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

Condition(s) targeted: Marfan Syndrome

Intervention: Losartan and nebivolol (Drug); Losartan (Drug); Nebivolol (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: IRCCS Policlinico S. Matteo

Official(s) and/or principal investigator(s):
Eloisa Arbustini, MD,FESC,FACC, Principal Investigator, Affiliation: IRCCS Foundation San Matteo Hospital, Pavia
Luigi Tavazzi, MD,FESC,FACC, Study Chair, Affiliation: IRCCS Foundation San Matteo Hospital, Pavia

Overall contact:
Eloisa Arbustini, MD,FESC,FACC, Phone: +390382501206, Email: e.arbustini@smatteo.pv.it

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).

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.

Study design: Treatment, Randomized, Double Blind (Investigator, Outcomes Assessor), Active Control, Parallel Assignment, Efficacy Study

Primary outcome: BSA and age-adjusted aortic root diameter (sinuses of Valsalva)

Secondary outcome:

The pharmacokinetics of the two drugs by age and dosages

Comparative evaluation of the serum levels of total and active TGFb

Quantitative assessment of the expression of the mutated gene (FBN1, both 5' and 3')

Pharmacogenetic bases of drug responsiveness (Losartan: CYP2C9 gene) (Nebivolol: CYP2D6 gene)

Aortic valve regurgitation severity

Left ventricular end-diastolic diameter

Left ventricular ejection fraction

Spirometric lung volumes and flows

QoL evaluation basing on SF-36 questionnaire

Arterial stiffness (carotids)

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.

We 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). We 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.

Minimum age: 12 Months. Maximum age: 55 Years. Gender(s): Both.

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 2. 5 measured at the level of the sinuses of Valsalva at

baseline 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.

Eloisa Arbustini, MD,FESC,FACC, Phone: +390382501206, Email: e.arbustini@smatteo.pv.it

IRCCS Foundation San Matteo Hospital, Pavia 27100, Italy; Recruiting
Eloisa Arbustini, MD,FESC,FACC, Phone: +390382501206, Email: e.arbustini@smatteo.pv.it
Fabiana I Gambarin, MD, Phone: +390382501206, Email: f.gambarin@smatteo.pv.it
Eloisa Arbustini, MD,FESC,FACC, Principal Investigator
Fabiana I Gambarin, MD, Sub-Investigator
Valentina Favalli, Engineer, Sub-Investigator
Alessandra Serio, MD, Sub-Investigator
Michele Pasotti, MD, Sub-Investigator
Mario Regazzi, MD, Sub-Investigator
Catherine Klersy, MD, Sub-Investigator
Savina Mannarino, MD, Sub-Investigator

home page of the Polyspecialistic Group for Marfan Syndrome diagnosis and management

Related publications:

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Starting date: July 2008
Ending date: July 2012
Last updated: August 27, 2009