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	Treatment or Intervention	Phase
Congestive Heart Failure	Drug: carvedilol	Phase III

Further Study Details: 

Expected Total Enrollment:  150

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.

Ages Eligible for Study:  up to  17 Years,  Genders Eligible for Study:  Both

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.

Alabama
      University of Alabama, Birmingham,  Alabama,  35249-6852,  United States
California
      Stanford University, Palo Alto,  California,  94303,  United States
      Children's Hospital Los Angeles, Los Angeles,  California,  90027,  United States
      Mattel Children's Hospital at UCLA, Los Angeles,  California,  90025,  United States
Colorado
      University of Colorado, Denver,  Colorado,  80218,  United States
Florida
      University of Southern Florida, St. Petersburg,  Florida,  33701,  United States
      University of Florida College of Medicine, Gainsville,  Florida,  32610,  United States
      University of Miami, Miami,  Florida,  33101,  United States
Georgia
      Emory University, Atlanta,  Georgia,  30329,  United States
Illinois
      Children's Memorial Hospital, Chicago,  Illinois,  60614,  United States
Massachusetts
      Children's Hospital, Boston, Boston,  Massachusetts,  02115,  United States
Michigan
      Children's Hospital of Michigan, Detroit,  Michigan,  48201-2196,  United States
      C.S. Mott Children's Hospital, Ann Arbor,  Michigan,  48109,  United States
Missouri
      Washington University, St. Louis,  Missouri,  63110-1014,  United States
New York
      NYU Medical Center, New York,  New York,  10016,  United States
      Columbia University, New York,  New York,  10032-1537,  United States
Ohio
      Cincinnati Children's Hospital, Cincinnati,  Ohio,  45229,  United States
Pennsylvania
      Children's Hospital of Pittsburgh, Pittsburgh,  Pennsylvania,  15213,  United States
      Children's Hospital of Philadelphia, Philadelphia,  Pennsylvania,  19104,  United States
Tennessee
      Vanderbilt Children's Hospital, Nashville,  Tennessee,  37332,  United States
Texas
      UT Southwestern Medical Center, Dallas,  Texas,  75235-7794,  United States
      Texas Children's Hospital, Houston,  Texas,  77030,  United States
      The University of Texas Health Science Center at San Antonio, San Antonio,  Texas,  78229,  United States
Utah
      University of Utah, Salt Lake City,  Utah,  84132,  United States
Washington
      Seattle Childrens Hospital and Regional Medical Center, Seattle,  Washington,  98105,  United States
Wisconsin
      Children's Hospital of Wisconsin, Milwaukee,  Wisconsin,  53226,  United States

Study chairs or principal investigators

Robert E. Shaddy, MD,  Principal Investigator,  University of Utah   

Study ID Numbers:  SB 105517-321
Record last reviewed:  September 2004
Last Updated:  October 13, 2004
Record first received:  January 21, 2003
ClinicalTrials.gov Identifier:  NCT00052026
Health Authority: United States: Food and Drug Administration
ClinicalTrials.gov processed this record on 2005-04-08