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

• Weight-for-age Z-score at 14 Months of Age [ Time Frame: Measured at baseline, 2 weeks after starting study drug, just prior to the Glenn surgery, 7 days after restarting drug following the Glenn surgery, at 10 months of age, and at 14 months of age ] [ Designated as safety issue: No ]
  Weight-for-age z-score at 14 months of age. In primary analysis outcome is defined as predicted mean of weight z-score at age 14 months based on longitudinal modeling(and adjusted for baseline values)
  
  

• Height-for-age Z-score [ Time Frame: Measured at baseline, 2 weeks after starting study drug, just prior to the Glenn surgery, 7 days after restarting drug following the Glenn surgery, at 10 months of age, and at 14 months of age ] [ Designated as safety issue: No ]
  Height-for-age z-score at 14 months of age. In primary analysis outcome is defined as predicted mean of height z-score at age 14 months based on longitudinal modeling (adjusted bor baseline value)
  
  
• Head Circumference-for-age Z-score [ Time Frame: Measured at baseline, 2 weeks after starting study drug, just prior to the Glenn surgery, 7 days after restarting drug following the Glenn surgery, at 10 months of age, and at 14 months of age ] [ Designated as safety issue: No ]
  Head circumference-for-age z-score at 14 months of age.In primary analysis outcome is defined as predicted mean of Head circumference z-score at age 14 months based on longitudinal modeling(and adjusted for baseline values)
  
  
• Number of Participants With Ross Heart Failure Class I [ Time Frame: Just prior to the pre-Glenn surgery ] [ Designated as safety issue: Yes ]
  Class I is defined as having no limitations or symptoms of heart failure. Classes II to IV include increasing degrees of growth failure, prolonged feeding time, tachypnea, diaphoresis, and in older children, dyspnea on exercise.
  
  
• Number of Participants With Ross Heart Failure Class I [ Time Frame: Measured at 14 months of age ] [ Designated as safety issue: No ]
  Class I is defined as having no limitations or symptoms of heart failure. Classes II to IV include increasing degrees of growth failure, prolonged feeding time, tachypnea, diaphoresis, and in older children, dyspnea on exercise.
  
  
• B-Type Natriuretic Peptide [ Time Frame: Measured just prior to the Glenn surgery ] [ Designated as safety issue: No ]
  B-Type Natriuretic Peptide (BNP) level.
  
  
• B-type Natriuretic Peptide Level [ Time Frame: at the time of the 14 month visit ] [ Designated as safety issue: No ]
  B-type natriuretic peptide (BNP) level.
  
  
• Neurodevelopmental Status (PDI): the Bayley Scales of Infant Development,Psychomotor Development Index Z-score [ Time Frame: at 14 months of age ] [ Designated as safety issue: No ]

  Neurodevelopmental status (PDI):

  the Bayley Scales of Infant Development: Psychomotor Development index z-score .

  
  
• Neurodevelopmental Status(MDI): Bayley Scales of Infant Development, Mental Developmental Index Z-score [ Time Frame: at 14 months of age ] [ Designated as safety issue: No ]
  Neurodevelopmental status(MDI):Bayley Scales of infant development, Mental Developmental Index z-score .
  
  
• Neurodevelopmental Status (FSII) [ Time Frame: at 14 months of age ] [ Designated as safety issue: No ]
  Functional status II (Revised) Total Score. Scale ranges up to 100.00, the higher the better. The score presents an instrument for assessing health status for children surviving long term with chronic physcial disorders.
  
  
• MacArthur-Bates Inventory -Phrases Understood [ Time Frame: at 14 months of age ] [ Designated as safety issue: No ]
  MacArthur-Bates Communicative Development inventory( Words and Gestures)-Phrases Understood z-score.
  
  
• MacArthur-Bates Inventory -Words Understood [ Time Frame: at 14 months of age ] [ Designated as safety issue: No ]
  MacArthur-Bates Communicative Development inventory( Words and Gestures)-Words Understood z-score.
  
  
• MacArthur-Bates Inventory -Total Gestures [ Time Frame: at 14 months of age ] [ Designated as safety issue: No ]
  MacArthur-Bates Communicative Development inventory( Words and Gestures)-Total Gestures z-score.
  
  
• MacArthur-Bates Inventory -Words Produced [ Time Frame: at 14 months of age ] [ Designated as safety issue: No ]
  MacArthur-Bates Communicative Development inventory( Words and Gestures)-Words Produced z-score.
  
  
• Ejection Fraction (%) [ Time Frame: just before the Glenn surgery ] [ Designated as safety issue: No ]
  Two-dimensional echocardiography endpoint -Total Ejection Fraction (%) per Core Laboratory assessment. Ejection Fraction % is defined as the percentage of the stroke volume (i.e. difference between end-diastolic and end-systolic volumes) in a ventricle relative to end-diastolic volume.
  
  
• Ejection Fraction (%) [ Time Frame: at 14 months of age ] [ Designated as safety issue: No ]
  Two-dimensional echocardiography endpoint -Total Ejection Fraction (%) per Core Laboratory assessment. Ejection Fraction (%) is defined as percentage of stroke volume of a ventricle (i.e. the difference between end diastolic and end systolic volumes)relative to end diastolic volume.
  
  
• Ventricular Mass [ Time Frame: just before the Glenn surgery ] [ Designated as safety issue: No ]
  Two-dimensional echocardiography endpoint - Total Ventricular mass (g) per Core Laboratory assessment.
  
  
• Ventricular Mass [ Time Frame: At 14 months of age ] [ Designated as safety issue: No ]
  Two-Dimensional Echocardiography endpoint-Total Ventricular mass (g) per Core Laboratory assessment. Range from 15.60 to 70.40
  
  
• Ventricular Mass Z-score [ Time Frame: just before the Glenn surgery ] [ Designated as safety issue: No ]
  Two-dimensional echocardiography endpoint -Total Ventricular mass z-score per Core Laboratory assessment.
  
  
• Ventricular Mass Z-score [ Time Frame: at 14 months of age ] [ Designated as safety issue: No ]
  Two-dimensional echocardiography endpoint -Total Ventricular mass z-score per Core Laboratory assessment.
  
  
• End-diastolic Volume [ Time Frame: just before the Glenn surgery ] [ Designated as safety issue: No ]
  Two-Dimensional Echocardiography endpoint - Total End-diastolic volume (ml) per Core Laboratory assessment.
  
  
• End-diastolic Volume [ Time Frame: at 14 months of age ] [ Designated as safety issue: No ]
  Two-Dimensional Echocardiography endpoint - Total End-diastolic volume (ml) per Core Laboratory assessment.
  
  
• End Diastolic Volume Z-score [ Time Frame: just before the Glenn surgery ] [ Designated as safety issue: No ]
  Two-dimensional echocardiography endpoint -total End diastolic volume z-score per Core Laboratory assessment.
  
  
• End-diastolic Volume Z-score [ Time Frame: at 14 months of age ] [ Designated as safety issue: No ]
  Two-dimensional echocardiography endpoint -total end-diastolic volume z-score per Core Laboratory assessment.
  
  
• Ventricular Mass to Volume Ratio [ Time Frame: Measured just before the Glenn surgery ] [ Designated as safety issue: No ]
  Two-Dimensional Echocardiography endpoint -Ventricular Mass to Volume ratio per Core Laboratory assessment.
  
  
• Ventricular Mass to Volume Ratio [ Time Frame: Measured at 14 months of age ] [ Designated as safety issue: No ]
  Two-Dimensional Echocardiography endpoint -Ventricular Mass to Volume ratio per Core Laboratory assessment.
  
  
• Ventricular Filling Pressure [ Time Frame: just before the Glenn surgery ] [ Designated as safety issue: No ]
  Ventricular filling pressure measured by catherization
  
  
• Number of Participants With Moderate to Severe AV Valve Regurgitation [ Time Frame: just before the pre-Glenn surgery ] [ Designated as safety issue: No ]
  Number of participants with Moderate to severe AV valve regurgitation.
  
  
• Number of Participants With Moderate to Severe AV Valve Regurgitation [ Time Frame: at age 14 months ] [ Designated as safety issue: No ]
  Number of participants with moderate to severe AV valve regurgitation.
  
  

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.