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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 Heart, Lung, and Blood Institute (NHLBI)
FDA Office of Orphan Products Development
National Marfan Foundation
Information provided by (Responsible Party):
New England Research Institutes
ClinicalTrials.gov Identifier:
NCT00429364
First received: January 29, 2007
Last updated: March 17, 2015
Last verified: January 2014

January 29, 2007
March 17, 2015
January 2007
February 2014   (final data collection date for primary outcome measure)
Annual Rate of Change in Aortic Root (Sinuses of Valsalva) Body-surface-area-adjusted Z-score [ Time Frame: Up to 3 years following randomization. ] [ Designated as safety issue: No ]
The rate of aortic root enlargement, expressed as the annual change in the maximum aortic-root-diameter z score indexed to body-surface area over a 3-year period following randomization
Rate of change in aortic root (sinuses of Valsalva) body-surface-area-adjusted Z-score
Complete list of historical versions of study NCT00429364 on ClinicalTrials.gov Archive Site
  • Annual Rate of Change in Aortic Root (Sinuses of Valsalva) Absolute Dimension [ Time Frame: Up to 3 years following randomization. ] [ Designated as safety issue: No ]
    The rate of change in the absolute dimension of the aortic root over a 3-year period following randomization
  • Annual Rate of Change in Ascending-aorta-diameter Z Score, Adjusted by Body-surface-area. [ Time Frame: Up to 3 years following randomization. ] [ Designated as safety issue: No ]
  • Annual Rate of Change in the Absolute Diameter of the Ascending Aorta [ Time Frame: Up to 3 years following randomization. ] [ Designated as safety issue: No ]
  • Annual Rate of Change in Aortic-annulus-diameter Z Score, Adjusted by Body-surface Area [ Time Frame: Up to 3 years following randomization. ] [ Designated as safety issue: No ]
  • Annual Rate of Change in the Absolute Diameter of the Aortic Annulus [ Time Frame: Up to 3 years following randomization. ] [ Designated as safety issue: No ]
  • Annual Rate of Change in Total Aortic Proximal Regurgitant Jet Area Indexed to Body-surface-area [ Time Frame: Up to 3 years following randomization. ] [ Designated as safety issue: No ]
  • Annual Rate of Change in Weight [ Time Frame: Up to 3 years following randomization. ] [ Designated as safety issue: No ]
  • Annual Rate of Change in Weight-for-age Z-score [ Time Frame: Up to 3 years following randomization. ] [ Designated as safety issue: No ]
  • Annual Rate of Change in Weight-for-height Z-score [ Time Frame: Up to 3 years following randomization. ] [ Designated as safety issue: No ]
  • Annual Rate of Change in Height [ Time Frame: Up to 3 years following randomization. ] [ Designated as safety issue: No ]
  • Annual Rate of Change in Height-for-age Z-score [ Time Frame: Up to 3 years following randomization. ] [ Designated as safety issue: No ]
  • Annual Rate of Change in Body Mass Index [ Time Frame: Up to 3 years following randomization. ] [ Designated as safety issue: No ]
  • Annual Rate of Change in Body Mass Index for Age Z-score [ Time Frame: Up to 3 years following randomization. ] [ Designated as safety issue: No ]
  • Annual Rate of Change in Arm Span to Height Ratio [ Time Frame: Up to 3 years following randomization. ] [ Designated as safety issue: No ]
  • Annual Rate of Change in Upper to Lower Segment Ratio [ Time Frame: Up to 3 years following randomization. ] [ Designated as safety issue: No ]
  • Number of Participants With Aortic Dissection. [ Time Frame: Up to 3 years following randomization. ] [ Designated as safety issue: Yes ]
  • Event Rate of Aortic Dissection. [ Time Frame: Up to 3 years following randomization. ] [ Designated as safety issue: Yes ]
    Percentage of participants who had aortic dissection over a 3-year period following randomization.
  • Number of Participants With Aortic-root Surgery. [ Time Frame: Up to 3 years following randomization. ] [ Designated as safety issue: Yes ]
  • Event Rate of Aortic-Root Surgery [ Time Frame: Up to 3 years following randomization. ] [ Designated as safety issue: Yes ]
    Percentage of participants who had aortic-root surgery over a 3-year period following randomization.
  • Number of Death. [ Time Frame: Up to 3 years following randomization. ] [ Designated as safety issue: Yes ]
  • Event Rate of Death [ Time Frame: Up to 3 years following randomization. ] [ Designated as safety issue: Yes ]
    Percentage of participants who died over a 3-year period following randomization.
  • Number of Participants With the Composite Adverse Clinical Outcomes, Including Aortic Dissection, Aortic-root Surgery and Death. [ Time Frame: Up to 3 years following randomization. ] [ Designated as safety issue: Yes ]
  • Event Rate of the Composite Adverse Clinical Outcomes, Including Aortic Dissection, Aortic-root Surgery and Death. [ Time Frame: Up to 3 years following randomization. ] [ Designated as safety issue: Yes ]
    Percentage of participants who had aortic dissection, aortic-root surgery or death over a 3-year period following randomization
  • Adverse Drug Reactions Reported at the Baseline Visit [ Time Frame: At baseline ] [ Designated as safety issue: Yes ]
  • Adverse Drug Reactions Reported During Routine Follow-up Surveillance [ Time Frame: From 6 months to 3 years following randomization. ] [ Designated as safety issue: Yes ]
  • Rate of change in aortic root (sinuses of Valsalva) absolute dimension
  • Rate of change in ascending aorta and aortic annulus absolute dimension and body-surface-area-adjusted Z-score
  • Rate of change of aortic and mitral regurgitation
  • Aortic dissection, aortic root surgery, or death at 36 months after randomization
  • Time to first occurrence of aortic dissection, aortic root surgery, or death up to 36 months after randomization
  • Rate of change in Z-scores for left ventricular size, wall thickness, and function by two-dimensional and M-mode echocardiography
  • Rate of change of aortic root and ascending aortic elastic modulus and stiffness index
  • Rate of change in Z-scores for somatic growth, where available
  • Rate of change in weight and body mass index with covariate adjustment for age
  • Incidence of adverse drug reactions reported during routine surveillance
Not Provided
Not Provided
 
Comparison of Two Medications Aimed at Slowing Aortic Root Enlargement in Individuals With Marfan Syndrome--Pediatric Heart Network
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.

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.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Outcomes Assessor)
Primary Purpose: Treatment
Marfan Syndrome
  • Drug: Losartan Potassium
    Losartan .3 - 1.4 mg/kg
  • Drug: Atenolol
    Atenolol .5 - 4 mg/kg
  • Active Comparator: Atenolol
    Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.5 - 4.0 mg/kg/day Atenolol (not to exceed a total dose of 250 mg), with a goal of a 20% or greater decrease in the mean heart rate.
    Intervention: Drug: Atenolol
  • Active Comparator: Losartan
    Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.4 - 1.4 mg/kg/day Losartan (not to exceed a total dose of 100 mg).
    Intervention: Drug: Losartan Potassium

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
608
February 2014
February 2014   (final data collection date for primary outcome measure)

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)
Both
6 Months to 25 Years   (Child, Adult)
No
Contact information is only displayed when the study is recruiting subjects
United States,   Belgium,   Canada
 
NCT00429364
461, U01HL068270
Yes
Not Provided
Not Provided
New England Research Institutes
New England Research Institutes
  • National Heart, Lung, and Blood Institute (NHLBI)
  • FDA Office of Orphan Products Development
  • National Marfan Foundation
Principal Investigator: Ron Lacro, MD Boston Children’s Hospital
New England Research Institutes
January 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP