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

IRCCS Policlinico S. Matteo

Status and phase: Unknown; Phase 3

Conditions: Marfan Syndrome

Treatments: Drug: Nebivolol; Drug: Losartan and nebivolol; Drug: Losartan

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT00683124

FARM7KP2PX

EudraCT 2008-001462-81

Details and patient eligibility

About

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).

Full 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.

Enrollment: 291 estimated patients

Sex: All

Ages: 12 months to 55 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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291 participants in 3 patient groups

Losartan

Experimental group

Description:

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.

Treatment:

Drug: Losartan

Nebivolol

Experimental group

Description:

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.

Treatment:

Drug: Nebivolol

Losartan+Nebivolol

Experimental group

Description:

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.

Treatment:

Drug: Losartan and nebivolol