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

Condition(s) targeted: Marfan Syndrome

Intervention: Losartan Potassium (Drug); Atenolol (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: National Heart, Lung, and Blood Institute (NHLBI)

Official(s) and/or principal investigator(s):
Ron Lacro, MD, Principal Investigator, Affiliation: Boston Children's Hospital

Overall contact:
Gloria Klein, MS, RD, Phone: 617-923-7747, Ext: 323, Email: gklein@neriscience.com

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.

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)

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

Primary outcome: Rate of change in aortic root (sinuses of Valsalva) body-surface-area-adjusted Z-score

Secondary outcome:

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

Time to first occurrence of aortic dissection, aortic root surgery, or death

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

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.

Minimum age: 6 Months. Maximum age: 25 Years. Gender(s): Both.

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)

Gloria Klein, MS, RD, Phone: 617-923-7747, Ext: 323, Email: gklein@neriscience.com

Stanford University School of Medicine, Stanford, California 94305, United States; Recruiting
Elisabeth Merkel, RN, Phone: 650-736-0644, Email: merkel@stanford.edu
David Liang, MD, Principal Investigator

Lucile Packard Children's Hospital, Palo Alto, California 94304, United States; Recruiting
Sunny Pellone, Phone: 650-725-8246, Email: spellone@stanfordmed.org
Daniel Murphy, MD, Principal Investigator

Cedars-Sinai Medical Center, Los Angeles, California 90048, United States; Recruiting
Mitchel Pariani, MS, Phone: 310-423-9861, Email: Mitchel.Pariani@cshs.org
David Rimoin, MD, PhD, Principal Investigator

Rady Children's Hospital / UCSD, San Diego, California 92123, United States; Recruiting
Terri McLees-Palinkas, Phone: 858-966-8066, Email: tmclees@rchsd.org
Lynn Nelles, RN, CCRC, Phone: (858) 966-8158, Email: lnelles@rchsd.org
Paul Grossfeld, MD, Principal Investigator

Ghent University Hospital, De Pintelaan, Gent 185 9000, Belgium; Recruiting
Bart Loeys, MD, Phone: 32-9-240.63.43, Email: Bart.Loeys@UGent.be
Sylvia De Nobele, RN, Phone: 32-9-240.36.03, Email: sylvia.denobele@ugent.be
Bart Loeys, MD, Principal Investigator

Children's Memorial Hospital, Chicago, Illinois 60614, United States; Recruiting
Megan Domenico, RN, BSN, Phone: 773-880-8331, Email: mdomenico@childrensmemorial.org
Luciana Young, MD, Principal Investigator

Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States; Recruiting
Mary Rykiel, Phone: 410-502-2014, Email: mrykiel1@jhmi.edu
Hal Dietz, MD, Principal Investigator

Children's Hospital Boston, Boston, Massachusetts 02115, United States; Recruiting
Martha King, Phone: 617-355-8239, Email: martha.king@cardio.chboston.org
Ronald V. Lacro, MD, Principal Investigator

Children's Hospital of Minnesota - St. Paul, St. Paul, Minnesota 55102, United States; Recruiting
Erin Olson, Phone: 612-813-7737, Email: erin.olson@childrensmn.org
Mary Ella Pierpont, MD, PhD, Principal Investigator

Washington University School of Medicine, St Louis, Missouri 63110, United States; Recruiting
Cheryl Rainey, Phone: 314-454-6147, Email: rainey_c@kids.wustl.edu
Angela Sharkey, MD, Principal Investigator
Alan Braverman, MD, Sub-Investigator

Columbia College of Physicians and Surgeons, New York, New York 10032, United States; Recruiting
Rosalind Korsin, Phone: 212-342-0524, Email: rk271@columbia.edu
Beth Printz, MD, Principal Investigator

Weill Medical College of Cornell University, New York, New York 10021, United States; Recruiting
Rosalind Korsin, Phone: 212-342-0524, Email: rk271@columbia.edu
Mary Roman, MD, Principal Investigator
Richard Devereux, MD, Sub-Investigator

Mount Sinai Medical Center, New York, New York 10029, United States; Recruiting
Tejani Mendez-Ramdeen, Phone: 212-241-6012, Email: Tejani.Mendiz-Ramdeen@mssm.edu
Bruce Gelb, MD, Principal Investigator

Duke University Medical Center, Durham, North Carolina 27710, United States; Recruiting
Ming Xu, Phone: 919-668-6352, Email: Mingfen.Xu@duke.edu
Jennifer Li, MD, Principal Investigator
Stephanie Wechsler, MD, Sub-Investigator

Brody School of Medicine at East Carolina University, Greenville, North Carolina 27834, United States; Recruiting
Lori Jo Sutton, Phone: 252-744-2161, Email: suttonlo@ecu.edu
Charlie Sang, MD, Principal Investigator
Karen Laurito, MD, Sub-Investigator

Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina 27157, United States; Recruiting
Kari Crawford, Phone: 336-713-2228, Email: kcrawfor@wfubmc.edu
Wesley Covitz, MD, Principal Investigator

Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, United States; Recruiting
Michell Hamstra, Phone: 513-636-3891, Email: Michelle.Hamstra@cchmc.org
D. Woodrow Benson, MD, PhD, Principal Investigator

Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada; Recruiting
Elizabeth Radojewski, Phone: 416-813-2179, Email: elizabeth.radojewski@sickkids.ca
Timothy Bradley, MD, Principal Investigator

Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, United States; Recruiting
Ruth Morgan, BS, RN, Phone: 267-426-5270, Email: MORGANRU@email.chop.edu
Stephen Paridon, MD, Principal Investigator

Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States; Recruiting
Ruth Morgan, BS, RN, Phone: 267-426-5270, Email: MORGANRU@email.chop.edu
Reed Pyeritz, MD, PhD, Principal Investigator

Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15213, United States; Recruiting
Kevin Steigler, RN, CCRC, Phone: 412-692-6516, Email: kevin.stiegler@chp.edu
Steven Webber, MBChB, MRCP, Principal Investigator
Stacey Drant, MD, Sub-Investigator

Medical University of South Carolina, Charleston, South Carolina 29425, United States; Recruiting
Patricia Infinger, Phone: 843-792-7857, Email: infingep@musc.edu
Philip Saul, MD, Principal Investigator
Geoffrey Forbus, MD, Sub-Investigator

Vanderbilt University Medical Center, Nashville, Tennessee 37212, United States; Recruiting
Cheryl Kinnard, RN, CCRC, Phone: 615-343-2880, Email: cheryl.kinnard@vanderbilt.edu
Larry Markham, MD, Principal Investigator

Texas Children's Hospital, Houston, Texas 77030, United States; Recruiting
Hugo Martinez, MD, Phone: 832-826-5667, Email: hrmartin@bcm.edu
John Lynn Jefferies, MD, Principal Investigator

Primary Children's Medical Center, Salt Lake City, Utah 84113, United States; Recruiting
Marian Shearrow, Phone: 801-662-5487, Email: Marian.Shearrow@intermountainmail.org
LuAnn Minich, MD, Principal Investigator
Angela Yetman, MD, Sub-Investigator

Seattle Children's Hospital, Seattle, Washington 98105, United States; Recruiting
Amy Payne, RN, CCRC, Phone: 206-987-5708, Email: amy.payne@seattlechildrens.org
Mark Lewin, MD, Principal Investigator

Click here for the Pediatric Heart Network Web site

Click here for the National Marfan Foundation Web site

Starting date: January 2007
Ending date: December 2013
Last updated: July 24, 2009