specific Aim 1:  To assess the feasibility, safety and preliminary efficacy of 
individualized, biomarker-guided corticosteroid dosing compared to usual care in 
critically ill patients with community acquired pneumonia and acute hypoxemic 
respiratory failure. We hypothesize that, compared to usual care; individualized, 
biomarker-guided corticosteroid dosing will lead to: 
• Lower cumulative exposure to corticosteroids 
• Lower incidence of adverse events (hyperglycemia, delirium, and nosocomial 
infections) 
• Improvement in pulmonary organ function based on requirements for oxygen and 
advanced respiratory support 
• Reduced hospital length of stay 
This pilot study is being conducted to assess the feasibility of recruiting patients and 
clinician adherence to steroid protocol, to refine the trial intervention and endpoints,  
and to calculate target sample sizes in preparation for a larger pragmatic clinical trial 
comparing the two approaches to corticosteroid administration. 
  
Specific Aim 2:  To evaluate the trajectories of C-reactive protein (CRP), 
pulmonary and non-pulmonary organ failures over time in patients from the two study 
arms.  
 
In addition to assessing the feasibility of individualized, biomarker guided steroid 
dosing, this pilot study is necessary to evaluate the usefulness of CRP as a predictive 
enrichment tool in identifying patients in whom steroid administration will be most 
beneficial and also as a prognostic enrichment tool (alongside severity of pulmonary 
and other organ failures) to identify patients at higher risk of poor outcomes. It will 
inform the target population and will help refine the thresholds for initiation, titration 
and discontinuation of individualized corticosteroid therapy used to reduce 
inflammation in patients with pneumonia and acute hypoxemic respiratory failure  
 
Specific Aim 3:  To evaluate the role of a biomarker-titrated adjuvant corticosteroid 
administration compared to usual care in patients admitted to hospital with SARS Co-
V 2 (COVID-19) infection. We hypothesize that, compared to usual care, 
individualized biomarker-titrated dosing will be associated with:  
a) Improvement in pulmonary organ function based on requirements for oxygen 
and advanced respiratory support 


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b) Reduced hospital length of stay 
c) Reduced cardiovascular complications including evidence of myocardial 
injury, need for inotropes and new/worsening arrhythmias  
 
 
II. Background and Significance 
Pneumonia and acute respiratory distress syndrome (ARDS), are common causes of hypoxemic 
respiratory failure, morbidity and mortality in the intensive care unit (ICU)(1). Although 
outcomes from these conditions have improved in recent decades, in part due to improved organ 
support, earlier antimicrobial treatment and the prevention of iatrogenic lung injury from lung-
injurious ventilator practices (2), the impact of pneumonia and ARDS on patient outcomes 
remains substantial. While inflammation is a hallmark pathologic feature of both pneumonia and 
ARDS, the pharmacological treatment of these conditions with corticosteroids and other anti-
inflammatory medications is controversial, and clinical practice remains heterogeneous.  
Observational and clinical trial data show almost 50% of patients with acute hypoxemic 
respiratory failure and ARDS receive steroids (3). Steroid prescribing practices are highly 
variable due to uncertainty regarding who will benefit, and whether concomitant processes such 
as chronic obstructive pulmonary disease (COPD) or septic shock are present. While smaller 
trials suggested possible beneficial effects of corticosteroid use on patient mortality and 
ventilator use (4) (5), other trials suggested potential adverse effects (6). A meta-analysis of 
clinical trials of corticosteroids in ARDS did not show benefit, although subgroup analyses 
suggested there may be benefit in those who received modest doses of corticosteroids early in the 
disease course (7).  Recent SCCM/ESICM guidelines cautiously recommend the use of 
corticosteroids in community acquired pneumonia and in ARDS (8). A 5−7 days duration at a 
daily dose of 1 mg/kg IV methylprednisolone equivalent has been recommended for pneumonia 
while a higher dose and longer duration has been recommended for patients meeting ARDS 
criteria (2 mg/kg/day IV methylprednisolone equivalent followed by slow tapering over 13 
days).   
A major barrier to the more precise and informed use of corticosteroids in patients with 
pneumonia and ARDS is clinicians’ inability to rapidly identify patients most likely to benefit 
from the use of anti-inflammatory medications. Increased levels of pro-inflammatory mediators 
are a prominent feature in many patients with pneumonia and ARDS, and distinct hyper-
inflammatory endophenotypes have been recently described(9). Prior studies have analyzed the 
effect of steroids on inflammatory biomarkers in ARDS including C-reactive protein (CRP) 
which is easily available in the clinical setting and can be completed quickly compared to other 
biomarkers that are difficult to obtain outside research setting.(10, 11)  More recently, studies 
investigating the treatment of pneumonia have utilized CRP to enrich a population that may 
benefit from corticosteroids. (12) This enrichment strategy suggested that patients with a high 


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inflammatory response (pneumonia with an admitting CRP > 150 mg/L) may benefit from 
modest dose corticosteroid administration. While the clinical practice guidelines specifically 
state that lower respiratory infections are characterized by persistent systemic inflammation(13) 
they recommend arbitrary dosing regimens irrespective of the degree of inflammation(8).  
Our objective is to better understand the role of steroids in pneumonia and ARDS, and to test the 
hypothesis that a precise, individualized steroid dosing algorithm will be more effective and safer 
than standard treatment recommended by controversial expert guidelines(8). Therefore we 
propose a pilot, prospective, single-center clinical trial to compare a biomarker-driven 
individualized dosing algorithm to a guideline-based fixed-dose algorithm in emergency room 
patients with pneumonia and acute hypoxemic respiratory failure whose bedside physicians 
intend to provide adjunctive corticosteroid treatment.  
In response to the emerging COVID-19 (SARS Co-V 2) pandemic, we additionally propose 
evaluating the role of biomarker-titrated adjuvant corticosteroid dosing in patients with COVID-
19. Limited data exists regarding the role of corticosteroids in this setting, and no biomarker-
titrated steroid administration has been studied. In a report of 149 patients with COVID-19 in 
China, 82 had elevated CRP(14). However, just 5 patients received corticosteroids in this cohort. 
In a larger cohort of 1099 patients with COVID-19 in Wuhan, China, 204 patients received 
steroids, with a higher percentage among those with severe disease than non-severe disease 
(44.5% vs. 13.7%)(15). Relative survival of those who received steroids versus those who did not 
was not reported. In another series of 52 patients with severe COVID-19 infection in China, 
corticosteroids were administered in 30 patients (58%)(16). Survivors were more likely to receive 
steroids compared to non-survivors (70% versus 50%).  
Furthermore, there is mounting evidence of cardiovascular complications of SARS-CoV-2 
infection including acute myocardial injury, shock and arrhythmias associated with worse 
outcomes(17). Potential mechanisms of these complications in  SARS-CoV-2 infection include 
exaggerated systemic inflammatory responses, cor pulmonale due to respiratory failure and 
direct myocardial toxicity/myocarditis thus rational therapeutic options should include anti-
inflammatory agents like corticosteroids, antiviral agents, and management of respiratory failure. 
Given the limited evidence of adjuvant steroid dosing in this setting, and the absence of any 
proven treatments for COVID-19, there is an urgent need to evaluate any potential therapies. 
 
III. Progress Report and Preliminary Studies 
We performed a retrospective review of patients admitted to the intensive care unit (ICU) at 
Mayo Clinic, Rochester with pneumonia and acute hypoxemic respiratory failure. In this group, 
we described current corticosteroid prescribing practices, and compared the efficacy and safety 
of steroid administration that is biomarker concordant (i.e. patients with a markedly elevated 


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CRP/procalcitonin who were treated with steroids or patients with a low CRP/procalcitonin who 
were not treated with corticosteroids), versus treatment that was biomarker-discordant. The 
threshold for an elevated CRP was 150mg/L and the threshold for an elevated procalcitonin was 
2.2ng/ml. After adjusting for severity of illness, early (within 12 hours of ICU admission) steroid 
administration in patients with pneumonia or ARDS was associated with decreased persistence 
or progression of pulmonary and other organ failures, reduced hospital and ICU length of stay 
and decreased hospital mortality(table 1). Patients with biomarker-concordant and biomarker-
discordant corticosteroid treatment had similar baseline severity of illness. Biomarker-
concordant corticosteroid treatment was associated with faster recovery of hypoxemia (table 2). 
No significant differences in mortality or hospital/ICU length of stay were seen between the 
biomarker-concordant versus the biomarker discordant group.  
 
Table1. Impact of early corticosteroid use on outcomes in ICU patients with pneumonia 
and ARDS 
 
Steroids ≤ 12h after 
ICU admission 
(N=1047) 
Steroids > 12h after 
ICU admission(N=567) 
P value 
SOFA Day 1 
5 (3-8) 
6 (4-8) 
0.006 
SOFA Day 2 
4 (2-6) 
5 (3-8) 
<0.001 
SOFA Day 3 
4 ( 2-7) 
5 (3-8) 
0.009 
PaO2/FiO2 at ICU 
admission 
173 (117-250) 
161 (108-240) 
0.16 
PaO2/FiO2 after 24h 
196 (143-265) 
183 (122-255) 
0.03 
PaO2/FiO2 after 48h 
209 (145-284) 
191 (129-255) 
0.03 
ICU length of stay 
1.98 (1.07-4.0) 
3.69 (1.95-7.24) 
<0.001 
Hospital Length of 
stay 
7.57 (4.55-14.07) 
10.4 (6.08-20.8) 
<0.001 
ICU Mortality 
102 (9.7%) 
69 (12.2%) 
0.15 
Hospital Mortality 
188 (17.9%) 
132 (23.3%) 
0.01 
 
 
 
 
 
 
 


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Table 2: Impact of steroid use that was concordant versus discordant with markers of 
inflammation on outcomes in critically ill patients with pneumonia 
 
Biomarker 
Concordant 
(N=130) 
Biomarker 
Discordant(N=114) 
P value 
FIO2 at ICU 
admission 
40 (30, 60) 
40 (30, 60) 
0.47 
FIO2 Day 2 
35 (28, 50) 
40 (31, 50) 
0.07 
FIO2 Day 3 
31 (21, 40) 
37 (29, 50) 
0.004 
FIO2 Day 4 
28.0 (21.0, 37.5) 
35 (28, 50) 
<.001 
FIO2 Day 5 
28 (21, 36) 
28 (24, 45) 
0.03 
ICU free days 
(Median estimate 
(95%CI) 
1.97 (-0.50, 4.45) 
0.00 (Ref) 
0.12 
Hospital free days 
(Median estimate 
(95%CI) 
1.79 (-0.98, 4.57) 
0.00 (Ref) 
0.21 
ICU Mortality (Hazard 
Ratio with 95% CI) 
0.93 (0.31, 2.74) 
1.00 (Ref) 
0.89 
Hospital Mortality 
(Hazard Ratio with 
95% CI) 
0.75 (0.36, 1.59) 
1.00 (Ref) 
0.45 
Delirium 
36 (27.7%) 
34 (29.8%) 
0.71 
Hyperglycemia 
30 (23.8%) 
26 (23.4%) 
0.94 
 
 
Team experience: Dr. Hemang Yadav is an Assistant Professor and Senior Associate Consultant 
in the Division of Pulmonary and Critical Care at the Mayo Clinic. He has expertise in ARDS 
epidemiology research and the incorporation of biomarkers in ARDS risk prediction. Dr. 
Yewande Odeyemi is a clinical fellow in Critical Care at Mayo Clinic, Rochester with an interest 
in critical care outcomes research. Dr. Herasevich is a research trainee at Mayo Clinic, Rochester 
also with an interest in critical care outcomes research. Dr. Erin Barreto is an assistant professor 
and clinical pharmacist at Mayo Clinic, Rochester with an interest in individualizing 
pharmacotherapy for critically ill patients with infections. Dr. Gajic is an internationally 
renowned leader in ARDS research and founder of our multidisciplinary clinical research 
laboratory (METRIC), and Director of Critical Care Research at Mayo. Within this group, we 
have adequate resources, expertise and training to achieve our scientific objectives.  
 
 
 
 
 


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IV. Research Design and Methods 
Figure 1 summarizes study design. A two-arm multicenter randomized trial  
 
A. Study Design or Overview  
Specific Aims 1 and 3: We plan to perform a two arm multi-center pilot phase II clinical trial. 
44 patients with pneumonia (additional strata to include patients with COVID-19 for specific 
aim 3) and acute respiratory failure defined by SpO2/FiO2 < 315 (SpO2 < 90% on room air or 
< 97% on 2L/min O2) will be included.   
• Control arm: Usual care 
• Intervention arm: individualized, biomarker concordant steroid use: dosing, titration 
and duration according to CRP level (Table 3).  
 
 
 
                                           Table 3. Biomarker-concordant steroid treatment 
CRP (mmol/L) 
Methylprednisolone (daily) 
<50 
None 
51 - 100 
0.5 mg/kg 
101 - 150 
0.75 mg/kg 
151 - 200 
1 mg/kg 
>200 
1.5 mg/kg 
 
*per ideal body weight 
 
                     


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Randomization will be stratified based on the need for high flow nasal cannula oxygen, 
noninvasive or invasive ventilator support. 
 
Definitions 
Pneumonia is defined as an acute infection of the lung parenchyma that is associated with clinical 
symptoms of community acquired pneumonia (cough, fever, pleuritic chest pain, and dyspnea) and 
a new radiographic infiltrate(18). ARDS complicating community acquired pneumonia will be 
defined in accordance with the Berlin Definition as acute respiratory failure with a PaO2/FiO2 ratio 
< 300 and the need for positive end expiratory pressure > 5 mmHg and bilateral pulmonary 
infiltrates within 1 week of the diagnosis of community organized pneumonia (19).  
Suspected COVID-19 defined as anyone in whom COVID-19 testing is requested 
Confirmed COVID-19 is defined as a patient with positive COVID-19 PCR on either 
nasopharyngeal swab or microbiological testing from lower respiratory sample sites (e.g. tracheal 
secretions, bronchial washings, bronchoalveolar lavage).  
 
Participating sites 
Mayo Clinic Rochester, Minnesota 
Mayo Clinic Health System, Mankato, Minnesota 
 
B. Study Subjects 
Inclusion criteria: Patients with pneumonia and acute respiratory failure defined by SpO2/FiO2 < 
315 (SpO2 < 90% on room air or < 97% on 2L/minute O2). 
Exclusion criteria:  
• 
Contraindications or unwilling to use steroids by patient or provider 
• 
Refractory septic shock(20)defined as a requirement of norepinephrine dose or equivalent 
above >0.1 mcg/kg min or 2 or more vasopressors 
• 
Pre-admission chronic use of steroids or other immunosuppressive medications 
• 
Recent or past history of bone marrow or solid organ transplantation  
• 
Adrenal insufficiency, as noted in the problem list/medical history 
• 
Comfort care 
• 
Hospital admission in the previous 30 days for severe community acquired pneumonia 
patients 


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• 
Leukopenia <1000/mm or neutropenia <500/mm (except if attributable to pneumonia) and 
HIV positive with a CD4 count <100 
• 
Suspected flare of Interstitial lung disease  (infectious and non-infectious) 
• 
Positive influenza testing or high suspicion for influenza 
Protocol: Patients who meet inclusion criteria will be randomized into usual care or the 
individualized biomarker-concordant arm. Patients will be eligible for inclusion if they have 
received an initial dose of steroids by the primary service. In this situation they would either be 
randomized to usual care (continued steroid administration at discretion of primary service) or the 
individualized CRP-guided protocol outlined in Table 3. 
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, 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. Steroid administration will be facilitated using 
standardized computerized physician order entry.  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. 
Glucose levels, new or worsening infections within 30 days of start of steroid (positive 
blood/sputum/urine culture) and Confusion Assessment Method in the ICU will be documented in 
case report forms. 
In the usual care arm, patients will receive daily CRP measurements for the first 5 days of the 
hospitalization, or until hospital discharge. However, these CRP measurements will not be 
accessible to the treating physicians.   
An oxygen titration protocol will be utilized to standardize oxygen weaning in both arms (please 
see appendix). 
Daily Troponin measurements will be added in both arms  
Primary outcomes: 
• Feasibility: a percentage of eligible patients adhered to the timely initiation  and daily 
treatment according to ESICM/SCCM clinical practice guideline (control group) or 
biomarker concordance (intervention group) 
Secondary outcomes 
• Death  
• Progression of disease as defined by the need for high flow nasal cannula oxygen, 
noninvasive or invasive ventilation. Given the proliferation of high flow nasal cannula 
oxygen use in lieu of mechanical ventilation, instead of ventilator-free days we opt for 


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using advanced respiratory support free days where “advanced respiratory support” 
includes both invasive and noninvasive mechanical ventilation and the high flow nasal 
cannula oxygen.  
• Evolution of respiratory and other organ failures measured by SOFA at time of ICU 
admission, after 24 hours, after 48 hours and after 72 hours and by the organ failure free 
days. In the absence of daily arterial blood gas analysis, for respiratory component of 
SOFA, PaO2/FiO2 ratio will be replaced by SpO2/FiO2 ratio 
• Need and duration of vasopressors and inotropes use (based on cardiovascular SOFA 
sub-score) 
• New onset/worsening arrhythmias 
• Evidence of myocardial injury determined by daily troponin peak and/or new diagnosis 
of LV dysfunction (LVEF <40%) or new diagnosis of cor pulmonale (≥moderate RV 
dysfunction) 
• Re-hospitalization for a primary cardiovascular diagnosis within 30 days 
• Side effects of steroid (Safety)  including  
o Hyperglycemia and its complications- Diabetic ketoacidosis (DKA) and 
Hyperosmolar hyperglycemic syndrome (HHS), the need for insulin 
o Delirium (measured by CAM-ICU) and  
o New infections in patients with pneumonia and/or ARDS  
• Length of ICU and hospital stay 
• Time to discontinue oxygen or return to baseline oxygen use 
• Requirement and duration of non-invasive and invasive mechanical ventilation 
• ICU, and 30, 60 and 90-day mortality 
• Discharge, 30, 60, and 90-day disposition (home vs other) 
 
C. Sample Size and Power: In this pilot study, we do not have the power to test the efficacy of the 
intervention on patient-centered outcomes. However, this pilot data will provide us with potential 
effect size data necessary for sample size determination for the future phase II/III study. 
 
D. Data Collection: Case Report Forms will be completed by research coordinators and entered in 
a REDCap database. 
 
 


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E. Data Handling:  
-Protected health information will be preserved by having patient data be de-identified and 
given a study number. 
-This data will be recorded using REDCap and JMP. Any written data will be stored in 
storage files in a locked access building. 
-Data will only be accessible to investigators/participating personnel. 
-The computers where the data will be stored meet strict security requirements imposed by 
Mayo Clinic. 
-No data containing PHI will be transported on data sticks or laptops without being encrypted 
or 
password protected. 
-No hardcopy information containing PHI will be transported/removed from the Mayo 
campus. 
-Any hard copies of archival source documentation will be stored in a locked, secure location 
only 
accessible to the study personnel. 
-No data will be disclosed to another institution and all identifiers linking to the patient will 
be destroyed after data collection is complete. 
 
f. Data Analysis  
 
Aims 1and 3:   Continuous outcomes will be compared between treatment arms using linear 
regression and  binary outcomes using chi-square or fishers exact tests. Secondary outcomes 
will be tested without adjustment for multiple comparisons.  Data from this study, including 
estimated effects of the intervention and sample variation in outcomes, will provide valuable 
information to plan a well-powered subsequent phase II trial. 
 
Aim 2: The correlation between CRP levels and corticosteroid dosing in those who receive 
individual-dose steroids versus usual care will be examined using Pearson’s correlation 
coefficient. The effect of CRP levels on the secondary outcomes will be evaluated using 
multivariable analysis adjusting for severity of illness.  The data from this study will help 
evaluate the usefulness of CRP as a predictive and prognostic enrichment tool and thus help 
inform and refine the thresholds for initiation, titration and discontinuation of corticosteroids in 
the subsequent larger study.  
 
 
Decision to proceed with a larger study: The decision to proceed with a phase II/III study will 
be based on the following criteria: 
- 
Ability to enroll an adequate number of eligible patients early in the course of illness. The 
expected hurdles include delayed identification of potentially eligible patients, 
provider/patient refusal, non-adherence to protocol, and inability to obtain CRP levels in a 
timely manner.   
- 
Safety; i.e. absence of significant adverse events.   


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- 
Preliminary efficacy: ability to show reduction in steroid use, reduced episodes of 
hyperglycemia and favorable trajectory of pulmonary organ dysfunction. 
 
The data collected will be essential to adequately plan the future study, estimate power and 
sample size, refine exclusion/inclusion criteria and determine the number and characteristics of 
future study sites.  
g. Feasibility and Time Frame:  
We believe that our project is feasible in the time frame of the grant; we hope to use the 
preliminary data generated from this pilot study to decide about moving forward with a phase 
II/III study involving a larger study group and more centers (Table 5).  
 
h. Strengths – This is a well-designed pilot study to examine the feasibility of this approach. Data 
from this study, including estimated effects of the intervention and sample variation in 
outcomes, will provide valuable information to plan a well-powered subsequent phase II/III 
trial. 
i. Limitation – Subject enrollment is dependent on availability of research coordinators, therefore 
we aim to enroll 44 patients within a 2 year period. Randomization by stratification might limit 
wide generalizability and feasibility if a high proportion of subjects with chronic obstructive 
lung disease are enrolled. We also acknowledge the fact that the lack of blinding of treating 
attending physicians and physicians in training is a strong limitation in our study. 
V. Human Subjects 
Informed consent: All subjects for this study will be provided a consent form describing this 
study and providing sufficient information for subjects to make an informed decision about their 
participation in this study.  This consent form will be submitted with the protocol for review and 
approval by the IRB for the study. 
The risk profile would justify deferred consent for those who are unable to give consent and have 
no legally authorized representative available within the short timeframe.  
Our inclusion and exclusion criteria have been carefully selected to maximize potential benefit 
and minimize risk to study subjects.  
For suspected/confirmed COVID-19 subjects: Due to the high infectivity of COVID-19, and the 
strict need to minimize contact between suspected COVID-19 patients and study staff, we 
propose consent be obtained verbally via telephone or via video.  
Patients would still receive a copy of the consent form describing the study. This would be given 
to the patient by the room nurse to be coordinated with other routine cares.  
For all other subjects: The consent form must be signed by the subject or the subject’s legally 
authorized representative, and the individual obtaining the informed consent. 
 


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Potential risks:. We will include a detailed description of potential risks and benefits of 
corticosteroid administration while obtaining patient consent. 
All the tests and procedures that will be included in the study are consistent with standard 
clinical care; there will no extra costs to the subjects who consent to study participation. CRP 
would be taken during routine daily lab draws; there may be one additional blood draw on the 
day of consent. All clinical assessments will be done through EMR.  
Potential benefits: The potential benefits include the importance of the knowledge to be gained 
from this study with the possibility of reduced adverse side effects of steroids associated with a 
lower dosing and shorter duration in the individualized arm.  
 
VI. Gender/Minority Mix 
This study will include minority patients and both gender. 
VII. References:  
REFERENCES 
1. 
Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, Gattinoni L, van Haren F, Larsson A, 
McAuley DF, Ranieri M, Rubenfeld G, Thompson BT, Wrigge H, Slutsky AS, Pesenti A. Epidemiology, 
Patterns of Care, and Mortality for Patients With Acute Respiratory Distress Syndrome in Intensive Care 
Units in 50 Countries. JAMA. 2016;315(8):788-800. Epub 2016/02/24. doi: 10.1001/jama.2016.0291. 
PubMed PMID: 26903337. 
2. 
Rios F, Iscar T, Cardinal-Fernandez P. What every intensivist should know about acute 
respiratory distress syndrome and diffuse alveolar damage. Rev Bras Ter Intensiva. 2017;29(3):354-63. 
Epub 2017/10/05. doi: 10.5935/0103-507x.20170044. PubMed PMID: 28977098; PMCID: PMC5632979. 
3. 
Peter JV, John P, Graham PL, Moran JL, George IA, Bersten A. Corticosteroids in the prevention 
and treatment of acute respiratory distress syndrome (ARDS) in adults: meta-analysis. BMJ : British 
Medical Journal. 2008;336(7651):1006-9. doi: 10.1136/bmj.39537.939039.BE. PubMed PMID: 
PMC2364864. 
4. 
Meduri GU, Headley AS, Golden E, Carson SJ, Umberger RA, Kelso T, Tolley EA. Effect of 
prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a 
randomized controlled trial. Jama. 1998;280(2):159-65. Epub 1998/07/21. PubMed PMID: 9669790. 
5. 
Meduri GU, Golden E, Freire AX, Taylor E, Zaman M, Carson SJ, Gibson M, Umberger R. 
Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial. Chest. 
2007;131(4):954-63. Epub 2007/04/12. doi: 10.1378/chest.06-2100. PubMed PMID: 17426195. 
6. 
Steinberg KP, Hudson LD, Goodman RB, Hough CL, Lanken PN, Hyzy R, Thompson BT, 
Ancukiewicz M. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. 
N Engl J Med. 2006;354(16):1671-84. Epub 2006/04/21. doi: 10.1056/NEJMoa051693. PubMed PMID: 
16625008. 
7. 
Lamontagne F, Briel M, Guyatt GH, Cook DJ, Bhatnagar N, Meade M. Corticosteroid therapy for 
acute lung injury, acute respiratory distress syndrome, and severe pneumonia: a meta-analysis of 
randomized controlled trials. J Crit Care. 2010;25(3):420-35. Epub 2009/11/10. doi: 
10.1016/j.jcrc.2009.08.009. PubMed PMID: 19896324. 


14 
 
1/4/2021
 
 
 
8. 
Pastores SM, Annane D, Rochwerg B. Guidelines for the Diagnosis and Management of Critical 
Illness-Related Corticosteroid Insufficiency (CIRCI) in Critically Ill Patients (Part II): Society of Critical Care 
Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017. Critical Care Medicine. 
2018;46(1):146-8. Epub 2017/11/03. doi: 10.1097/CCM.0000000000002840. PubMed PMID: 29095205. 
9. 
Calfee CS, Delucchi K, Parsons PE, Thompson BT, Ware LB, Matthay MA. Subphenotypes in acute 
respiratory distress syndrome: latent class analysis of data from two randomised controlled trials. Lancet 
Respir Med. 2014;2(8):611-20. Epub 2014/05/24. doi: 10.1016/S2213-2600(14)70097-9. PubMed PMID: 
24853585; PMCID: 4154544. 
10. 
Schwingshackl A, Kimura D, Rovnaghi CR, Saravia JS, Cormier SA, Teng B, West AN, Meduri UG, 
Anand KJS. Regulation of Inflammatory Biomarkers by Intravenous Methylprednisolone in Pediatric 
ARDS Patients: Results from a Double-Blind, Placebo-Controlled Randomized Pilot Trial. Cytokine. 
2016;77:63-71. doi: 10.1016/j.cyto.2015.10.007. PubMed PMID: PMC4666843. 
11. 
Kimura D, Saravia J, Rovnaghi CR, Meduri GU, Schwingshackl A, Cormier SA, Anand KJ. Plasma 
Biomarker Analysis in Pediatric ARDS: Generating Future Framework from a Pilot Randomized Control 
Trial of Methylprednisolone: A Framework for Identifying Plasma Biomarkers Related to Clinical 
Outcomes in Pediatric ARDS. Frontiers in Pediatrics. 2016;4:31. doi: 10.3389/fped.2016.00031. PubMed 
PMID: PMC4815896. 
12. 
Torres A, Sibila O, Ferrer M, et al. Effect of corticosteroids on treatment failure among 
hospitalized patients with severe community-acquired pneumonia and high inflammatory response: A 
randomized clinical trial. JAMA. 2015;313(7):677-86. doi: 10.1001/jama.2015.88. 
13. 
Martinez R, Menendez R, Reyes S, Polverino E, Cilloniz C, Martinez A, Esquinas C, Filella X, 
Ramirez P, Torres A. Factors associated with inflammatory cytokine patterns in community-acquired 
pneumonia. The European respiratory journal. 2011;37(2):393-9. Epub 2010/07/03. doi: 
10.1183/09031936.00040710. PubMed PMID: 20595152. 
14. 
Yang W, Cao Q, Qin L, Wang X, Cheng Z, Pan A, Dai J, Sun Q, Zhao F, Qu J, Yan F. Clinical 
characteristics and imaging manifestations of the 2019 novel coronavirus disease (COVID-19):A multi-
center study in Wenzhou city, Zhejiang, China. J Infect. 2020. Epub 2020/03/01. doi: 
10.1016/j.jinf.2020.02.016. PubMed PMID: 32112884. 
15. 
Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, Du B, Li LJ, Zeng G, 
Yuen KY, Chen RC, Tang CL, Wang T, Chen PY, Xiang J, Li SY, Wang JL, Liang ZJ, Peng YX, Wei L, Liu Y, Hu 
YH, Peng P, Wang JM, Liu JY, Chen Z, Li G, Zheng ZJ, Qiu SQ, Luo J, Ye CJ, Zhu SY, Zhong NS, China Medical 
Treatment Expert Group for C. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J 
Med. 2020. Epub 2020/02/29. doi: 10.1056/NEJMoa2002032. PubMed PMID: 32109013. 
16. 
Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, Wu Y, Zhang L, Yu Z, Fang M, Yu T, Wang Y, Pan S, Zou X, 
Yuan S, Shang Y. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in 
Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020. Epub 
2020/02/28. doi: 10.1016/S2213-2600(20)30079-5. PubMed PMID: 32105632. 
17. 
Shi S, Qin M, Shen B, Cai Y, Liu T, Yang F, Gong W, Liu X, Liang J, Zhao Q, Huang H, Yang B, Huang 
C. Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, China. 
JAMA Cardiology. 2020. doi: 10.1001/jamacardio.2020.0950. 
18. 
Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, Dowell SF, File TM, 
Jr., Musher DM, Niederman MS, Torres A, Whitney CG. Infectious Diseases Society of America/American 
Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. 
Clin Infect Dis. 2007;44 Suppl 2:S27-72. Epub 2007/02/06. doi: 10.1086/511159. PubMed PMID: 
17278083. 
19. 
The ADTF. Acute respiratory distress syndrome: The berlin definition. JAMA. 2012;307(23):2526-
33. doi: 10.1001/jama.2012.5669. 


15 
 
1/4/2021
 
 
 
20. 
Annane D, Renault A, Brun-Buisson C, Megarbane B, Quenot JP, Siami S, Cariou A, Forceville X, 
Schwebel C, Martin C, Timsit JF, Misset B, Ali Benali M, Colin G, Souweine B, Asehnoune K, Mercier E, 
Chimot L, Charpentier C, Francois B, Boulain T, Petitpas F, Constantin JM, Dhonneur G, Baudin F, Combes 
A, Bohe J, Loriferne JF, Amathieu R, Cook F, Slama M, Leroy O, Capellier G, Dargent A, Hissem T, Maxime 
V, Bellissant E. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. The New England 
journal of medicine. 2018;378(9):809-18. Epub 2018/03/01. doi: 10.1056/NEJMoa1705716. PubMed 
PMID: 29490185. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 1  
Oxygen Titration Protocol 
 
• 
Consult the patient specific SpO2 targets (per diagnosis category)  
• 
SPO2 target range 90-95% 
o COPD in exacerbation:  SPO2 preferred target 88-92% 
o ARDS:  SPO2 preferred target 88-95%  
• 
Decision support tool should be utilized in stabilized patients only 
• 
Assess for titration minimally every 60 mins (with vital sign assessments) 
• 
Overall goal: Discontinue oxygen or wean to baseline need (NC, CPAP) 
 
SpO2 
NC, NP, 
SFM 
CPAP/BPAP 
High flow 
NC 
Invasive 
mechanical 
ventilation 
Hyperoxia  
SpO2>95% 
COPD SpO2>92% 
 
Reduce flow 
rate by 1 
L/min or if 
SpO2>98% 
reduce by 2 
L/min 
Ɨ Reduce 
FiO2 by 0.1 
 
Reduce 
FiO2 by 0.1 
Reduce FiO2 
by 0.1 
Follow 
ARDSnet 
PEEP/FiO2 
Target 
Range 
SpO2 90-95% 
COPD SpO2 88-92% 
ARDS SpO2 88-95% 
No Change 
No Change 
No Change 
No Change 
Hypoxia 
SpO2<88% 
Titrate per 
order 
Titrate per 
order 
Titrate per 
order 
Titrate per 
order 
NC: Nasal Cannula, NP: Nasal Pendant, SFM: Simple face mask, Severe COPD:  GOLD III or IV, ARDS:  Acute 
Respiratory Distress Syndrome. 
Ɨ After FiO2 <0.4. Decrease EPAP/CPAP per RT, (Minimum EPAP/CPAP 5 cm H20) 
 


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