Comparison of Two Medications Aimed at Slowing Aortic Root Enlargement in Individuals With Marfan Syndrome

NCT00429364 | Completed Phase 3 Results DMC

• 2 other identifiers: 461U01HL068270
• Study Type: interventional
• Target: 608
• Locations: 3 countries
• Sites: 26

Brief 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.

Conditions

Marfan Syndrome

Keywords

Aortic Root Dissection; Aortic Root Dilation; Pediatric Heart Network

Outcome Measures

Primary Outcomes (1)

• 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.

Secondary Outcomes (25)

• Annual Rate of Change in Aortic Root (Sinuses of Valsalva) Absolute Dimension

  Up to 3 years following randomization.

• Annual Rate of Change in Ascending-aorta-diameter Z Score, Adjusted by Body-surface-area.

  Up to 3 years following randomization.

• Annual Rate of Change in the Absolute Diameter of the Ascending Aorta

  Up to 3 years following randomization.

• Annual Rate of Change in Aortic-annulus-diameter Z Score, Adjusted by Body-surface Area

  Up to 3 years following randomization.

• Annual Rate of Change in the Absolute Diameter of the Aortic Annulus

  Up to 3 years following randomization.

Study Arms (2)

Atenolol

ACTIVE COMPARATOR

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.

Drug: Atenolol

Losartan

ACTIVE COMPARATOR

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).

Drug: Losartan Potassium

Interventions

Losartan Potassium DRUG

Losartan .3 - 1.4 mg/kg

Also known as: Cozaar

Losartan

Atenolol DRUG

Atenolol .5 - 4 mg/kg

Also known as: Tenormin

Atenolol

Eligibility Criteria

• Age: 6 Months - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Carelon Research: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator
• FDA Office of Orphan Products Development: collaborator
• National Marfan Foundation: collaborator

Study Sites (26)

Cedars-Sinai Medical Center

Los Angeles, California, 90048, United States

Location

Lucile Packard Children's Hospital

Palo Alto, California, 94304, United States

Location

Rady Children's Hospital / UCSD

San Diego, California, 92123, United States

Location

Stanford University School of Medicine

Stanford, California, 94305, United States

Location

Children's Memorial Hospital

Chicago, Illinois, 60614, United States

Location

Johns Hopkins University School of Medicine

Baltimore, Maryland, 21205, United States

Location

Children's Hospital Boston

Boston, Massachusetts, 02115, United States

Location

Children's Hospital of Minnesota - St. Paul

Saint Paul, Minnesota, 55102, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Weill Medical College of Cornell University

New York, New York, 10021, United States

Location

Mount Sinai Medical Center

New York, New York, 10029, United States

Location

Columbia College of Physicians and Surgeons

New York, New York, 10032, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Brody School of Medicine at East Carolina University

Greenville, North Carolina, 27834, United States

Location

Wake Forest University Baptist Medical Center

Winston-Salem, North Carolina, 27157, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, 15213, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37212, United States

Location

Texas Children's Hospital

Houston, Texas, 77030, United States

Location

Primary Children's Medical Center

Salt Lake City, Utah, 84113, United States

Location

Seattle Children's Hospital

Seattle, Washington, 98105, United States

Location

Ghent University Hospital

Ghent, Gent, 185 9000, Belgium

Location

Hospital for Sick Children

Toronto, Ontario, M5G 1X8, Canada

Location

Related Publications (3)

• Hoskoppal A, Menon S, Trachtenberg F, Burns KM, De Backer J, Gelb BD, Gleason M, James J, Lai WW, Liou A, Mahony L, Olson AK, Pyeritz RE, Sharkey AM, Stylianou M, Wechsler SB, Young L, Levine JC, Tierney ESS, Lacro RV, Bradley TJ; Pediatric Heart Network Investigators. Predictors of Rapid Aortic Root Dilation and Referral for Aortic Surgery in Marfan Syndrome. Pediatr Cardiol. 2018 Oct;39(7):1453-1461. doi: 10.1007/s00246-018-1916-6. Epub 2018 Jun 11.

  PMID: 29948025 DERIVED

• Lacro RV, Dietz HC, Sleeper LA, Yetman AT, Bradley TJ, Colan SD, Pearson GD, Selamet Tierney ES, Levine JC, Atz AM, Benson DW, Braverman AC, Chen S, De Backer J, Gelb BD, Grossfeld PD, Klein GL, Lai WW, Liou A, Loeys BL, Markham LW, Olson AK, Paridon SM, Pemberton VL, Pierpont ME, Pyeritz RE, Radojewski E, Roman MJ, Sharkey AM, Stylianou MP, Wechsler SB, Young LT, Mahony L; Pediatric Heart Network Investigators. Atenolol versus losartan in children and young adults with Marfan's syndrome. N Engl J Med. 2014 Nov 27;371(22):2061-71. doi: 10.1056/NEJMoa1404731. Epub 2014 Nov 18.

  PMID: 25405392 DERIVED

• Lacro RV, Guey LT, Dietz HC, Pearson GD, Yetman AT, Gelb BD, Loeys BL, Benson DW, Bradley TJ, De Backer J, Forbus GA, Klein GL, Lai WW, Levine JC, Lewin MB, Markham LW, Paridon SM, Pierpont ME, Radojewski E, Selamet Tierney ES, Sharkey AM, Wechsler SB, Mahony L; Pediatric Heart Network Investigators. Characteristics of children and young adults with Marfan syndrome and aortic root dilation in a randomized trial comparing atenolol and losartan therapy. Am Heart J. 2013 May;165(5):828-835.e3. doi: 10.1016/j.ahj.2013.02.019. Epub 2013 Mar 26.

  PMID: 23622922 DERIVED

Related Links

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

MeSH Terms

Conditions

Marfan Syndrome; Dissection, Ascending Aorta

Interventions

Losartan; Atenolol

Condition Hierarchy (Ancestors)

Bone Diseases, Developmental; Bone Diseases; Musculoskeletal Diseases; Heart Defects, Congenital; Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Dissection, Thoracic Aorta; Aortic Dissection; Dissection, Blood Vessel; Aneurysm; Vascular Diseases; Acute Aortic Syndrome; Aortic Diseases

Intervention Hierarchy (Ancestors)

Biphenyl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Tetrazoles; Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Propanols; Amines

Limitations and Caveats

The effect of losartan on TGF-β was not assessed. The study results do not apply to Marfan subjects whose BSA-adj. aortic-root z score is ≤3. Subjects may find their treatment based on the appearance of the drug.

Results Point of Contact

• Title: Paul Stark, PhD
• Organization: New England Research Institutes, Inc.

pstark@neriscience.com

617-972-3362

Study Officials

• Ron Lacro, MD

  Boston Children's Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 29, 2007
• First Posted: January 31, 2007
• Study Start: January 1, 2007
• Primary Completion: February 1, 2014
• Study Completion: February 1, 2014
• Last Updated: March 7, 2025
• Results First Posted: April 1, 2015

Record last verified: 2014-01

Locations

BE (1); US (24); CA (1)