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

Study Overview
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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.

Official Title
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Trial of ACE Inhibition in Infants With Single Ventricle (A Trial Conducted by the Pediatric Heart Network)

Conditions
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Heart Defects, Congenital, Heart Failure, Congestive

Intervention / Treatment
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* Drug: Enalapril
* Drug: Placebo


Participation Criteria
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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

Ages Eligible for Study
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Maximum Age: 45 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Enalapril<br>Enalapril (angiotensin converting enzyme inhibitor) | Drug: Enalapril<br>* Enalapril to target dose of .4mg/kg/day divided to twice per day (BID)<br>|
| Placebo Comparator: Placebo<br>Placebo (Ora-Plus and Ora-Sweet) | Drug: Placebo<br>* Participants will receive placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 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) | 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. | 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. | Measured at 14 months of age | 
| B-Type Natriuretic Peptide | B-Type Natriuretic Peptide (BNP) level. | Measured just prior to the Glenn surgery | 
| B-type Natriuretic Peptide Level | B-type natriuretic peptide (BNP) level. | 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 . | 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 . | 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. | at 14 months of age | 
| MacArthur-Bates Inventory -Phrases Understood | MacArthur-Bates Communicative Development inventory( Words and Gestures)-Phrases Understood z-score. | at 14 months of age | 
| MacArthur-Bates Inventory -Words Understood | MacArthur-Bates Communicative Development inventory( Words and Gestures)-Words Understood z-score. | at 14 months of age | 
| MacArthur-Bates Inventory -Total Gestures | MacArthur-Bates Communicative Development inventory( Words and Gestures)-Total Gestures z-score. | at 14 months of age | 
| MacArthur-Bates Inventory -Words Produced | MacArthur-Bates Communicative Development inventory( Words and Gestures)-Words Produced z-score. | 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. | 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. | at 14 months of age | 
| Ventricular Mass | Two-dimensional echocardiography endpoint - Total Ventricular mass (g) per Core Laboratory assessment. | 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 | At 14 months of age | 
| Ventricular Mass Z-score | Two-dimensional echocardiography endpoint -Total Ventricular mass z-score per Core Laboratory assessment. | just before the Glenn surgery | 
| Ventricular Mass Z-score | Two-dimensional echocardiography endpoint -Total Ventricular mass z-score per Core Laboratory assessment. | at 14 months of age | 
| End-diastolic Volume | Two-Dimensional Echocardiography endpoint - Total End-diastolic volume (ml) per Core Laboratory assessment. | just before the Glenn surgery | 
| End-diastolic Volume | Two-Dimensional Echocardiography endpoint - Total End-diastolic volume (ml) per Core Laboratory assessment. | at 14 months of age | 
| End Diastolic Volume Z-score | Two-dimensional echocardiography endpoint -total End diastolic volume z-score per Core Laboratory assessment. | just before the Glenn surgery | 
| End-diastolic Volume Z-score | Two-dimensional echocardiography endpoint -total end-diastolic volume z-score per Core Laboratory assessment. | at 14 months of age | 
| Ventricular Mass to Volume Ratio | Two-Dimensional Echocardiography endpoint -Ventricular Mass to Volume ratio per Core Laboratory assessment. | Measured just before the Glenn surgery | 
| Ventricular Mass to Volume Ratio | Two-Dimensional Echocardiography endpoint -Ventricular Mass to Volume ratio per Core Laboratory assessment. | Measured at 14 months of age | 
| Ventricular Filling Pressure | Ventricular filling pressure measured by catherization | 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. | 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. | at age 14 months |