Clinical Trial: Nebivolol Versus Losartan Versus Nebivolol+Losartan Against Aortic Root Dilation in Genotyped Marfan Patients

Study Status: Recruiting
Recruit Status: Unknown status
Study Type: Interventional

Official Title: Effects of Losartan vs. Nebivolol vs. the Association of Both on the Progression of Aortic Root Dilation in Marfan Syndrome (MFS) With FBN1 Gene Mutations.

Brief Summary: The major clinical problems in patients with Marfan Syndrome (MFS) are aortic root dilation (ARD), dissection and rupture. Although the available treatments (beta-blockers, BBs) improve the evolution of the disease, they do not protect MFS patients from progression of ARD and dissection. A key molecule that negatively influences cell growth, differentiation, survival and death in MFS is TGFb which is antagonised by existing drugs employed in the clinical practice, the Angiotensin II receptor blockers (ARB).

Detailed Summary:

Marfan Syndrome is a rare disease (1:5000)(MIM#154700) caused by mutations of the Fibrillin 1 (FBN1) gene. The major clinical problem is aortic aneurysm with risk of dissection when root diameter is 5 cm.

The investigators designed a clinical trial in which a new generation Beta-Blocker Nebivolol with expected effects on shear stress, heart rate and potential anti-stiffness benefits is compared to Losartan, and Angiotensin receptor blocker anti TGF-beta effects, and to the association of both molecules in patients with Marfan Syndrome. Nebivolol is a patented drug that differs chemically, pharmacologically and therapeutically from all other BBs. Nebivolol shows the highest selectivity for ß1 receptors among the currently available BBs, influences the arterial stiffness through an agonistic effect on ß2-receptors and preserves the arterial compliance. We expect a significantly lower progression of the Aortic Root Dilation in the arm of Nebivolol plus Losartan vs. single drug (primary end-point).The investigators further expect: decrease of arterial stiffness higher in the arm treated with both drugs than in solely Nebivolol or Losartan; a decrease of serum levels of active TGFb in both Losartan arms, a drug & age-dependant variation of the expression of the mutated FBN1 gene. As for other end-points, the potential results are the improvement of valve function, hard events & delay of surgical timing for the aortic root. The enrolment period will last 12 months, while the overall follow-up period will be of 4 years. An interim analysis for the primary outcome is programmed at month 24.


Sponsor: IRCCS Policlinico S. Matteo

Current Primary Outcome: BSA and age-adjusted aortic root diameter (sinuses of Valsalva) [ Time Frame: every 12 months ]

Original Primary Outcome: Same as current

Current Secondary Outcome:

  • The pharmacokinetics of the two drugs by age and dosages [ Time Frame: every 12 months ]
  • Comparative evaluation of the serum levels of total and active TGFb [ Time Frame: every 12 months ]
  • Quantitative assessment of the expression of the mutated gene (FBN1, both 5' and 3') [ Time Frame: every 12 months ]
  • Pharmacogenetic bases of drug responsiveness (Losartan: CYP2C9 gene) (Nebivolol: CYP2D6 gene) [ Time Frame: every 12 months ]
  • Aortic valve regurgitation severity [ Time Frame: every 12 months ]
  • Left ventricular end-diastolic diameter [ Time Frame: every 12 months ]
  • Left ventricular ejection fraction [ Time Frame: every 12 months ]
  • Spirometric lung volumes and flows [ Time Frame: every 12 months ]
  • QoL evaluation basing on SF-36 questionnaire [ Time Frame: every 12 months ]
  • Arterial stiffness (carotids) [ Time Frame: every 12 months ]


Original Secondary Outcome: Same as current

Information By: IRCCS Policlinico S. Matteo

Dates:
Date Received: May 21, 2008
Date Started: July 2008
Date Completion: July 2013
Last Updated: July 20, 2011
Last Verified: July 2011