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

Heart Failure, Congestive Clinical Trial

— ISV  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00113087
• Other study ID #: 177
• Secondary ID: U01HL068270U01HL
• Status: Completed
• Phase: Phase 3
• First received: June 3, 2005
• Last updated: September 16, 2010
• Start date: August 2003
• Est. completion date: July 2008

Study information

• Verified date: September 2009
• Source: National Heart, Lung, and Blood Institute (NHLBI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 230
• Est. completion date: July 2008
• Est. primary completion date: July 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 45 Days

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Congenital Abnormalities
• Heart Defects, Congenital
• Heart Failure
• Heart Failure, Congestive

Intervention

Drug:
• Enalapril
Enalapril to target dose of .4mg/kg/day divided to twice per day (BID)
• Placebo
Participants will receive placebo

Locations

Country	Name	City	State
Canada	Hospital for Sick Children	Toronto	Ontario
United States	Children's Hospital Boston	Boston	Massachusetts
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Duke University Medical Center	Durham	North Carolina
United States	Children's Hospital of Wisconsin	Milwaukee	Wisconsin
United States	Columbia College of Physicians and Surgeons	New York	New York
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Primary Children's Hospital	Salt Lake City	Utah

Sponsors (2)

Lead Sponsor	Collaborator
National Heart, Lung, and Blood Institute (NHLBI)	Pediatric Heart Network

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	Yes
Secondary	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	No
Secondary	B-Type Natriuretic Peptide	B-Type Natriuretic Peptide (BNP) level.	Measured just prior to the Glenn surgery	No
Secondary	B-type Natriuretic Peptide Level	B-type natriuretic peptide (BNP) level.	at the time of the 14 month visit	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	MacArthur-Bates Inventory -Phrases Understood	MacArthur-Bates Communicative Development inventory( Words and Gestures)-Phrases Understood z-score.	at 14 months of age	No
Secondary	MacArthur-Bates Inventory -Words Understood	MacArthur-Bates Communicative Development inventory( Words and Gestures)-Words Understood z-score.	at 14 months of age	No
Secondary	MacArthur-Bates Inventory -Total Gestures	MacArthur-Bates Communicative Development inventory( Words and Gestures)-Total Gestures z-score.	at 14 months of age	No
Secondary	MacArthur-Bates Inventory -Words Produced	MacArthur-Bates Communicative Development inventory( Words and Gestures)-Words Produced z-score.	at 14 months of age	No
Secondary	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	No
Secondary	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	No
Secondary	Ventricular Mass	Two-dimensional echocardiography endpoint - Total Ventricular mass (g) per Core Laboratory assessment.	just before the Glenn surgery	No
Secondary	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	No
Secondary	Ventricular Mass Z-score	Two-dimensional echocardiography endpoint -Total Ventricular mass z-score per Core Laboratory assessment.	just before the Glenn surgery	No
Secondary	Ventricular Mass Z-score	Two-dimensional echocardiography endpoint -Total Ventricular mass z-score per Core Laboratory assessment.	at 14 months of age	No
Secondary	End-diastolic Volume	Two-Dimensional Echocardiography endpoint - Total End-diastolic volume (ml) per Core Laboratory assessment.	just before the Glenn surgery	No
Secondary	End-diastolic Volume	Two-Dimensional Echocardiography endpoint - Total End-diastolic volume (ml) per Core Laboratory assessment.	at 14 months of age	No
Secondary	End Diastolic Volume Z-score	Two-dimensional echocardiography endpoint -total End diastolic volume z-score per Core Laboratory assessment.	just before the Glenn surgery	No
Secondary	End-diastolic Volume Z-score	Two-dimensional echocardiography endpoint -total end-diastolic volume z-score per Core Laboratory assessment.	at 14 months of age	No
Secondary	Ventricular Mass to Volume Ratio	Two-Dimensional Echocardiography endpoint -Ventricular Mass to Volume ratio per Core Laboratory assessment.	Measured just before the Glenn surgery	No
Secondary	Ventricular Mass to Volume Ratio	Two-Dimensional Echocardiography endpoint -Ventricular Mass to Volume ratio per Core Laboratory assessment.	Measured at 14 months of age	No
Secondary	Ventricular Filling Pressure	Ventricular filling pressure measured by catherization	just before the Glenn surgery	No
Secondary	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	No
Secondary	Number of Participants With Moderate to Severe AV Valve Regurgitation	Number of participants with moderate to severe AV valve regurgitation.	at age 14 months	No