Trial of Angiotensin Converting Enzyme Inhibition in Infants With Single Ventricle--Pediatric Heart Network

Study Results

Results available

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

230 participants

Study Classification

INTERVENTIONAL

Study Start Date

2003-08-31

Study Completion Date

2008-07-31

Brief Summary

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This study will evaluate the efficacy and safety of administering an angiotensin converting enzyme inhibitor (ACE-I) (enalapril) to infants with a functional single ventricle. The study will also compare the effect of ACE-I therapy to placebo on somatic growth and compare the effect of ACE-I therapy to placebo on signs and symptoms of heart failure, neurodevelopmental and functional status, ventricular geometry, function, and atrioventricular (AV) valve regurgitation. In addition, the study will determine the relationship between genetic polymorphisms linked to ventricular hypertrophy (enlarged heart) and the response to ACE-I therapy and compare the incidence of adverse events in subjects treated with ACE-I with those in subjects treated with placebo.

Detailed Description

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BACKGROUND:

Growth impairment is common in infants and children with congenital heart disease, most often in the presence of congestive heart failure and/or cyanosis. Growth failure is noted in many infants with a single ventricle who manifest both cyanosis and heart failure that commonly persist after palliative surgery. Whether this impairment is related to persistent or progressive abnormalities in cardiac structure and function is not known. ACE-Is are widely used in the treatment of infants with severe congestive heart failure to improve cardiac function and somatic growth. The ability of an ACE-I to improve somatic growth in infants with a single ventricle has not been previously studied.

This study has been approved by the Institutional Review Boards/Research Ethics Boards of all participating clinical centers:

Hospital for Sick Children, Toronto, Canada

Children's Hospital Boston, Boston, MA

Columbia College of Physicians and Surgeons, New York, NY

Children's Hospital of Philadelphia, Philadelphia, PA

Duke University Medical Center, Durham, NC

Brody School of Medicine at East Carolina University, Greenville, NC

Wake Forest Baptist Medical Center, Winston Salem, NC

Medical University of South Carolina, Charleston, SC

Primary Children's Medical Center, Salt Lake City, UT

Children's Hospital of Wisconsin, Milwaukee, WI

Cincinnati Children's Hospital Medical Center, Cincinnati, OH

DESIGN NARRATIVE:

This is a prospective, randomized, double-blind, placebo-controlled trial of ACE-I in infants with a single ventricle. After stratification by ventricular anatomy, neonates will be randomly assigned to receive enalapril or placebo and then followed for 14 months.

Conditions

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Heart Defects, Congenital Heart Failure, Congestive

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

TRIPLE

Participants Investigators Outcome Assessors

Study Groups

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Enalapril

Enalapril (angiotensin converting enzyme inhibitor)

Group Type ACTIVE_COMPARATOR

Enalapril

Intervention Type DRUG

Enalapril to target dose of .4mg/kg/day divided to twice per day (BID)

Placebo

Placebo (Ora-Plus and Ora-Sweet)

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type DRUG

Participants will receive placebo

Interventions

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Enalapril

Enalapril to target dose of .4mg/kg/day divided to twice per day (BID)

Intervention Type DRUG

Placebo

Participants will receive placebo

Intervention Type DRUG

Eligibility Criteria

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Inclusion Criteria

* Less than or equal to 45 days of age
* Age greater than 1 week if born at 35 weeks gestation
* Single ventricle physiology
* Stable systemic and pulmonary blood flow
* Planned Glenn shunt surgery (or variant known as hemi-Fontan)

Exclusion Criteria

* Birth weight less than or equal to 2.5 kg if gestational age is greater than or equal to 38 weeks
* Birth weight less than the 10th percentile for gestational age if gestational age is 35 to 37 weeks
* Less than 35 weeks gestation
* Anatomic diagnosis of pulmonary atresia with intact ventricular septum
* Less than 3 days after palliative cardiac surgical procedure, if performed
* Aortic oxygen saturation less than 65%
* Current mechanical ventilatory support
* Current intravenous inotropic support
* Creatinine greater than 1.0 mg/dL
* Absolute neutrophil count less than 1,000 cells/mL
* Chromosomal or recognizable phenotypic syndrome of noncardiac congenital abnormalities associated with growth failure (e.g., Trisomy 21, Noonan's syndrome, Turner's syndrome)
* Prior ACE inhibitor use for greater than 7 consecutive days

Maximum Eligible Age

45 Days

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Responsible Party

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New England Research Institutes

Principal Investigators

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Page Anderson, MD

Role: PRINCIPAL_INVESTIGATOR

Duke University Medical Center, Durham, NC

Daphne Hsu, MD

Role: PRINCIPAL_INVESTIGATOR

The Children's Hospital at Montefiore, NYC, NY

Brian McCrindle, MD

Role: PRINCIPAL_INVESTIGATOR

The Hospital for Sick Children

LuAnn Minich, MD

Role: PRINCIPAL_INVESTIGATOR

Primary Children's Hospital, Salt Lake City, UT

Jane Newburger, MD

Role: PRINCIPAL_INVESTIGATOR

Children's Hospital Boston, Boston, MA

J. Philip Saul, MD

Role: PRINCIPAL_INVESTIGATOR

Medical University of South Carolina

Lynn Sleeper, Sc.D.

Role: PRINCIPAL_INVESTIGATOR

New England Research Institute, Watertown, MA

Victoria Vetter, MD

Role: PRINCIPAL_INVESTIGATOR

Children's Hospital of Philadelphia, Philadelphia, PA

Woodrow Benson, MD

Role: PRINCIPAL_INVESTIGATOR

Cincinnati Children's Medical Center, Cincinnati, OH

Locations

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Children's Hospital Boston

Boston, Massachusetts, United States

Site Status

Columbia College of Physicians and Surgeons

New York, New York, United States

Site Status

Duke University Medical Center

Durham, North Carolina, United States

Site Status

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

Site Status

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Site Status

Medical University of South Carolina

Charleston, South Carolina, United States

Site Status

Primary Children's Hospital

Salt Lake City, Utah, United States

Site Status

Children's Hospital of Wisconsin

Milwaukee, Wisconsin, United States

Site Status

Hospital for Sick Children

Toronto, Ontario, Canada

Site Status

Countries

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United States Canada

References

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Miller TA, Zak V, Shrader P, Ravishankar C, Pemberton VL, Newburger JW, Shillingford AJ, Dagincourt N, Cnota JF, Lambert LM, Sananes R, Richmond ME, Hsu DT, Miller SG, Zyblewski SC, Williams RV; Pediatric Heart Network Investigators. Growth Asymmetry, Head Circumference, and Neurodevelopmental Outcomes in Infants with Single Ventricles. J Pediatr. 2016 Jan;168:220-225.e1. doi: 10.1016/j.jpeds.2015.09.041. Epub 2015 Oct 17.

Reference Type DERIVED

PMID: 26490132 (View on PubMed)

Ravishankar C, Zak V, Williams IA, Bellinger DC, Gaynor JW, Ghanayem NS, Krawczeski CD, Licht DJ, Mahony L, Newburger JW, Pemberton VL, Williams RV, Sananes R, Cook AL, Atz T, Khaikin S, Hsu DT; Pediatric Heart Network Investigators. Association of impaired linear growth and worse neurodevelopmental outcome in infants with single ventricle physiology: a report from the pediatric heart network infant single ventricle trial. J Pediatr. 2013 Feb;162(2):250-6.e2. doi: 10.1016/j.jpeds.2012.07.048. Epub 2012 Aug 30.

Reference Type DERIVED

PMID: 22939929 (View on PubMed)

Cnota JF, Allen KR, Colan S, Covitz W, Graham EM, Hehir DA, Levine JC, Margossian R, McCrindle BW, Minich LL, Natarajan S, Richmond ME, Hsu DT; Pediatric Heart Network Investigators. Superior cavopulmonary anastomosis timing and outcomes in infants with single ventricle. J Thorac Cardiovasc Surg. 2013 May;145(5):1288-96. doi: 10.1016/j.jtcvs.2012.07.069. Epub 2012 Aug 28.

Reference Type DERIVED

PMID: 22939855 (View on PubMed)

Pike NA, Pemberton V, Allen K, Jacobs JP, Hsu DT, Lewis AB, Ghanayem N, Lambert L, Crawford K, Atz T, Korsin R, Xu M, Ravishankar C, Cnota J, Pearson GD. Challenges and successes of recruitment in the "angiotensin-converting enzyme inhibition in infants with single ventricle trial" of the Pediatric Heart Network. Cardiol Young. 2013 Apr;23(2):248-57. doi: 10.1017/S1047951112000832. Epub 2012 Jul 5.

Reference Type DERIVED

PMID: 22931751 (View on PubMed)

Williams RV, Zak V, Ravishankar C, Altmann K, Anderson J, Atz AM, Dunbar-Masterson C, Ghanayem N, Lambert L, Lurito K, Medoff-Cooper B, Margossian R, Pemberton VL, Russell J, Stylianou M, Hsu D; Pediatric Heart Network Investigators. Factors affecting growth in infants with single ventricle physiology: a report from the Pediatric Heart Network Infant Single Ventricle Trial. J Pediatr. 2011 Dec;159(6):1017-22.e2. doi: 10.1016/j.jpeds.2011.05.051. Epub 2011 Jul 23.

Reference Type DERIVED

PMID: 21784436 (View on PubMed)

Mital S, Chung WK, Colan SD, Sleeper LA, Manlhiot C, Arrington CB, Cnota JF, Graham EM, Mitchell ME, Goldmuntz E, Li JS, Levine JC, Lee TM, Margossian R, Hsu DT; Pediatric Heart Network Investigators. Renin-angiotensin-aldosterone genotype influences ventricular remodeling in infants with single ventricle. Circulation. 2011 May 31;123(21):2353-62. doi: 10.1161/CIRCULATIONAHA.110.004341. Epub 2011 May 16.

Reference Type DERIVED

PMID: 21576655 (View on PubMed)

Hsu DT, Zak V, Mahony L, Sleeper LA, Atz AM, Levine JC, Barker PC, Ravishankar C, McCrindle BW, Williams RV, Altmann K, Ghanayem NS, Margossian R, Chung WK, Border WL, Pearson GD, Stylianou MP, Mital S; Pediatric Heart Network Investigators. Enalapril in infants with single ventricle: results of a multicenter randomized trial. Circulation. 2010 Jul 27;122(4):333-40. doi: 10.1161/CIRCULATIONAHA.109.927988. Epub 2010 Jul 12.

Reference Type DERIVED

PMID: 20625111 (View on PubMed)

Hsu DT, Mital S, Ravishankar C, Margossian R, Li JS, Sleeper LA, Williams RV, Levine JC, McCrindle BW, Atz AM, Servedio D, Mahony L; Pediatric Heart Network Investigators. Rationale and design of a trial of angiotensin-converting enzyme inhibition in infants with single ventricle. Am Heart J. 2009 Jan;157(1):37-45. doi: 10.1016/j.ahj.2008.08.030.

Reference Type DERIVED

PMID: 19081394 (View on PubMed)