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

Study Overview
=================
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 Description
-----------------
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.

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.

Conditions
-----------------
Marfan Syndrome

Intervention / Treatment
-----------------
* Drug: Losartan and nebivolol
* Drug: Losartan
* Drug: Nebivolol


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of MFS: Ghent criteria and genetically proven defect of the FBN1 gene Age: 12 months to 55 years BSA-adjusted aortic z score = or >2 measured at the level of the sinuses of Valsalva at baseline according to Roman's method, or absolute aortic root diameter >38mm for females and >40 mm for males Exclusion Criteria: Prior aortic surgery and/or dissection Aortic root diameter at the level of the sinuses of Valsalva 5 cm Planned aortic surgery within 6 months of enrollment for a rate of ARD progression>5 mm/year even in pts with ARD less than 5 cm Clinical or molecular diagnosis of non-MFS connective tissue diseases sharing some features with MFS (Shprintzen-Goldberg syndrome or Loeys-Dietz syndromes) Un-renounceable therapeutic (systemic hypertension, arrhythmia, ventricular dysfunction, valve regurgitation) use of drugs such as ACE inhibitors, BBs, or calcium-channel blockers Known side-effects while taking an ARB or a BB Intolerance to ARB that resulted in termination of therapy Intolerance to BB that resulted in termination of therapy Renal dysfunction (creatinine level more than upper limit of age-related normal values) Diabetes mellitus Pregnancy or planned pregnancy within 48 months of enrollment Technical limitations for the imaging studies including poor acoustic windows with limits the accurate measurement of aortic root Asthma.

Ages Eligible for Study
-----------------
Minimum Age: 12 Months
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Losartan<br>Losartan administered as maximal tolerated dosage, not to exceed the maximal theorical dosage of 100 mg/day for adults and 1,6 mg/kg/die for children minor than 16 years. | Drug: Losartan<br>* Losartan is administered orally as pills. It is given preferentially once a day or, if not well tolerated because of hypotension, the total daily dosage is given in two administrations<br>|
| Experimental: Nebivolol<br>Nebivolol administered as maximal tolerated dosage, not to exceed the maximal theorical dosage of 10 mg/day for adults and 0,16 mg/kg/die for children minor than 16 years. | Drug: Nebivolol<br>* Nebivolol is administered orally as pills. It is given preferentially once a day in the morning or, if not well tolerated because of hypotension, the total daily dosage is given in two administrations<br>|
| Experimental: Losartan+Nebivolol<br>Losartan administered as maximal tolerated dosage, not to exceed the maximal theorical dosage of 100 mg/day for adults and 1,6 mg/kg/die for children minor than 16 years. Nebivolol administered as maximal tolerated dosage, not to exceed the maximal theorical dosage of 10 mg/day for adults and 0,16 mg/kg/die for children minor than 16 years. | Drug: Losartan and nebivolol<br>* Nebivolol is administered orally as pills. It is given preferentially once a day in the morning or, if not well tolerated because of hypotension, the total daily dosage is given in two administrations. Losartan is administered orally as pills. It is given preferentially once a day or, if not well tolerated because of hypotension, the total daily dosage is given in two administrations<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BSA and age-adjusted aortic root diameter (sinuses of Valsalva) |  | every 12 months | 

Secondary Outcome Measures

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

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Marfan Syndrome, Losartan, Nebivolol, Transforming Growth Factor Beta, Aortic Root Dilation