STeroids to REduce Systemic Inflammation After Infant Heart Surgery

NCT03229538 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: Pro000781061U01TR001803-01
• Study Type: interventional
• Target: 1,263
• Locations: 1 country
• Sites: 23

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.

Conditions

Congenital Heart Disease in Children; Inflammatory Response

Outcome Measures

Primary Outcomes (1)

• Number of Participants at Each Global Rank Endpoint Based Upon Their Most-severe Outcome

  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.

  Until hospital discharge, up to 4 months

Secondary Outcomes (12)

• 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

• 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

• Number of Participants With a Post-operative Length of Stay Greater Than 90 Days

  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

Study Arms (2)

Methylprednisolone Arm

EXPERIMENTAL

IV Methylprednisolone

Drug: Methylprednisolone

Placebo Arm

PLACEBO COMPARATOR

IV Isotonic Saline

Drug: Isotonic saline

Interventions

Methylprednisolone DRUG

IV Steroid pre-operative and intra-operative

Methylprednisolone Arm

Isotonic saline DRUG

Isotonic saline pre-operative and intra-operative

Placebo Arm

Eligibility Criteria

• Age: Up to 12 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• \< 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

Sponsors & Collaborators

• Kevin Hill: lead
• National Center for Advancing Translational Sciences (NCATS): collaborator

Study Sites (23)

Children's Hospital of Los Angeles

Los Angeles, California, 90027, United States

Location

University of Colorado, Denver

Aurora, Colorado, 80045, United States

Location

University of Florida Health - Shands Hospital

Gainesville, Florida, 32608, United States

Location

Ann & Robert Lurie Children's Hospital of Chicago

Chicago, Illinois, 60611-2605, United States

Location

Advocate Children's Hospital

Oak Lawn, Illinois, 60453, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21205, United States

Location

Children's Hospital and Clinics of Minnesota

Minneapolis, Minnesota, 55404, United States

Location

Children's Mercy Hospital

Kansas City, Missouri, 64108, United States

Location

St. Louis Children's Hospital

St Louis, Missouri, 63110, United States

Location

Children's Hospital and Medical Center

Omaha, Nebraska, 68114, United States

Location

Morgan Stanley Children's Hospital of New York Presbyterian

New York, New York, 10032-3702, United States

Location

University of Rochester Medical Center

Rochester, New York, 14642, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Children's Hospital Medical Center

Cincinnati, Ohio, 45229-3039, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

Location

Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, 15224, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

Location

The University of Texas Southwestern Medical Center

Dallas, Texas, 75390-9020, United States

Location

Baylor College of Medicine, Texas Children's Hospital

Houston, Texas, 77030, United States

Location

Utah/Primary Children's Medical Center

Salt Lake City, Utah, 84113, United States

Location

Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

Related Publications (25)

• 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.

  PMID: 9381406 BACKGROUND

• 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.

  PMID: 12239736 BACKGROUND

• 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.

  PMID: 17022030 BACKGROUND

• 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.

  PMID: 9358267 BACKGROUND

• 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.

  PMID: 12600913 BACKGROUND

• 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.

  PMID: 235375 BACKGROUND

• 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.

  PMID: 7554206 BACKGROUND

• 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.

  PMID: 9315800 BACKGROUND

• 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.

  PMID: 16242437 BACKGROUND

• 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.

  PMID: 10881828 BACKGROUND

• 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.

  PMID: 12794414 BACKGROUND

• 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.

  PMID: 21440149 BACKGROUND

• 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.

  PMID: 21600592 BACKGROUND

• 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.

  PMID: 23870160 BACKGROUND

• 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.

  PMID: 7377659 BACKGROUND

• 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.

  PMID: 24892482 BACKGROUND

• 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.

  PMID: 22271697 BACKGROUND

• 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.

  PMID: 24598306 BACKGROUND

• 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.

  PMID: 24717907 BACKGROUND

• 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.

  PMID: 22835225 BACKGROUND

• 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.

  PMID: 16340373 BACKGROUND

• Hill KD, Koerner J, Hong H, Li JS, Hornik C, Kannankeril PJ, Jacobs JP, Baldwin HS, Jacobs ML, Graham EM, Blasiole B, Vener DF, Husain AS, Kumar SR, Benscoter A, Wald E, Karamlou T, Van Bergen AH, Overman D, Eghtesady P, Butts R, Kim JS, Scott JP, Anderson BR, Swartz MF, O'Brien SM. A Bayesian re-analysis of the STRESS trial. Am Heart J. 2026 Feb;292:107282. doi: 10.1016/j.ahj.2025.09.014. Epub 2025 Sep 25.

  PMID: 41015071 DERIVED

• 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.

  PMID: 36342116 DERIVED

• 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.

  PMID: 33045104 DERIVED

• 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.

  PMID: 31855716 DERIVED

Related Links

• 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).

MeSH Terms

Interventions

Methylprednisolone; Sodium Chloride

Intervention Hierarchy (Ancestors)

Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Results Point of Contact

• Title: Kevin Hill, MD
• Organization: Duke University

kevin.hill@duke.edu

919-681-6846

Study Officials

• Kevin Hill

  Duke University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor of Pediatrics

Study Record Dates

• First Submitted: July 5, 2017
• First Posted: July 25, 2017
• Study Start: October 18, 2017
• Primary Completion: March 31, 2022
• Study Completion: March 31, 2022
• Last Updated: January 5, 2026
• Results First Posted: May 10, 2023

Record last verified: 2023-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF

Locations

US (23)