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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
230
Children's Hospital Boston
Boston, Massachusetts, United States
Columbia College of Physicians and Surgeons
New York, New York, United States
Duke University Medical Center
Durham, North Carolina, United States
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States
Medical University of South Carolina
Charleston, South Carolina, United States
Primary Children's Hospital
Salt Lake City, Utah, United States
Children's Hospital of Wisconsin
Milwaukee, Wisconsin, United States
Hospital for Sick Children
Toronto, Ontario, Canada
Weight-for-age Z-score at 14 Months of Age
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)
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
Height-for-age Z-score
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)
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
Head Circumference-for-age Z-score
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)
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
Number of Participants With Ross Heart Failure Class I
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.
Time frame: Just prior to the pre-Glenn surgery
Number of Participants With Ross Heart Failure Class I
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.
Time frame: Measured at 14 months of age
B-Type Natriuretic Peptide
B-Type Natriuretic Peptide (BNP) level.
Time frame: Measured just prior to the Glenn surgery
B-type Natriuretic Peptide Level
B-type natriuretic peptide (BNP) level.
Time frame: at the time of the 14 month visit
Neurodevelopmental Status (PDI): the Bayley Scales of Infant Development,Psychomotor Development Index Z-score
Neurodevelopmental status (PDI): the Bayley Scales of Infant Development: Psychomotor Development index z-score .
Time frame: at 14 months of age
Neurodevelopmental Status(MDI): Bayley Scales of Infant Development, Mental Developmental Index Z-score
Neurodevelopmental status(MDI):Bayley Scales of infant development, Mental Developmental Index z-score .
Time frame: at 14 months of age
Neurodevelopmental Status (FSII)
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.
Time frame: at 14 months of age
MacArthur-Bates Inventory -Phrases Understood
MacArthur-Bates Communicative Development inventory( Words and Gestures)-Phrases Understood z-score.
Time frame: at 14 months of age
MacArthur-Bates Inventory -Words Understood
MacArthur-Bates Communicative Development inventory( Words and Gestures)-Words Understood z-score.
Time frame: at 14 months of age
MacArthur-Bates Inventory -Total Gestures
MacArthur-Bates Communicative Development inventory( Words and Gestures)-Total Gestures z-score.
Time frame: at 14 months of age
MacArthur-Bates Inventory -Words Produced
MacArthur-Bates Communicative Development inventory( Words and Gestures)-Words Produced z-score.
Time frame: at 14 months of age
Ejection Fraction (%)
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.
Time frame: just before the Glenn surgery
Ejection Fraction (%)
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.
Time frame: at 14 months of age
Ventricular Mass
Two-dimensional echocardiography endpoint - Total Ventricular mass (g) per Core Laboratory assessment.
Time frame: just before the Glenn surgery
Ventricular Mass
Two-Dimensional Echocardiography endpoint-Total Ventricular mass (g) per Core Laboratory assessment. Range from 15.60 to 70.40
Time frame: At 14 months of age
Ventricular Mass Z-score
Two-dimensional echocardiography endpoint -Total Ventricular mass z-score per Core Laboratory assessment.
Time frame: just before the Glenn surgery
Ventricular Mass Z-score
Two-dimensional echocardiography endpoint -Total Ventricular mass z-score per Core Laboratory assessment.
Time frame: at 14 months of age
End-diastolic Volume
Two-Dimensional Echocardiography endpoint - Total End-diastolic volume (ml) per Core Laboratory assessment.
Time frame: just before the Glenn surgery
End-diastolic Volume
Two-Dimensional Echocardiography endpoint - Total End-diastolic volume (ml) per Core Laboratory assessment.
Time frame: at 14 months of age
End Diastolic Volume Z-score
Two-dimensional echocardiography endpoint -total End diastolic volume z-score per Core Laboratory assessment.
Time frame: just before the Glenn surgery
End-diastolic Volume Z-score
Two-dimensional echocardiography endpoint -total end-diastolic volume z-score per Core Laboratory assessment.
Time frame: at 14 months of age
Ventricular Mass to Volume Ratio
Two-Dimensional Echocardiography endpoint -Ventricular Mass to Volume ratio per Core Laboratory assessment.
Time frame: Measured just before the Glenn surgery
Ventricular Mass to Volume Ratio
Two-Dimensional Echocardiography endpoint -Ventricular Mass to Volume ratio per Core Laboratory assessment.
Time frame: Measured at 14 months of age
Ventricular Filling Pressure
Ventricular filling pressure measured by catherization
Time frame: just before the Glenn surgery
Number of Participants With Moderate to Severe AV Valve Regurgitation
Number of participants with Moderate to severe AV valve regurgitation.
Time frame: just before the pre-Glenn surgery
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
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