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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
Results First Received: February 25, 2015  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Single Blind (Outcomes Assessor);   Primary Purpose: Treatment
Condition: Marfan Syndrome
Interventions: Drug: Losartan Potassium
Drug: Atenolol

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
From January 2007 through February 2011, a total of 21 clinical centers enrolled 608 participants into the study.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
For subjects on prophylactic therapy with atenolol or other BB, ARB, ACEi, or calcium-channel blocker, before the study, the drug will be weaned over a 14-day period. After that, a drug washout period of 14–21 days will take place before baseline assessment and randomization.

Reporting Groups
  Description
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.
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).

Participant Flow:   Overall Study
    Atenolol     Losartan  
STARTED     303     305  
COMPLETED     271     272  
NOT COMPLETED     32     33  
Withdrawal by Subject                 11                 5  
Physician Decision                 4                 2  
Lost to Follow-up                 7                 6  
Death                 0                 1  
Underwent aortic root surgery                 10                 18  
Pregnancy                 0                 1  



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
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.
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).
Total Total of all reporting groups

Baseline Measures
    Atenolol     Losartan     Total  
Number of Participants  
[units: participants]
  303     305     608  
Age  
[units: years]
Mean (Standard Deviation)
  11.5  (6.5)     11.0  (6.2)     11.2  (6.3)  
Age, Customized [1]
[units: participants]
     
Young adult     76     75     151  
Child     227     230     457  
Gender  
[units: participants]
     
Female     123     119     242  
Male     180     186     366  
Ethnicity (NIH/OMB) [2]
[units: participants]
     
Hispanic or Latino     36     46     82  
Not Hispanic or Latino     266     259     525  
Unknown or Not Reported     1     0     1  
Race/Ethnicity, Customized [2]
[units: participants]
     
White     266     260     526  
Black     21     25     46  
Asian     6     10     16  
Other     10     10     20  
Presence of causal FBN1 mutation  
[units: participants]
     
Yes     93     88     181  
No     9     15     24  
Unknown     201     202     403  
Family history of Marfan  
[units: participants]
     
Yes     180     181     361  
No     115     109     224  
Unknown     8     15     23  
Maximum aortic-root diameter, cm [3]
[units: centimeter]
Mean (Standard Deviation)
  3.4  (0.7)     3.4  (0.7)     3.4  (0.7)  
Maximum aortic-root diameter z-score [3]
[units: z-score]
Median (Inter-Quartile Range)
  4.0  
  (3.5 to 4.8)  
  4.0  
  (3.3 to 5.0)  
  4.0  
  (3.4 to 4.9)  
Maximum aortic-root diameter z-score [3]
[units: participants]
     
≥z-score of 4.5     106     114     220  
<z-score of 4.5     197     191     388  
Had medical history of cardiac surgery  
[units: participants]
     
Yes     6     6     12  
No     297     299     596  
Had medical history of cardiovascular disorder [4]
[units: participants]
     
Yes     39     36     75  
No     264     269     533  
Prior use of beta-blocker  
[units: participants]
     
Yes     173     171     344  
No     130     134     264  
Had medical history of endocrine disorder [5]
[units: participants]
     
Yes     7     0     7  
No     296     305     601  
Had medical history of neurodevelopmental disorder [6]
[units: participants]
     
Yes     56     61     117  
No     247     244     491  
Had medical history of psychiatric disorder [7]
[units: participants]
     
Yes     23     16     39  
No     280     289     569  
[1] Young adults were defined as male participants who were 16 to 25 years of age and female participants who were 15 to 25 years of age.
[2] Data on race and ethnicity provided by the participant or a family member at the time of enrollment.
[3] Data are based on readings at a central echocardiographic laboratory. Echocardiographic data were missing for one participant in the losartan group because of an unreadable echocardiogram.
[4] Cardiovascular disorder was defined by exercise intolerance, syncope; arrhythmia, hypertension, or hypotension requiring therapy; chest pain, shortness of breath; or other cardiovascular conditions.
[5] Endocrine disorder was defined by either the use of hormone therapy to limit growth, delayed puberty.
[6] Neurodevelopmental disorder was defined as attention deficit-hyperactivity disorder requiring therapy, developmental delay requiring therapy, learning disability requiring services, or other neurodevelopmental conditions.
[7] Psychiatric disorder was defined as depression requiring therapy, anxiety, or other psychiatric conditions.



  Outcome Measures
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1.  Primary:   Annual Rate of Change in Aortic Root (Sinuses of Valsalva) Body-surface-area-adjusted Z-score   [ Time Frame: Up to 3 years following randomization. ]

2.  Secondary:   Annual Rate of Change in Aortic Root (Sinuses of Valsalva) Absolute Dimension   [ Time Frame: Up to 3 years following randomization. ]

3.  Secondary:   Annual Rate of Change in Ascending-aorta-diameter Z Score, Adjusted by Body-surface-area.   [ Time Frame: Up to 3 years following randomization. ]

4.  Secondary:   Annual Rate of Change in the Absolute Diameter of the Ascending Aorta   [ Time Frame: Up to 3 years following randomization. ]

5.  Secondary:   Annual Rate of Change in Aortic-annulus-diameter Z Score, Adjusted by Body-surface Area   [ Time Frame: Up to 3 years following randomization. ]

6.  Secondary:   Annual Rate of Change in the Absolute Diameter of the Aortic Annulus   [ Time Frame: Up to 3 years following randomization. ]

7.  Secondary:   Annual Rate of Change in Total Aortic Proximal Regurgitant Jet Area Indexed to Body-surface-area   [ Time Frame: Up to 3 years following randomization. ]

8.  Secondary:   Annual Rate of Change in Weight   [ Time Frame: Up to 3 years following randomization. ]

9.  Secondary:   Annual Rate of Change in Weight-for-age Z-score   [ Time Frame: Up to 3 years following randomization. ]

10.  Secondary:   Annual Rate of Change in Weight-for-height Z-score   [ Time Frame: Up to 3 years following randomization. ]

11.  Secondary:   Annual Rate of Change in Height   [ Time Frame: Up to 3 years following randomization. ]

12.  Secondary:   Annual Rate of Change in Height-for-age Z-score   [ Time Frame: Up to 3 years following randomization. ]

13.  Secondary:   Annual Rate of Change in Body Mass Index   [ Time Frame: Up to 3 years following randomization. ]

14.  Secondary:   Annual Rate of Change in Body Mass Index for Age Z-score   [ Time Frame: Up to 3 years following randomization. ]

15.  Secondary:   Annual Rate of Change in Arm Span to Height Ratio   [ Time Frame: Up to 3 years following randomization. ]

16.  Secondary:   Annual Rate of Change in Upper to Lower Segment Ratio   [ Time Frame: Up to 3 years following randomization. ]

17.  Secondary:   Number of Participants With Aortic Dissection.   [ Time Frame: Up to 3 years following randomization. ]

18.  Secondary:   Event Rate of Aortic Dissection.   [ Time Frame: Up to 3 years following randomization. ]

19.  Secondary:   Number of Participants With Aortic-root Surgery.   [ Time Frame: Up to 3 years following randomization. ]

20.  Secondary:   Event Rate of Aortic-Root Surgery   [ Time Frame: Up to 3 years following randomization. ]

21.  Secondary:   Number of Death.   [ Time Frame: Up to 3 years following randomization. ]

22.  Secondary:   Event Rate of Death   [ Time Frame: Up to 3 years following randomization. ]

23.  Secondary:   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. ]

24.  Secondary:   Event Rate of the Composite Adverse Clinical Outcomes, Including Aortic Dissection, Aortic-root Surgery and Death.   [ Time Frame: Up to 3 years following randomization. ]

25.  Secondary:   Adverse Drug Reactions Reported at the Baseline Visit   [ Time Frame: At baseline ]

26.  Secondary:   Adverse Drug Reactions Reported During Routine Follow-up Surveillance   [ Time Frame: From 6 months to 3 years following randomization. ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data

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.



  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Paul Stark, PhD
Organization: New England Research Institutes, Inc.
phone: 617-972-3362
e-mail: pstark@neriscience.com


Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: New England Research Institutes
ClinicalTrials.gov Identifier: NCT00429364     History of Changes
Other Study ID Numbers: 461
U01HL068270 ( US NIH Grant/Contract Award Number )
Study First Received: January 29, 2007
Results First Received: February 25, 2015
Last Updated: March 17, 2015
Health Authority: United States: Food and Drug Administration
Belgium: Federal Agency for Medicines and Health Products, FAMHP
Canada: Health Canada