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

This study has been completed.
Sponsor:
Collaborator:
Pediatric Heart Network
Information provided by:
National Heart, Lung, and Blood Institute (NHLBI)
ClinicalTrials.gov Identifier:
NCT00113087
First received: June 3, 2005
Last updated: September 16, 2010
Last verified: September 2009
  Purpose

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.


Condition Intervention Phase
Heart Defects, Congenital
Heart Failure, Congestive
Drug: Enalapril
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Trial of ACE Inhibition in Infants With Single Ventricle (A Trial Conducted by the Pediatric Heart Network)

Resource links provided by NLM:


Further study details as provided by National Heart, Lung, and Blood Institute (NHLBI):

Primary Outcome Measures:
  • Weight-for-age Z-score at 14 Months of Age [ 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 ] [ Designated as safety issue: No ]
    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)


Secondary Outcome Measures:
  • Height-for-age Z-score [ 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 ] [ Designated as safety issue: No ]
    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)

  • Head Circumference-for-age Z-score [ 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 ] [ Designated as safety issue: No ]
    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)

  • Number of Participants With Ross Heart Failure Class I [ Time Frame: Just prior to the pre-Glenn surgery ] [ Designated as safety issue: Yes ]
    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.

  • Number of Participants With Ross Heart Failure Class I [ Time Frame: Measured at 14 months of age ] [ Designated as safety issue: No ]
    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.

  • B-Type Natriuretic Peptide [ Time Frame: Measured just prior to the Glenn surgery ] [ Designated as safety issue: No ]
    B-Type Natriuretic Peptide (BNP) level.

  • B-type Natriuretic Peptide Level [ Time Frame: at the time of the 14 month visit ] [ Designated as safety issue: No ]
    B-type natriuretic peptide (BNP) level.

  • Neurodevelopmental Status (PDI): the Bayley Scales of Infant Development,Psychomotor Development Index Z-score [ Time Frame: at 14 months of age ] [ Designated as safety issue: No ]

    Neurodevelopmental status (PDI):

    the Bayley Scales of Infant Development: Psychomotor Development index z-score .


  • Neurodevelopmental Status(MDI): Bayley Scales of Infant Development, Mental Developmental Index Z-score [ Time Frame: at 14 months of age ] [ Designated as safety issue: No ]
    Neurodevelopmental status(MDI):Bayley Scales of infant development, Mental Developmental Index z-score .

  • Neurodevelopmental Status (FSII) [ Time Frame: at 14 months of age ] [ Designated as safety issue: No ]
    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.

  • MacArthur-Bates Inventory -Phrases Understood [ Time Frame: at 14 months of age ] [ Designated as safety issue: No ]
    MacArthur-Bates Communicative Development inventory( Words and Gestures)-Phrases Understood z-score.

  • MacArthur-Bates Inventory -Words Understood [ Time Frame: at 14 months of age ] [ Designated as safety issue: No ]
    MacArthur-Bates Communicative Development inventory( Words and Gestures)-Words Understood z-score.

  • MacArthur-Bates Inventory -Total Gestures [ Time Frame: at 14 months of age ] [ Designated as safety issue: No ]
    MacArthur-Bates Communicative Development inventory( Words and Gestures)-Total Gestures z-score.

  • MacArthur-Bates Inventory -Words Produced [ Time Frame: at 14 months of age ] [ Designated as safety issue: No ]
    MacArthur-Bates Communicative Development inventory( Words and Gestures)-Words Produced z-score.

  • Ejection Fraction (%) [ Time Frame: just before the Glenn surgery ] [ Designated as safety issue: No ]
    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.

  • Ejection Fraction (%) [ Time Frame: at 14 months of age ] [ Designated as safety issue: No ]
    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.

  • Ventricular Mass [ Time Frame: just before the Glenn surgery ] [ Designated as safety issue: No ]
    Two-dimensional echocardiography endpoint - Total Ventricular mass (g) per Core Laboratory assessment.

  • Ventricular Mass [ Time Frame: At 14 months of age ] [ Designated as safety issue: No ]
    Two-Dimensional Echocardiography endpoint-Total Ventricular mass (g) per Core Laboratory assessment. Range from 15.60 to 70.40

  • Ventricular Mass Z-score [ Time Frame: just before the Glenn surgery ] [ Designated as safety issue: No ]
    Two-dimensional echocardiography endpoint -Total Ventricular mass z-score per Core Laboratory assessment.

  • Ventricular Mass Z-score [ Time Frame: at 14 months of age ] [ Designated as safety issue: No ]
    Two-dimensional echocardiography endpoint -Total Ventricular mass z-score per Core Laboratory assessment.

  • End-diastolic Volume [ Time Frame: just before the Glenn surgery ] [ Designated as safety issue: No ]
    Two-Dimensional Echocardiography endpoint - Total End-diastolic volume (ml) per Core Laboratory assessment.

  • End-diastolic Volume [ Time Frame: at 14 months of age ] [ Designated as safety issue: No ]
    Two-Dimensional Echocardiography endpoint - Total End-diastolic volume (ml) per Core Laboratory assessment.

  • End Diastolic Volume Z-score [ Time Frame: just before the Glenn surgery ] [ Designated as safety issue: No ]
    Two-dimensional echocardiography endpoint -total End diastolic volume z-score per Core Laboratory assessment.

  • End-diastolic Volume Z-score [ Time Frame: at 14 months of age ] [ Designated as safety issue: No ]
    Two-dimensional echocardiography endpoint -total end-diastolic volume z-score per Core Laboratory assessment.

  • Ventricular Mass to Volume Ratio [ Time Frame: Measured just before the Glenn surgery ] [ Designated as safety issue: No ]
    Two-Dimensional Echocardiography endpoint -Ventricular Mass to Volume ratio per Core Laboratory assessment.

  • Ventricular Mass to Volume Ratio [ Time Frame: Measured at 14 months of age ] [ Designated as safety issue: No ]
    Two-Dimensional Echocardiography endpoint -Ventricular Mass to Volume ratio per Core Laboratory assessment.

  • Ventricular Filling Pressure [ Time Frame: just before the Glenn surgery ] [ Designated as safety issue: No ]
    Ventricular filling pressure measured by catherization

  • Number of Participants With Moderate to Severe AV Valve Regurgitation [ Time Frame: just before the pre-Glenn surgery ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    Number of participants with moderate to severe AV valve regurgitation.


Enrollment: 230
Study Start Date: August 2003
Study Completion Date: July 2008
Primary Completion Date: July 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Enalapril
Enalapril (angiotensin converting enzyme inhibitor)
Drug: Enalapril
Enalapril to target dose of .4mg/kg/day divided to twice per day (BID)
Other Name: Enalapril
Placebo Comparator: Placebo
Placebo (Ora-Plus and Ora-Sweet)
Drug: Placebo
Participants will receive placebo
Other Name: 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

Ages Eligible for Study:   up to 45 Days
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00113087

Locations
United States, Massachusetts
Children's Hospital Boston
Boston, Massachusetts, United States, 02115
United States, New York
Columbia College of Physicians and Surgeons
New York, New York, United States, 10032
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
United States, Ohio
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States, 45229
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
United States, South Carolina
Medical University of South Carolina
Charleston, South Carolina, United States, 29425
United States, Utah
Primary Children's Hospital
Salt Lake City, Utah, United States, 84113
United States, Wisconsin
Children's Hospital of Wisconsin
Milwaukee, Wisconsin, United States, 53226
Canada, Ontario
Hospital for Sick Children
Toronto, Ontario, Canada, M5G 1X8
Sponsors and Collaborators
Pediatric Heart Network
Investigators
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: Brian McCrindle, MD The Hospital for Sick Children
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
  More Information

No publications provided by National Heart, Lung, and Blood Institute (NHLBI)

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Lynn Sleeper, PI, New England Research Institutes
ClinicalTrials.gov Identifier: NCT00113087     History of Changes
Other Study ID Numbers: 177, U01HL068270, U01HL068279, U01HL068281, U01HL068285, U01HL068288, U01HL068290, U01HL068292, U01HL068269
Study First Received: June 3, 2005
Results First Received: September 4, 2009
Last Updated: September 16, 2010
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Congenital Abnormalities
Heart Defects, Congenital
Heart Failure
Cardiovascular Abnormalities
Cardiovascular Diseases
Heart Diseases
Angiotensin-Converting Enzyme Inhibitors
Enalapril
Enalaprilat
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antihypertensive Agents
Cardiovascular Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on April 17, 2014