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

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

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.

Study Overview

• Status: Completed
• Conditions: Heart Defects, Congenital; Heart Failure, Congestive
• Intervention / Treatment: Drug: Placebo; Drug: Enalapril

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.

• Study Type: Interventional
• Enrollment (Actual): 230
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for sick children
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Children's Hospital Boston
  • New York
    • New York, New York, United States, 10032
      • Columbia College of Physicians and Surgeons
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • Primary Children's Hospital
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Children's Hospital of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 1 month (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Collaborators: Pediatric Heart Network
• Investigators: Principal Investigator: Brian McCrindle, MD, The Hospital For Sick Children; Principal Investigator: Page Anderson, MD, Duke University Medical Center, Durham, NC; Principal Investigator: Daphne Hsu, MD, The Children's Hospital at Montefiore, NYC, NY; Principal Investigator: LuAnn Minich, MD, Primary Children's Hospital, Salt Lake City, UT; Principal Investigator: Jane Newburger, MD, Children's Hospital Boston, Boston, MA; Principal Investigator: J. Philip Saul, MD, Medical University of South Carolina; Principal Investigator: Lynn Sleeper, Sc.D., New England Research Institute, Watertown, MA; Principal Investigator: Victoria Vetter, MD, Children's Hospital of Philadelphia, Philadelphia, PA; Principal Investigator: Woodrow Benson, MD, Cincinnati Children's Medical Center, Cincinnati, OH

Publications and helpful links

General Publications

• Miller TA, Zak V, Shrader P, Ravishankar C, Pemberton VL, Newburger JW, Shillingford AJ, Dagincourt N, Cnota JF, Lambert LM, Sananes R, Richmond ME, Hsu DT, Miller SG, Zyblewski SC, Williams RV; Pediatric Heart Network Investigators. Growth Asymmetry, Head Circumference, and Neurodevelopmental Outcomes in Infants with Single Ventricles. J Pediatr. 2016 Jan;168:220-225.e1. doi: 10.1016/j.jpeds.2015.09.041. Epub 2015 Oct 17.
• Ravishankar C, Zak V, Williams IA, Bellinger DC, Gaynor JW, Ghanayem NS, Krawczeski CD, Licht DJ, Mahony L, Newburger JW, Pemberton VL, Williams RV, Sananes R, Cook AL, Atz T, Khaikin S, Hsu DT; Pediatric Heart Network Investigators. Association of impaired linear growth and worse neurodevelopmental outcome in infants with single ventricle physiology: a report from the pediatric heart network infant single ventricle trial. J Pediatr. 2013 Feb;162(2):250-6.e2. doi: 10.1016/j.jpeds.2012.07.048. Epub 2012 Aug 30.
• Cnota JF, Allen KR, Colan S, Covitz W, Graham EM, Hehir DA, Levine JC, Margossian R, McCrindle BW, Minich LL, Natarajan S, Richmond ME, Hsu DT; Pediatric Heart Network Investigators. Superior cavopulmonary anastomosis timing and outcomes in infants with single ventricle. J Thorac Cardiovasc Surg. 2013 May;145(5):1288-96. doi: 10.1016/j.jtcvs.2012.07.069. Epub 2012 Aug 28.
• Pike NA, Pemberton V, Allen K, Jacobs JP, Hsu DT, Lewis AB, Ghanayem N, Lambert L, Crawford K, Atz T, Korsin R, Xu M, Ravishankar C, Cnota J, Pearson GD. Challenges and successes of recruitment in the "angiotensin-converting enzyme inhibition in infants with single ventricle trial" of the Pediatric Heart Network. Cardiol Young. 2013 Apr;23(2):248-57. doi: 10.1017/S1047951112000832. Epub 2012 Jul 5. Erratum In: Cardiol Young. 2013 Apr;23(2):314.
• 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.
• 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.
• 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.
• Hsu DT, Mital S, Ravishankar C, Margossian R, Li JS, Sleeper LA, Williams RV, Levine JC, McCrindle BW, Atz AM, Servedio D, Mahony L; Pediatric Heart Network Investigators. Rationale and design of a trial of angiotensin-converting enzyme inhibition in infants with single ventricle. Am Heart J. 2009 Jan;157(1):37-45. doi: 10.1016/j.ahj.2008.08.030.

Study record dates

Study Major Dates

• Study Start: August 1, 2003
• Primary Completion (Actual): July 1, 2008
• Study Completion (Actual): July 1, 2008

Study Registration Dates

• First Submitted: June 3, 2005
• First Submitted That Met QC Criteria: June 3, 2005
• First Posted (Estimate): June 6, 2005

Study Record Updates

• Last Update Posted (Estimate): September 28, 2010
• Last Update Submitted That Met QC Criteria: September 16, 2010
• Last Verified: September 1, 2009

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Cardiovascular Abnormalities; Heart Failure; Congenital Abnormalities; Heart Defects, Congenital; Univentricular Heart; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Enzyme Inhibitors; Protease Inhibitors; Angiotensin-Converting Enzyme Inhibitors; Enalapril
• Other Study ID Numbers: 177; U01HL068292 (U.S. NIH Grant/Contract); U01HL068290 (U.S. NIH Grant/Contract); U01HL068288 (U.S. NIH Grant/Contract); U01HL068285 (U.S. NIH Grant/Contract); U01HL068281 (U.S. NIH Grant/Contract); U01HL068279 (U.S. NIH Grant/Contract); U01HL068270 (U.S. NIH Grant/Contract); U01HL068269 (U.S. NIH Grant/Contract)