Marfan Syndrome Clinical Trial
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.
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).
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.
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Investigator, Outcomes Assessor), Primary Purpose: Treatment
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