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

Marfan Syndrome Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00429364
• Other study ID #: 461
• Secondary ID: U01HL068270
• Status: Completed
• Phase: Phase 3
• First received: January 29, 2007
• Last updated: March 17, 2015
• Start date: January 2007
• Est. completion date: February 2014

Study information

• Verified date: January 2014
• Source: New England Research Institutes
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationBelgium: Federal Agency for Medicines and Health Products, FAMHPCanada: Health Canada
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 608
• Est. completion date: February 2014
• Est. primary completion date: February 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 6 Months to 25 Years

Eligibility

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)

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Marfan Syndrome
• Syndrome

Intervention

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

Locations

Country	Name	City	State
Belgium	Ghent University Hospital	De Pintelaan	Gent
Canada	Hospital for Sick Children	Toronto	Ontario
United States	Johns Hopkins University School of Medicine	Baltimore	Maryland
United States	Children's Hospital Boston	Boston	Massachusetts
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Children's Memorial Hospital	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Duke University Medical Center	Durham	North Carolina
United States	Brody School of Medicine at East Carolina University	Greenville	North Carolina
United States	Texas Children's Hospital	Houston	Texas
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Columbia College of Physicians and Surgeons	New York	New York
United States	Mount Sinai Medical Center	New York	New York
United States	Weill Medical College of Cornell University	New York	New York
United States	Lucile Packard Children's Hospital	Palo Alto	California
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania
United States	Primary Children's Medical Center	Salt Lake City	Utah
United States	Rady Children's Hospital / UCSD	San Diego	California
United States	Seattle Children's Hospital	Seattle	Washington
United States	Washington University School of Medicine	St Louis	Missouri
United States	Children's Hospital of Minnesota - St. Paul	St. Paul	Minnesota
United States	Stanford University School of Medicine	Stanford	California
United States	Wake Forest University Baptist Medical Center	Winston-Salem	North Carolina

Sponsors (4)

Lead Sponsor	Collaborator
New England Research Institutes	FDA Office of Orphan Products Development, National Heart, Lung, and Blood Institute (NHLBI), National Marfan Foundation

Countries where clinical trial is conducted

United States,  Belgium,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Annual Rate of Change in Aortic Root (Sinuses of Valsalva) Body-surface-area-adjusted Z-score	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	Up to 3 years following randomization.	No
Secondary	Annual Rate of Change in Aortic Root (Sinuses of Valsalva) Absolute Dimension	The rate of change in the absolute dimension of the aortic root over a 3-year period following randomization	Up to 3 years following randomization.	No
Secondary	Annual Rate of Change in Ascending-aorta-diameter Z Score, Adjusted by Body-surface-area.		Up to 3 years following randomization.	No
Secondary	Annual Rate of Change in the Absolute Diameter of the Ascending Aorta		Up to 3 years following randomization.	No
Secondary	Annual Rate of Change in Aortic-annulus-diameter Z Score, Adjusted by Body-surface Area		Up to 3 years following randomization.	No
Secondary	Annual Rate of Change in the Absolute Diameter of the Aortic Annulus		Up to 3 years following randomization.	No
Secondary	Annual Rate of Change in Total Aortic Proximal Regurgitant Jet Area Indexed to Body-surface-area		Up to 3 years following randomization.	No
Secondary	Annual Rate of Change in Weight		Up to 3 years following randomization.	No
Secondary	Annual Rate of Change in Weight-for-age Z-score		Up to 3 years following randomization.	No
Secondary	Annual Rate of Change in Weight-for-height Z-score		Up to 3 years following randomization.	No
Secondary	Annual Rate of Change in Height		Up to 3 years following randomization.	No
Secondary	Annual Rate of Change in Height-for-age Z-score		Up to 3 years following randomization.	No
Secondary	Annual Rate of Change in Body Mass Index		Up to 3 years following randomization.	No
Secondary	Annual Rate of Change in Body Mass Index for Age Z-score		Up to 3 years following randomization.	No
Secondary	Annual Rate of Change in Arm Span to Height Ratio		Up to 3 years following randomization.	No
Secondary	Annual Rate of Change in Upper to Lower Segment Ratio		Up to 3 years following randomization.	No
Secondary	Number of Participants With Aortic Dissection.		Up to 3 years following randomization.	Yes
Secondary	Event Rate of Aortic Dissection.	Percentage of participants who had aortic dissection over a 3-year period following randomization.	Up to 3 years following randomization.	Yes
Secondary	Number of Participants With Aortic-root Surgery.		Up to 3 years following randomization.	Yes
Secondary	Event Rate of Aortic-Root Surgery	Percentage of participants who had aortic-root surgery over a 3-year period following randomization.	Up to 3 years following randomization.	Yes
Secondary	Number of Death.		Up to 3 years following randomization.	Yes
Secondary	Event Rate of Death	Percentage of participants who died over a 3-year period following randomization.	Up to 3 years following randomization.	Yes
Secondary	Number of Participants With the Composite Adverse Clinical Outcomes, Including Aortic Dissection, Aortic-root Surgery and Death.		Up to 3 years following randomization.	Yes
Secondary	Event Rate of the Composite Adverse Clinical Outcomes, Including Aortic Dissection, Aortic-root Surgery and Death.	Percentage of participants who had aortic dissection, aortic-root surgery or death over a 3-year period following randomization	Up to 3 years following randomization.	Yes
Secondary	Adverse Drug Reactions Reported at the Baseline Visit		At baseline	Yes
Secondary	Adverse Drug Reactions Reported During Routine Follow-up Surveillance		From 6 months to 3 years following randomization.	Yes

External Links

•   Click here for the National Marfan Foundation Web site
•   Click here for the Pediatric Heart Network Web site