Safety and Efficacy Study of Carvedilol to Treat Children With Congestive Heart Failure

This study has been completed.
Sponsor:
Collaborator:
University of Utah
Information provided by:
Shaddy, Robert, M.D.
ClinicalTrials.gov Identifier:
NCT00052026
First received: January 21, 2003
Last updated: December 24, 2008
Last verified: December 2008
  Purpose

The purpose of this study is to determine whether a new medicine, called carvedilol, improves symptoms and heart function in children who have congestive heart failure (diminished function of their heart muscle that pumps blood to the body). To accomplish this, we will give carvedilol to some patients who have diminished heart function and congestive heart failure and see whether symptoms and heart function are better at the end of an 8 month period in those who received carvedilol compared to the other patients who did not receive carvedilol. We will be testing 2 different doses of carvedilol compared to no additional medicine.


Condition Intervention Phase
Congestive Heart Failure
Drug: carvedilol
Drug: placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Multicenter, Placebo-Controlled, 8-Month Study of the Effect of Twice Daily Carvedilol in Children With Congestive Heart Failure Due to Systemic Ventricular Systolic Dysfunction

Resource links provided by NLM:


Further study details as provided by Shaddy, Robert, M.D.:

Primary Outcome Measures:
  • The primary efficacy variable is a CHF composite response. [ Time Frame: 8 months ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Selected individual components of the CHF composite of clinical outcomes [ Time Frame: 8 months ] [ Designated as safety issue: Yes ]

Enrollment: 161
Study Start Date: May 2000
Study Completion Date: July 2006
Primary Completion Date: June 2005 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: 1
Placebo
Drug: placebo
administered twice daily for 8 months
Experimental: 2
Low-dose carvedilol
Drug: carvedilol
low-dose carvedilol administered twice daily for 8 months
Other Name: Coreg
Experimental: 3
high-dose carvedilol
Drug: carvedilol
high-dose carvedilol administered twice daily for 8 months
Other Name: Coreg

Detailed Description:

Overactivity of the sympathetic nervous system is thought to contribute to the pathophysiology of congestive heart failure (CHF). Blockade of the sympathetic nervous system with β-adrenergic inhibitors could be expected to ameliorate these detrimental effects in a manner analogous to the effects of the angiotensin converting enzyme inhibitors on the overactive renin-angiotensin system.

Carvedilol may be superior to pure beta-blockers in the treatment of CHF through its mechanism of action of blocking not only β-receptors but also α-receptors, which would allow vasodilation to reduce the afterload on the failing heart. Since beta-blockers may initially produce a negative inotropic effect on the heart, long term treatment has been needed to show benefits of removal of the adrenergic stimulation. The investigators will monitor the safety and efficacy of carvedilol administration in children with chronic CHF due to systemic ventricular dysfunction.

  Eligibility

Ages Eligible for Study:   up to 17 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

INCLUSION CRITERIA

  1. Male or female children from birth through 17 years of age with chronic symptomatic CHF due to systemic ventricular systolic dysfunction who are receiving standard heart failure therapy will be eligible. Since adolescents with left ventricular dysfunction are very similar to adults with this disease, this study will focus recruitment in the prepubertal age group of children, including children from birth through Tanner Stage 3. The number of adolescents enrolled will be limited to approximately 10% of study enrollment. However, teenagers with single ventricles or morphologic right ventricles as systemic ventricles represent an important population that is unique to pediatric cardiology. The 10% limitation will only apply to teenagers who have dilated cardiomyopathies since these patients may be similar to young adults with dilated cardiomyopathies. Adolescents will be defined as Tanner Stage 4 through age 17.
  2. A diagnosis of CHF by NYHA Class II-IV (generally, children older than 5 years of age) or Ross' classification of CHF Class II-IV (12) (generally, children less than 5 years old) for at least 1 month (at least 2 weeks, for neonates) prior to screening.
  3. An estimated ejection fraction less than 40% in patients with systemic left ventricular dysfunction or qualitative evidence of a dilated ventricle with moderate systemic ventricular systolic dysfunction in patients with right ventricular or single ventricular physiology, documented within 4 weeks of randomization. Patients may be enrolled based on these criteria as determined by the site. However, all echocardiograms will be reviewed and interpreted by the Data Coordinating Center (DCC) at the University of Utah. Upon subsequent review by the DCC, if it is determined that either the ejection fraction is greater than or equal to 40% or the ventricular function is not moderate to severely decreased, patients will be enrolled. However, their data analysis will be based upon the findings from the DCC at the University of Utah.
  4. The etiology of the cardiomyopathy will include idiopathic dilated cardiomyopathy, post-viral myocarditis cardiomyopathy, anthracycline-induced cardiomyopathy, ischemic cardiomyopathies (e.g., Kawasaki's disease, repaired anomalous left coronary artery arising from the pulmonary artery, d-TGA s/p arterial switch), cardiomyopathies associated with single ventricle with ventricular systolic dysfunction, corrected transposition, etc. Excluded from enrollment will be dilated cardiomyopathies secondary to muscular dystrophies, hemoglobinopathies, HIV, carnitine deficiency, and systemic ventricular dysfunction due to ventricular outflow obstruction.
  5. Patients undergoing treatment for CHF with standard CHF therapy, such as diuretic, digoxin and ACE inhibitors. All patients should be receiving ACE inhibitors prior to enrollment in this study unless contraindicated or intolerant. If intolerance has been established, the patient must have been withdrawn from these drugs for at least one month prior to randomization. Other medications such as hydralazine, nitrates or amiodarone may also be used. Therapy with amiodarone should not have started or stopped within 2 months of randomization.
  6. All patients should be receiving diuretics prior to enrollment in this study unless contraindicated or intolerant. Patients must be in optimal fluid status prior to enrollment.
  7. Patients must be receiving a stable regimen of standard CHF medications for a period of at least one month (2 weeks in neonates) at the time of randomization into the study.

EXCLUSION CRITERIA

Patients with any of the following will be excluded from the study:

  1. NYHA or Ross' CHF Classification Class I (asymptomatic).
  2. Patients actively listed for transplantation at time of entry into the study or anticipated to undergo heart transplantation or corrective heart surgery during the 8 months following entry into the study. However, those patients in whom listing for transplantation is anticipated but may be waiting a long period of time (greater than 8 months), such as Status 2 patients, may be considered for enrollment in this study.
  3. Sustained or symptomatic ventricular dysrhythmias uncontrolled by drug therapy or the use of an implantable defibrillator, and/or significant cardiac conduction defects, e.g., 2nd degree or 3rd degree AV block, or sick sinus syndrome, unless a functioning pacemaker is in place.
  4. Uncorrected primary obstructive or severe regurgitative valvular disease, nondilated (restrictive) or hypertrophic cardiomyopathy, or significant systemic ventricular outflow obstruction.
  5. Dilated cardiomyopathies secondary to muscular dystrophies, hemoglobinopathies, HIV, carnitine deficiency, and systemic ventricular dysfunction due to ventricular outflow obstruction.
  6. Active myocarditis.
  7. Unacceptable blood pressures and heart rates. Sitting (supine in infants) systolic blood pressure must be > 85 mm Hg in teens, > 75 mm Hg in school-aged children, and > 65 mm Hg in infants (12). Resting heart rate must be greater than the 2nd percentile for age (13).
  8. Renovascular hypertension or evidence of pulmonary hypertension (pulmonary vascular resistance index > 6 Wood units-m2) unresponsive to vasodilator agents such as oxygen, nitroprusside, or nitric oxide.
  9. History or current clinical evidence of moderate-to-severe obstructive pulmonary disease or reactive airway diseases (e.g., asthma) requiring therapy.
  10. Significant renal (serum creatinine >2.0), hepatic (serum AST and/or ALT > 3 times upper limit of normal), gastrointestinal, or biliary disorders that could impair absorption, metabolism, or excretion of orally administered medications.
  11. Concurrent terminal illness or other severe disease (e.g., active neoplasm) or other significant laboratory value(s) which, in the opinion of the investigator, could preclude participation or survival.
  12. Endocrine disorders such as primary aldosteronism, pheochromocytoma, hyper- or hypothyroidism, insulin-dependent diabetes mellitus.
  13. Unwillingness or inability to cooperate, or for the parents or guardians to give consent, or for the child to give assent, or any condition of sufficient severity to impair cooperation in the study.
  14. Girls of child bearing potential who are pregnant, lactating, or sexually active and not taking adequate contraceptive precautions (e.g., IUD or oral contraceptives for 3 months prior to entry into the study).
  15. Use of an investigational drug within 30 days of randomization, or within 5 half-lives of the investigational drug (the longer period will apply); investigational vaccines or biological agents (e.g., the monoclonal antibody Synagis), may be granted exceptions through consultation with the principal investigator and GlaxoSmithKline.
  16. History of drug sensitivity or allergic reaction to a-blockers or ß-blockers.
  17. Use of any of the following medications within two weeks of randomization:

    • Monoamine oxidase (MAO) inhibitors
    • Calcium entry blockers
    • Alpha blockers, or labetalol
    • Disopyramide, flecainide, encainide, moricizine, propafenone
    • Intravenous ß-adrenergic agonists (including intravenous inotropes such as dobutamine) or intravenous vasodilator agents such as amrinone or milrinone
    • Intravenous CHF medications (e.g., diuretics, digoxin)
  18. Treatment with b-adrenergic blockers, including sotalol or carvedilol within 2 months of randomization.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00052026

Locations
United States, Alabama
University of Alabama
Birmingham, Alabama, United States, 35249-6852
United States, California
Children's Hospital Los Angeles
Los Angeles, California, United States, 90027
Mattel Children's Hospital at UCLA
Los Angeles, California, United States, 90025
Stanford University
Palo Alto, California, United States, 94303
United States, Colorado
University of Colorado
Denver, Colorado, United States, 80218
United States, Florida
University of Miami
Miami, Florida, United States, 33101
University of Southern Florida
St. Petersburg, Florida, United States, 33701
United States, Illinois
Children's Memorial Hospital
Chicago, Illinois, United States, 60614
United States, Massachusetts
Children's Hospital, Boston
Boston, Massachusetts, United States, 02115
United States, Michigan
C.S. Mott Children's Hospital
Ann Arbor, Michigan, United States, 48109
Children's Hospital of Michigan
Detroit, Michigan, United States, 48201-2196
United States, Missouri
Washington University
St. Louis, Missouri, United States, 63110-1014
United States, New York
NYU Medical Center
New York, New York, United States, 10016
Columbia University
New York, New York, United States, 10032-1537
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
Children's Hospital of Pittsburgh
Pittsburgh, Pennsylvania, United States, 15213
United States, Tennessee
Vanderbilt Children's Hospital
Nashville, Tennessee, United States, 37332
United States, Texas
UT Southwestern Medical Center
Dallas, Texas, United States, 75235-7794
Texas Children's Hospital
Houston, Texas, United States, 77030
United States, Utah
University of Utah
Salt Lake City, Utah, United States, 84132
United States, Washington
Seattle Childrens Hospital and Regional Medical Center
Seattle, Washington, United States, 98105
Sponsors and Collaborators
Shaddy, Robert, M.D.
University of Utah
Investigators
Principal Investigator: Robert E. Shaddy, MD University of Utah
  More Information

Publications:
Bristow MR, O'Connell JB, Gilbert EM, et al. Dose response of chronic beta-blocker treatment in heart failure from either idiopathic dilated cardiomyopathy or ischemic cardiomyopathy. Circulation 1994;23:943-50.
From Nadas AS, Fyler DC: Pediatric Cardiology. 3rd Ed. WB Saunders, Philadelphia, 1972.
From Harriet Lane Handbook, 14th Edition, page 132.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Robert E Shaddy, MD, The Children's Hospital of Philadelphia
ClinicalTrials.gov Identifier: NCT00052026     History of Changes
Other Study ID Numbers: SB 105517-321
Study First Received: January 21, 2003
Last Updated: December 24, 2008
Health Authority: United States: Food and Drug Administration

Keywords provided by Shaddy, Robert, M.D.:
Adolescent
Adrenergic alpha-Antagonists/therapeutic use
Adrenergic alpha-Antagonists/pharmacokinetics
Adrenergic alpha-Antagonists/administration & dosage
Adrenergic beta-Antagonists/therapeutic use
Adrenergic beta-Antagonists/pharmacokinetics
Adrenergic beta-Antagonists/administration & dosage
Age Factors
Carbazoles/therapeutic use
Carbazoles/administration & dosage
Child
Child, Preschool
Drug Administration Schedule
Female
Heart Failure, Congestive/etiology
Heart Failure, Congestive/drug therapy
Heart Failure, Congestive/blood
Human
Infant
Infant, Newborn
Male
Natriuretic Peptide, Brain/blood
Placebos
Propanolamines/therapeutic use
Propanolamines/administration & dosage
Prospective Studies
Support, Non-U.S. Gov't
Treatment Outcome
Ventricular Dysfunction/drug therapy
Ventricular Dysfunction/complications

Additional relevant MeSH terms:
Heart Failure
Heart Diseases
Cardiovascular Diseases
Adrenergic alpha-Antagonists
Carvedilol
Adrenergic beta-Antagonists
Natriuretic Peptide, Brain
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Natriuretic Agents
Cardiovascular Agents
Therapeutic Uses
Antihypertensive Agents
Vasodilator Agents
Adrenergic alpha-1 Receptor Antagonists

ClinicalTrials.gov processed this record on August 20, 2014