STeroids to REduce Systemic Inflammation After Infant Heart Surgery

Phase 3

Completed

Conditions: Inflammatory Response
Congenital Heart Disease in Children

Interventions: Drug: Isotonic saline
Drug: Methylprednisolone

Registration Number: NCT03229538

Lead Sponsor: Kevin Hill

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 1263

Inclusion Criteria

Age < 1 year at the time of surgery
Undergoing heart surgery with CPB as part of standard clinical care
Availability and willingness of the parent/legally authorized representative to provide written informed consent

Exclusion Criteria

< 37 weeks adjusted gestational age at time of surgery
Any oral or intravenous steroid treatment within two days of surgery
Any patient receiving any of the following medications within 2 days of surgery:

Amphotericin B, aminoglutethimide, anticholinesterases, 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 and verapamil.

Infection contraindicating steroid use
Preoperative mechanical circulatory support or active resuscitation at the time of randomization
Emergent surgery precluding steroid administration 8-12 hours before surgery

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo Arm	Isotonic saline	IV Isotonic Saline
Methylprednisolone Arm	Methylprednisolone	IV Methylprednisolone

Primary Outcome Measures

Name	Time	Method
Number of Participants at Each Global Rank Endpoint Based Upon Their Most-severe Outcome	Until hospital discharge, up to 4 months	A composite mortality, major morbidity and length of stay global rank endpoint with endpoints ranked according to severity. For this endpoint, each randomized patient will be assigned a rank based upon their most-severe outcome. Rank of 91 = Post-operative length of stay \> 90 days, 92 = Post-op cardiac arrest, multi-system organ failure, renal failure with temporary dialysis, or prolonged ventilator support, 93 = Reoperation for bleeding, unplanned delayed sternal closure, or post-op unplanned interventional cardiac catheterization, 94 = Post-operative mechanical circulatory support or unplanned cardiac reoperation (exclusive of reoperation for bleeding), 95 = Renal failure with permanent dialysis, neurologic deficit persistent at discharge, or respiratory failure requiring tracheostomy; 96 = Heart transplant (during hospitalization); 97 = Operative mortality. Ranks 1 through 90 correspond to the post-operative length of stay in days.

Secondary Outcome Measures

Name	Time	Method
PK/PD - Volume of Distribution (Vd)	Pre-2nd dose and minimum of 2 of any of the following 5 time points (0-30 minutes after the start of CPB, 0-30 minutes after MUF, 1-2 hours after completion of CPB, 4-6 hours after completion of CPB, or 16-24 hours after completion of CPB)
Number of Participants With Occurrence of Any One or More of the Following STS-CHSD-defined Major Post-operative Infectious Complications: Postprocedural Infective Endocarditis, Pneumonia, Sepsis, Deep Wound Infection, Mediastinitis.	Until hospital discharge, up to 4 months
Number of Participants With Prolonged Mechanical Ventilation (Greater Than 7 Days)	Until hospital discharge, up to 4 months
Number of Participants With Post-operative Low Cardiac Output Syndrome	Until hospital discharge, up to 4 months	Based upon the STS-CHSD registry defined "cardiac dysfunction resulting in low cardiac output" complication variable.
Number of Participants With Any Other Post-operative Complications From the Start of Study Drug Administration Until Hospital Discharge.	Until hospital discharge, up to 4 months
PK/PD - Clearance (CL)	Pre-2nd dose and minimum of 2 of any of the following 5 time points (0-30 minutes after the start of CPB, 0-30 minutes after MUF, 1-2 hours after completion of CPB, 4-6 hours after completion of CPB, or 16-24 hours after completion of CPB)
Number of Participants With Death or Major Complication as Defined by an Outcome in One of the 7 Highest Global Ranking Categories	Until hospital discharge, up to 4 months	The 7 highest global ranking categories range from 91 (postoperative length of hospital stay \> 90 days) to 97 (operative mortality).
Number of Participants With a Post-operative Length of Stay Greater Than 90 Days	Until hospital discharge, up to 4 months	Calculated as discharge date minus surgery date.
PK/PD - Maximum Concentration (Cmax)	Pre-2nd dose and minimum of 2 of any of the following 5 time points (0-30 minutes after the start of CPB, 0-30 minutes after MUF, 1-2 hours after completion of CPB, 4-6 hours after completion of CPB, or 16-24 hours after completion of CPB)
Number of Participants With Mortality, Including In-hospital Mortality or Mortality After Hospital Discharge But Within 30 Days of the Last Dose of Study Drug	up to 30 days
PK/PD - Time to Maximum Concentration (Tmax)	Pre-2nd dose and minimum of 2 of any of the following 5 time points (0-30 minutes after the start of CPB, 0-30 minutes after MUF, 1-2 hours after completion of CPB, 4-6 hours after completion of CPB, or 16-24 hours after completion of CPB)
Post-operative Biomarkers of the Inflammatory Response to Cardiopulmonary Bypass Including Interleukins 6 and 8	Pre-2nd dose; a minimum of 2 of any of the following 5 time points (0-30 min after the start of CPB, 0-30 min after MUF, 1-2 hrs after CPB end, 4-6 hrs after CPB end, or 16-24 hrs after CPB end); and 36-48 hrs after CPB end	Only to be collected at select centers and in those patients whose parent/legally authorized representative have granted consent to blood draws

Trial Locations

Locations (23): Children's Hospital of Los Angeles
🇺🇸
Los Angeles, California, United States
University of Colorado, Denver
🇺🇸
Aurora, Colorado, United States
Children's Mercy Hospital
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Kansas City, Missouri, United States
Ann & Robert Lurie Children's Hospital of Chicago
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Chicago, Illinois, United States
Advocate Children's Hospital
🇺🇸
Oak Lawn, Illinois, United States
Johns Hopkins University
🇺🇸
Baltimore, Maryland, United States
St. Louis Children's Hospital
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Saint Louis, Missouri, United States
Morgan Stanley Children's Hospital of New York Presbyterian
🇺🇸
New York, New York, United States
University of Rochester Medical Center
🇺🇸
Rochester, New York, United States
Nationwide Children's Hospital
🇺🇸
Columbus, Ohio, United States
Children's Hospital of Pittsburgh
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Pittsburgh, Pennsylvania, United States
The University of Texas Southwestern Medical Center
🇺🇸
Dallas, Texas, United States
Children's Hospital and Medical Center
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Omaha, Nebraska, United States
Children's Hospital Medical Center
🇺🇸
Cincinnati, Ohio, United States
Children's Hospital and Clinics of Minnesota
🇺🇸
Minneapolis, Minnesota, United States
Duke University Medical Center
🇺🇸
Durham, North Carolina, United States
Cleveland Clinic
🇺🇸
Cleveland, Ohio, United States
Medical College of Wisconsin
🇺🇸
Milwaukee, Wisconsin, United States
Vanderbilt University Medical Center
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Nashville, Tennessee, United States
Baylor College of Medicine, Texas Children's Hospital
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Houston, Texas, United States
Utah/Primary Children's Medical Center
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Salt Lake City, Utah, United States
University of Florida Health - Shands Hospital
🇺🇸
Gainesville, Florida, United States
Medical University of South Carolina
🇺🇸
Charleston, South Carolina, United States