Conditions: Congenital Heart Disease in Children Inflammatory Response
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1263
Healthy volunteers: no

Brief summary:
This study's objective is to determine the pharmacokinetics (PK)/pharmacodynamics (PD), safety and efficacy of methylprednisolone in infants undergoing heart surgery with cardiopulmonary bypass. This is a prospective, double blind, multi-center, placebo-controlled safety and efficacy study. Blood samples will be collected from a subset of enrolled study participants to evaluate multiple dose methylprednisolone PK/PD. Participants will be randomized in a 1:1 fashion to intravenous methylprednisolone versus placebo. Study drug/placebo will be administered 8 to 12 hours before the anticipated start time of surgery and in the operating room at the time of initiation of cardiopulmonary bypass. Patients will be followed for primary and secondary outcomes for the duration of their hospitalization. Serious study drug-related adverse events will be collected for 7 days after the last dose of study drug.

Detailed description:
Overview:

Congenital heart diseases (CHD) are the most common birth defects, occurring in nearly 1% of live births. Every year, an estimated 40,000 infants born in the U.S. suffer from CHD. Despite advances in surgical management, CHD requiring neonatal surgery is associated with poor outcomes; national registry data demonstrates post-operative major morbidity in 23% and 10% do not survive to hospital discharge.

Poor outcomes after neonatal heart surgery are often attributable to a severe systemic inflammatory response to cardiopulmonary bypass (CPB). CPB is necessary for most neonatal CHD surgeries. Therefore, to reduce the post-CPB inflammatory reaction, many surgeons administer pre-or intra-operative steroids. Steroids have been shown to reduce inflammatory markers after neonatal heart surgery. However, steroids also have potential harmful effects including an increased risk of post-operative infection. The recent SIRS trial evaluated the safety and efficacy of steroids after CPB in adults and demonstrated no beneficial effect of steroids but increased risk of post-CPB myocardial infarction and other major adverse events.

Adult trial results cannot be reliably extrapolated to neonates because the neonatal response to CPB is markedly different to that seen in adults; neonates demonstrate both a more pronounced inflammatory reaction and a different post-operative complication profile. For these reasons approximately 2/3rds of congenital heart surgeons continue to administer perioperative steroids to neonates undergoing heart surgery. Yet this practice is not evidence based as no safety/efficacy trial has ever evaluated steroids in neonates undergoing heart surgery with CPB. Several smaller steroid trials (all enrolling \< 75 patients) have focused on surrogate outcome measures, but none have provided conclusive data.

The major barrier to performing a steroid trial in neonates with CHD has been the high cost associated with trial conduct for these relatively rare defects. To overcome this barrier, the investigators will use a novel approach leveraging existing registry infrastructure at CHD surgical sites that participate in the Society of Thoracic Surgeons Congenital Heart Surgery Database (STS-CHSD). Sites participating in the STS-CHSD collect data into their institutional databases using standardized case report forms so that the data can be exported to the STS-CHSD. These sites already employ data coordinating specialists to capture patient demographics, procedural variables, and post-operative outcomes (including a list of over 60 complication variables) using strict and consistent data element definitions. By leveraging these site-specific resources the investigators project that the investigators can reduce trial costs by \>75%.

Background:

Some surgeons/centers currently administer perioperative high dose (20mg to 60mg) intravenous methylprednisolone before neonatal heart surgery with CPB. In a national registry study of \> 3000 neonates with data capture spanning 2004 to 2008, 62% of neonates undergoing surgery with CPB received perioperative methylprednisolone while 38% did not. Of those receiving methylprednisolone, 22% received methylprednisolone on both the day before, and day of surgery, 12% on the day before surgery only, and 28% on the day of surgery only. Results of a survey of surgeons from the Congenital Heart Surgeon's Society were similar; 28% did not routinely use steroids for neonatal heart surgery. Of the 72% that did routinely use steroids, \~1/3rd administered steroids pre-operatively and intra-operatively and the remainder gave intra-operative steroids only.

Several previous small translationally focused clinical trials have evaluated the safety and efficacy of methylprednisolone. In the largest contemporary trial, neonates scheduled for cardiac surgery were prospectively randomized to receive either 2-dose (8 hours preoperatively and operatively, n = 39) or single-dose (operatively, n = 37) methylprednisolone at 30 mg/kg IV per dose in a prospective double-blind trial. Neonates receiving pre-operative methylprednisolone therapy demonstrated significantly reduced pre-operative pro-inflammatory cytokines including interleukin-6 and 8. There were no differences between the two groups in post-operative pro-inflammatory markers and no differences in the incidence of post-operative low cardiac output syndrome. Methylprednisolone was well tolerated with no adverse drug reactions. The overall incidence of post-operative infection was 13% (10/76) and 4% (3/76) received a post-operative insulin infusion for hyperglycemia.

A meta-analysis evaluated six previous steroid trials in children undergoing heart surgery with CPB. The combined enrollment of these six trials was 232 participants including 116 receiving peri-operative steroids; two of these studies used methylprednisolone at doses of 30mg/kg IV per dose (n=67 patients). The results of this meta-analysis demonstrated a nonsignificant trend of reduced mortality in steroid-treated patients (11 \[4.7%\] vs 4 \[1.7%\] patients; odds ratio, 0.41; 95% CI, 0.14-1.15; p = 0.089). Steroids had no effects on mechanical ventilation time (117.4 ± 95.9 hr vs 137.3 ± 102.4 hr; p = 0.43) and ICU length of stay (9.6 ± 4.6 d vs 9.9 ± 5.9 d; p = 0.8). Perioperative steroid administration reduced the prevalence of renal dysfunction (13 \[54.2%\] vs 2 \[8%\] patients; odds ratio, 0.07; 95% CI, 0.01-0.38; p = 0.002). There were no significant differences in the adverse event profiles for patients receiving steroids versus placebo.

The conclusions of the aforementioned studies, as well as several associated editorials have all been that a large, randomized, controlled trial is needed to evaluate the safety and efficacy of perioperative steroids for neonatal heart surgery with CPB.

Design:

This study is a prospective, double-blind, multi-center, placebo-controlled safety and efficacy study of methylprednisolone in neonates undergoing heart surgery with CPB. The study will enroll up to 1500 neonates (\< 30 days of age) and the total study duration is expected to be approximately 48 months. An ancillary PK/PD/Biomarker study will enroll subjects at select centers. This study is unique in that it is designed to leverage existing registry infrastructure at participating sites so as to reduce trial costs. Participants will be randomized and will receive a randomization ID. This ID will also serve as a unique patient identifier allowing us to crosslink datasets. Participants will then receive two doses of study drug/placebo. The first dose will be administered 8 to 12 hours before anticipated heart surgery and the second dose will be administered into the pump prime during cardiopulmonary bypass. All study participants will then receive routine post-operative care. Participating centers will enter all demographic, preoperative, operative and outcomes data into their existing institutional databases for submission to the STS-CHSD as they currently do. These data will be used to evaluate trial outcomes.

Arms:
arm 1: IV Methylprednisolone arm 2: IV Isotonic Saline

Interventions: intervention 1: Methylprednisolone intervention 2: Isotonic saline
Intervention descriptions: intervention 1: IV Steroid pre-operative and intra-operative intervention 2: Isotonic saline pre-operative and intra-operative

Protocol document:
Prot_SAP_001.pdf: 
STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 1 of 96 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STeroids to REduce Systemic inflammation after infant heart Surgery 
(STRESS trial) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version/Date:   Version 6.0 / Amendment 5 27 March 2022 
Replaces:   
Version 5.0 / Amendment 4 15 September 2020 
 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 2 of 96 
 
 
 
Table of contents 
1 
Overview ........................................................................................................................... 4 
2 
PROTOCOL SYNOPSIS ................................................................................................... 5 
3 
BACKGROUND INFORMATION ...................................................................................... 7 
3.1 
Summary of Experience in the Perioperative Setting in Children with CHD .... 7 
4 
Trial design and methods .................................................................................................. 8 
4.1 
Overview .......................................................................................................... 8 
4.2 
Procedures to Minimize/Avoid Bias ................................................................. 8 
4.2.1 
Randomization .................................................................................................................................. 8 
4.2.2 
Blinding ............................................................................................................................................ 9 
4.3 
Study measures ............................................................................................... 9 
4.3.1 
Primary Endpoint .............................................................................................................................. 9 
4.3.2 
Secondary Endpoints (see section 11.2 for data element definitions) ............................................... 9 
4.3.3 
Timeframe for collection of safety and efficacy endpoints ............................................................. 10 
4.4 
Schedule of events ........................................................................................ 10 
5 
Selection and withdrawal of subjects .............................................................................. 11 
5.1 
Inclusion criteria ............................................................................................. 11 
5.2 
Exclusion criteria ........................................................................................... 11 
5.3 
Subject withdrawal ......................................................................................... 12 
5.4 
Recruitment/enrollment procedures protocol ................................................. 12 
6 
Study procedures ............................................................................................................ 12 
6.1 
Preoperative Assessment – Screening Procedures and Baseline 
Measurements ............................................................................................... 12 
6.2 
Baseline/Pre-Dose Assessment .................................................................... 12 
6.3 
Study Procedures During Study Drug Administration .................................... 13 
6.4 
Study Procedures After Study Drug Administration During Hospitalization ... 13 
6.5 
PK/PD/Biomarker sampling procedures (select sites) ................................... 14 
7 
Treatments to be administered ....................................................................................... 14 
7.1 
Description of Study Treatments ................................................................... 14 
7.2 
Route of Administration ................................................................................. 15 
7.3 
Storage and Administration ........................................................................... 15 
8 
Study drug accountability ................................................................................................ 15 
8.1 
Medications/Treatments Permitted and Not Permitted during the Study ....... 15 
8.1.1 
Rescue Medication, Emergency Procedures and Additional Treatments(s) ................................... 15 
8.1.2 
Restrictions regarding concomitant treatment ................................................................................ 15 
8.2 
Emergency Unblinding .................................................................................. 15 
9 
Safety assessments and monitoring ............................................................................... 16 
9.1 
Collection and Reporting ............................................................................... 16 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 3 of 96 
 
 
 
9.2 
Definitions of Adverse Events (AEs), Suspected Adverse Reaction and 
Serious Adverse Events ................................................................................ 16 
9.3 
Assessment of Severity ................................................................................. 17 
9.4 
Assessment of Causal Relationship .............................................................. 17 
9.5 
Identification of Safety Events ....................................................................... 18 
9.6 
Safety Monitoring ........................................................................................... 18 
9.7 
Halting Rules ................................................................................................. 18 
9.8 
Reporting Adverse Events to Institutional Review Boards for NIH-Supported 
Multi-Center Clinical Trials ............................................................................. 19 
9.9 
Follow-up of Subjects after Adverse Events .................................................. 19 
9.10 
Study Suspension .......................................................................................... 19 
10 
Statistics .......................................................................................................................... 19 
10.1 
Planned Sample Size ....................................................................................... 19 
10.2 
Statistical Analysis Plan ................................................................................. 20 
10.3 
Analysis of the Primary Endpoint ................................................................... 20 
10.4 
Analysis of Secondary Safety and Efficacy Endpoints .................................. 21 
10.5 
Interim Analyses ............................................................................................ 21 
10.6 
Data Monitoring Committee ........................................................................... 22 
10.7 
Population for Analysis .................................................................................. 22 
11 
Data management ........................................................................................................... 23 
11.1 
Data entry ...................................................................................................... 23 
11.2 
Data Element Definitions ............................................................................... 23 
12 
Ethics and human subjects consideration ....................................................................... 28 
12.1 
Institutional Review Board/Independent Ethics Committee Approval ............ 28 
12.2 
Signed Informed Consent / Authorization ...................................................... 28 
12.3 
Duties of the Investigator ............................................................................... 28 
12.4 
Records of the Study ..................................................................................... 28 
12.5 
Patient Privacy / Authorization ....................................................................... 29 
12.6 
Informed Consent .......................................................................................... 29 
13 
Pharmacology and Toxicology Information ..................................................................... 32 
14 
Previous Human Experience ........................................................................................... 33 
15 
Appendices ..................................................................................................................... 34 
15.1 
Appendix A1: Case report form for the STS-CHSD ....................................... 34 
15.2 
Appendix A2: Data element definitions for the STS-CHSD ........................... 73 
15.3 
Appendix B: Package insert for intravenous methylprednisolone ................. 74 
15.4 
Appendix C: Plasma PK sampling and handling ........................................... 92 
15.5 
Appendix D: Protocol Amendments ............................................................... 93 
15.6 
Appendix D: Site Specific Protocol – Site 103 (Duke University Medical 
Center) ........................................................................................................... 94 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 4 of 96 
 
 
 
1 
OVERVIEW 
Congenital heart diseases (CHD) are the most common birth defects, occurring in nearly 1% of live births. 
Every year, an estimated 40,000 infants born in the U.S. suffer from CHD. Despite advances in surgical 
management, CHD requiring neonatal surgery is associated with poor outcomes; national registry data 
demonstrates post-operative major morbidity in 23% and 10% do not survive to hospital discharge.[1-4]  
Poor outcomes after pediatric heart surgery are often attributable to a severe systemic inflammatory 
response to cardiopulmonary bypass (CPB).[5-8]  CPB is necessary for most infant CHD surgeries. 
Therefore, to reduce the post-CPB inflammatory reaction, many surgeons administer pre-or intra-
operative steroids.[9-15] Steroids have been shown to reduce inflammatory markers after neonatal heart 
surgery.[13, 16] However, steroids also have potential harmful effects including an increased risk of post-
operative infection.[17] The recent SIRS trial evaluated the safety and efficacy of steroids after CPB in 
adults and demonstrated no beneficial effect of steroids but increased risk of post-CPB myocardial 
infarction and other major adverse events.[18, 19]  
Adult trial results cannot be reliably extrapolated to infants because the neonatal response to CPB is 
markedly different to that seen in adults; infants demonstrate both a more pronounced inflammatory 
reaction and a different post-operative complication profile. For these reasons approximately 60% of 
congenital heart surgeons continue to administer perioperative steroids to infants undergoing heart 
surgery.[17] Yet this practice is not evidence based as no safety/efficacy trial has ever evaluated steroids 
in infants undergoing heart surgery with CPB. Several smaller steroid trials (all enrolling < 75 patients) 
have focused on surrogate outcome measures, but none have provided conclusive data.[16, 20]  
The major barrier to performing a steroid trial in infants with CHD has been the high cost associated with 
trial conduct for these relatively rare defects. To overcome this barrier, we will use a novel approach 
leveraging existing registry infrastructure at CHD surgical sites that participate in the Society of Thoracic 
Surgeons Congenital Heart Surgery Database (STS-CHSD).  Sites participating in the STS-CHSD collect 
data into their institutional databases using standardized case report forms (see Appendix A) so that the 
data can be exported to the STS-CHSD. These sites already employ data coordinating specialists to 
capture patient demographics, procedural variables, and post-operative outcomes (including a list of over 
60 complication variables) using strict and consistent data element definitions. By leveraging these site-
specific resources we project that we can reduce trial costs by >75%.   


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 5 of 96 
 
 
 
 
2 
PROTOCOL SYNOPSIS 
Protocol Title 
STeroids to REduce Systemic inflammation after infant heart Surgery 
(STRESS trial) 
US IND Number 
129266 
Grant number 
UO1TR001803-01 
Product 
Intravenous methylprednisolone 
Objectives: 
To determine the pharmacokinetics (PK)/pharmacodynamics (PD), safety and efficacy of 
methylprednisolone in infants undergoing planned heart surgery with cardiopulmonary 
bypass  
Study Design: 
This is a prospective, double blind, multi-center, placebo-controlled safety and efficacy 
study. Blood samples will be collected from a subset of enrolled study participants to 
evaluate single dose methylprednisolone PK/PD. After informed consent is obtained, 
participants will be randomized in a 1:1 fashion to intravenous methylprednisolone versus 
placebo. Study drug/placebo will be administered in the operating room at the time of 
initiation of cardiopulmonary bypass. Patients will be followed for primary and secondary 
outcomes for the duration of their hospitalization.    Serious study drug-related adverse 
events will be collected for 7 days after the administration of study drug.  
Rationale for study 
design 
The study design will allow for evaluation of safety and efficacy to neonates receiving the 
drug. The proposed design will also allow for characterization of single dose 
methylprednisolone PK/PD. 
Study Population: 
Up to 1500 infants ages < 1 year undergoing planned heart surgery with cardiopulmonary 
bypass including a minimum of 400 neonates ≤ 30 days at the time of surgery. 
Number of Sites: 
Up to 40 
Duration of Subject 
Participation: 
Until hospital discharge  
Dose ranges to be 
studied 
Intravenous methylprednisolone will be administered using a preservative free formulation. 
The dosage in this study will be 30 mg/kg 
Dose Schedule: 
Intraoperative methylprednisolone/placebo administered as a single IV dose into the 
cardiopulmonary bypass pump prime  
Diagnosis and Main 
Criteria for Inclusion 
Inclusion criteria: 
1. Age < 1 year at the time of surgery 
2. Undergoing planned heart surgery with CPB as part of standard clinical 
care. 
3. Availability and willingness of the parent/legally authorized representative 
to provide written informed consent. 
 
Exclusion criteria: 
1. < 37 weeks adjusted gestational age at time of surgery 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 6 of 96 
 
 
 
2. Any oral or intravenous steroid treatment within two days of surgery 
3. Infection contraindicating steroid use 
4. Any patient receiving any of the following medications within 2 days of 
surgery: Amphoteracin B, aminoglutethimide, anticholesterases, warfarin, 
P450 3A4 inducers including (but not limited to) carbamazepine, 
phenobarbital, phenytoin, rifampin, bosentan and nafcillin or P450 3A4 
inhibitors including (but not limited to) clarithromycin, voriconazole, 
itraconazole, ketoconazole, ciprofloxacin, diltiazem, fluconazole, 
erythromycin, azithromycin and verapamil. 
5. Preoperative mechanical circulatory support or active resuscitation at the 
time of randomization 
6. Previous enrollment in the STRESS trial 
 
Estimated Start: 
September 2017 
Estimated Finish: 
August 2021 
Primary endpoints 
Primary efficacy and safety outcome measures will be compared between infants receiving 
any methylprednisolone and placebo.  
 
Primary endpoint - efficacy: 
The primary outcome measure will consist of a composite mortality, major morbidity and 
length of stay global rank endpoint with endpoints ranked according to  severity.    
For this endpoint each randomized patient recieving study drug will be assigned a rank 
based upon their most-severe outcome. 
Secondary endpoints 
Efficacy: 
• 
Mortality including in-hospital mortality or mortality after hospital discharge but 
within 30 days of the last dose of study drug 
• 
Death or major complication as defined by an outcome in one of the 6 highest 
global ranking categories  
• 
Post-operative hospital length of stay 
• 
Prevalence of prolonged (> 7 days) post-operative mechanical ventilation 
• 
Occurrence of post-operative low cardiac output syndrome  
Safety: 
• 
Occurence of any one or more of the following major post-operative infectious 
complications: 
o Postprocedural infective endocarditis 
o Pneumonia 
o Sepsis 
o Deep wound infection 
o Mediastinitis 
• 
Other post-operative complications will be collected from the start of study drug 
administration until hospital discharge. 
PK/PD/Biomarkers: 
• 
Time to maximum concentration (Tmax) 
• 
Maximum concentration (Cmax) 
• 
Clearance (CL)  
• 
Volume of distribution (Vd) 
• 
Post-operative blood markers of inflammation 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 7 of 96 
 
 
 
PK/PD/Biomarkers: 
Blood samples will be obtained from patients at various time points after the study drug 
infusion. PK parameters will be estimated by non-compartmental analysis using 
WinNonLin software. Study participants as well as enrolling centers will be given the 
opportunity to not participate in the PK/PD and/or Biomarker studies as these require 
needle sticks.  Therefore it is expected that PK/PD and/or biomarker data will not be 
collected on every participant enrolled in the STRESS trial  
Criteria for 
evaluation 
Safety/Efficacy:  Safety and efficacy data will be collected at participating sites using their 
existing surgical databases (STS-CHSD). The majority of efficacy and safety outcomes 
represent data elements that sites are currently collecting for submission to the STS-CHSD. 
A separate clinical database will be used for expedited reporting of any study drug-related 
serious adverse events. An independent Data Monitoring Board (DMC) will monitor the 
conduct of the trial for performance (e.g., recruitment, flow and quality control of data, 
adherence to the protocol) and patient safety. The DMC may review the data at any time. 
At any time and for any reason, the DMC may recommend to the sponsor that the trial be 
interrupted or discontinued. 
Pharmacokinetics:  Methylprednisolone concentrations will be measured in plasma. 
Samples will be measured at a central lab using a validated bioanalytical assay. 
Statistical 
Consideration: 
This protocol has sufficient enrollment to evaluate PK/PD, safety and efficacy of IV 
methylprednisolone  
 
3 
BACKGROUND INFORMATION 
3.1 Summary of Experience in the Perioperative Setting in Children with CHD 
Some surgeons/centers currently administer perioperative high dose (20mg to 60mg) intravenous 
methylprednisolone before pediatric heart surgery with CPB.  In a national registry study of > 3000 
neonates with data capture spanning 2004 to 2008, 62% of neonates undergoing surgery with CPB 
received perioperative methylprednisolone while 38% did not.  Of those receiving methylprednisolone, 
22% received methylprednisolone on both the day before, and day of surgery, 12% on the day before 
surgery only, and 28% on the day of surgery only. In a 2nd national registry study including > 25,000 
infants undergoing CPB operations (2003-2008), 57% received perioperative corticosteroids while 43% 
did not.[21] Results of a survey of surgeons from the Congenital Heart Surgeon’s Society were similar; 
28% did not routinely use steroids for neonatal heart surgery.  Of the 72% that did routinely use steroids, 
~1/3rd administered steroids pre-operatively and intra-operatively and the remainder gave intra-operative 
steroids only.[22] 
 
Several previous small translationally focused clinical trials have evaluated the safety and efficacy of 
methylprednisolone.  In the largest contemporary trial, neonates scheduled for cardiac surgery were 
prospectively randomized to receive either 2-dose (8 hours preoperatively and operatively, n = 39) or 
single-dose (operatively, n = 37) methylprednisolone at 30 mg/kg IV per dose in a prospective double-
blind trial. Neonates receiving pre-operative methylprednisolone therapy demonstrated significantly 
reduced pre-operative pro-inflammatory cytokines including interleukin-6 and 8.  There were no 
differences between the two groups in post-operative pro-inflammatory markers and no differences in the 
incidence of post-operative low cardiac output syndrome. [13, 14] Methylprednisolone was well tolerated 
with no adverse drug reactions.  The overall incidence of post-operative infection was 13% (10/76) and 
4% (3/76) received a post-operative insulin infusion for hyperglycemia.  
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 8 of 96 
 
 
 
A meta-analysis evaluated six previous steroid trials in children undergoing heart surgery with CPB. The 
combined enrollment of these six trials was 232 participants including 116 receiving peri-operative 
steroids; two of these studies used methylprednisolone at doses of 30mg/kg IV per dose (n=67 patients). 
The results of this meta-analysis demonstrated a nonsignificant trend of reduced mortality in steroid-
treated patients (11 [4.7%] vs 4 [1.7%] patients; odds ratio, 0.41; 95% CI, 0.14–1.15; p = 0.089). Steroids 
had no effects on mechanical ventilation time (117.4 ± 95.9 hr vs 137.3 ± 102.4 hr; p = 0.43) and ICU 
length of stay (9.6 ± 4.6 d vs 9.9 ± 5.9 d; p = 0.8). Perioperative steroid administration reduced the 
prevalence of renal dysfunction (13 [54.2%] vs 2 [8%] patients; odds ratio, 0.07; 95% CI, 0.01–0.38; p = 
0.002). There were no significant differences in the adverse event profiles for patients receiving steroids 
versus placebo.[20]  
 
The conclusions of the aforementioned studies, as well as several associated editorials have all been that a 
large, randomized, controlled trial is needed to evaluate the safety and efficacy of perioperative steroids 
for infant heart surgery with CPB.[13, 14, 16, 20] 
 
4 
TRIAL DESIGN AND METHODS 
4.1 Overview  
This study is a prospective, double-blind, multi-center, placebo-controlled safety and efficacy study of 
methylprednisolone in infants undergoing planned heart surgery with CPB.  The study will enroll up to 
1500 infants (< 1 year of age) including a minimum of 400 neonates ≤ 30 days at the time of surgery.  
The total study duration is expected to be approximately 48 months.  An ancillary PK/PD/Biomarker 
study will enroll subjects at select centers. This study is unique in that it is designed to leverage existing 
registry infrastructure at participating sites so as to reduce trial costs.  Participants will be randomized and 
will receive a subject ID.  This ID will also serve as a unique patient identifier allowing us to crosslink 
datasets.  Participants will then receive study drug/placebo administered into the pump prime during 
cardiopulmonary bypass.  All study participants will then receive routine post-operative care.  
Participating centers will enter all demographic, preoperative, operative and outcomes data into their 
existing institutional databases for submission to the STS-CHSD as they currently do. These data will be 
used to evaluate trial outcomes.  
 
4.2 Procedures to Minimize/Avoid Bias 
4.2.1 
Randomization 
 
Eligible participants will be randomized prior to their electively scheduled surgery in a 1:1 fashion to the 
treatment groups summarized in table 2 below.  A block randomization scheme will be employed to 
ensure equal allocation by study site. Randomization assignments will be generated by a web-based 
system at the data coordinating center (DCC), after confirmation of trial eligibility. Trial sites will enter 
the randomization number into two databases that will be used for this trial (see section 6.4):  the 
participating center’s surgical database (for submission to the STS-CHSD), and an IBM Clinical 
Development database that will be used to capture some adverse event data, timing of drug delivery and 
timing of PK samples (for participating centers only) and a subset of laboratory values from the electronic 
health record.   
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 9 of 96 
 
 
 
Table 1. Study Drug dosing 
Group 
N 
Intra-operative 
1 
up to 750 
IV methylprednisolone in the CPB prime 
2 
Up to 750 
Placebo 
 
4.2.2 
Blinding 
 
The study medication and the placebo will be identical in appearance to assure masking of study 
medication.  The randomization assignment will be seen only by the statistician at the DCC and the 
investigational pharmacist preparing the study medication.  The family/subject, study coordinator and 
investigators will remain masked as to treatment group assignment until after all trial data are analyzed. 
4.3 Study measures 
Study outcomes were determined after trial simulations. Based upon these data we selected the following 
primary and secondary outcome measures. 
 
4.3.1 
Primary Endpoint 
 
A composite mortality, major morbidity and length of stay global rank endpoint with endpoints ranked 
according to  severity. The global rank score has been previously described.[23]  Subjects will receive a 
rank score based upon the lowest ranking (worst) endpoint that they experience during the study trial.   
 
Table 2. Global Rank Endpoint Details 
Rank Score 
Description 
1 
Operative mortality 
2 
Heart transplant (during hospitalization) 
3 
Renal failure with permanent dialysis, neurologic deficit persistent at discharge, or respiratory 
failure requiring tracheostomy 
4 
Post-operative mechanical circulatory support or unplanned cardiac reoperation (exclusive of 
reoperation for bleeding) 
5 
Reoperation for bleeding, delayed sternal closure, or post-op unplanned interventional cardiac 
catheterization  
6 
Post-op cardiac arrest, multi-system organ failure,  
renal failure with temporary dialysis, or prolonged ventilator support (> 7 days) 
7 
Post-operative length of stay > 90 days 
8-97 
Post-operative length of stay 
 
 
4.3.2 
Secondary Endpoints (see section 11.2 for data element 
definitions) 
 
Efficacy: 
• 
Mortality including in-hospital mortality or mortality after hospital discharge but within 30 days 
of the last dose of study drug 
• 
Death or major complication as defined by an outcome in one of the 6 highest global ranking 
categories  
• 
Post-operative hospital length of stay 
• 
Prevalence of prolonged (> 7 days) post-operative mechanical ventilation 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 10 of 96 
 
 
 
• 
Occurrence of post-operative low cardiac output syndrome  
 
Safety: 
• 
Occurence of any one or more of the following STS-CHSD-defined major post-operative 
infectious complications: 
o Postprocedural infective endocarditis 
o Pneumonia 
o Sepsis 
o Deep wound infection 
o Mediastinitis 
• 
Other post-operative complications will be collected from the start of study drug/placebo 
administration until hospital discharge. 
 
PK/PD/Biomarkers: 
• 
Time to maximum concentration (Tmax) 
• 
Maximum concentration (Cmax) 
• 
Clearance (CL)  
• 
Volume of distribution (Vd) 
• 
Post-operative blood markers of inflammation 
PK/PD and Biomarker data will only be collected at select centers and in those patients whose 
parent/legally authorized representative have granted consent to blood draws.  An opt in/out clause is 
included in the informed consent forms for study participants and centers will be allowed to 
participate in this part of the study if they prefer.  Parent/legally authorized representative of 
participants may elect to participate in the PK/PD, the Biomarker studies or both.  Time points for 
blood collection will be the same for both the PK/PD and biomarker studies. Biomarkers being 
collected represent blood markers of inflammation. 
 
 
4.3.3 
Timeframe for collection of safety and efficacy endpoints 
 
With respect to primary and secondary outcome measures, participants will be followed for the duration 
of their hospitalization.  Data will be collected consistent with standard STS-CHSD reporting protocol.  
Participants that are discharged within the first 30 days after their initial cardiac surgery, or any 
participants that receive study drug/placebo but then do not undergo surgery, will be followed to assess 
for mortality through 30 days after administration of study drug/placebo. If patients remain hospitalized 
for > 4 months after the final study subject has been enrolled then they will be assigned the worst rank 
outcome that they have encountered to that point.  Patients still hospitalized with mechanical 
circulatory support and listed for heart transplant will assigned to the “heart transplant” outcome 
(See missing data section for exceptions). Serious study drug-related adverse events will be collected 
through 7 days after administration of study drug. Based upon an 18 hour estimated half- life of 
methylprednisolone, this duration of follow up (> 10 half-lives) will ensure collection of all potentially 
study drug-related serious adverse events but avoids capturing unnecessary serious adverse events in this 
high morbidity patient population. 
 
4.4 Schedule of events  
Participants will be enrolled at the time of their electively scheduled surgery.  Sites will receive a 
randomization ID that will be entered into the two relevant databases:  the sites’ surgical database (STS-


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 11 of 96 
 
 
 
CHSD), and an IBM Clinical Development clinical database.  The study drug/placebo will be 
administered in the CPB pump prime at the time of initiation of CPB.  Participants will then undergo 
surgery with CPB per standard of care.  Participants will receive routine post-operative care. Post-
operative outcomes including post-operative hospital length of stay, discharge mortality, and 
complication data will be recorded in the sites institutional surgical database (STS-CHSD) consistent with 
current practices at the enrolling sites.  STS-CHSD data element definitions of particular relevance to the 
STRESS trial are included in Section 11.2. A subset of additional safety endpoints and select safety 
laboratory values from the electronic health record will be collected into a separate clinical database, IBM 
Clinical Development (see section 6.4). Plasma samples including PK/PD/Biomarker samples will be 
evaluated in a subset of enrolled patients at select centers using a limited sampling scheme. Sample 
acquisition, handling, and shipping instructions are outlined in Appendix C.  
 
Table 3. Schedule of events 
Procedure 
Pre-
dose 
Day 1  
Day 2 
Day 3 
Day 4-7 
Duration of 
hospitalization3 
Informed Consent 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Elective surgery with CPB 
 
X 
 
 
 
 
Administer study drug/placebo1 
 
X 
 
 
 
 
Timed PK/PD/Biomarker Samples2 
 
X 
X 
 
 
 
Study drug-related SAEs 
X 
X 
X 
X 
X 
 
STS-CHSD data (1○ / 2ndary endpoints) 
 
X 
X 
X 
X 
X 
1 Study drug/placebo will be administered at the time of initiation of CPB 
2 Specific times of PK/PD/Biomarker sampling TBD based upon preliminary analysis of an on-going population PK 
study 
3 Mortality data will be collected for the duration of hospitalization or until 30 days after study drug / placebo 
administration for patients that are discharged. If patients remain hospitalized for > 4 months after the final study subject has 
been enrolled then mortality data for the hospitalization will not be collected and they will be assigned the worst rank outcome that 
they have encountered to that point. 
 
 
5 
SELECTION AND WITHDRAWAL OF SUBJECTS 
5.1 Inclusion criteria  
 
1. 
Age < 1 year at the time of surgery 
2. 
Planned heart surgery with CPB as part of standard clinical care. 
3. 
Availability and willingness of the parent/legally authorized representative to provide 
written informed consent. 
 
5.2 Exclusion criteria  
1. 
< 37 weeks adjusted gestational age at time of surgery 
2. 
Any oral or intravenous steroid treatment within two days of surgery 
3. 
Any patient receiving any of the following medications within 2 days of surgery: 
Amphoteracin B, aminoglutethimide, anticholesterases, warfarin, P450 3A4 inducers 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 12 of 96 
 
 
 
including (but not limited to) carbamazepine, phenobarbital, phenytoin, rifampin, 
bosentanand nafcillin or P450 3A4 inhibitors including (but not limited to) clarithromycin, 
voriconazole, itraconazole, ketoconazole, ciprofloxacin, diltiazem, fluconazole, erythromycin, 
azithromycin and verapamil. 
4. 
Infection contraindicating steroid use 
5. 
Preoperative mechanical circulatory support or active resuscitation at the time of 
randomization 
6. 
Previous enrollment in the STRESS trial 
 
5.3 Subject withdrawal 
Participants that are randomized but do not receive study drug/placebo before 1 year of life will be 
withdrawn from the study. 
 
5.4 Recruitment/enrollment procedures protocol 
Expected duration of accrual of subjects is approximately 48 months. Recruitment will be conducted 
using standard procedures. To help with recruitment, information describing the study will be developed 
for print, electronic, and social media. Subjects’ parent/guardian will be approached for participation, 
either in person or by telephone, by site study coordinators or investigators, who will obtain parental 
consent following standard procedures. The specific procedures will be in compliance with the 
requirements of each site’s Institutional Review Board. 
 
6 
STUDY PROCEDURES 
6.1 Preoperative Assessment – Screening Procedures and Baseline 
Measurements 
1. Obtain a signed and dated Informed Consent Form (ICF) prior to any study related procedures. 
2. Enter all demographic, preoperative risk factor and past medical/surgical history data into the STS-
CHSD as per routine  
3. Obtain a unique subject ID from the IBM Clinical Development database.  This subject ID will also 
serve as a unique patient identifier allowing cross-linking across databases.  It must also be entered 
into the site’s surgical database under the study identifier tab as the “STS-related clinical trial ID” 
(see section 6.4). In addition the STS “Operation ID” must be entered into both databases and will 
serve as a double check in the event that the IBM Clinical Development subject ID is incorrectly 
entered into either of the 2 databases. 
4. Perform routine preoperative assessment 
 
6.2 Baseline/Pre-Dose Assessment 
After the parent or legally authorized representative has signed the IRB-approved informed 
consent form, and after it has been determined that the patient satisfies all inclusion and exclusion 
criteria, the following evaluations will be performed and entered directly into the study database 
(STS-CHSD): 
1. Baseline demographics (race, gender, date of birth, age, weight, age and weight at surgery) 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 13 of 96 
 
 
 
2. Fundamental cardiac diagnosis as defined by the STS-CHSD 
3. Presence of any of the 41 STS-CHSD defined preoperative risk factors including mechanical 
ventilation to treat cardiorespiratory failure, sepsis, stroke, renal failure or hepatic 
dysfunction as defined by the STS-CHSD. 
4. Presence of any non-cardiac anatomic abnormality, genetic syndrome or chromosomal 
anomaly as defined by the STS-CHSD. 
 
6.3 Study Procedures During Study Drug Administration 
The following procedures or evaluations will be performed during and immediately following the 
drug administration and the data recorded as indicated: 
1. Record study drug/placebo dosing information including dose and timing of drug 
administration into the IBM Clinical Development database. 
2. Immediately (within 1 business day of first becoming aware of the adverse event) enter all 
serious, study drug-related adverse events into the IBM Clinical Development database. 
6.4 Study Procedures After Study Drug Administration During Hospitalization 
The following information will be collected using the standard STS-CHSD data collection forms 
consistent with usual institutional practice: 
1. Record all post-operative complications using standard STS-CHSD data element definitions 
(see section 11.2 for definitions) 
2. Record all subsequent surgeries (CPB or non-CPB cardiovascular or non-cardiovascular)  
3. Record duration of mechanical ventilation  
4. Record post-operative hospital length of stay 
5. Record operative mortality (in-hospital death or death after hospital discharge but within 30 
days of the surgery/administration of study drug/placebo) 
 
All other aspects of care, including administration of clinically indicated medications can be 
provided per routine standard of care. 
 
Serious, study drug-related adverse events may require expedited reporting and must be 
submitted into the IBM Clinical Development database. Sites must report these events within 1 
business day of first becoming aware of the event.   
 
The variables listed in Table 4 are not collected by the STS-CHSD and will need to be collected 
directly from the Electronic Health Record.  These variables must be entered directly into the 
relevant databases as specified in Table 4. 
 
 
Table 4: Additional variables to be captured from the electronic health record 
Variable 
 
Definition 
Database 
Post-operative highest blood 
glucose 
Enter the highest post-operative blood glucose within 72hrs of 
surgery 
IBM Clinical 
Development  
Post-operative insulin 
administration 
Was insulin administered within 24 hours of surgery? 
IBM Clinical 
Development 
Post-operative adrenal suppression 
Was hydrocortisone administered within 72 hours of surgery? 
IBM Clinical 
Development 
Preoperative creatinine 
Enter the last serum creatinine level obtained prior to surgery 
IBM Clinical 
Development 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 14 of 96 
 
 
 
Highest post-operative creatinine 
Enter the highest serum creatinine within 72 hours of surgery 
IBM Clinical 
Development 
Lowest post-operative potassium 
Enter the lowest post-operative potassium within 72 hours of 
surgery 
IBM Clinical 
Development 
Highest post-operative AST 
Enter the highest AST within 72 hours of surgery 
IBM Clinical 
Development  
Highest post-operative ALT 
Enter the highest ALT within 72 hours of surgery 
IBM Clinical 
Development 
Highest post-operative lactate 
Enter the highest lactate within 72 hours of surgery 
IBM Clinical 
Development  
Lowest post-operative serum 
cortisol 
Enter the lowest serum cortisol level obtained within 72hrs of 
surgery 
IBM Clinical 
Development 
 
 
6.5 PK/PD/Biomarker sampling procedures (select sites) 
A limited PK/PD/Biomarker sampling scheme will be employed such that no more than 5600 μl 
(7 samples, 800 μl per sample) of blood is obtained (Table 5).  Blood samples will be collected in 
800 µL aliquots. Children who have only 1 evaluable PK sample will be included in the analysis, 
but additional participants may be enrolled to ensure at least 100 children with < 4 adequate PK 
samples.   
 
Table 5. PK/PD/Biomarker sampling scheme 
Sample 
Number 
Per Patient Prioritization 
Time 
Per patient blood 
collection 
1 
Please always try to collect this 
Pre-dose (biomarker only) 
4 x 200 uL = 800 uL 
2 
Collect a minimum of 2 of any 
of these 5 time points to collect 
a minimum total of 3 time 
points per participant. 
0-30 minutes after the start of CPB 
4 x 200 uL = 800 uL 
4 x 200 uL = 800 uL 
3 
0-30 minutes after MUF 
4 
1-2 hours after completion of CPB 
5 
4-6 hours after completion of CPB 
6 
16-24 hours after completion of 
CPB 
7 
If participating in the 
biomarker arm, then please 
always try to collect this 
36-48 hours after completion of 
CPB 
4x 200 uL = 800 uL 
 
 
Timed PK/PD/Biomarker sample handling procedures (plasma):   
Assays to measure methylprednisolone concentrations and measures of the inflammatory 
response to CPB in plasma will be conducted at a central lab using validated bioanalytical assays.  
The date and time will be recorded for the administration of study drug/placebo, and the 
acquisition time of the PK sample.   
  
7 
TREATMENTS TO BE ADMINISTERED 
7.1 Description of Study Treatments 
Eligible subjects will be randomized prior to their electively scheduled surgery in a 1:1 fashion to 
methylprednisolone (30mg/kg) versus placebo as summarized in table 2 above. The dosages for 
administration (30 mg/kg) are based upon expert consensus regarding current practice and a previous 
dosing study. Intravenous methylprednisolone is available in a preservative free single use “Act-O-Vial 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 15 of 96 
 
 
 
System” containing powder (40mg, 125mg, 500mg and 1000mg options are available) and diluent.  Study 
drug will be provided “off the shelf” by study sites and prepared following local pharmacy protocols.  
Only preservative-free solutions will be used for this trial due to safety concerns with the administration 
of benzyl alcohol preservatives in infants. Study drug will be mixed with isotonic saline in a syringe to 
create a solution.  Placebo preparations will consist of isotonic saline only and will be prepared in 
identical syringes so as to be physically indistinguishable from study drug. 
 
7.2 Route of Administration 
For the purposes of this trial methylprednisolone will be administered as a bolus dose 
administered directly into the CPB priming solution (intraoperative administration). 
 
7.3 
Storage and Administration 
Study drug/placebo will be prepared by the site investigational pharmacy and delivered to the operating 
room from the investigational pharmacy on the day of study drug/placebo administration.  All co-
investigators, staff administering study drug/placebo and other care providers will be blinded to study 
drug/placebo allocation. Start and stop times of study drug administration must be documented by the 
investigational pharmacy in the IBM Clinical Development database. 
8 
STUDY DRUG ACCOUNTABILITY 
8.1 Medications/Treatments Permitted and Not Permitted during the Study 
8.1.1 
Rescue Medication, Emergency Procedures and Additional 
Treatments(s) 
Management would be symptomatic treatment (e.g., severe hypertension) or observation and monitoring 
(e.g., mild hyperglycemia).  
 
8.1.2 
Restrictions regarding concomitant treatment 
Subjects may be treated with other medications at the discretion of their physicians. 
 
8.2 Emergency Unblinding 
An emergency code break can be requested from the site research pharmacist after full discussion with the 
STRESS PI. This code break may be used in rare life-threatening or emergency situations when the 
identity of the study drug must be known to the investigator in order to provide appropriate medical 
treatment or if required to assure safety of trial participants. If the code break for a subject is required, the 
DCC must be informed within one working day of the event. The reason for breaking the code will be 
documented by the Data Coordinating Center (Duke Clinical Research Institute) accordingly. 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 16 of 96 
 
 
 
9 
SAFETY ASSESSMENTS AND MONITORING 
9.1 Collection and Reporting 
Due to the unique study design, adverse events will be recorded by the site as complications and/or other 
adverse event data variables specifically captured by the site’s surgical database using STS-CHSD data 
element definitions (see Section 11.2).   
 
Serious, study drug-related adverse events will be reported by site investigators or qualified designee 
from the time of study drug administration through 7 days after study drug administration on the SAE 
eCRF in the IBM Clinical Development database within 1 business day of first becoming aware of the 
event. The site investigator’s reported relationship assessment to study drug will be confirmed or assessed 
otherwise by a Safety Medical Monitor at the Duke Clinical Research Institute.  
 
9.2 Definitions of Adverse Events (AEs), Suspected Adverse Reaction and 
Serious Adverse Events 
The FDA Final Rule on IND Safety Reporting Requirements 
[http://edocket.access.gpo.gov/2010/pdf/2010-24296.pdf] provides the following definitions:  
 
Adverse events (AEs) An AE is any untoward medical occurrence associated with the use of a drug in a 
subject whether or not considered drug- or biologic-related. An AE can therefore be any unfavorable and 
unintended sign, symptom, or disease temporally associated with the use of a pharmaceutical product or 
biologic.  
 
A suspected adverse reaction (SAR) is any adverse event for which there is a reasonable possibility that 
the drug caused the adverse event. A “reasonable possibility” suggests there is a causal relationship 
between the drug and the adverse event. “Suspected adverse reaction” implies a lesser degree of certainty 
about causality than adverse reaction, which means any adverse event caused by a drug.  
 
Serious adverse events: An adverse event or suspected adverse reaction is considered serious if, in the 
view of either the site investigator or the IND sponsor, it results in any of the following outcomes: 
 
1. Death 
2. Life-threatening AE: Places the subject at immediate risk of death at the time of the event as it 
occurred. It does not include an AE that, had it occurred in a more severe form, might have 
caused death.  
3. Persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions 
4. Inpatient hospitalization or prolongation of existing hospitalization 
 
An important medical event that may not result in death, be life threatening, or require hospitalization 
may be considered a serious adverse event when, based upon appropriate medical judgment, it may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in the definition above. This determination is based on the opinion of either the investigator or 
sponsor (e.g., if either believes it is serious, it must be considered serious).  
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 17 of 96 
 
 
 
Laboratory abnormalities are not specifically captured by institutions as part of their STS-CHSD and will 
not be considered AEs unless they result in a post-operative complication that sites report to the STS-
CHSD. In this case, the clinical diagnosis rather than the laboratory term will be used by the reporting 
investigator (e.g., renal failure versus elevated creatinine). 
 
9.3 Assessment of Severity 
The determination of severity rests on medical judgment of a medically qualified investigator. For 
adverse events captured by the site’s surgical database, the data monitoring committee will review these 
events every 6-months following transfer of data to the data coordinating center at the Duke Clinical 
Research Institute.  For suspected unexpected serious adverse reactions, monitoring will be performed 
continuously and event severity will be graded by the study sponsor.  The severity of suspected adverse 
reactions and study drug related SAEs will be graded using the following definitions: 
 
1.    MILD: Participant is aware of symptoms or has minor findings but tolerates them well and no or 
minimal intervention required. 
2.    MODERATE: Participant experiences discomfort enough to cause interference with usual activity 
and may warrant intervention.  
3.    SEVERE: Participant experiences symptoms that are incapacitating with inability to do usual 
activities or that significantly affect clinical status and warrant intervention.  
 
Study personnel will enter the study drug-related serious adverse event data into the IBM Clinical 
Development database. The STRESS Trial PI / IND sponsor will be responsible for adjudicating severity 
and relatedness of these events and determining which events should be reported in expedited fashion to 
FDA. The IND sponsor or designee will submit expedited safety reports (IND Safety Reports) to the FDA 
and other regulatory agencies as necessary, and will inform the investigators of such regulatory reports. 
Investigators must submit safety reports as required by their Institutional Review Board (IRB). 
Documentation of the submission to and receipt by the IRB should be retained for each IND safety report. 
 
9.4 Assessment of Causal Relationship 
A medically qualified investigator must assess the relationship of any adverse event to the use of the 
study drug, based on available information using the following guidelines:  
 
1.    Not related: There is not a reasonable causal relationship to the investigational product and the 
adverse event.  
2.    Unlikely related: No temporal association, or the cause of the event has been identified, or the drug 
or biologic cannot be implicated.  
3.    Possibly related: There is reasonable evidence to suggest a causal relationship between the drug and 
adverse event.  
4.    Related: There is evidence to suggest a causal relationship, and the influence of other factors is 
unlikely.  
Relatedness to these complications will not be specifically assigned by the Data Monitoring Committee 
unless they are separately reported as suspected unexpected serious adverse reactions (SUSARs).   
Expectedness 
The expectedness of an adverse event or suspected adverse reaction shall be assessed by a DCRI Safety 
Medical Monitor according to the package insert. Any AE that is not identified in nature, severity, or 
specificity in the current package insert is considered unexpected. Events that are not mentioned in the 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 18 of 96 
 
 
 
package insert as occurring with a class of drugs or as anticipated from the pharmacological properties of 
the drug, but not specifically mentioned as occurring with the particular drug under investigation, are 
considered unexpected.  
 
9.5 Identification of Safety Events 
As subjects in this study may have pre-existing medical conditions and will be currently hospitalized, 
those pre-existing conditions will not be considered as adverse events unless they worsen or increase in 
frequency or intensity after administration of study drug. New events that occur or the worsening in 
frequency or intensity of pre-existing conditions will be reported as adverse events or, if serious reporting 
criteria are met, serious adverse events. Events that do not qualify as a study drug-related serious adverse 
event for the STRESS trial and should not be recorded in the IBM Clinical Development clinical database 
are: 
• 
Medical or surgical procedures (e.g. surgery, transfusion); however, the condition that required 
the procedure is considered an adverse event if the situation developed or worsened due to study 
drug administration 
• 
Pre-existing diseases or baseline conditions present or detected before the start of study drug that 
do not worsen in frequency or intensity due to study drug administration. 
• 
Any events considered to be related to the patients underlying heart disease or recovery from 
his/her cardiac surgery, including any of the post-operative complications listed in the STS-
CHSD. 
• 
Serious Adverse Events that are assessed by the site investigator as Not related or Unlikely 
related to study drug 
 
9.6 Safety Monitoring 
The data coordinating center (DCC) will monitor safety during the conduct of the study. The study 
sponsor will review all potential unexpected study drug related serious adverse events at the time of SAE 
notification by DCRI Safety Surveillance and confirm whether the event is a suspected unexpected 
serious adverse reaction (SUSAR). The data monitoring committee (DMC) will monitor safety every 6 
months as per the DMC charter. Annual and expedited reports will be submitted to the FDA as required.  
 
 
9.7 Halting Rules 
All patients who receive study medication will be followed for safety. An independent data monitoring 
committee consisting of three physicians will conduct an internal review of study safety every 6-months 
of study enrollment.  The safety review will include all SAEs and all AEs captured in either the STS-
CHSD or the separate IBM Clinical Development clinical database that the data monitoring committee 
determine are possibly or probably related to the study drug and all patients who discontinued 
participation in the study early. If >3 subjects experience active (not placebo) study drug-related SAEs 
of the same Preferred Term (MedDRA coding), the DMC will be notified.  Decisions to halt the trial will 
be at the discretion of the DMC.  
 
If the study is halted, the AEs will be thoroughly evaluated and study enrollment will not resume until the 
safety review is completed. 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 19 of 96 
 
 
 
 
9.8 Reporting Adverse Events to Institutional Review Boards for NIH-Supported 
Multi-Center Clinical Trials 
The site Investigator or designee is responsible for reporting all serious adverse events to the local 
IRB/REB in accordance with local policies and procedures. 
 
9.9 Follow-up of Subjects after Adverse Events 
For Serious AEs with a positive causal relationship to the study drug, follow-up by the investigator is 
required until the event or its sequelae resolve or stabilize at a level acceptable to the investigator. 
 
9.10 
Study Suspension 
Study enrollment and administration of study drug/placebo will be stopped for a safety review based upon 
the recommendations of the DMC. 
 
 
 
10 
STATISTICS 
10.1 
Planned Sample Size 
The trial's sample size was formulated to provide high power (>90%) for detecting a clinically important 
treatment benefit in patients randomized to steroids versus placebo as measured by the trial's primary 
global ranking endpoint categories with testing based on the Wilcoxon rank sum test or, equivalently, the 
proportional odds logistic regression model score test [24]. The magnitude of the hypothesized treatment 
effect of steroids versus placebo was quantified by the win difference 
 where 
 is the probability 
that a randomly selected patient in the steroids group will have a better outcome (higher global ranking 
category) than a randomly selected patient in the placebo group and 
 is the probability that a randomly 
selected patient in the steroids group will have a worse outcome (lower global ranking category) than a 
randomly selected patient the placebo group. As shown in Table 6, a sample size of approximately 1,200 
participants will provide approximately 85% power if the win difference is 
 and will provide 95% 
power if the win difference is 0.12. Thus, the study has good power to detect a meaningful improvement 
in the probability of a better outcome with steroids compared to placebo. For an alternative perspective on 
the study's power, the treatment effect of steroids versus placebo may be quantified by specifying the 
extent to which the odds of having an outcome in one of the  lowest (worst) global ranking categories is 
reduced in patients randomized to steroids versus placebo, where 
 refers to the odds of death, 
 
refers to the odds of death or heart transplant, etc.  Specifically, the treatment effect may be quantified by 
the set of odds ratios 
 
where for simplicity we may assume that 
. As shown in Table 6, a sample 
size of 1,200 participants will provide approximate 82% power if the odds ratio is 0.75 (i.e. a 25% 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 20 of 96 
 
 
 
reduction in the odds) and approximately 95% power if the odds ratio is 0.70 (i.e. a 30% reduction in the 
odds). Thus, the study is well powered under a range of clinically relevant and plausible risk reduction 
scenarios. For simplicity, power statements above are based on approximate power using a Wilcoxon test 
ignoring baseline covariates. However, to increase statistical power, analysis of the primary endpoint will 
be adjusted for baseline covariates, as described in Section 10.3 below. Based on Monte Carlo simulations, 
a covariate adjusted analysis will increase power by an amount ranging from 3 to 5 percentage points 
compared to an unadjusted analysis under assumptions consistent with 80%-90% power for the 
unadjusted analysis. 
 
Table 6. Estimated power as a function of the effect size as quantified by the win difference or odds 
ratio assuming N = 1,200 (600 per group) 
Effect Size Parameter 
Win Difference (
) 
Odds Ratio (OR) 
Numerical Effect Size 
0.10 
0.11 
0.12 
0.75 
0.725 
0.70 
Power (N = 1,200) 
85% 
91% 
94% 
82% 
90% 
95% 
 
Assumptions: Based on two-sided alpha=0.05. Power was calculated as 
 where 
 
denotes a chi-squared random variable with 1 degree of freedom and non-centrality parameter 
, where 
 and 
 (derived from formulas in Zhao et al.[24]) or 
 (derived from formulas in Whitehead [26]) where  is the probability that 3 
randomly selected trial participants will not all have outcomes in the same global ranking category. The 
quantity  reflects the reduction in variance due to ties and was set to its maximum possible value 
(
) in order to obtain a conservative lower bound approximation of power for a specified win 
difference. Calculations do not account for an expected slight loss of power after decreasing alpha to 
account for interim analyses.  
 
10.2 
Statistical Analysis Plan 
All major treatment comparisons between the randomized groups will be performed according to 
the principle of "intention-to-treat"; that is, subjects who received study drug/placebo will be 
analyzed (and endpoints attributed) according to the group to which subjects were randomized, 
regardless of subsequent medications or treatment crossover. Statistical comparisons will be 
performed using 2-sided significance tests.  
 
10.3 
Analysis of the Primary Endpoint 
The trial's global ranking endpoint outcome is an ordinal categorical variable having  levels, where 
category 1 represents the worst possible outcome (e.g. death) and category  represents the best possible 
outcome (e.g. a short hospital stay free of death or major complications) according to a pre-specified 
subjective global ranking algorithm (see above). Table 7 summarizes the distribution of ranking endpoints 
in neonates and infants in a historical cohort of patients from the STS database. The actual observed 
distribution of ranking categories in the trial will be compared across treatment groups using a stratified 
non-parametric Wilcoxon rank sum test (also known as the van Elteren test [27]) with stratification by 
categories of pre-randomization predicted mortality or morbidity risk or by using a regression-based 
analog of the van Elteren test which allows adjusting for multiple pre-randomization prognostic factors in 
order to maximize statistical power [28]. Covariates for stratification or covariate adjustment will be 
determined prospectively and will be pre-specified in the statistical analysis plan. The level of 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 21 of 96 
 
 
 
significance for the assessment of the primary endpoint will be α=0.05 (two-sided). The magnitude of the 
treatment effect will be described by presenting summary measures of the frequency distribution of 
ranking categories by treatment group and by estimating the probability that a randomly selected steroids 
group participant will have a better or worse outcome than a randomly selected placebo group participant 
(e.g. the win ratio [29]). If the data provide evidence of an overall difference in outcome between 
treatment groups, we will further examine whether the therapeutic effect is similar for all participants, or 
whether it varies according to specific participant characteristics, which will be pre-specified in the 
statistical analysis plan. These analyses will use ordinal regression models and will involve testing for 
interactions between treatment and these specific baseline variables. Effect estimates for subgroups will 
be carefully (conservatively) interpreted in conjunction with the formal interaction tests. 
 
Table 7. Cumulative frequency of endpoints included in the global rank outcome 
Global Rank Endpoints 
Age ≤ 30d 
Age < 1yr 
Operative mortality 
8.9% 
4.5% 
Heart transplant (during hospitalization) 
9.2% 
5.4% 
Renal failure with permanent dialysis, neurologic deficit persistent at 
discharge, or respiratory failure requiring tracheostomy 
10.8% 
6.6% 
Post-operative mechanical circulatory support or unplanned cardiac 
reoperation (exclusive of reoperation for bleeding) 
19.2% 
11.8% 
Reoperation for bleeding,  delayed sternal closure or post-op unplanned 
interventional cardiac catheterization  
27.1% 
16.7% 
Post-op cardiac arrest, multi-system organ failure, renal failure with 
temporary dialysis, or prolonged ventilator support (> 7 days) 
36.1% 
21.9% 
Prolonged post-op length of stay  (> 90 days, binary endpoint) 
36.6% 
22.3% 
*Data compiled from the STS Congenital Heart Surgery National Registry (2010-2015) 
 
10.4 
Analysis of Secondary Safety and Efficacy Endpoints 
Secondary endpoints will be analyzed via regression modeling with adjustment for pre-
randomization covariates. For secondary endpoints that are binary (e.g. mortality, composite 
mortality or major complications, low cardiac output syndrome), the form of the model will be a 
logistic regression comparing the endpoint event rate across the two treatment groups. For 
continuous outcomes with skewed distributions (e.g., post-operative hospital length of stay, 
duration of mechanical ventilation) the outcome will be approximated by a skewed distribution 
such as log-normal, Weibull or negative binomial, or modeled semi-parametrically. For safety 
analyses, we will summarize the number of adverse events overall, by severity, and by each 
Medical Dictionary for Regulatory Activities system organ class and preferred term. We will 
tabulate adverse event data by procedural risk cohort (STAT levels). 
 
10.5 
Interim Analyses 
Interim examination of clinical endpoints and key safety events will be performed at regular 
intervals during the course of the trial. An independent Data Monitoring Committee (DMC) will 
monitor participant safety and review performance of the trial. The primary objective of these 
interim analyses will be to ensure the safety of the participants enrolled in the trial and evaluate 
the accumulating endpoint data by treatment group to test for possible differences favoring either 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 22 of 96 
 
 
 
of the two randomized management strategies. In addition, interim monitoring will involve a 
review of participant recruitment, compliance with the study protocol, status of data collection, 
and other factors which reflect the overall progress and integrity of the study. 
 
Formal interim treatment group comparisons will focus on comparing the distribution of the primary 
global ranking endpoint categories by treatment group.  To account for repeated significance testing of the 
accumulating data, the group sequential method of Lan and DeMets will be used as a guide for 
interpreting these interim analyses.  Monitoring boundaries for the primary endpoint will be based on a 
two-sided symmetric O’Brien-Fleming type spending function with an overall two-sided significance 
level of α = 0.05. The O’Brien-Fleming approach requires large critical values early in the study but 
relaxes (i.e., decreases) the critical value as the trial progresses. These proposed monitoring boundaries 
are intended as a guide for interpreting the interim analyses and not as a strict rule for early termination. 
The first interim analysis using alpha spending will be targeted to occur after completion of data 
collection for the first ~600 to 800 subjects depending on timing of the STS data harvest. Additional 
interim analyses will be performed at intervals determined by the DMC. Study enrollment will be allowed 
to continue pending compilation of the interim data and review/recommendations from the DMC. 
 
Update 15 September 2020: Due to a delay in receiving the STS-CHSD data harvest, the DMC Chair is 
agreeable to proceed with the interim analysis in the following manner.  The unblinded statistical team 
will plan to access and compile Length of Stay (LOS) and mortality data by treatment allocation from the 
IBM Clinical Development clinical database.  This data will be reviewed by the DMC during a convened 
DMC meeting.  If these data suggest any safety concerns, the study team will proceed with the previously 
planned interim analysis whenever the STS-CHSD data are available. If there are no identified safety 
concerns then enrollment will continue to trial completion. 
10.6 
Data Monitoring Committee 
A DMC will be appointed by the trial's leadership to monitor participant safety and to review 
performance of the trial. A DMC charter that outlines the operating guidelines for the committee 
and the procedures for the interim evaluations of study data will be developed by the trial's 
leadership and agreed upon by the DMC. Reports will be prepared regularly in accordance with 
the plan outlined in the charter and as requested by the DMC chair, and will include interim 
analyses of primary and secondary endpoints; additional safety events; and other information as 
requested by the committee. After each meeting, the DMC will make recommendations to the 
trial's leadership about the continuation of the study. After approval by trial leadership, a 
summary of the DMC report and recommendations will be forwarded to site investigators for 
submission to their local IRB.  
 
10.7 
Population for Analysis 
• 
Efficacy: 
All participants who receive study drug/placebo. 
• 
Safety:   
All participants who receive study drug/placebo.  
• 
PK/PD/Biomarkers: All participants who receive methylprednisolone and have at least 
1 evaluable PK sample. 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 23 of 96 
 
 
 
11 
DATA MANAGEMENT 
11.1 
Data entry 
The majority of data for the STRESS trial will be captured via the STS-CHSD.  Sites must enter the IBM 
Clinical Development subject ID into the participating subjects STS-CHSD record under the “STS-related 
clinical trial ID” tab/variable.  This identifier must be entered into the STS database immediately after it is 
assigned. This identifier will be used to link the two databases.   For other variables, the STS-CHSD 
includes specific data element definitions that must be closely followed (see section 11.2). 
 
Serious, unexpected, study drug-related adverse events may require expedited reporting and 
therefore must be collected in an expedited fashion.  Since the STS-CHSD data are only 
harvested every 6-months, a separate IBM Clinical Development database has been developed to 
capture these events.  Study drug-related serious adverse events must be submitted into the IBM 
Clinical Development database within 1 business day of first becoming aware of the event.  The 
IBM Clinical Development  database will also be used to capture a select subset of additional 
variables including timing of medication administration, adverse events of interest that are felt to 
be study drug-related (see section 9.2) and timing of PK/PD/Biomarker sample collection (for 
participating sites). 
 
In addition, a small subset of select post-operative laboratory administration variables (Table 4) need to 
be captured but are not incorporated into the STS-CHSD.  These data must be collected from the 
electronic health record and the data entered directly into the IBM Clinical Development database.   
 
As summarized above, the IBM Clinical Development subject ID will be used to link the two databases. 
As a safety control, sites will enter the STS "Operation ID” into the IBM Clinical Development database.  
In the event that the IBM Clinical Development subject ID is miss-entered into one of the databases, the 
STS Operation ID will be used to ensure accurate linkage. 
 
 
11.2 
Data Element Definitions 
All STRESS data element definitions are based upon the STS-CHSD data element definitions which are 
available on-line at: 
http://www.sts.org/sites/default/files/documents/CongenitalDataSpecsV3_3_Updated.pdf.  Some specific 
definitions of particular relevance to the STRESS trial are listed below: 
 
Fundamental diagnosis: The fundamental diagnosis is a diagnosis that is carried with a patient 
throughout life, through all operations and hospitalizations. The fundamental diagnosis is the most 
complex cardiac anomaly or condition (congenital or acquired) of the patient. Most frequently, the 
primary diagnosis will also be the fundamental diagnosis. For some operations, however, the fundamental 
diagnosis and primary diagnosis will be different. For example, consider a child who underwent repair of 
subaortic stenosis, subsequently develops complete atrioventricular (AV) block, and undergoes 
pacemaker placement within the same hospitalization. The primary diagnosis for the pacemaker surgery is 
“Arrhythmia, Heart block, Acquired”, while the fundamental diagnosis is “Aortic stenosis, Subvalvar”. 
Similarly, a patient who has a complete AV canal defect and undergoes either palliation or repair of the 
defect has a primary and fundamental diagnosis of “AVC (AVSD), Complete CAVSD”. Subsequently, 
the child develops mitral insufficiency and is re-hospitalized for mitral valve replacement. The primary 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 24 of 96 
 
 
 
diagnosis for the mitral valve replacement operation is “Mitral regurgitation”, but the fundamental 
diagnosis is “AVC (AVSD), Complete CAVSD.” The utilization of the fundamental diagnosis field, it is 
hoped, will clarify designation of a primary diagnosis, and enable greater specificity in the lesion specific 
report analyses. 
 
STS-CHSD data element definitions for primary outcome measures: 
 
Death: For the purposes of STRESS, we will use the following definition of operative mortality which 
includes: (1) all deaths, regardless of cause, occurring during the hospitalization in which the operation 
was performed, even if after 30 days (including patients transferred to other acute care facilities); and (2) 
all deaths, regardless of cause, occurring after discharge from the hospital, but before 30 days after 
administration of study drug/placebo. 
 
Heart transplantation: Includes any technique, allograft or xenograft. 
 
Renal failure requiring permanent dialysis at discharge: Renal failure - acute renal failure (ROOT 
Definition) + with new postoperative/postprocedural requirement for dialysis, including peritoneal 
dialysis and/or hemodialysis. Code this complication if the patient requires dialysis at the time of hospital 
discharge or death in the hospital. (This complication should be chosen only if the dialysis was associated 
with acute renal failure.) {"Renal failure - acute renal failure" ROOT Definition = Acute renal failure is 
defined as new onset oliguria with sustained urine output < 0.5 cc/kg/hr for 24 hours and/or a rise in 
creatinine > 1.5 times upper limits of normal for age (or twice the most recent preoperative/preprocedural 
values if these are available), with eventual need for dialysis (including peritoneal dialysis and/or 
hemodialysis) or hemofiltration. Acute renal failure that will be counted as an operative or procedural 
complication must occur prior to hospital discharge or after hospital discharge but within 30 days of the 
procedure. The complication is to be coded even if the patient required dialysis, but the treatment was not 
instituted due to patient or family refusal. 
 
Neurological deficit persisting at discharge:  Newly recognized and/or newly acquired deficit of 
neurologic function leading to inpatient referral, therapy, or intervention not otherwise practiced for a 
similar unaffected inpatient, with a persisting neurologic deficit present at hospital discharge. In other 
words, new (onset intraoperatively or postoperatively – or intraprocedurally or postprocedurally) 
neurological deficit persisting and present at discharge from hospital. 
 
Respiratory failure, requiring tracheostomy: Failure to wean from mechanical ventilation necessitating 
the creation of a surgical airway. 
 
Renal failure requiring temporary dialysis: Acute renal failure (ROOT Definition) + With new 
postoperative/postprocedural requirement for temporary dialysis, including peritoneal dialysis and/or 
hemodialysis. Code this complication if the patient does not require dialysis at the time of hospital 
discharge or death in the hospital. (This complication should be chosen only if the dialysis was associated 
with acute renal failure.) {"Renal failure – acute renal failure" ROOT Definition = Acute renal failure is 
defined as new onset oliguria with sustained urine output < 0.5 cc/kg/hr for 24 hours and/or a rise in 
creatinine > 1.5 times upper limits of normal for age (or twice the most recent preoperative/preprocedural 
values if these are available), with eventual need for dialysis (including peritoneal dialysis and/or 
hemodialysis) or hemofiltration. Acute renal failure that will be counted as an operative or procedural 
complication must occur prior to hospital discharge or after hospital discharge but within 30 days of the 
procedure.  
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 25 of 96 
 
 
 
Postoperative/Postprocedural mechanical circulatory support: Utilization of 
postoperative/postprocedural mechanical support, of any type (IABP, VAD, ECMO, or CPS), for 
resuscitation/CPR or support, during the 
postoperative/postprocedural time period. Code this complication if it occurs (1) within 30 days after 
surgery or 
intervention regardless of the date of hospital discharge, or (2) after 30 days during the same 
hospitalization subsequent to the operation or intervention. 
 
Unplanned cardiac operation during the postoperative or postprocedural time period, exclusive of 
reoperation for bleeding: Any additional unplanned cardiac operation occurring (1) within 30 days after 
surgery or intervention in or out of the hospital, or (2) after 30 days during the same hospitalization 
subsequent to the operation or intervention. A cardiac operation is defined as any operation that is of the 
operation type of "CPB" or "No CPB Cardiovascular". The following operations will always be coded as 
"Planned Reoperation": (1) Delayed Sternal Closure, (2) ECMO Decannulation, (3) VAD Decannulation, 
(4) Removal of Broviac catheter. The following operations will always be coded as "Unplanned 
Reoperation": (1) Mediastinal exploration for infection, (2) Mediastinal exploration for hemodynamic 
instability, (3) Emergent mediastinal exploration for initiation of ECMO or VAD, (4) Reoperation for 
residual or recurrent lesion. Mediastinal exploration for bleeding is always coded separately as "Bleeding, 
Requiring reoperation". 
 
Reoperation for bleeding: Postoperative/postprocedural bleeding requiring reoperation. 
 
Unplanned non-cardiac reoperation: Any additional unplanned non-cardiac operation occurring (1) 
within 30 days after surgery or intervention in or out of the hospital, or (2) after 30 days during the same 
hospitalization subsequent to the operation or intervention. 
 
Unplanned interventional cardiovascular catheterization procedure: Any unplanned interventional 
cardiovascular catheterization procedure occurring (1) within 30 days after surgery or intervention in or 
out of the hospital, or (2) after 30 days during the same hospitalization subsequent to the operation or 
intervention. 
 
Cardiac arrest: A cardiac arrest is the cessation of effective cardiac mechanical function. This 
complication should be selected if the cardiac arrest developed after OR Entry Date and Time. Do not 
select this complication for patients under hospice care or DNR. 
 
Multi-System Organ Failure: Note – this is the only complication variable where the STS-CHSD 
definition has been modified.  The current STS-CHSD definition is non-specific therefore we have 
developed the following definition for specific use during the STRESS trial.  
 
Multi-system Organ Failure requires two or more of the following to be present: 
 Neurologic dysfunction: any permanent or transient neurologic injury including clinical seizure  
 Renal dysfunction: serum creatinine > 2 times baseline or temporary or permanent dialysis 
 Hepatic dysfunction: AST or ALT > 2 times normal  
 GI dysfunction: Any surgical or medically treated episode of Necrotizing enterocolitis  
 Respiratory dysfunction: Mechanical ventilation > 7 days  
 
Please code the individual organ system failures as well. If multi-system organ failure is associated with 
sepsis as well, please also code: "Sepsis, Multisystem Organ Failure".  


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 26 of 96 
 
 
 
 
STS-CHSD data element definitions for infectious complications  
 
Pneumonia: A “respiratory disease characterized by inflammation of the lung parenchyma (including 
alveolar spaces and interstitial tissue), most commonly caused by infection”. Pneumonia is diagnosed by 
appropriate clinical findings (such as fever, leukopenia or leukocytosis, and new onset of purulent 
sputum) and one or more of the following: positive cultures (of sputum or pulmonary secretions) and / or 
pulmonary infiltrate on chest x-ray. An endotracheal tube culture may or may not be positive. Patients 
commonly demonstrate an evolving area of focal lung consolidation accompanied by fever (>38.5). 
Pneumonia (pneumonitis) may affect an entire lobe (lobar pneumonia), a segment of a lobe (segmental or 
lobular pneumonia), alveoli contiguous to bronchi (bronchopneumonia), or interstitial tissue (interstitial 
pneumonia). These distinctions are generally based on x-ray observations. 
 
Sepsis: Evidence of serious infection accompanied by a deleterious systemic response. In the time period 
of the first 48 postoperative or postprocedural hours, the diagnosis of sepsis requires the presence of a 
Systemic Inflammatory Response Syndrome (SIRS) resulting from a proven infection (such as 
bacteremia, fungemia or urinary tract infection). In the time period after the first 48 postoperative or 
postprocedural hours, sepsis may be diagnosed by the presence of a SIRS resulting from suspected or 
proven infection. During the first 48 hours, a SIRS may result from the stress associated with surgery 
and/or cardiopulmonary bypass. Thus, the clinical criteria for sepsis during this time period should be 
more stringent. A systemic inflammatory response syndrome (SIRS) is present when at least two of the 
following criteria are present: hypo- or hyperthermia (>38.5 or <36.0), tachycardia or bradycardia, 
tachypnea, leukocytosis or leukopenia, and thrombocytopenia. 
Deep wound infection: A deep wound infection involves the deep soft tissues (e.g., fascial and muscle 
layers) of the incision AND the patient has at least ONE of the following numbered features: 1) Purulent 
drainage from the deep portion of the incision (but not from the organ / space component of the surgical 
site and no evidence of sternal osteomyelitis), 2) The deep incision spontaneously dehisces or is 
deliberately opened by a surgeon when the patient has ONE of the following lettered signs or symptoms 
(unless the incision is culture negative): A) fever, B) localized pain, or C) tenderness, 3) An abscess or 
other evidence of infection involving the deep incision is found on direct examination, during reoperation, 
or by histopathologic or radiologic examination, or 4) A diagnosis of a deep wound infection by a 
surgeon or by an attending physician. 
 
Wound infection-Mediastinitis: The diagnosis of mediastinitis must meet one of the following criteria: 
Criterion 1: Patient has organisms cultured from mediastinal tissue or fluid that is obtained during a 
surgical operation or by needle aspiration. Criterion 2: Patient has evidence of mediastinitis by 
histopathologic examination or visual evidence of mediastinitis seen during a surgical operation. Criterion 
3: Patient has at least ONE of the following numbered signs or symptoms with no other recognized cause: 
1) fever, 2) chest pain, or 3) sternal instability AND at least one of the following numbered features: 1) 
purulent mediastinal drainage, 2) organisms cultured from mediastinal blood, drainage or tissue, or 3) 
widening of the cardio-mediastinal silhouette. Criterion 4: Patient ≤ 1 year of age has at least one of the 
following numbered signs or symptoms with no other recognized cause: 1) fever, 2) hypothermia, 3) 
apnea, 4) bradycardia, or 5) sternal instability AND at least one of the following numbered features: 1) 
purulent mediastinal discharge, 2) organisms cultured from mediastinal blood, drainage or tissue, or 3) 
widening of the cardio-mediastinal silhouette. Infections of the sternum (sternal osteomyelitis) should be 
classified as mediastinitis. Sternal instability that is not associated with a wound infection or mediastinitis 
is documented as "Sternal instability". 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 27 of 96 
 
 
 
Postprocedural infective endocarditis: Infective endocarditis in the setting of a heart which has been 
altered by surgery or intervention. Duke Criteria for the Diagnosis of Infective Endocarditis (IE): The 
definitive diagnosis of infective endocarditis requires one of the following four situations: 1) Histologic 
and/or microbiologic evidence of infection at surgery or autopsy such as positive valve culture or 
histology; 2) Two major criteria; 3) One major criterion and three minor criteria; 4) Five minor criteria. 
The two major criteria are: 1) Blood cultures positive for IE 2) Evidence of endocardial involvement. 
Blood cultures positive for IE requires: 1) Typical microorganism consistent with IE isolated from 2 
separate blood cultures, as noted in number two below (viridans streptococci, Streptococcus bovis, 
Staphylococcus aureus, or HACEK group [HACEK, Haemophilus species {H. aprophilus and H. 
paraaphrophilus}, Actinobacillus actinoinycetemcomitans, Cardiobacterium hominis, Eikenella 
corrodens, and Kingella kingae.]) or (Community-acquired enterococci in the absence of a primary 
focus); 2) Microorganisms consistent with IE isolated from persistently positive blood cultures defined as: 
(At least 2 positive cultures of blood samples obtained > 12 hours apart) or (All of 3 or a majority of 4 or 
more separate cultures of blood, the first and the last sample obtained > 1 hr apart); 3) Single blood 
culture positive for Coxiella burnetii or an antiphase I IgG antibody titer of >1 :800. Evidence of 
endocardial involvement requires 1) Positive results of echocardiography for IE defined as: (Oscillating 
intracardiac mass on the valve or supporting structures in the path of regurgitant jets or on implanted 
material in the absence of an alternative anatomic explanation) or (Abscess) or (New partial dehiscence of 
a valvular prosthesis) or 2) New valvular regurgitation (worsening or changing or preexisting murmur not 
sufficient). The six minor criteria are: 1) Predisposing heart disease or injection drug use (IVDA); 2) 
Temperature of > 38C; 3) Vascular phenomenon (major arterial emboli, septic pulmonary infarcts, 
mycotic aneurysm, intracranial or conjunctival hemorrhage, Janeway's lesions); 4) Immunologic 
phenomenon (glomerulonephritis, Osler's nodes, Roth's spots, rheumatoid factor); 5) Microbiologic 
evidence (a positive blood culture that does not meet a major criterion as noted above) or serologic 
evidence of active infection with an organism consistent with IE; 6) Echocardiographic findings that are 
consistent with IE but do not meet a major criterion as noted above. References: 1) Dhawan VK 
Infectious Endocarditis in Elderly Patients. Clin. Infect. Dis. 2002;34:806- 812. 2) Durack DT, Lukes AS, 
Bright DK. New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic 
findings. Duke Endocarditis Service. Am. J. Med. 1994;96:200-209. 3) Li IS, Sexton DJ, Mick N, et al. 
Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin. Infect. Dis. 
2000;30:633-638. 4) http://gold.aecom.yu.edu/id/almanac/dukeendocarditis.htm, accessed July 5, 2006. 
 
 
Select STS-CHSD data element definitions of particular relevance 
 
Cardiac dysfunction resulting in low cardiac output: Low cardiac output state characterized by some 
of the following: tachycardia, oliguria, decreased skin perfusion, need for increased inotropic support 
(10% above baseline at admission), metabolic acidosis, widened Arterial – Venous oxygen saturation, 
need to open the chest, or need for mechanical support. If the cardiac dysfunction is of a severity that 
results in inotrope dependence, mechanical circulatory support, or listing for cardiac transplantation, 
please also code as "Cardiac failure (severe cardiac dysfunction)". A patient will be considered to have 
“inotrope dependence” if they cannot be weaned from inotropic support (10% above baseline at 
admission) after any period of 48 consecutive hours that occurs after the time of OR Exit Date and Time, 
and either (1) within 30 days after surgery in or out of the hospital, and (2) after 30 days during the same 
hospitalization subsequent to the operation. If patient meets criteria for severe cardiac dysfunction, only 
code "severe". 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 28 of 96 
 
 
 
12 
ETHICS AND HUMAN SUBJECTS CONSIDERATION 
12.1 
Institutional Review Board/Independent Ethics Committee Approval 
Prior to its implementation, this protocol, including any subsequent amendments, must be IRB approved 
at each respective site, according to federal regulations.  
12.2 
Signed Informed Consent / Authorization 
Prior to any study-related procedures, the investigator or designee will obtain from the patient’s legally 
authorized representative (i.e., parent/legal guardian), a signed and dated written Informed 
Consent/Authorization consistent with FDA/ICH regulations, the HIPAA Privacy Rule.  A HIPAA 
Privacy Rule Authorization language will be included in the Informed Consent/Authorization Form 
(where the Informed Consent and Authorization are combined in one document) and it will be IRB 
approved. 
12.3 
Duties of the Investigator 
The investigator is obligated to conduct this study in accordance with U.S. federal regulation 21 CFR 
312.60-69 as specified on the signed form FDA 1572, applicable state laws, and the International 
Conference on Harmonization: Good Clinical Practice: Consolidation Guideline. The investigator is 
responsible for informing the IRB of any safety issues related to the study and the study drug including 
reports of serious adverse events, if required, and all IND safety reports.  
 
12.4 
Records of the Study 
A STS-CHSD will be used to record all patient data including all historical subject information and study 
data as specified by this protocol. The STS-CHSD data entry must be completed by designated and 
trained study personnel. 
 
Source documents are defined as the results of original observations and activities of a clinical 
investigation. Source documents may include, but are not limited to, study progress notes, e-mail 
correspondences, computer printouts, laboratory data and recorded data from automated instruments.  
 
It will be the responsibility of the Investigator(s) to assure that the study file at the site is maintained. The 
study file will contain, but will not be limited to: 
• 
Current Package Insert and all previous versions over course of study 
• 
Final study protocol 
• 
Protocol Amendments (if applicable) 
• 
Operations Manual (if applicable) 
• 
Informed Consent Form (blank) 
• 
Revised Informed Consent forms and/or all addenda (blank) 
• 
DHHS Number for IRB or other documentation of IRB compliance with FDA regulations (if 
applicable) 
• 
Documentation of IRB approval of protocol, consent form, any protocol amendments and any 
consent form revisions. 
• 
Annual IRB updates and approvals 
• 
All correspondence between the Investigator and IRB 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 29 of 96 
 
 
 
12.5 
Patient Privacy / Authorization 
The principal investigator will ensure that the use and disclosure of protected health information obtained 
during a research study complies with the HIPAA Privacy Rule. The Rule provides U.S. federal 
protection for the privacy of protected health information by implementing standards to protect and guard 
against the misuse of individually identifiable health information of patients participating in Clinical 
Trials. “Authorization” is required from each research patient, i.e., specific permission granted by an 
individual to a covered entity for the use or disclosure of an individual’s protected health information. A 
valid authorization must meet the implementation specifications under the HIPAA Privacy Rule. 
Authorization will be combined in the Informed Consent document (approved by the IRB). 
 
12.6 
Informed Consent 
Informed consent will be obtained and documented in accordance with U.S. 21 CFR Part 50.25, §§ 116, 
117 and 408 of 45 CFR Part 46  and all other applicable regulatory requirements.  Prior to any study 
procedures being performed, the investigator or his/her designee will inform the subject’s legally 
authorized representative (e.g., parent, guardian) of all aspects pertaining to study participation.  
Information should be given in both oral and written form whenever possible and deemed appropriate by 
the IRB.  The subject’s legally authorized representative (parent or guardian) must be given ample 
opportunity to inquire about details of the study.  The description of the study procedures will include the 
purpose of the research and procedures, risks and benefits of the research, alternative procedures, 
confidentiality, legal rights, parental or guardian permission, the contact person and phone number if 
there are any questions, and the voluntary nature of participation.  It will be emphasized that participation 
is voluntary and participants may withdraw from the study at any time without any effect on standard care. 
Both the investigator or his/her designee, and the subject’s legally authorized representative must sign and 
date the informed permission form prior to the subject being enrolled in the study.  An original signed 
informed consent will be retained in the site study records.  The subject’s legally authorized 
representative will receive a copy of the signed and dated informed permission form and a copy of the 
signed assent (if applicable).   
 
Permission forms must be in a language fully comprehensible to the subject’s legally authorized 
representative.  Permission shall be documented by the use of a written consent form approved by the IRB 
and signed and dated by the subject’s legally authorized representative.  The written parental/legal 
guardian permission document will embody the elements of informed consent as described in the 
Declaration of Helsinki, the Code of Federal Regulations, and the ICH Guidelines and will comply with 
local regulations. This form may be read to the subject’s legally authorized representative, but, in any 
event, the investigator shall give the representative adequate opportunity to read it before it is signed and 
dated.  Permission must be documented by the dated signature of the subject’s legally authorized 
representative.  The signature confirms the permission is based on information that has been understood.  
Each signed permission form must be kept on file by the investigators for possible inspection by 
Regulatory Authorities. 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 30 of 96 
 
 
 
 
References 
 
1. 
Petrini, J., K. Damus, and R.B. Johnston, Jr., An overview of infant mortality and birth 
defects in the United States. Teratology, 1997. 56(1-2): p. 8-10. 
2. 
Petrini, J., et al., Contribution of birth defects to infant mortality in the United States. 
Teratology, 2002. 66 Suppl 1: p. S3-6. 
3. 
Yang, Q., et al., Racial differences in infant mortality attributable to birth defects in the 
United States, 1989-2002. Birth Defects Res A Clin Mol Teratol, 2006. 76(10): p. 706-13. 
4. 
Yang, Q., M.J. Khoury, and D. Mannino, Trends and patterns of mortality associated 
with birth defects and genetic diseases in the United States, 1979-1992: an analysis of 
multiple-cause mortality data. Genet Epidemiol, 1997. 14(5): p. 493-505. 
5. 
Hoffman, T.M., et al., Efficacy and safety of milrinone in preventing low cardiac output 
syndrome in infants and children after corrective surgery for congenital heart disease. 
Circulation, 2003. 107(7): p. 996-1002. 
6. 
Parr, G.V., E.H. Blackstone, and J.W. Kirklin, Cardiac performance and mortality early 
after intracardiac surgery in infants and young children. Circulation, 1975. 51(5): p. 867-
74. 
7. 
Wernovsky, G., et al., Postoperative course and hemodynamic profile after the arterial 
switch operation in neonates and infants. A comparison of low-flow cardiopulmonary 
bypass and circulatory arrest. Circulation, 1995. 92(8): p. 2226-35. 
8. 
Wan, S., J.L. LeClerc, and J.L. Vincent, Inflammatory response to cardiopulmonary 
bypass: mechanisms involved and possible therapeutic strategies. Chest, 1997. 112(3): p. 
676-92. 
9. 
Ando, M., et al., Steroid supplementation: a legitimate pharmacotherapy after neonatal 
open heart surgery. Ann Thorac Surg, 2005. 80(5): p. 1672-8; discusison 1678. 
10. 
Bronicki, R.A., et al., Dexamethasone reduces the inflammatory response to 
cardiopulmonary bypass in children. Ann Thorac Surg, 2000. 69(5): p. 1490-5. 
11. 
Checchia, P.A., et al., Dexamethasone reduces postoperative troponin levels in children 
undergoing cardiopulmonary bypass. Crit Care Med, 2003. 31(6): p. 1742-5. 
12. 
Clarizia, N.A., et al., Improved outcomes associated with intraoperative steroid use in 
high-risk pediatric cardiac surgery. Ann Thorac Surg, 2011. 91(4): p. 1222-7. 
13. 
Graham, E.M., et al., Standardized preoperative corticosteroid treatment in neonates 
undergoing cardiac surgery: results from a randomized trial. J Thorac Cardiovasc Surg, 
2011. 142(6): p. 1523-9. 
14. 
Graham, E.M., et al., Preoperative steroid treatment does not improve markers of 
inflammation after cardiac surgery in neonates: results from a randomized trial. J Thorac 
Cardiovasc Surg, 2014. 147(3): p. 902-8. 
15. 
Toledo-Pereyra, L.H., et al., Steroids in heart surgery: a clinical double-blind and 
randomized study. Am Surg, 1980. 46(3): p. 155-60. 
16. 
Graham, E.M., The utility of steroids in pediatric cardiac operations*. Pediatr Crit Care 
Med, 2014. 15(5): p. 492-3. 
17. 
Pasquali, S.K., et al., Perioperative methylprednisolone and outcome in neonates 
undergoing heart surgery. Pediatrics, 2012. 129(2): p. e385-91. 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 31 of 96 
 
 
 
18. 
Garg, A.X., et al., Steroids In caRdiac Surgery (SIRS) trial: acute kidney injury substudy 
protocol of an international randomised controlled trial. BMJ Open, 2014. 4(3): p. 
e004842. 
19. 
United States Food and Drug Administration: Pediatric Study Plans: Content of and 
Process for Submitting Initial Pediatric Study Plans and Amended Initial Pediatric Study 
Plans Guidance for Industry (Draft). Accessed on-line at: 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM360507.pdf (February 1st, 2016). 
20. 
Scrascia, G., et al., Perioperative steroids administration in pediatric cardiac surgery: a 
meta-analysis of randomized controlled trials*. Pediatr Crit Care Med, 2014. 15(5): p. 
435-42. 
21.  
Pasquali, S.K., et al., Corticosteroids and outcome in children undergoing congenital 
heart surgery: analysis of the Pediatric Health Information Systems database. 
Circulation, 2010. 122(21): p. 2123-30. 
22. 
Ungerleider, R.M., Practice patterns in neonatal cardiopulmonary bypass. ASAIO J, 
2005. 51(6): p. 813-5. 
23. 
Felker, G.M. and A.S. Maisel, A global rank end point for clinical trials in acute heart 
failure. Circ Heart Fail, 2010. 3(5): p. 643-6. 
24. 
McCullagh, P. Regression models for ordinal data (with discussion). J. R. Statist. Soc. 
1980: B, 42, 109–142. 
25. 
Zhao, Y.D., D. Rahardja, and Y. Qu, Sample size calculation for the Wilcoxon-Mann-
Whitney test adjusting for ties. Stat Med, 2008. 27(3): p. 462-8. 
26. 
Whitehead, J., Sample size calculations for ordered categorical data. Stat Med, 1993. 
12(24): p. 2257-71. 
27. 
van Elteren PH. On the combination of independent two-sample tests of Wilcoxon. 
Bulletin of the International Statistical Institute 1960; 37:351--361. 
28. 
Hauck, W.W., S. Anderson, and S.M. Marcus, Should we adjust for covariates in 
nonlinear regression analyses of randomized trials? Control Clin Trials, 1998. 19(3): p. 
249-56. 
29. 
Pocock, S.J., et al., The win ratio: a new approach to the analysis of composite endpoints 
in clinical trials based on clinical priorities. Eur Heart J, 2012. 33(2): p. 176-82. 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 32 of 96 
 
 
 
13 
PHARMACOLOGY AND TOXICOLOGY INFORMATION 
The Sponsor has not and will not conduct non-clinical studies of methylprednisolone. Information on its 
pharmacology and toxicology can be found in the sample product label, see Section 10.3 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 33 of 96 
 
 
 
 
14 
PREVIOUS HUMAN EXPERIENCE 
Please refer to product label (Appendix B). 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 34 of 96 
 
 
 
15 
APPENDICES 
15.1 
 Appendix A1: Case report form for the STS-CHSD 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 35 of 96 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 36 of 96 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 37 of 96 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 38 of 96 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 39 of 96 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 40 of 96 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 41 of 96 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 42 of 96 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 43 of 96 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 44 of 96 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 45 of 96 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 46 of 96 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 47 of 96 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 48 of 96 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 49 of 96 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 50 of 96 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 51 of 96 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 52 of 96 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 53 of 96 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 54 of 96 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 55 of 96 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 56 of 96 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 57 of 96 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 58 of 96 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 59 of 96 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 60 of 96 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 61 of 96 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 62 of 96 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 63 of 96 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 64 of 96 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 65 of 96 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 66 of 96 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 67 of 96 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 68 of 96 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 69 of 96 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 70 of 96 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 71 of 96 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 72 of 96 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 73 of 96 
 
 
 
15.2 
Appendix A2: Data element definitions for the STS-CHSD 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 74 of 96 
 
 
 
15.3 
Appendix B: Package insert for intravenous methylprednisolone 
 
SOLU-MEDROL
® (methylprednisolone sodium succinate for injection, USP)  
The formulations containing benzyl alcohol should not be used in neonates.  
For Intravenous or Intramuscular Administration  
  
DESCRIPTION  
SOLU-MEDROL Sterile Powder is an anti-inflammatory glucocorticoid, which contains 
methylprednisolone sodium succinate as the active ingredient. Methylprednisolone sodium succinate, 
USP, is the sodium succinate ester of methylprednisolone, and it occurs as a white, or nearly white, 
odorless hygroscopic, amorphous solid. It is very soluble in water and in alcohol; it is insoluble in 
chloroform and is very slightly soluble in acetone.  
The chemical name for methylprednisolone sodium succinate is pregna-1,4-diene-3,20dione,21-(3-
carboxy-1-oxopropoxy)-11,17-dihydroxy-6-methyl-monosodium salt, (6α, 11β), and the molecular 
weight is 496.53. The structural formula is represented below:  
 
Methylprednisolone sodium succinate is soluble in water; it may be administered in a small volume 
of diluent and is well suited for intravenous use in situations where high blood levels of 
methylprednisolone are required rapidly.  
SOLU-MEDROL is available in preservative and preservative-free formulations: 
Preservative-free Formulations  
40 mg Act-O-Vial System (Single-Use Vial)—Each mL (when mixed) contains 
methylprednisolone sodium succinate equivalent to 40 mg methylprednisolone; also 1.6 mg 
monobasic sodium phosphate anhydrous; 17.46 mg dibasic sodium phosphate dried; and 25 
mg lactose hydrous.  
125 mg Act-O-Vial System (SingleUse Vial)—Each 2 mL (when mixed) contains 
methylprednisolone sodium succinate equivalent to 125 mg methylprednisolone; also 1.6 mg 
monobasic sodium phosphate anhydrous; and 17.4 mg dibasic sodium phosphate dried.  


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 75 of 96 
 
 
 
500 mg Act-O-Vial System (SingleUse Vial)—Each 4 mL (when mixed) contains 
methylprednisolone sodium succinate equivalent to 500 mg methylprednisolone; also 6.4 mg 
monobasic sodium phosphate anhydrous; and 69.6 mg dibasic sodium phosphate dried.  
1 gram Act-O-Vial System (SingleUse Vial)—Each 8 mL (when mixed) contains 
methylprednisolone sodium succinate equivalent to 1 gram methylprednisolone; also 12.8 mg 
monobasic sodium phosphate anhydrous; and 139.2 mg dibasic sodium phosphate dried.  
 
Formulations preserved with Benzyl Alcohol 
40 mg Act-O-Vial System (Single-Use Vial)—Each mL (when mixed) contains 
methylprednisolone sodium succinate equivalent to 40 mg methylprednisolone; also 1.6 mg 
monobasic sodium phosphate anhydrous; 17.46 mg dibasic sodium phosphate dried; 25 mg 
lactose hydrous; 8.8 mg benzyl alcohol added as preservative.  
125 mg Act-O-Vial System (Single-Use Vial)—Each 2 mL (when mixed) contains 
methylprednisolone sodium succinate equivalent to 125 mg methylprednisolone; also 1.6 mg 
monobasic sodium phosphate anhydrous; 17.4 mg dibasic sodium phosphate dried; 17.6 mg 
benzyl alcohol added as preservative.  
500 mg Act-O-Vial System (Single-Use Vial)—Each 4 mL (when mixed) contains 
methylprednisolone sodium succinate equivalent to 500 mg methylprednisolone; also 6.4 mg 
monobasic sodium phosphate anhydrous; 69.6 mg dibasic sodium phosphate dried; 33.7 mg 
benzyl alcohol added as preservative.  
1 gram Act-O-Vial System (Single-Use Vial)—Each 8 mL (when mixed) contains 
methylprednisolone sodium succinate equivalent to 1 gram methylprednisolone; also 12.8 mg 
monobasic sodium phosphate anhydrous; 139.2 mg dibasic sodium phosphate dried; 66.8 mg 
benzyl alcohol added as preservative.  
500 mg Vial—Each 8 mL (when mixed as directed) contains methylprednisolone sodium 
succinate equivalent to 500 mg methylprednisolone; also 6.4 mg monobasic sodium 
phosphate anhydrous; 69.6 mg dibasic sodium phosphate dried. This package does not 
contain diluent. Recommended diluent (Bacteriostatic water) contains benzyl alcohol as a 
preservative.  
1 gram Vial—Each 16 mL (when mixed as directed) contains methylprednisolone sodium 
succinate equivalent to 1 gram methylprednisolone; also 12.8 mg monobasic sodium 
phosphate anhydrous; 139.2 mg dibasic sodium phosphate dried. This package does not 
contain diluent. Recommended diluent (Bacteriostatic water) contains benzyl alcohol as a 
preservative.  
2 gram Vial with Diluent—Each 30.6 mL (when mixed as directed) contains 
methylprednisolone sodium succinate equivalent to 2 grams methylprednisolone; also 25.6 
mg monobasic sodium phosphate anhydrous; 278 mg dibasic sodium phosphate dried; 273 
mg benzyl alcohol added as preservative. The packaged diluent (Bacteriostatic Water for 
Injection) contains benzyl alcohol as a preservative.  
IMPORTANT — Use only the accompanying diluent or Bacteriostatic Water For Injection 
with Benzyl Alcohol when reconstituting SOLU-MEDROL. 
Use within 48 hours after mixing. 
 
When necessary, the pH of each formula was adjusted with sodium hydroxide so that the pH of the 
reconstituted solution is within the USP specified range of 7 to 8 and the tonicities are, for the 40 
mg per mL solution, 0.50 osmolar; for the 125 mg per 2 mL solution, 0.40 osmolar; for the 1 gram 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 76 of 96 
 
 
 
per 8 mL solution, 0.44 osmolar; for the 2 gram per 30.6 mL solutions, 0.42 osmolar. (Isotonic 
saline = 0.28 osmolar.)  
 
CLINICAL PHARMACOLOGY  
Glucocorticoids, naturally occurring and synthetic, are adrenocortical steroids that are readily 
absorbed from the gastrointestinal tract.  
Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt-retaining 
properties, are used as replacement therapy in adrenocortical deficiency states. Their synthetic 
analogs are primarily used for their potent anti-inflammatory effects in disorders of many organ 
systems.  
Glucocorticoids cause profound and varied metabolic effects. In addition, they modify the body's 
immune responses to diverse stimuli.  
Methylprednisolone is a potent anti-inflammatory steroid with greater anti-inflammatory potency 
than prednisolone and even less tendency than prednisolone to induce sodium and water retention.  
Methylprednisolone sodium succinate has the same metabolic and anti-inflammatory actions as 
methylprednisolone. When given parenterally and in equimolar quantities, the two compounds are 
equivalent in biologic activity. Following the intravenous injection of methylprednisolone sodium 
succinate, demonstrable effects are evident within one hour and persist for a variable period. 
Excretion of the administered dose is nearly complete within 12 hours. Thus, if constantly high blood 
levels are required, injections should be made every 4 to 6 hours. This preparation is also rapidly 
absorbed when administered intramuscularly and is excreted in a pattern similar to that observed 
after intravenous injection.  
 
INDICATIONS AND USAGE  
When oral therapy is not feasible, and the strength, dosage form, and route of administration of the 
drug reasonably lend the preparation to the treatment of the condition, the intravenous or 
intramuscular use of SOLU-MEDROL Sterile Powder is indicated as follows:  
Allergic states: Control of severe or incapacitating allergic conditions intractable to adequate trials of 
conventional treatment in asthma, atopic dermatitis, contact dermatitis, drug hypersensitivity 
reactions, perennial or seasonal allergic rhinitis, serum sickness, transfusion reactions. 
 
Dermatologic diseases: Bullous dermatitis herpetiformis, exfoliative erythroderma, mycosis 
fungoides, pemphigus, severe erythema multiforme (Stevens-Johnson syndrome).  
Endocrine disorders: Primary or secondary adrenocortical insufficiency (hydrocortisone or 
cortisone is the drug of choice; synthetic analogs may be used in conjunction with 
mineralocorticoids where applicable; in infancy, mineralocorticoid supplementation is of particular 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 77 of 96 
 
 
 
importance), congenital adrenal hyperplasia, hypercalcemia associated with cancer, nonsuppurative 
thyroiditis.  
Gastrointestinal diseases: To tide the patient over a critical period of the disease in regional 
enteritis (systemic therapy) and ulcerative colitis.  
Hematologic disorders: Acquired (autoimmune) hemolytic anemia, congenital (erythroid) 
hypoplastic anemia (Diamond-Blackfan anemia), idiopathic thrombocytopenic purpura in adults 
(intravenous administration only; intramuscular administration is contraindicated), pure red cell 
aplasia, selected cases of secondary thrombocytopenia.  
Miscellaneous: Trichinosis with neurologic or myocardial involvement, tuberculous meningitis 
with subarachnoid block or impending block when used concurrently with appropriate 
antituberculous chemotherapy.  
Neoplastic diseases: For the palliative management of leukemias and lymphomas.  
Nervous System: Acute exacerbations of multiple sclerosis; cerebral edema associated with 
primary or metastatic brain tumor, or craniotomy.  
Ophthalmic diseases: Sympathetic ophthalmia, uveitis and ocular inflammatory conditions 
unresponsive to topical corticosteroids.  
Renal diseases: To induce diuresis or remission of proteinuria in idiopathic nephrotic syndrome 
or that due to lupus erythematosus.  
Respiratory diseases: Berylliosis, fulminating or disseminated pulmonary tuberculosis when used 
concurrently with appropriate antituberculous chemotherapy, idiopathic eosinophilic pneumonias, 
symptomatic sarcoidosis.  
Rheumatic disorders: As adjunctive therapy for short-term administration (to tide the patient over an 
acute episode or exacerbation) in acute gouty arthritis; acute rheumatic carditis; ankylosing 
spondylitis; psoriatic arthritis; rheumatoid arthritis, including juvenile rheumatoid arthritis (selected 
cases may require low-dose maintenance therapy). For the treatment of dermatomyositis, temporal 
arteritis, polymyositis, and systemic lupus erythematosus. 
 
CONTRAINDICATIONS 
SOLU-MEDROL Sterile Powder is contraindicated: 
• 
in systemic fungal infections and patients with known hypersensitivity to the product and its 
constituents. 
• 
for intrathecal administration. Reports of severe medical events have been associated with this 
route of administration. 
 
Intramuscular corticosteroid preparations are contraindicated for idiopathic thrombocytopenic 
purpura. 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 78 of 96 
 
 
 
 
Additional contraindication for the use of SOLU-MEDROL Sterile Powder preserved with 
benzyl alcohol: 
Formulations preserved with benzyl alcohol are contraindicated for use in premature infants. 
(See WARNINGS and PRECAUTIONS, Pediatric Use. 
WARNINGS 
Serious Neurologic Adverse Reactions with Epidural Administration 
Serious neurologic events, some resulting in death, have been reported with epidural injection 
of corticosteroids. Specific events reported include, but are not limited to, spinal cord 
infarction, paraplegia, quadriplegia, cortical blindness, and stroke. These serious neurologic 
events have been reported with and without use of fluoroscopy. The safety and effectiveness of 
epidural administration of corticosteroids have not been established, and corticosteroids are not 
approved for this use. 
 
GENERAL 
Formulations with preservative (see DESCRIPTION) contain benzyl alcohol, which is 
potentially toxic when administered locally to neural tissue. Exposure to excessive amounts 
of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), 
particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm 
infants. There have been rare reports of deaths, primarily in preterm infants, associated with 
exposure to excessive amounts of benzyl alcohol. The amount of benzyl alcohol from 
medications is usually considered negligible compared to that received in flush solutions 
containing benzyl alcohol. Administration of high dosages of medications containing this 
preservative must take into account the total amount of benzyl alcohol administered. The 
amount of benzyl alcohol at which toxicity may occur is not known. If the patient requires 
more than the recommended dosages or other medications containing this preservative, the 
practitioner must consider the daily metabolic load of benzyl alcohol from these combined 
sources (see PRECAUTIONS, Pediatric Use). 
 
Injection of SOLU-MEDROL may result in dermal and/or subdermal changes forming 
depressions in the skin at the injection site. In order to minimize the incidence of dermal and 
subdermal atrophy, care must be exercised not to exceed recommended doses in injections. 
Injection into the deltoid muscle should be avoided because of a high incidence of 
subcutaneous atrophy. 
 
Rare instances of anaphylactoid reactions have occurred in patients receiving 
corticosteroid therapy (see ADVERSE REACTIONS). 
 
Increased dosage of rapidly acting corticosteroids is indicated in patients on corticosteroid 
therapy who are subjected to any unusual stress before, during, and after the stressful 
situation. 
 
Results from one multicenter, randomized, placebo-controlled study with methylprednisolone 
hemisuccinate, an intravenous corticosteroid, showed an increase in early (at 2 weeks) and late 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 79 of 96 
 
 
 
(at 6 months) mortality in patients with cranial trauma who were determined not to have other 
clear indications for corticosteroid treatment. High doses of systemic corticosteroids, including 
SOLU-MEDROL, should not be used for the treatment of traumatic brain injury. 
 
Cardio-renal 
Average and large doses of corticosteroids can cause elevation of blood pressure, salt and water 
retention, and increased excretion of potassium. These effects are less likely to occur with the 
synthetic derivatives except when used in large doses. Dietary salt restriction and potassium 
supplementation may be necessary. All corticosteroids increase calcium excretion. 
 
Literature reports suggest an apparent association between the use of corticosteroids and left 
ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with 
corticosteroids should be used with great caution in these patients. 
 
Endocrine 
Hypothalamic-pituitary adrenal (HPA) axis suppression, Cushing’s syndrome, and 
hyperglycemia. Monitor patients for these conditions with chronic use. 
 
Corticosteroids can produce reversible HPA axis suppression with the potential for 
glucocorticosteroid insufficiency after withdrawal of treatment. Drug induced secondary 
adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of 
relative insufficiency may persist for months after discontinuation of therapy; therefore, in any 
situation of stress occurring during that period, hormone therapy should be reinstituted. 
 
Drug-Induced Liver Injury 
Rarely, high doses of cyclically pulsed intravenous methylprednisolone (usually for the 
treatment of exacerbations of multiple sclerosis at doses of 1 gram/day) can induce a toxic form 
of acute hepatitis. The time to onset of this form of steroid-induced liver injury can be several 
weeks or longer. Resolution has been observed after discontinuation of treatment. However, 
serious liver injury can occur, sometimes resulting in acute liver failure and death. Discontinue 
intravenous methylprednisolone if toxic hepatitis occurs.  Since recurrence has occurred after 
re-challenge, avoid use of high dose intravenous 
 
methylprednisolone in patients with a history of toxic hepatitis caused by methylprednisolone.  
 
Infections  
General  
Patients who are on corticosteroids are more susceptible to infections than are healthy individuals. 
There may be decreased resistance and inability to localize infection when corticosteroids are used. 
Infections with any pathogen (viral, bacterial, fungal, protozoan, or helminthic) in any location of the 
body may be associated with the use of corticosteroids alone or in combination with other 
immunosuppressive agents.  


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 80 of 96 
 
 
 
These infections may be mild, but can be severe and at times fatal. With increasing doses of 
corticosteroids, the rate of occurrence of infectious complications increases. Corticosteroids may 
also mask some signs of current infection. Do not use intraarticularly, intrabursally or for 
intratendinous administration for local effect in the presence of acute local infection.  
A study has failed to establish the efficacy of methylprednisolone sodium succinate in the treatment 
of sepsis syndrome and septic shock. The study also suggests that treatment of these conditions with 
methylprednisolone sodium succinate may increase the risk of mortality in certain patients (i.e., 
patients with elevated serum creatinine levels or patients who develop secondary infections after 
methylprednisolone sodium succinate).  
Fungal infections  
Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the 
presence of such infections unless they are needed to control drug reactions. There have been cases 
reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac 
enlargement and congestive heart failure (see CONTRAINDICATIONS and PRECAUTIONS, 
Drug Interactions, Amphotericin B injection and potassium-depleting agents).  
Special pathogens  
Latent disease may be activated or there may be an exacerbation of intercurrent infections due to 
pathogens, including those caused by Amoeba, Candida, Cryptococcus, Mycobacterium, Nocardia, 
Pneumocystis, Toxoplasma.  
It is recommended that latent amebiasis or active amebiasis be ruled out before initiating 
corticosteroid therapy in any patient who has spent time in the tropics or in any patient with 
unexplained diarrhea.  
Similarly, corticosteroids should be used with great care in patients with known or suspected 
Strongyloides (threadworm) infestation. In such patients, corticosteroid-induced immunosuppression 
may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often 
accompanied by severe enterocolitis and potentially fatal gram-negative septicemia. 
 
Corticosteroids should not be used in cerebral malaria. There is currently no evidence of benefit 
from steroids in this condition.  
Tuberculosis  
The use of corticosteroids in active tuberculosis should be restricted to those cases of 
fulminating or disseminated tuberculosis in which the corticosteroid is used for the management 
of the disease in conjunction with appropriate antituberculous regimen.  
If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close 
observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid 
therapy, these patients should receive chemoprophylaxis.  
Vaccination  


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 81 of 96 
 
 
 
Administration of live or live, attenuated vaccines is contraindicated in patients receiving 
immunosuppressive doses of corticosteroids. Killed or inactivated vaccines may be 
administered. However, the response to such vaccines cannot be predicted. Immunization 
procedures may be undertaken in patients receiving corticosteroids as replacement therapy, e.g., for 
Addison’s disease.  
Viral infections  
Chicken pox and measles can have a more serious or even fatal course in pediatric and adult patients 
on corticosteroids. In pediatric and adult patients who have not had these diseases, particular care 
should be taken to avoid exposure. The contribution of the underlying disease and/or prior 
corticosteroid treatment to the risk is also not known. If exposed to chicken pox, prophylaxis with 
varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with 
immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and 
IG prescribing information.) If chicken pox develops, treatment with antiviral agents should be 
considered.  
Neurologic  
Reports of severe medical events have been associated with the intrathecal route of 
administration (see ADVERSE REACTIONS, Gastrointestinal and Neurologic/Psychiatric).  
Ophthalmic  
Use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage 
to the optic nerves, and may enhance the establishment of secondary ocular infections due to 
bacteria, fungi, or viruses. The use of oral corticosteroids is not recommended in the treatment of 
optic neuritis and may lead to an increase in the risk of new episodes. Corticosteroids should be used 
cautiously in patients with ocular herpes simplex because of corneal perforation. Corticosteroids 
should not be used in active ocular herpes simplex. 
 
PRECAUTIONS  
 
General  
This product, like many other steroid formulations, is sensitive to heat. Therefore, it should not 
be autoclaved when it is desirable to sterilize the exterior of the vial.  
The lowest possible dose of corticosteroid should be used to control the condition under treatment. 
When reduction in dosage is possible, the reduction should be gradual.  
Since complications of treatment with glucocorticoids are dependent on the size of the dose and 
the duration of treatment, a risk/benefit decision must be made in each individual case as to dose 
and duration of treatment and as to whether daily or intermittent therapy should be used.  
Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often 
for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement.  
Cardio-renal  


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 82 of 96 
 
 
 
As sodium retention with resultant edema and potassium loss may occur in patients receiving 
corticosteroids, these agents should be used with caution in patients with congestive heart 
failure, hypertension, or renal insufficiency.  
Endocrine  
Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction 
of dosage. This type of relative insufficiency may persist for months after discontinuation of 
therapy; therefore, in any situation of stress occurring during that period, hormone therapy 
should be reinstituted.  
Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in 
hyperthyroid patients. Changes in thyroid status of the patient may necessitate adjustment in dosage.  
Gastrointestinal  
Steroids should be used with caution in active or latent peptic ulcers, diverticulitis, fresh intestinal 
anastomoses, and nonspecific ulcerative colitis, since they may increase the risk of a perforation. 
Signs of peritoneal irritation following gastrointestinal perforation in patients receiving 
corticosteroids may be minimal or absent.  
There is an enhanced effect due to decreased metabolism of corticosteroids in patients with 
cirrhosis. 
Musculoskeletal  
Corticosteroids decrease bone formation and increase bone resorption both through their effect on 
calcium regulation (i.e., decreasing absorption and increasing excretion) and inhibition of osteoblast 
function. This, together with a decrease in the protein matrix of the bone secondary to an increase in 
protein catabolism, and reduced sex hormone production, may lead to inhibition of bone growth 
in pediatric patients and the development of osteoporosis at any age. Special consideration 
should be given to patients at increased risk of osteoporosis (i.e., postmenopausal women) 
before initiating corticosteroid therapy. 
 
Local injection of a steroid into a previously infected site is not usually recommended. 
 
Neurologic-Psychiatric 
Although controlled clinical trials have shown corticosteroids to be effective in speeding the 
resolution of acute exacerbations of multiple sclerosis, they do not show that corticosteroids 
affect the ultimate outcome or natural history of the disease. The studies do show that 
relatively high doses of corticosteroids are necessary to demonstrate a significant effect. (See 
DOSAGE AND ADMINISTRATION.) 
 
An acute myopathy has been observed with the use of high doses of corticosteroids, most often 
occurring in patients with disorders of neuromuscular transmission (e.g., myasthenia gravis), 
or in patients receiving concomitant therapy with neuromuscular blocking drugs (e.g., 
pancuronium). This acute myopathy is generalized, may involve ocular and respiratory 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 83 of 96 
 
 
 
muscles, and may result in quadriparesis. Elevations of creatine kinase may occur. Clinical 
improvement or recovery after stopping corticosteroids may require weeks to years. 
 
Psychic derangements may appear when corticosteroids are used, ranging from euphoria, 
insomnia, mood swings, personality changes, and severe depression, to frank psychotic 
manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated 
by corticosteroids. 
 
Ophthalmic 
Intraocular pressure may become elevated in some individuals. If steroid therapy is continued 
for more than 6 weeks, intraocular pressure should be monitored. 
 
Information for Patients 
Patients should be warned not to discontinue the use of corticosteroids abruptly or without 
medical supervision, to advise any medical attendants that they are taking corticosteroids, and 
to seek medical advice at once should they develop fever or other signs of infection. 
 
Persons who are on corticosteroids should be warned to avoid exposure to chicken pox or 
measles. Patients should also be advised that if they are exposed, medical advice should be 
sought without delay. 
 
Drug Interactions 
Aminoglutethimide: Aminoglutethimide may lead to a loss of corticosteroid-induced adrenal 
suppression. 
Amphotericin B injection and potassium-depleting agents: When corticosteroids are administered 
concomitantly with potassium-depleting agents (i.e., amphotericin B, diuretics), patients should be 
observed closely for development of hypokalemia. There have been cases reported in which 
concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and 
congestive heart failure.  
Antibiotics: Macrolide antibiotics have been reported to cause a significant decrease in 
corticosteroid clearance (see Drug Interactions, Hepatic Enzyme Inhibitors).  
Anticholinesterases: Concomitant use of anticholinesterase agents and corticosteroids may 
produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase 
agents should be withdrawn at least 24 hours before initiating corticosteroid therapy.  
Anticoagulants, oral: Coadministration of corticosteroids and warfarin usually results in inhibition 
of response to warfarin, although there have been some conflicting reports. Therefore, coagulation 
indices should be monitored frequently to maintain the desired anticoagulant effect.  
Antidiabetics: Because corticosteroids may increase blood glucose concentrations, dosage 
adjustments of antidiabetic agents may be required.  
Antitubercular drugs: Serum concentrations of isoniazid may be decreased.  


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 84 of 96 
 
 
 
Cholestyramine: Cholestyramine may increase the clearance of corticosteroids.  
Cyclosporine: Increased activity of both cyclosporine and corticosteroids may occur when the two 
are used concurrently. Convulsions have been reported with this concurrent use.  
Digitalis glycosides: Patients on digitalis glycosides may be at increased risk of 
arrhythmias due to hypokalemia.  
Estrogens, including oral contraceptives: Estrogens may decrease the hepatic metabolism of certain 
corticosteroids, thereby increasing their effect.  
Hepatic Enzyme Inducers (e.g., barbiturates, phenytoin, carbamazepine, rifampin): Drugs which 
induce cytochrome P450 3A4 enzyme activity may enhance the metabolism of corticosteroids and 
require that the dosage of the corticosteroid be increased.  
Hepatic Enzyme Inhibitors (e.g., ketoconazole, macrolide antibiotics such as erythromycin and 
troleandomycin): Drugs which inhibit cytochrome P450 3A4 have the potential to result in increased 
plasma concentrations of corticosteroids. 
 
Ketoconazole: Ketoconazole has been reported to significantly decrease the metabolism of certain 
corticosteroids by up to 60%, leading to an increased risk of corticosteroid side effects.  
Nonsteroidal anti-inflammatory agents (NSAIDs): Concomitant use of aspirin (or other 
nonsteroidal anti-inflammatory agents) and corticosteroids increases the risk of gastrointestinal 
side effects. Aspirin should be used cautiously in conjunction with corticosteroids in 
hypoprothrombinemia. The clearance of salicylates may be increased with concurrent use of 
corticosteroids.  
Skin tests: Corticosteroids may suppress reactions to skin tests.  
Vaccines: Patients on prolonged corticosteroid therapy may exhibit a diminished response to toxoids 
and live or inactivated vaccines due to inhibition of antibody response. Corticosteroids may also 
potentiate the replication of some organisms contained in live attenuated vaccines. Routine 
administration of vaccines or toxoids should be deferred until corticosteroid therapy is discontinued 
if possible (see WARNINGS, Infections, Vaccination).  
Carcinogenesis, Mutagenesis, Impairment of Fertility  
No adequate studies have been conducted in animals to determine whether corticosteroids have a 
potential for carcinogenesis or mutagenesis.  
Steroids may increase or decrease motility and number of spermatozoa in some patients.  
Corticosteroids have been shown to impair fertility in male rats.  
Pregnancy: Teratogenic effects: Pregnancy Category C.  


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 85 of 96 
 
 
 
Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to 
the human dose. Animal studies in which corticosteroids have been given to pregnant mice, rats, and 
rabbits have yielded an increased incidence of cleft palate in the offspring. There are no adequate and 
well-controlled studies in pregnant women. Corticosteroids should be used during pregnancy only if 
the potential benefit justifies the potential risk to the fetus. Infants born to mothers who have received 
corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism.  
This product contains benzyl alcohol as a preservative. Benzyl alcohol can cross the placenta. See 
PRECAUTIONS: Pediatric use.  
Nursing Mothers 
Systemically administered corticosteroids appear in human milk and could suppress growth, interfere 
with endogenous corticosteroid production, or cause other untoward effects. Because of the potential 
for serious adverse reactions in nursing infants from corticosteroids, a decision should be made 
whether to continue nursing, or discontinue the drug, taking into account the importance of the drug 
to the mother. 
 
Pediatric Use 
Some formulations of this product contain benzyl alcohol as a preservative (see 
DESCRIPTION). Carefully examine vials to determine formulation that is being used. 
 
Benzyl alcohol, a component of this product, has been associated with serious adverse events 
and death, particularly in pediatric patients. The “gasping syndrome” (characterized by central 
nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl 
alcohol and its metabolites found in the blood and urine) has been associated with benzyl 
alcohol dosages >99 mg/kg/day in neonates and low-birth-weight neonates. Additional 
symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, 
hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, 
bradycardia, and cardiovascular collapse. Although normal therapeutic doses of this product 
ordinarily delivers amounts of benzyl alcohol that are substantially lower than those reported in 
association with the “gasping syndrome”, the minimum amount of benzyl alcohol at which 
toxicity may occur is not known. The risk of benzyl alcohol toxicity depends on the quantity 
administered and the hepatic capacity to detoxify the chemical. Premature and low-birth-weight 
infants, as well as patients receiving high dosages, may be more likely to develop toxicity. 
Practitioners administering this and other medications containing benzyl alcohol should 
consider the combined daily metabolic load of benzyl alcohol from all sources. 
 
The efficacy and safety of corticosteroids in the pediatric population are based on the well-
established course of effect of corticosteroids which is similar in pediatric and adult 
populations. Published studies provide evidence of efficacy and safety in pediatric patients for 
the treatment of nephrotic syndrome (>2 years of age), and aggressive lymphomas and 
leukemias (>1 month of age). Other indications for pediatric use of corticosteroids, e.g., severe 
asthma and wheezing, are based on adequate and well- controlled trials conducted in adults, on 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 86 of 96 
 
 
 
the premises that the course of the diseases and their pathophysiology are considered to be 
substantially similar in both populations. 
 
The adverse effects of corticosteroids in pediatric patients are similar to those in adults (see 
ADVERSE REACTIONS). Like adults, pediatric patients should be carefully observed with 
frequent measurements of blood pressure, weight, height, intraocular pressure, and clinical 
evaluation for the presence of infection, psychosocial disturbances, thromboembolism, peptic 
ulcers, cataracts, and osteoporosis. Pediatric patients who are treated with corticosteroids by any 
route, including systemically administered corticosteroids, may experience a decrease in their 
growth velocity. This negative impact of corticosteroids on growth has been observed at low 
systemic doses and in the absence of laboratory evidence of HPA axis suppression (i.e., 
cosyntropin stimulation and basal cortisol plasma levels). Growth velocity may therefore be a 
more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some 
commonly used tests of HPA axis function. The linear growth of pediatric patients treated with 
corticosteroids should be monitored, and the potential growth effects of prolonged treatment 
should be weighed against clinical benefits obtained and the availability of treatment 
alternatives. In order to minimize the potential growth effects of corticosteroids, pediatric 
patients should be titrated to the lowest effective dose. 
 
Geriatric Use  
Clinical studies did not include sufficient numbers of subjects aged 65 and over to determine 
whether they respond differently from younger subjects. Other reported clinical experience has 
not identified differences in responses between the elderly and younger patients. In general, dose 
selection for an elderly patient should be cautious, usually starting at the low end of the dosing 
range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of 
concomitant disease or other drug therapy.  
 
ADVERSE REACTIONS  
The following adverse reactions have been reported with SOLU-MEDROL or other 
corticosteroids:  
Allergic reactions: Allergic or hypersensitivity reactions, anaphylactoid reaction, 
anaphylaxis, angioedema.  
Blood and lymphatic system disorders: Leukocytosis.  
Cardiovascular: Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory 
collapse, congestive heart failure, fat embolism, hypertension, hypertrophic cardiomyopathy in 
premature infants, myocardial rupture following recent myocardial infarction (see WARNINGS), 
pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis.  
Dermatologic: Acne, allergic dermatitis, burning or tingling (especially in the perineal area after 
intravenous injection), cutaneous and subcutaneous atrophy, dry scaly skin, ecchymoses and 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 87 of 96 
 
 
 
petechiae, edema, erythema, hyperpigmentation, hypopigmentation, impaired wound healing, 
increased sweating, rash, sterile abscess, striae, suppressed reactions to skin tests, thin fragile 
skin, thinning scalp hair, urticaria.  
Endocrine: Decreased carbohydrate and glucose tolerance, development of cushingoid state, 
glycosuria, hirsutism, hypertrichosis, increased requirements for insulin or oral hypoglycemic 
agents in diabetes, manifestations of latent diabetes mellitus, menstrual irregularities, secondary 
adrenocortical and pituitary unresponsiveness (particularly in times of stress, as in trauma, 
surgery, or illness), suppression of growth in pediatric patients.  
Fluid and electrolyte disturbances: Congestive heart failure in susceptible patients, fluid retention, 
hypokalemic alkalosis, potassium loss, sodium retention.  
Gastrointestinal: Abdominal distention, bowel/bladder dysfunction (after intrathecal 
administration), elevation in serum liver enzyme levels (usually reversible upon discontinuation), 
hepatomegaly, increased appetite, nausea, pancreatitis, peptic ulcer with possible perforation and 
hemorrhage, perforation of the small and large intestine (particularly in patients with inflammatory 
bowel disease), ulcerative esophagitis. 
 
Hepatobiliary: Hepatitis (see WARNINGS, Drug-Induced Liver Injury). 
 
Metabolic: Negative nitrogen balance due to protein catabolism. 
 
Musculoskeletal: Aseptic necrosis of femoral and humeral heads, Charcot-like arthropathy, 
loss of muscle mass, muscle weakness, osteoporosis, pathologic fracture of long bones, 
postinjection flare (following intra-articular use), steroid myopathy, tendon rupture, vertebral 
compression fractures. 
 
Neurologic/Psychiatric: Convulsions, depression, emotional instability, euphoria, headache, 
increased intracranial pressure with papilledema (pseudotumor cerebri) usually following 
discontinuation of treatment, insomnia, mood swings, neuritis, neuropathy, paresthesia, 
personality changes, psychic disorders, vertigo. Arachnoiditis, meningitis, 
paraparesis/paraplegia, and sensory disturbances have occurred after intrathecal administration 
(see WARNINGS, Neurologic). 
 
Ophthalmic: Exophthalmos, glaucoma, increased intraocular pressure, posterior subcapsular 
cataracts, rare instances of blindness associated with periocular injections. 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 88 of 96 
 
 
 
Other: Abnormal fat deposits, decreased resistance to infection, hiccups, increased or 
decreased motility and number of spermatozoa, injection site infections following non- sterile 
administration (see WARNINGS), malaise, moon face, weight gain. 
 
OVERDOSAGE 
Treatment of acute overdosage is by supportive and symptomatic therapy. For chronic 
overdosage in the face of severe disease requiring continuous steroid therapy, the dosage of the 
corticosteroid may be reduced only temporarily, or alternate day treatment may be introduced. 
 
DOSAGE AND ADMINISTRATION 
NOTE: Some of the SOLU-MEDROL formulations contain benzyl alcohol (see 
DESCRIPTION, WARNINGS and PRECAUTIONS, Pediatric Use) 
Because of possible physical incompatibilities, SOLU-MEDROL should not be 
diluted or mixed with other solutions. 
 
Use only the accompanying diluent or Bacteriostatic Water For Injection with Benzyl 
Alcohol when reconstituting SOLU-MEDROL (see DESCRIPTION). Use within 48 hours 
after mixing. 
 
Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration, whenever solution and container permit. 
 
This preparation may be administered by intravenous injection, by intravenous infusion, or by 
intramuscular injection, the preferred method for initial emergency use being intravenous 
injection. Following the initial emergency period, consideration should be given to employing a 
longer acting injectable preparation or an oral preparation.  
 
There are reports of cardiac arrhythmias and/or cardiac arrest following the rapid administration of 
large intravenous doses of SOLU-MEDROL (greater than 0.5 gram administered over a period of 
less than 10 minutes). Bradycardia has been reported during or after the administration of large 
doses of methylprednisolone sodium succinate, and may be unrelated to the speed or duration of 
infusion. When high dose therapy is desired, the recommended dose of SOLU-MEDROL Sterile 
Powder is 30 mg/kg administered intravenously over at least 30 minutes. This dose may be 
repeated every 4 to 6 hours for 48 hours.  
In general, high dose corticosteroid therapy should be continued only until the patient’s condition 
has stabilized; usually not beyond 48 to 72 hours.  


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 89 of 96 
 
 
 
In other indications, initial dosage will vary from 10 to 40 mg of methylprednisolone depending 
on the specific disease entity being treated. However, in certain overwhelming, acute, life-
threatening situations, administrations in dosages exceeding the usual dosages may be justified 
and may be in multiples of the oral dosages. It Should Be Emphasized that Dosage Requirements 
are Variable and Must Be Individualized on the Basis of the Disease Under Treatment and the 
Response of the Patient. After a favorable response is noted, the proper maintenance dosage 
should be determined by decreasing the initial drug dosage in small decrements at appropriate 
time intervals until the lowest dosage which will maintain an adequate clinical response is 
reached. Situations which may make dosage adjustments necessary are changes in clinical status 
secondary to remissions or exacerbations in the disease process, the patient’s individual drug 
responsiveness, and the effect of patient exposure to stressful situations not directly related to the 
disease entity under treatment. In this latter situation, it may be necessary to increase the dosage 
of the corticosteroid for a period of time consistent with the patient’s condition. If after long-term 
therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than 
abruptly.  
 
SOLU-MEDROL may be administered by intravenous or intramuscular injection or by intravenous 
infusion, the preferred method for initial emergency use being intravenous injection. To administer 
by intravenous (or intramuscular) injection, prepare solution as directed. The desired dose may be 
administered intravenously over a period of several minutes. If desired, the medication may be 
administered in diluted solutions by adding Water for Injection or other suitable diluent (see below) 
to the Act-O-Vial and withdrawing the indicated dose.  
To prepare solutions for intravenous infusion, first prepare the solution for injection as directed. 
This solution may then be added to indicated amounts of 5% dextrose in water, isotonic saline 
solution, or 5% dextrose in isotonic saline solution. 
 
In pediatric patients, the initial dose of methylprednisolone may vary depending on the specific 
disease entity being treated. The range of initial doses is 0.11 to 1.6 mg/kg/day in three or four 
divided doses (3.2 to 48 mg/m2bsa/day). 
 
The National Heart, Lung, and Blood Institute (NHLBI) recommended dosing for systemic 
prednisone, prednisolone, or methylprednisolone in pediatric patients whose asthma is 
uncontrolled by inhaled corticosteroids and long-acting bronchodilators is 1-2 mg/kg/day in 
single or divided doses. It is further recommended that short course, or “burst” therapy, be 
continued until the patient achieves a peak expiratory flow rate of 80% of his or her personal 
best or until symptoms resolve. This usually requires 3 to 10 days of treatment, although it can 
take longer. There is no evidence that tapering the dose after improvement will prevent a 
relapse. 
 
Dosage may be reduced for infants and children but should be governed more by the severity of 
the condition and response of the patient than by age or size. It should not be less than 0.5 mg 
per kg every 24 hours. 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 90 of 96 
 
 
 
Dosage must be decreased or discontinued gradually when the drug has been administered for 
more than a few days. If a period of spontaneous remission occurs in a chronic condition, 
treatment should be discontinued. Routine laboratory studies, such as urinalysis, two-hour 
postprandial blood sugar, determination of blood pressure and body weight, and a chest X-ray 
should be made at regular intervals during prolonged therapy. Upper GI X-rays are desirable 
in patients with an ulcer history or significant dyspepsia. 
 
In treatment of acute exacerbations of multiple sclerosis, daily doses of 160 mg of 
methylprednisolone for a week followed by 64 mg every other day for 1 month have been 
shown to be effective (see PRECAUTIONS, Neurologic-psychiatric). 
 
For the purpose of comparison, the following is the equivalent milligram dosage of the various 
glucocorticoids: 
 
 
These dose relationships apply only to oral or intravenous administration of these compounds. 
When these substances or their derivatives are injected intramuscularly or into joint spaces, 
their relative properties may be greatly altered. 
 
DIRECTIONS FOR USING THE ACT-O-VIAL SYSTEM  
1. 
Press down on plastic activator to force diluent into the lower compartment.  
2. 
Gently agitate to effect solution.  
3. 
Remove plastic tab covering center of stopper.  
4. 
Sterilize top of stopper with a suitable germicide.  
5. 
Insert needle squarely through center of stopper until tip is just visible. Invert vial 
and withdraw dose.  
 
 
 
STORAGE CONDITIONS  
Protect from light.  
Store unreconstituted product at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].  
Cortisone, 25 
Triamcinolone, 4 
Hydrocortisone, 20 
Paramethasone, 2 
Prednisolone, 5 
Betamethasone, 0.75 
Prednisone, 5 
Dexamethasone, 0.75 
Methylprednisolone, 4 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 91 of 96 
 
 
 
Store solution at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].  
Use solution within 48 hours after mixing.  
HOW SUPPLIED  
SOLU-MEDROL Sterile Powder preserved with benzyl alcohol is available in the following 
packages:  
500 mg (Multi-Dose Vial)   
 
 
1 gram (Multi-Dose Vial) 
        8 mL NDC 0009-0758-01  
 
 
          16 mL NDC 0009-0698-01 
2 gram Vial with Diluent 
          NDC 0009-0796-01 
 
SOLU-MEDROL Sterile Powder preservative-free is available in the following packages: 
 
40 mg Act-O-Vial System (Single-Use  
 
1 gram Act-O-Vial System (Single-
Use Vial) Vial) 
 
 
 
 
 
 
 
8 mL NDC 0009-
0018-20 
   25 x1 mL NDC 0009-0039-28   
 
125 mg Act-O-Vial System (Single-Use Vial) 
   25 x 2 mL NDC 0009-0047-22 
500 mg Act-O-Vial System (Single-Use Vial) 
       4 mL NDC 0009-0003-02 
 
 
LAB-0161-8.2 Revised July 2016 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 92 of 96 
 
 
 
15.4 
Appendix C: Plasma PK sampling and handling  
Timing of samples will treat the time of initial drug administration as time (0). The date and time will be 
recorded for the time of drug administration and for the acquisition time of the PK sample.  The 
PK/PD/Biomarker samples will be obtained in sodium heparin collection tubes.  
 
1. For the scheduled pharmacokinetic draws, one 800uL blood sample will be collected from a 
peripheral IV or central line site into the provided sodium heparin tubes, and placed on ice. 
2. Immediately, within one-half hour of the blood draw, centrifuge at 3,500 g for 5 minutes at 
approximately 4°C. 
3. Transfer plasma into the provided polypropylene screw cap transfer tubes. 
4. Transfer tubes should be labeled with a pre-printed label containing site, patient number, and 
protocol collection time. Ensure that the pre-printed label corresponds to the recorded date and 
time of collection on the CRF. 
5. Immediately freeze the specimens (-70°C) in an upright position. Notify the Protocol Chair 
immediately if the samples become thawed or damaged. 
6. Ship frozen at times specified, to the designated specialty laboratory. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 93 of 96 
 
 
 
15.5 
Appendix D: Protocol Amendments  
 
Amendment # 
Date 
Change 
#1 
02 September 2017 
Changes the dosing regimen from a two dose 
regimen including pre-operative + intraoperative 
methylprednisolone (30mg/kg/dose)/placebo, to a 
single dose regimen consisting of only intra-
operative methylprednisolone (30mg/kg)/placebo. 
#2 
29 June 2018 
Expands the inclusion criteria from neonates < 30 
days of age at time of heart surgery with 
cardiopulmonary bypass (CPB) to infants < 1 year 
of age undergoing surgery. 
#3 
16 October 2018 
Removes Digoxin from the list of medications that 
would exclude a patient if they have been taken 
within 2 days of the cardiopulmonary bypass (CPB) 
surgery 
#4 
15 September 2020 
Correctly defines neonate as age ≤30 days to be 
consistent with SAS code in the STS-CHSD 
database and updates plan for the interim analysis. 
#5 
27 March 2022 
Amends protocol to note we will follow study 
participants for a minimum of 4 months from date of 
surgery (changed from 6 months).  The rationale for 
the change is patients remain hospitalized at the end 
of the study, and to complete the study statistical 
analysis before the end of the project period, we 
need to limit the duration of follow up to 4 months. 
Also amends protocol to assign a worst outcome of 
heart transplant to subjects hospitalized, listed for 
transplant and receiving mechanical support.  The 
rationale for this is that heart transplant is the second 
worst outcome on our rank list and, in this scenario, 
itis more appropriate than a lower order outcome 
assignment. 
 
 
 
 
 
 
 
 
 
 
 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 94 of 96 
 
 
 
 
 
 
 
 
 
 
 
 
 
15.6 
Appendix D: Site Specific Protocol – Site 103 (Duke University Medical 
Center) 
 
Protocol type:  Site Specific Sub-Study 
 
Parent Protocol:  STeroids to REduce Systemic inflammation after infant heart Surgery (STRESS) 
 
Site(s) engaged:  Duke University (STRESS site 103) 
 
Protocol Title: AKI protection with acetaminophen 
 
Version/Date:  Version 1.0/ 01 March 2019 
 
 
Sub-study Background and Rationale:  
Nearly 20,000 U.S. infants undergo congenital heart defect (CHD) surgery every year. Infant CHD 
surgery is associated with poor outcomes - mortality in ~3-5% and major morbidity in ~ 30%.1  A major 
contributor to poor outcomes is post-operative acute kidney injury (AKI).  Factors that contribute to 
post-surgical AKI include renal ischemia, reperfusion injury, oxidation, inflammation and 
cardiopulmonary bypass associated hemolysis.2-5 Hemolysis from cardiopulmonary bypass is a major 
contributor that might be amenable to intervention. Hemolysis causes AKI by increasing plasma-free 
hemoglobin.  This results in hemeprotein-mediated lipid peroxidation and renal vasoconstriction, thus 
producing renal injury.2,6  
 The risk of AKI may be reduced by perioperative administration of commonly used medications.  
For example, findings from in vitro and mouse studies demonstrate that acetaminophen reduces 
nephrotoxic hemoglobin radicals7,8 and lipid peroxidation to decrease the incidence of AKI.9  Further, in 
children undergoing cardiopulmonary bypass, acetaminophen attenuates markers of lipid peroxidation6 
and is associated with reduced odds of AKI.10   
For 
many 
medications, 
including 
acetaminophen, 
the 
pharmacokinetics 
(PK) 
and 
pharmacodynamics (PD) are not defined in the post-operative CHD population for AKI prevention.  For 
many commonly used medications, the PK and PD likely differ when used for prevention and/or 
treatment of AKI after CHD surgery as compared to healthy subjects.  Therefore, a crucial step to ensure 
successful future studies is defining the PK and exposure-response profiles for the treatment/prevention 
of AKI in infants after CHD surgery. 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 95 of 96 
 
 
 
The parent STRESS trial provides an ideal platform for the sub-study as the existing trial 
infrastructure and protocol can be leveraged without compromising the parent study operations or 
outcomes.  All PK sampling can occur with the existing collection scheme and protocol without 
compromising the assay results.  Furthermore, the existing parent trial protocol will capture nearly all 
data required to complete the sub-study.  The modifications to the existing protocol do not incur any 
significant additional risks to the subjects.  The primary modification is the addition of urine biomarker 
sample collection in the first 24 post-operative hours. 
Study Design: 
In subjects enrolled at Duke University who participate in the optional PK/PD and/or biomarker 
sampling, we will conduct a single-arm, open label standard of care dosing study of drugs affecting renal 
injury received in the first 24 hours after cardiopulmonary bypass -- primarily trageting acetaminophen, 
which is used commonly, but also to evaluate other potentially nephrotoxic or renal protective agents.  
Patient inclusion and exclusion criteria will be identical to the parent study.  In addition to the already 
collected plasma samples,  urinary biomarker samples will be collected and validated bioanalytical 
assays will be performed at a central lab.     
Sampling Procedure:  
Serum: No additional drug plasma samples will be collected during this study.  As available, 
excess plasma from the parent study sampling scheme (see Table 5 of main protocol) will be used to 
characterize PK for medications (e.g. acetaminophen and metabolites) given per standard of care and 
associated with post-bypass renal protection.  
 
Urine: Urinary biomarkers of renal injury, including NGAL, will be collected in sampling schemes 
noted in Appendix Table 1.  Sampling will only occur for patients with indwelling urinary catheters at the 
time of sample collection. 
 
Appendix Table 1: Urine biomarker sampling scheme 
Sample Number 
Time 
Per patient urine collection 
1 
Pre-cardiopulmonary bypass (CPB) 
1 x 3mL (minimum 1mL) 
2 
2-6 hours after completion of CPB 
1 x 3mL (minimum 1mL) 
3 
18-24 hours after completion of CPB 
1 x 3mL (minimum 1mL) 
 
Sample Handling Procedures: 
Similar to the parent study, assays to measure drug levels/metabolites in plasma, as well as 
biomarkers of renal injury in urine, will be conducted at a central lab using validate bioanalytical assays.  
For plasma, date and time will be recorded for the administration of parent study drug/placebo, 
acetaminophen and the acquisition time of the PK sample.  For urine, date and time will be recorded for 
completion of CPB and acquisition time of the biomarker sample.  All samples will be stored at -80°C 
until analysis.   
 
Analytic approach:  
Plasma PK data will be analyzed with a nonlinear mixed-effects model to determine drug and 
metabolite volume of distribution and clearance.  Dose-exposure simulations will predict AUC0-24.  Linked 
PK/PD compartmental analysis will be performed to determine the acetaminophen exposure association 
to the primary pharmacodynamic outcome, staged KDIGO-defined AKI, and model optimal dosing. An 
exploratory pharmacodynamic outcome of concentration of urinary neutrophil gelatinase-associated 
lipocalin (NGAL) will also be included in analysis.   
 
Safety Monitoring: 


STRESS Trial Protocol 
  
Version 6.0  
 
NCT03229538 
 
 
 
Page 96 of 96 
 
 
 
 
This amended sub-study involves the investigation of medications given as standard of care.  An 
investigational new drug (IND) approval is not required.  The investigators will monitor for adverse 
events through reports and laboratory values obtained per routine care.   
 
 
References 
1.           Jacobs JP, Mayer JE, Jr., Pasquali SK, Hill KD, Overman DM, St Louis JD, Kumar 
SR, Backer CL, Fraser CD, Tweddell JS and Jacobs ML. The Society of Thoracic Surgeons 
Congenital Heart Surgery Database: 2018 Update on Outcomes and Quality. Ann Thorac 
Surg. 2018;105:680-689. 
2.           O'Neal JB, Shaw AD and Billings FTt. Acute kidney injury following cardiac surgery: 
current understanding and future directions. Crit Care. 2016;20:187. 
3. Agarwal A, Dong Z, Harris R, Murray P, Parikh SM, Rosner MH, Kellum JA, Ronco C and 
Acute Dialysis Quality Initiative XWG. Cellular and Molecular Mechanisms of AKI. J Am 
Soc Nephrol. 2016;27:1288-99. 
4.           Cooper DS, Basu RK, Price JF, Goldstein SL and Krawczeski CD. The Kidney in 
Critical Cardiac Disease: Proceedings From the 10th International Conference of the Pediatric 
Cardiac Intensive Care Society. World J Pediatr Congenit Heart Surg. 2016;7:152-63. 
5.           Mamikonian LS, Mamo LB, Smith PB, Koo J, Lodge AJ and Turi JL. 
Cardiopulmonary bypass is associated with hemolysis and acute kidney injury in neonates, 
infants, and children*. Pediatr Crit Care Med. 2014;15:e111-9. 
6.           Simpson SA, Zaccagni H, Bichell DP, Christian KG, Mettler BA, Donahue BS, 
Roberts LJ, 2nd and Pretorius M. Acetaminophen attenuates lipid peroxidation in children 
undergoing cardiopulmonary bypass. Pediatr Crit Care Med. 2014;15:503-10. 
7.           Aronoff DM, Oates JA and Boutaud O. New insights into the mechanism of action of 
acetaminophen: Its clinical pharmacologic characteristics reflect its inhibition of the two 
prostaglandin H2 synthases. Clin Pharmacol Ther. 2006;79:9-19. 
8.           Gonzalez-Sanchez MI, Manjabacas MC, Garcia-Carmona F and Valero E. Mechanism 
of acetaminophen oxidation by the peroxidase-like activity of methemoglobin. Chem Res 
Toxicol. 2009;22:1841-50. 
9.           Boutaud O, Moore KP, Reeder BJ, Harry D, Howie AJ, Wang S, Carney CK, 
Masterson TS, Amin T, Wright DW, Wilson MT, Oates JA and Roberts LJ, 2nd. 
Acetaminophen inhibits hemoprotein-catalyzed lipid peroxidation and attenuates 
rhabdomyolysis-induced renal failure. Proc Natl Acad Sci U S A. 2010;107:2699-704.  
10.           Van Driest SL, Jooste EH, Shi Y, Choi L, Darghosian L, Hill KD, Smith AH, 
Kannankeril PJ, Roden DM and Ware LB. Association Between Early Postoperative 
Acetaminophen Exposure and Acute Kidney Injury in Pediatric Patients Undergoing Cardiac 
Surgery. JAMA Pediatr. 2018;172:655-663.