Clinical trial NCT00429364: Comparison of Two Medications Aimed 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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Marfan Syndrome
Keywords: Aortic Root Dissection
Aortic Root Dilation
Pediatric Heart Network
Lead sponsor: Carelon Research
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: FDA Office of Orphan Products Development
name: National Marfan Foundation
First posted: 2007-01-31
Enrollment: 608
Sex: ALL
Minimum age (years): 6
Maximum age (years): 25
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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)

Primary outcomes:
measure: Annual Rate of Change in Aortic Root (Sinuses of Valsalva) Body-surface-area-adjusted Z-score
timeFrame: Up to 3 years following randomization.
Secondary outcomes:
measure: Annual Rate of Change in Aortic Root (Sinuses of Valsalva) Absolute Dimension
timeFrame: Up to 3 years following randomization.
measure: Annual Rate of Change in Ascending-aorta-diameter Z Score, Adjusted by Body-surface-area.
timeFrame: Up to 3 years following randomization.
measure: Annual Rate of Change in the Absolute Diameter of the Ascending Aorta
timeFrame: Up to 3 years following randomization.
measure: Annual Rate of Change in Aortic-annulus-diameter Z Score, Adjusted by Body-surface Area
timeFrame: Up to 3 years following randomization.
measure: Annual Rate of Change in the Absolute Diameter of the Aortic Annulus
timeFrame: Up to 3 years following randomization.
measure: Annual Rate of Change in Total Aortic Proximal Regurgitant Jet Area Indexed to Body-surface-area
timeFrame: Up to 3 years following randomization.
measure: Annual Rate of Change in Weight
timeFrame: Up to 3 years following randomization.
measure: Annual Rate of Change in Weight-for-age Z-score
timeFrame: Up to 3 years following randomization.
measure: Annual Rate of Change in Weight-for-height Z-score
timeFrame: Up to 3 years following randomization.
measure: Annual Rate of Change in Height
timeFrame: Up to 3 years following randomization.
measure: Annual Rate of Change in Height-for-age Z-score
timeFrame: Up to 3 years following randomization.
measure: Annual Rate of Change in Body Mass Index
timeFrame: Up to 3 years following randomization.
measure: Annual Rate of Change in Body Mass Index for Age Z-score
timeFrame: Up to 3 years following randomization.
measure: Annual Rate of Change in Arm Span to Height Ratio
timeFrame: Up to 3 years following randomization.
measure: Annual Rate of Change in Upper to Lower Segment Ratio
timeFrame: Up to 3 years following randomization.
measure: Number of Participants With Aortic Dissection.
timeFrame: Up to 3 years following randomization.
measure: Event Rate of Aortic Dissection.
timeFrame: Up to 3 years following randomization.
measure: Number of Participants With Aortic-root Surgery.
timeFrame: Up to 3 years following randomization.
measure: Event Rate of Aortic-Root Surgery
timeFrame: Up to 3 years following randomization.
measure: Number of Death.
timeFrame: Up to 3 years following randomization.
measure: Event Rate of Death
timeFrame: Up to 3 years following randomization.
measure: Number of Participants With the Composite Adverse Clinical Outcomes, Including Aortic Dissection, Aortic-root Surgery and Death.
timeFrame: Up to 3 years following randomization.
measure: Event Rate of the Composite Adverse Clinical Outcomes, Including Aortic Dissection, Aortic-root Surgery and Death.
timeFrame: Up to 3 years following randomization.
measure: Adverse Drug Reactions Reported at the Baseline Visit
timeFrame: At baseline
measure: Adverse Drug Reactions Reported During Routine Follow-up Surveillance
timeFrame: From 6 months to 3 years following randomization.
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Palo Alto
country: United States
facility: Lucile Packard Children's Hospital
state: California
city: San Diego
country: United States
facility: Rady Children's Hospital / UCSD
state: California
city: Stanford
country: United States
facility: Stanford University School of Medicine
state: California
city: Chicago
country: United States
facility: Children's Memorial Hospital
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins University School of Medicine
state: Maryland
city: Boston
country: United States
facility: Children's Hospital Boston
state: Massachusetts
city: Saint Paul
country: United States
facility: Children's Hospital of Minnesota - St. Paul
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New York
country: United States
facility: Weill Medical College of Cornell University
state: New York
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: New York
country: United States
facility: Columbia College of Physicians and Surgeons
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Greenville
country: United States
facility: Brody School of Medicine at East Carolina University
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Baptist Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's Medical Center
state: Utah
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Ghent
country: Belgium
facility: Ghent University Hospital
state: Gent
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
Study officials:
affiliation: Boston Children's Hospital
name: Ron Lacro, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.