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)”

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.

Study Type: Interventional

Study Design: Treatment, Randomized, Single Blind (Outcomes Assessor), Active Control, Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: January 2012

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.

Intervention(s) in this Clinical Trial

• Drug: Losartan Potassium
  • Losartan .3 - 1.4 mg/kg
• Drug: Atenolol
  • Atenolol .5 - 4 mg/kg

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: 1
  • Atenolol
• Active Comparator: 2
  • Losartan

Primary Measures

• Rate of change in aortic root (sinuses of Valsalva) body-surface-area-adjusted Z-score
  • Time Frame: Measured at Month 36
    Safety Issue?: No

Secondary Measures

• Rate of change in aortic root (sinuses of Valsalva) absolute dimension
  • Time Frame: Measured at Month 36
    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
    Safety Issue?: No
• Rate of change of aortic and mitral regurgitation
  • Time Frame: Measured at Month 36
    Safety Issue?: No
• Time to first occurrence of aortic dissection, aortic root surgery, or death
  • Time Frame: Measured at Month 36
    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
    Safety Issue?: No
• Rate of change of aortic root and ascending aortic elastic modulus and stiffness index
  • Time Frame: Measured at Month 36
    Safety Issue?: No
• Rate of change in Z-scores for somatic growth, where available
  • Time Frame: Measured at Month 36
    Safety Issue?: No
• Rate of change in weight and body mass index with covariate adjustment for age
  • Time Frame: Measured at Month 36
    Safety Issue?: No
• Incidence of adverse drug reactions reported during routine surveillance
  • Time Frame: Measured at Month 36
    Safety Issue?: Yes

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)

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 6 Months

Maximum Age for this Clinical Trial: 25 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Overall Clinical Trial Officials and Contacts

Ron Lacro, MD Principal Investigator Boston Children's Hospital  

Overall Contact: Gloria Klein, MS, RD 617-923-7747 gklein@neriscience.com

Information obtained from ClinicalTrials.gov on October 10, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00429364

Study ID Number: 461

ClinicalTrials.gov Identifier: NCT00429364

Health Authority: United States: Food and Drug Administration

Click here for the Pediatric Heart Network Web site

Click here for the National Marfan Foundation Web site