Clinical trial NCT03229538: STeroids to REduce Systemic Inflammation After Infant Heart Surgery
Official title: STeroids to REduce Systemic Inflammation After Infant Heart Surgery (STRESS)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Congenital Heart Disease in Children
Inflammatory Response
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: National Center for Advancing Translational Sciences (NCATS)
First posted: 2017-07-25
Enrollment: 1263
Sex: ALL
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants at Each Global Rank Endpoint Based Upon Their Most-severe Outcome
timeFrame: Until hospital discharge, up to 4 months
Secondary outcomes:
measure: 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
timeFrame: up to 30 days
measure: Number of Participants With Death or Major Complication as Defined by an Outcome in One of the 7 Highest Global Ranking Categories
timeFrame: Until hospital discharge, up to 4 months
measure: Number of Participants With a Post-operative Length of Stay Greater Than 90 Days
timeFrame: Until hospital discharge, up to 4 months
measure: Number of Participants With Prolonged Mechanical Ventilation (Greater Than 7 Days)
timeFrame: Until hospital discharge, up to 4 months
measure: Number of Participants With Post-operative Low Cardiac Output Syndrome
timeFrame: Until hospital discharge, up to 4 months
measure: 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.
timeFrame: Until hospital discharge, up to 4 months
measure: Number of Participants With Any Other Post-operative Complications From the Start of Study Drug Administration Until Hospital Discharge.
timeFrame: Until hospital discharge, up to 4 months
measure: PK/PD - Time to Maximum Concentration (Tmax)
timeFrame: 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)
measure: PK/PD - Maximum Concentration (Cmax)
timeFrame: 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)
measure: PK/PD - Clearance (CL)
timeFrame: 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)
measure: PK/PD - Volume of Distribution (Vd)
timeFrame: 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)
measure: Post-operative Biomarkers of the Inflammatory Response to Cardiopulmonary Bypass Including Interleukins 6 and 8
timeFrame: 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
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Children's Hospital of Los Angeles
state: California
city: Aurora
country: United States
facility: University of Colorado, Denver
state: Colorado
city: Gainesville
country: United States
facility: University of Florida Health - Shands Hospital
state: Florida
city: Chicago
country: United States
facility: Ann & Robert Lurie Children's Hospital of Chicago
state: Illinois
city: Oak Lawn
country: United States
facility: Advocate Children's Hospital
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Minneapolis
country: United States
facility: Children's Hospital and Clinics of Minnesota
state: Minnesota
city: Kansas City
country: United States
facility: Children's Mercy Hospital
state: Missouri
city: Saint Louis
country: United States
facility: St. Louis Children's Hospital
state: Missouri
city: Omaha
country: United States
facility: Children's Hospital and Medical Center
state: Nebraska
city: New York
country: United States
facility: Morgan Stanley Children's Hospital of New York Presbyterian
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: Children's Hospital Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: The University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine, Texas Children's Hospital
state: Texas
city: Salt Lake City
country: United States
facility: Utah/Primary Children's Medical Center
state: Utah
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Duke University
name: Kevin Hill
role: PRINCIPAL_INVESTIGATOR
References:
citation: Petrini J, Damus K, Johnston RB Jr. An overview of infant mortality and birth defects in the United States. Teratology. 1997 Jul-Aug;56(1-2):8-10. doi: 10.1002/(SICI)1096-9926(199707/08)56:1/23.0.CO;2-U. No abstract available.
citation: Petrini J, Damus K, Russell R, Poschman K, Davidoff MJ, Mattison D. Contribution of birth defects to infant mortality in the United States. Teratology. 2002;66 Suppl 1:S3-6. doi: 10.1002/tera.90002.
citation: Yang Q, Chen H, Correa A, Devine O, Mathews TJ, Honein MA. Racial differences in infant mortality attributable to birth defects in the United States, 1989-2002. Birth Defects Res A Clin Mol Teratol. 2006 Oct;76(10):706-13. doi: 10.1002/bdra.20308.
citation: Yang Q, Khoury MJ, Mannino D. 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):493-505. doi: 10.1002/(SICI)1098-2272(1997)14:53.0.CO;2-2.
citation: Hoffman TM, Wernovsky G, Atz AM, Kulik TJ, Nelson DP, Chang AC, Bailey JM, Akbary A, Kocsis JF, Kaczmarek R, Spray TL, Wessel DL. Efficacy and safety of milrinone in preventing low cardiac output syndrome in infants and children after corrective surgery for congenital heart disease. Circulation. 2003 Feb 25;107(7):996-1002. doi: 10.1161/01.cir.0000051365.81920.28.
citation: Parr GV, Blackstone EH, Kirklin JW. Cardiac performance and mortality early after intracardiac surgery in infants and young children. Circulation. 1975 May;51(5):867-74. doi: 10.1161/01.cir.51.5.867.
citation: Wernovsky G, Wypij D, Jonas RA, Mayer JE Jr, Hanley FL, Hickey PR, Walsh AZ, Chang AC, Castaneda AR, Newburger JW, Wessel DL. 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 Oct 15;92(8):2226-35. doi: 10.1161/01.cir.92.8.2226.
citation: Wan S, LeClerc JL, Vincent JL. Inflammatory response to cardiopulmonary bypass: mechanisms involved and possible therapeutic strategies. Chest. 1997 Sep;112(3):676-92. doi: 10.1378/chest.112.3.676.
citation: Ando M, Park IS, Wada N, Takahashi Y. Steroid supplementation: a legitimate pharmacotherapy after neonatal open heart surgery. Ann Thorac Surg. 2005 Nov;80(5):1672-8; discusison 1678. doi: 10.1016/j.athoracsur.2005.04.035.
citation: Bronicki RA, Backer CL, Baden HP, Mavroudis C, Crawford SE, Green TP. Dexamethasone reduces the inflammatory response to cardiopulmonary bypass in children. Ann Thorac Surg. 2000 May;69(5):1490-5. doi: 10.1016/s0003-4975(00)01082-1.
citation: Checchia PA, Backer CL, Bronicki RA, Baden HP, Crawford SE, Green TP, Mavroudis C. Dexamethasone reduces postoperative troponin levels in children undergoing cardiopulmonary bypass. Crit Care Med. 2003 Jun;31(6):1742-5. doi: 10.1097/01.CCM.0000063443.32874.60.
citation: Clarizia NA, Manlhiot C, Schwartz SM, Sivarajan VB, Maratta R, Holtby HM, Gruenwald CE, Caldarone CA, Van Arsdell GS, McCrindle BW. Improved outcomes associated with intraoperative steroid use in high-risk pediatric cardiac surgery. Ann Thorac Surg. 2011 Apr;91(4):1222-7. doi: 10.1016/j.athoracsur.2010.11.005.
citation: Graham EM, Atz AM, Butts RJ, Baker NL, Zyblewski SC, Deardorff RL, DeSantis SM, Reeves ST, Bradley SM, Spinale FG. Standardized preoperative corticosteroid treatment in neonates undergoing cardiac surgery: results from a randomized trial. J Thorac Cardiovasc Surg. 2011 Dec;142(6):1523-9. doi: 10.1016/j.jtcvs.2011.04.019. Epub 2011 May 20.
citation: Graham EM, Atz AM, McHugh KE, Butts RJ, Baker NL, Stroud RE, Reeves ST, Bradley SM, McGowan FX Jr, Spinale FG. Preoperative steroid treatment does not improve markers of inflammation after cardiac surgery in neonates: results from a randomized trial. J Thorac Cardiovasc Surg. 2014 Mar;147(3):902-8. doi: 10.1016/j.jtcvs.2013.06.010. Epub 2013 Jul 16.
citation: Toledo-Pereyra LH, Lin CY, Kundler H, Replogle RL. Steroids in heart surgery: a clinical double-blind and randomized study. Am Surg. 1980 Mar;46(3):155-60.
citation: Graham EM. The utility of steroids in pediatric cardiac operations*. Pediatr Crit Care Med. 2014 Jun;15(5):492-3. doi: 10.1097/PCC.0000000000000139. No abstract available.
citation: Pasquali SK, Li JS, He X, Jacobs ML, O'Brien SM, Hall M, Jaquiss RD, Welke KF, Peterson ED, Shah SS, Gaynor JW, Jacobs JP. Perioperative methylprednisolone and outcome in neonates undergoing heart surgery. Pediatrics. 2012 Feb;129(2):e385-91. doi: 10.1542/peds.2011-2034. Epub 2012 Jan 23.
citation: Garg AX, Vincent J, Cuerden M, Parikh C, Devereaux PJ, Teoh K, Yusuf S, Hildebrand A, Lamy A, Zuo Y, Sessler DI, Shah P, Abbasi SH, Quantz M, Yared JP, Noiseux N, Tagarakis G, Rochon A, Pogue J, Walsh M, Chan MT, Lamontagne F, Salehiomran A, Whitlock R; SIRS Investigators. Steroids In caRdiac Surgery (SIRS) trial: acute kidney injury substudy protocol of an international randomised controlled trial. BMJ Open. 2014 Mar 5;4(3):e004842. doi: 10.1136/bmjopen-2014-004842.
citation: Scrascia G, Rotunno C, Guida P, Amorese L, Polieri D, Codazzi D, Paparella D. Perioperative steroids administration in pediatric cardiac surgery: a meta-analysis of randomized controlled trials*. Pediatr Crit Care Med. 2014 Jun;15(5):435-42. doi: 10.1097/PCC.0000000000000128.
citation: Jacobs ML, O'Brien SM, Jacobs JP, Mavroudis C, Lacour-Gayet F, Pasquali SK, Welke K, Pizarro C, Tsai F, Clarke DR. An empirically based tool for analyzing morbidity associated with operations for congenital heart disease. J Thorac Cardiovasc Surg. 2013 Apr;145(4):1046-1057.e1. doi: 10.1016/j.jtcvs.2012.06.029. Epub 2012 Jul 24.
citation: Ungerleider RM. Practice patterns in neonatal cardiopulmonary bypass. ASAIO J. 2005 Nov-Dec;51(6):813-5. doi: 10.1097/01.mat.0000183473.93237.10. No abstract available.
citation: Hill KD, Kannankeril PJ, Jacobs JP, Baldwin HS, Jacobs ML, O'Brien SM, Bichel DP, Graham EM, Blasiole B, Resheidat A, Husain AS, Kumar SR, Kirchner JL, Gallup DS, Turek JW, Bleiweis M, Mettler B, Benscoter A, Wald E, Karamlou T, Van Bergen AH, Overman D, Eghtesady P, Butts R, Kim JS, Scott JP, Anderson BR, Swartz MF, McConnell PI, Vener DF, Li JS; STRESS Network Investigators. Methylprednisolone for Heart Surgery in Infants - A Randomized, Controlled Trial. N Engl J Med. 2022 Dec 8;387(23):2138-2149. doi: 10.1056/NEJMoa2212667. Epub 2022 Nov 6.
citation: Gibbison B, Villalobos Lizardi JC, Aviles Martinez KI, Fudulu DP, Medina Andrade MA, Perez-Gaxiola G, Schadenberg AW, Stoica SC, Lightman SL, Angelini GD, Reeves BC. Prophylactic corticosteroids for paediatric heart surgery with cardiopulmonary bypass. Cochrane Database Syst Rev. 2020 Oct 12;10(10):CD013101. doi: 10.1002/14651858.CD013101.pub2.
citation: Hill KD, Baldwin HS, Bichel DP, Butts RJ, Chamberlain RC, Ellis AM, Graham EM, Hickerson J, Hornik CP, Jacobs JP, Jacobs ML, Jaquiss RD, Kannankeril PJ, O'Brien SM, Torok R, Turek JW, Li JS; STRESS Network Investigators. Rationale and design of the STeroids to REduce Systemic inflammation after infant heart Surgery (STRESS) trial. Am Heart J. 2020 Feb;220:192-202. doi: 10.1016/j.ahj.2019.11.016. Epub 2019 Dec 9.