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Heart Defects, CongenitalPhase 3ISVNCT00113087

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

A Phase 3 study testing Enalapril in people with Heart Defects, Congenital and Heart Failure, Congestive, run by National Heart, Lung, and Blood Institute (NHLBI) at 9 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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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… Read more about this study

Who is it for?
Ages Up to 45 days
What is being tested?
Enalapril
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
230 participants
Where
9 sitesin 2 countries
Study dates
Aug 2003to Jul 2008
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages Up to 45 days
  • All sexes
  • No healthy volunteers
  • Child

Who may be able to join

  • 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)

Who cannot join

  • 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%
Show all 12Show fewer
  • 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

Trial locations and contacts

9 sites in 2 countries.

9 sites in 2 countries

United States8 sites
  • Children's Hospital Boston

    Boston, Massachusetts, 02115

  • Medical University of South Carolina

    Charleston, South Carolina, 29425

  • Cincinnati Children's Hospital Medical Center

    Cincinnati, Ohio, 45229

  • Duke University Medical Center

    Durham, North Carolina, 27710

  • Children's Hospital of Wisconsin

    Milwaukee, Wisconsin, 53226

  • Columbia College of Physicians and Surgeons

    New York, New York, 10032

  • Children's Hospital of Philadelphia

    Philadelphia, Pennsylvania, 19104

  • Primary Children's Hospital

    Salt Lake City, Utah, 84113

Other trials in United States

Canada1 site
  • Hospital for Sick Children

    Toronto, Ontario, M5G 1X8

Other trials in Canada

About this study

Official title: 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.

Read the 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.

Being tested
Enalapril, Placebo
Medical subject headings
Heart Defects, Congenital, Heart Failure

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • EnalaprilDrug

    Enalapril to target dose of .4mg/kg/day divided to twice per day (BID)

  • PlaceboDrug

    Participants will receive placebo

Study groups in NCT00113087
Study groupRoleWhat they receive
EnalaprilActive comparatorEnalapril (angiotensin converting enzyme inhibitor)
Receives: Drug: Enalapril
PlaceboPlacebo comparatorPlacebo (Ora-Plus and Ora-Sweet)
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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: 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 (28)
  1. 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: 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

  2. 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: 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

  3. 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: Just prior to the pre-Glenn surgery

  4. 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: Measured at 14 months of age

  5. B-Type Natriuretic Peptide

    B-Type Natriuretic Peptide (BNP) level.

    Measured: Measured just prior to the Glenn surgery

  6. B-type Natriuretic Peptide Level

    B-type natriuretic peptide (BNP) level.

    Measured: at the time of the 14 month visit

  7. 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 .

    Measured: at 14 months of age

  8. 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 .

    Measured: at 14 months of age

  9. 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.

    Measured: at 14 months of age

  10. MacArthur-Bates Inventory -Phrases Understood

    MacArthur-Bates Communicative Development inventory( Words and Gestures)-Phrases Understood z-score.

    Measured: at 14 months of age

  11. MacArthur-Bates Inventory -Words Understood

    MacArthur-Bates Communicative Development inventory( Words and Gestures)-Words Understood z-score.

    Measured: at 14 months of age

  12. MacArthur-Bates Inventory -Total Gestures

    MacArthur-Bates Communicative Development inventory( Words and Gestures)-Total Gestures z-score.

    Measured: at 14 months of age

  13. MacArthur-Bates Inventory -Words Produced

    MacArthur-Bates Communicative Development inventory( Words and Gestures)-Words Produced z-score.

    Measured: at 14 months of age

  14. 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.

    Measured: just before the Glenn surgery

  15. 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.

    Measured: at 14 months of age

  16. Ventricular Mass

    Two-dimensional echocardiography endpoint - Total Ventricular mass (g) per Core Laboratory assessment.

    Measured: just before the Glenn surgery

  17. Ventricular Mass

    Two-Dimensional Echocardiography endpoint-Total Ventricular mass (g) per Core Laboratory assessment. Range from 15.60 to 70.40

    Measured: At 14 months of age

  18. Ventricular Mass Z-score

    Two-dimensional echocardiography endpoint -Total Ventricular mass z-score per Core Laboratory assessment.

    Measured: just before the Glenn surgery

  19. Ventricular Mass Z-score

    Two-dimensional echocardiography endpoint -Total Ventricular mass z-score per Core Laboratory assessment.

    Measured: at 14 months of age

  20. End-diastolic Volume

    Two-Dimensional Echocardiography endpoint - Total End-diastolic volume (ml) per Core Laboratory assessment.

    Measured: just before the Glenn surgery

  21. End-diastolic Volume

    Two-Dimensional Echocardiography endpoint - Total End-diastolic volume (ml) per Core Laboratory assessment.

    Measured: at 14 months of age

  22. End Diastolic Volume Z-score

    Two-dimensional echocardiography endpoint -total End diastolic volume z-score per Core Laboratory assessment.

    Measured: just before the Glenn surgery

  23. End-diastolic Volume Z-score

    Two-dimensional echocardiography endpoint -total end-diastolic volume z-score per Core Laboratory assessment.

    Measured: at 14 months of age

  24. Ventricular Mass to Volume Ratio

    Two-Dimensional Echocardiography endpoint -Ventricular Mass to Volume ratio per Core Laboratory assessment.

    Measured: Measured just before the Glenn surgery

  25. Ventricular Mass to Volume Ratio

    Two-Dimensional Echocardiography endpoint -Ventricular Mass to Volume ratio per Core Laboratory assessment.

    Measured: Measured at 14 months of age

  26. Ventricular Filling Pressure

    Ventricular filling pressure measured by catherization

    Measured: just before the Glenn surgery

  27. Number of Participants With Moderate to Severe AV Valve Regurgitation

    Number of participants with Moderate to severe AV valve regurgitation.

    Measured: just before the pre-Glenn surgery

  28. Number of Participants With Moderate to Severe AV Valve Regurgitation

    Number of participants with moderate to severe AV valve regurgitation.

    Measured: at age 14 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted6 Jun 2005 (estimated)
  2. Study startAug 2003
  3. Primary completionJul 2008
  4. Study completionJul 2008

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Triple blind
Who is masked
Participant, Investigator, Outcomes assessor
Enrolment
230 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00113087
Sponsor's protocol ID
177
Other IDs
U01HL068270, U01HL068279, U01HL068281, U01HL068285, U01HL068288, U01HL068290, U01HL068292, U01HL068269
Acronym
ISV
Status last verified
Sep 2009
First submitted
3 Jun 2005
Last updated
28 Sep 2010
Data monitoring committee
Yes

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.

    PubMed 26490132
  • 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.

    PubMed 22939929
  • 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.

    PubMed 22939855
  • 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.

    PubMed 22931751
  • 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.

    PubMed 21784436
  • 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.

    PubMed 21576655
  • 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.

    PubMed 20625111
  • 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.

    PubMed 19081394

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Enalapril in people with Heart Defects, Congenital and Heart Failure, Congestive, run by National Heart, Lung, and Blood Institute (NHLBI) at 9 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 28 Sep 2010. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 9 sites in United States, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 16 Sep 2010). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00113087, which also lists 8 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Sep 2010.

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