Comparison of Two Medications Aimed at Slowing Aortic Root Enlargement in Individuals With Marfan Syndrome--Pediatric Heart Network

This study has been completed.
Sponsor:
Collaborators:
National Marfan Foundation
Information provided by (Responsible Party):
New England Research Institutes
ClinicalTrials.gov Identifier:
NCT00429364
First received: January 29, 2007
Last updated: April 9, 2014
Last verified: January 2014
  Purpose

Marfan syndrome is a hereditary connective tissue disorder. Many individuals with this condition die because of the associated heart and blood vessel abnormalities. This study will compare the effectiveness of two medications, losartan and atenolol, at slowing aortic root enlargement in individuals with Marfan syndrome.


Condition Intervention Phase
Marfan Syndrome
Drug: Losartan Potassium
Drug: Atenolol
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Trial of Beta Blocker Therapy (Atenolol) Versus Angiotensin II Receptor Blocker Therapy (Losartan) in Individuals With Marfan Syndrome (A Trial Conducted by the Pediatric Heart Network)

Resource links provided by NLM:


Further study details as provided by New England Research Institutes:

Primary Outcome Measures:
  • Rate of change in aortic root (sinuses of Valsalva) body-surface-area-adjusted Z-score [ Time Frame: Measured at Month 36 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Rate of change in aortic root (sinuses of Valsalva) absolute dimension [ Time Frame: Measured at Month 36 ] [ Designated as safety issue: No ]
  • Rate of change in ascending aorta and aortic annulus absolute dimension and body-surface-area-adjusted Z-score [ Time Frame: Measured at Month 36 ] [ Designated as safety issue: No ]
  • Rate of change of aortic and mitral regurgitation [ Time Frame: Measured at Month 36 ] [ Designated as safety issue: No ]
  • Time to first occurrence of aortic dissection, aortic root surgery, or death [ Time Frame: Measured at Month 36 ] [ Designated as safety issue: No ]
  • Rate of change in Z-scores for left ventricular size, wall thickness, and function by two-dimensional and M-mode echocardiography [ Time Frame: Measured at Month 36 ] [ Designated as safety issue: No ]
  • Rate of change of aortic root and ascending aortic elastic modulus and stiffness index [ Time Frame: Measured at Month 36 ] [ Designated as safety issue: No ]
  • Rate of change in Z-scores for somatic growth, where available [ Time Frame: Measured at Month 36 ] [ Designated as safety issue: No ]
  • Rate of change in weight and body mass index with covariate adjustment for age [ Time Frame: Measured at Month 36 ] [ Designated as safety issue: No ]
  • Incidence of adverse drug reactions reported during routine surveillance [ Time Frame: Measured at Month 36 ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 604
Study Start Date: January 2007
Study Completion Date: February 2014
Primary Completion Date: February 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 1
Atenolol
Drug: Atenolol
Atenolol .5 - 4 mg/kg
Active Comparator: 2
Losartan
Drug: Losartan Potassium
Losartan .3 - 1.4 mg/kg

Detailed Description:

Marfan syndrome is an inheritable disorder that affects the body's connective tissue. An abnormal protein results in connective tissue that is weaker than normal. Because connective tissue is found throughout the body, Marfan syndrome can affect many body systems, including the skeleton, eyes, nervous system, skin, lungs, heart, and blood vessels. Overall, heart and blood vessel abnormalities are the leading cause of death in individuals with Marfan syndrome. A common blood vessel abnormality associated with this disease involves the aorta, which is the large artery that carries blood away from the heart to the rest of the body. The aortic root, the portion of the aorta that is attached to the heart, may enlarge and tear or even rupture. A tear or rupture is considered a life-threatening emergency. Recent studies have shown that the medication losartan may reduce aortic root growth and improve heart function. The purpose of this study is to compare the effectiveness of losartan versus atenolol at slowing aortic root growth in individuals with Marfan syndrome.

This 3-year study will enroll individuals with Marfan syndrome. Participants will be randomly assigned to receive either losartan or atenolol on a daily basis. All participants will initially receive a low dose of their assigned medication. This dose will be gradually increased every 3 to 4 weeks until the maximum tolerated dose is reached. A continuous electrocardiogram (ECG) that monitors heart rate and activity in 24-hour intervals will be used to determine the proper dose increase for each participant. Participants will then receive the maximum tolerated dose for the remainder of the study. Study visits will occur at baseline and Months 6, 12, 24, and 36. Each study visit will include a physical examination, a medical history review, an ECG, an echocardiogram, and questionnaires. Additionally, at the baseline study visit blood will be collected for laboratory testing.

  Eligibility

Ages Eligible for Study:   6 Months to 25 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of Marfan syndrome, according to Ghent criteria (more information can be found in Appendix D of the protocol)
  • Aortic root Z-score greater than 3.0

Exclusion Criteria:

  • Prior aortic surgery
  • Aortic root dimension at the sinuses of Valsalva greater than 5 cm
  • Planned aortic surgery within 6 months of study entry
  • Aortic dissection
  • Shprintzen-Goldberg syndrome
  • Loeys-Dietz syndrome
  • Therapeutic (i.e., for arrhythmia, ventricular dysfunction, or valve regurgitation) rather than prophylactic use of angiotensin-converting enzyme (ACE) inhibitor, beta-blocker, or calcium channel blocker
  • History of angioedema while taking an ACE inhibitor or beta-blocker
  • Intolerance to losartan or other angiotensin II receptor blocker (ARB) that resulted in termination of therapy
  • Intolerance to atenolol or other beta-blocker that resulted in termination of therapy
  • Kidney dysfunction (i.e., creatinine greater than the upper limit of age-related normal values)
  • Asthma of sufficient severity to prohibit the use of a beta-blocker
  • Chronic use of steroids and/or beta-adrenergic agents with exacerbations of asthma that are frequent (averaging three or more per year) or severe (requiring hospitalization)
  • Diabetes mellitus
  • Pregnant or planning to become pregnant within 36 months of study entry
  • Inability to complete study procedures, including history of poor acoustic windows (i.e., inability to obtain accurate measurement of aortic root)
  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: NCT00429364

  Hide Study Locations
Locations
United States, California
Cedars-Sinai Medical Center
Los Angeles, California, United States, 90048
Lucile Packard Children's Hospital
Palo Alto, California, United States, 94304
Rady Children's Hospital / UCSD
San Diego, California, United States, 92123
Stanford University School of Medicine
Stanford, California, United States, 94305
United States, Illinois
Children's Memorial Hospital
Chicago, Illinois, United States, 60614
United States, Maryland
Johns Hopkins University School of Medicine
Baltimore, Maryland, United States, 21205
United States, Massachusetts
Children's Hospital Boston
Boston, Massachusetts, United States, 02115
United States, Minnesota
Children's Hospital of Minnesota - St. Paul
St. Paul, Minnesota, United States, 55102
United States, Missouri
Washington University School of Medicine
St Louis, Missouri, United States, 63110
United States, New York
Columbia College of Physicians and Surgeons
New York, New York, United States, 10032
Weill Medical College of Cornell University
New York, New York, United States, 10021
Mount Sinai Medical Center
New York, New York, United States, 10029
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
Brody School of Medicine at East Carolina University
Greenville, North Carolina, United States, 27834
Wake Forest University Baptist Medical Center
Winston-Salem, North Carolina, United States, 27157
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
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
Children's Hospital of Pittsburgh
Pittsburgh, Pennsylvania, United States, 15213
United States, South Carolina
Medical University of South Carolina
Charleston, South Carolina, United States, 29425
United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37212
United States, Texas
Texas Children's Hospital
Houston, Texas, United States, 77030
United States, Utah
Primary Children's Medical Center
Salt Lake City, Utah, United States, 84113
United States, Washington
Seattle Children's Hospital
Seattle, Washington, United States, 98105
Belgium
Ghent University Hospital
De Pintelaan, Gent, Belgium, 185 9000
Canada, Ontario
Hospital for Sick Children
Toronto, Ontario, Canada, M5G 1X8
Sponsors and Collaborators
New England Research Institutes
National Marfan Foundation
Investigators
Principal Investigator: Ron Lacro, MD Children's Hospital Boston
  More Information

Additional Information:
No publications provided by New England Research Institutes

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: New England Research Institutes
ClinicalTrials.gov Identifier: NCT00429364     History of Changes
Other Study ID Numbers: 461, U01HL068270, U01 HL68270
Study First Received: January 29, 2007
Last Updated: April 9, 2014
Health Authority: United States: Food and Drug Administration
Belgium: Federal Agency for Medicines and Health Products, FAMHP
Canada: Health Canada

Keywords provided by New England Research Institutes:
Aortic Root Dissection
Aortic Root Dilation
Pediatric Heart Network

Additional relevant MeSH terms:
Marfan Syndrome
Arachnodactyly
Bone Diseases, Developmental
Bone Diseases
Musculoskeletal Diseases
Heart Defects, Congenital
Cardiovascular Abnormalities
Cardiovascular Diseases
Heart Diseases
Abnormalities, Multiple
Congenital Abnormalities
Genetic Diseases, Inborn
Connective Tissue Diseases
Limb Deformities, Congenital
Musculoskeletal Abnormalities
Atenolol
Losartan
Angiotensin Receptor Antagonists
Anti-Arrhythmia Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Antihypertensive Agents
Sympatholytics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Adrenergic beta-1 Receptor Antagonists
Adrenergic beta-Antagonists
Adrenergic Antagonists

ClinicalTrials.gov processed this record on July 28, 2014