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

NCT00052026 | Completed Phase 3 DMC

• 1 other identifier: SB 105517-321
• Study Type: interventional
• Target: 161
• Locations: 1 country
• Sites: 21

Brief Summary

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.

Conditions

Congestive Heart Failure

Keywords

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; Ventricular Dysfunction/blood; Ventricular Function/drug effects; Ventricular Remodeling/drug effects

Outcome Measures

Primary Outcomes (1)

• The primary efficacy variable is a CHF composite response.

  8 months

Secondary Outcomes (1)

• Selected individual components of the CHF composite of clinical outcomes

  8 months

Study Arms (3)

1

PLACEBO COMPARATOR

Placebo

Drug: placebo

2

EXPERIMENTAL

Low-dose carvedilol

Drug: carvedilol

3

EXPERIMENTAL

high-dose carvedilol

Drug: carvedilol

Interventions

carvedilol DRUG

low-dose carvedilol administered twice daily for 8 months

Also known as: Coreg

2

placebo DRUG

administered twice daily for 8 months

1

Eligibility Criteria

• Age: 1 Day - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

You may not qualify if:

• Patients with any of the following will be excluded from the study:
• NYHA or Ross' CHF Classification Class I (asymptomatic).
• 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.
• 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.
• Uncorrected primary obstructive or severe regurgitative valvular disease, nondilated (restrictive) or hypertrophic cardiomyopathy, or significant systemic ventricular outflow obstruction.
• Dilated cardiomyopathies secondary to muscular dystrophies, hemoglobinopathies, HIV, carnitine deficiency, and systemic ventricular dysfunction due to ventricular outflow obstruction.
• Active myocarditis.
• 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).
• 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.
• History or current clinical evidence of moderate-to-severe obstructive pulmonary disease or reactive airway diseases (e.g., asthma) requiring therapy.
• 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.
• 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.
• Endocrine disorders such as primary aldosteronism, pheochromocytoma, hyper- or hypothyroidism, insulin-dependent diabetes mellitus.
• 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.
• 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).

Sponsors & Collaborators

• Shaddy, Robert, M.D.: lead
• University of Utah: collaborator

Study Sites (21)

University of Alabama

Birmingham, Alabama, 35249-6852, United States

Location

Mattel Children's Hospital at UCLA

Los Angeles, California, 90025, United States

Location

Children's Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

Stanford University

Palo Alto, California, 94303, United States

Location

University of Colorado

Denver, Colorado, 80218, United States

Location

University of Miami

Miami, Florida, 33101, United States

Location

University of Southern Florida

St. Petersburg, Florida, 33701, United States

Location

Children's Memorial Hospital

Chicago, Illinois, 60614, United States

Location

Children's Hospital, Boston

Boston, Massachusetts, 02115, United States

Location

C.S. Mott Children's Hospital

Ann Arbor, Michigan, 48109, United States

Location

Children's Hospital of Michigan

Detroit, Michigan, 48201-2196, United States

Location

Washington University

St Louis, Missouri, 63110-1014, United States

Location

NYU Medical Center

New York, New York, 10016, United States

Location

Columbia University

New York, New York, 10032-1537, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, 15213, United States

Location

Vanderbilt Children's Hospital

Nashville, Tennessee, 37332, United States

Location

UT Southwestern Medical Center

Dallas, Texas, 75235-7794, United States

Location

Texas Children's Hospital

Houston, Texas, 77030, United States

Location

University of Utah

Salt Lake City, Utah, 84132, United States

Location

Seattle Childrens Hospital and Regional Medical Center

Seattle, Washington, 98105, United States

Location

Related Publications (16)

• Shaddy RE, Curtin EL, Sower B, Tani LY, Burr J, LaSalle B, Boucek MM, Mahony L, Hsu DT, Pahl E, Burch GH, Schlencker-Herceg R. The Pediatric Randomized Carvedilol Trial in Children with Heart Failure: rationale and design. Am Heart J. 2002 Sep;144(3):383-9. doi: 10.1067/mhj.2002.124402.

  PMID: 12228773 BACKGROUND

• Boucek MM, Novick RJ, Bennett LE, Fiol B, Keck BM, Hosenpud JD. The Registry of the International Society of Heart and Lung Transplantation: first official pediatric report--1997. J Heart Lung Transplant. 1997 Dec;16(12):1189-206. No abstract available.

  PMID: 9436131 BACKGROUND

• Gilbert EM, Anderson JL, Deitchman D, Yanowitz FG, O'Connell JB, Renlund DG, Bartholomew M, Mealey PC, Larrabee P, Bristow MR. Long-term beta-blocker vasodilator therapy improves cardiac function in idiopathic dilated cardiomyopathy: a double-blind, randomized study of bucindolol versus placebo. Am J Med. 1990 Mar;88(3):223-9. doi: 10.1016/0002-9343(90)90146-5.

  PMID: 1968710 BACKGROUND

• Waagstein F, Bristow MR, Swedberg K, Camerini F, Fowler MB, Silver MA, Gilbert EM, Johnson MR, Goss FG, Hjalmarson A. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group. Lancet. 1993 Dec 11;342(8885):1441-6. doi: 10.1016/0140-6736(93)92930-r.

  PMID: 7902479 BACKGROUND

• Shaddy RE, Olsen SL, Bristow MR, Taylor DO, Bullock EA, Tani LY, Renlund DG. Efficacy and safety of metoprolol in the treatment of doxorubicin-induced cardiomyopathy in pediatric patients. Am Heart J. 1995 Jan;129(1):197-9. doi: 10.1016/0002-8703(95)90061-6. No abstract available.

  PMID: 7817916 BACKGROUND

• Shaddy RE. Beta-blocker therapy in young children with congestive heart failure under consideration for heart transplantation. Am Heart J. 1998 Jul;136(1):19-21. doi: 10.1016/s0002-8703(98)70176-0.

  PMID: 9665213 BACKGROUND

• Shaddy RE, Tani LY, Gidding SS, Pahl E, Orsmond GS, Gilbert EM, Lemes V. Beta-blocker treatment of dilated cardiomyopathy with congestive heart failure in children: a multi-institutional experience. J Heart Lung Transplant. 1999 Mar;18(3):269-74. doi: 10.1016/s1053-2498(98)00030-8.

  PMID: 10328154 BACKGROUND

• Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, Shusterman NH. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med. 1996 May 23;334(21):1349-55. doi: 10.1056/NEJM199605233342101.

  PMID: 8614419 BACKGROUND

• Bristow MR, Gilbert EM, Abraham WT, Adams KF, Fowler MB, Hershberger RE, Kubo SH, Narahara KA, Ingersoll H, Krueger S, Young S, Shusterman N. Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. MOCHA Investigators. Circulation. 1996 Dec 1;94(11):2807-16. doi: 10.1161/01.cir.94.11.2807.

  PMID: 8941106 BACKGROUND

• Olsen SL, Gilbert EM, Renlund DG, Taylor DO, Yanowitz FD, Bristow MR. Carvedilol improves left ventricular function and symptoms in chronic heart failure: a double-blind randomized study. J Am Coll Cardiol. 1995 May;25(6):1225-31. doi: 10.1016/0735-1097(95)00012-S.

  PMID: 7722114 BACKGROUND

• Richards AM, Doughty R, Nicholls MG, Macmahon S, Ikram H, Sharpe N, Espiner EA, Frampton C, Yandle TG. Neurohumoral prediction of benefit from carvedilol in ischemic left ventricular dysfunction. Australia-New Zealand Heart Failure Group. Circulation. 1999 Feb 16;99(6):786-92. doi: 10.1161/01.cir.99.6.786.

  PMID: 9989964 BACKGROUND

• Ross RD, Daniels SR, Schwartz DC, Hannon DW, Shukla R, Kaplan S. Plasma norepinephrine levels in infants and children with congestive heart failure. Am J Cardiol. 1987 Apr 1;59(8):911-4. doi: 10.1016/0002-9149(87)91118-0.

  PMID: 3825955 BACKGROUND

• Bristow MR, O'Connell JB, Gilbert EM, French WJ, Leatherman G, Kantrowitz NE, Orie J, Smucker ML, Marshall G, Kelly P, et al. Dose-response of chronic beta-blocker treatment in heart failure from either idiopathic dilated or ischemic cardiomyopathy. Bucindolol Investigators. Circulation. 1994 Apr;89(4):1632-42. doi: 10.1161/01.cir.89.4.1632.

  PMID: 7908610 BACKGROUND

• From Nadas AS, Fyler DC: Pediatric Cardiology. 3rd Ed. WB Saunders, Philadelphia, 1972.

  BACKGROUND

• From Harriet Lane Handbook, 14th Edition, page 132.

  BACKGROUND

• Shaddy RE, Boucek MM, Hsu DT, Boucek RJ, Canter CE, Mahony L, Ross RD, Pahl E, Blume ED, Dodd DA, Rosenthal DN, Burr J, LaSalle B, Holubkov R, Lukas MA, Tani LY; Pediatric Carvedilol Study Group. Carvedilol for children and adolescents with heart failure: a randomized controlled trial. JAMA. 2007 Sep 12;298(10):1171-9. doi: 10.1001/jama.298.10.1171.

  PMID: 17848651 DERIVED

MeSH Terms

Conditions

Heart Failure; Ventricular Dysfunction

Interventions

Carvedilol

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Carbazoles; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 3-Ring

Study Officials

• Robert E. Shaddy, MD

  University of Utah

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDIV

Study Record Dates

• First Submitted: January 21, 2003
• First Posted: January 23, 2003
• Study Start: May 1, 2000
• Primary Completion: June 1, 2005
• Study Completion: July 1, 2006
• Last Updated: December 25, 2008

Record last verified: 2008-12

Locations

US (21)