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

  Show 26 Study Locations
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:
Arachnodactyly
Marfan Syndrome
Syndrome
Abnormalities, Multiple
Bone Diseases
Bone Diseases, Developmental
Cardiovascular Abnormalities
Cardiovascular Diseases
Congenital Abnormalities
Connective Tissue Diseases
Disease
Genetic Diseases, Inborn
Heart Defects, Congenital
Heart Diseases
Limb Deformities, Congenital
Musculoskeletal Abnormalities
Musculoskeletal Diseases
Pathologic Processes
Atenolol
Losartan
Adrenergic Agents
Adrenergic Antagonists
Adrenergic beta-1 Receptor Antagonists
Adrenergic beta-Antagonists
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Anti-Arrhythmia Agents
Antihypertensive Agents
Autonomic Agents
Cardiovascular Agents

ClinicalTrials.gov processed this record on October 22, 2014