Clinical trial NCT00113087: Trial of Angiotensin Converting Enzyme Inhibition in Infants With Single Ventricle--Pediatric Heart Network
Official title: Trial of ACE Inhibition in Infants With Single Ventricle (A Trial Conducted by the Pediatric Heart Network)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Heart Defects, Congenital
Heart Failure, Congestive
Lead sponsor: National Heart, Lung, and Blood Institute (NHLBI)
Sponsor class: NIH
Collaborators: name: Pediatric Heart Network
First posted: 2005-06-06
Enrollment: 230
Sex: ALL
Maximum age (years): 45
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Weight-for-age Z-score at 14 Months of Age
timeFrame: 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 outcomes:
measure: Height-for-age Z-score
timeFrame: 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
measure: Head Circumference-for-age Z-score
timeFrame: 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
measure: Number of Participants With Ross Heart Failure Class I
timeFrame: Just prior to the pre-Glenn surgery
measure: Number of Participants With Ross Heart Failure Class I
timeFrame: Measured at 14 months of age
measure: B-Type Natriuretic Peptide
timeFrame: Measured just prior to the Glenn surgery
measure: B-type Natriuretic Peptide Level
timeFrame: at the time of the 14 month visit
measure: Neurodevelopmental Status (PDI): the Bayley Scales of Infant Development,Psychomotor Development Index Z-score
timeFrame: at 14 months of age
measure: Neurodevelopmental Status(MDI): Bayley Scales of Infant Development, Mental Developmental Index Z-score
timeFrame: at 14 months of age
measure: Neurodevelopmental Status (FSII)
timeFrame: at 14 months of age
measure: MacArthur-Bates Inventory -Phrases Understood
timeFrame: at 14 months of age
measure: MacArthur-Bates Inventory -Words Understood
timeFrame: at 14 months of age
measure: MacArthur-Bates Inventory -Total Gestures
timeFrame: at 14 months of age
measure: MacArthur-Bates Inventory -Words Produced
timeFrame: at 14 months of age
measure: Ejection Fraction (%)
timeFrame: just before the Glenn surgery
measure: Ejection Fraction (%)
timeFrame: at 14 months of age
measure: Ventricular Mass
timeFrame: just before the Glenn surgery
measure: Ventricular Mass
timeFrame: At 14 months of age
measure: Ventricular Mass Z-score
timeFrame: just before the Glenn surgery
measure: Ventricular Mass Z-score
timeFrame: at 14 months of age
measure: End-diastolic Volume
timeFrame: just before the Glenn surgery
measure: End-diastolic Volume
timeFrame: at 14 months of age
measure: End Diastolic Volume Z-score
timeFrame: just before the Glenn surgery
measure: End-diastolic Volume Z-score
timeFrame: at 14 months of age
measure: Ventricular Mass to Volume Ratio
timeFrame: Measured just before the Glenn surgery
measure: Ventricular Mass to Volume Ratio
timeFrame: Measured at 14 months of age
measure: Ventricular Filling Pressure
timeFrame: just before the Glenn surgery
measure: Number of Participants With Moderate to Severe AV Valve Regurgitation
timeFrame: just before the pre-Glenn surgery
measure: Number of Participants With Moderate to Severe AV Valve Regurgitation
timeFrame: at age 14 months
Other outcomes:
Locations:
city: Boston
country: United States
facility: Children's Hospital Boston
state: Massachusetts
city: New York
country: United States
facility: Columbia College of Physicians and Surgeons
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Salt Lake City
country: United States
facility: Primary Children's Hospital
state: Utah
city: Milwaukee
country: United States
facility: Children's Hospital of Wisconsin
state: Wisconsin
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
Study officials:
affiliation: Duke University Medical Center, Durham, NC
name: Page Anderson, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: The Children's Hospital at Montefiore, NYC, NY
name: Daphne Hsu, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: The Hospital for Sick Children
name: Brian McCrindle, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Primary Children's Hospital, Salt Lake City, UT
name: LuAnn Minich, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Hospital Boston, Boston, MA
name: Jane Newburger, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Medical University of South Carolina
name: J. Philip Saul, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: New England Research Institute, Watertown, MA
name: Lynn Sleeper, Sc.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Hospital of Philadelphia, Philadelphia, PA
name: Victoria Vetter, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Cincinnati Children's Medical Center, Cincinnati, OH
name: Woodrow Benson, MD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: 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.
citation: 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.
citation: 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.
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