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

Marfan Syndrome research study

What is the primary objective of this study?

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).

Who is eligible to participate?

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.

Which medical condition, disease, disorder, syndrome, illness, or injury is researched?

Marfan Syndrome

Study Interventions

Interventions can include giving participants drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available or noninvasive approaches such as surveys, education, and interviews.

Drug:Losartan and nebivololNebivolol 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

Drug:LosartanLosartan 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

Drug:NebivololNebivolol 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

Study Arms

Research studies and clinical trials typically have two or more research arms. An arm is a group of people who receive the same treatment in the study.

LosartanLosartan 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.

NebivololNebivolol 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.

Losartan+NebivololLosartan 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.

Study Status

Unknown status

Start Date: July 2008

Completed Date: July 2013

Phase: Phase 3

Type: Interventional

Design:

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

Secondary Outcome: The pharmacokinetics of the two drugs by age and dosages

Study sponsors, principal investigator, and references

Principal Investigator: Eloisa Arbustini, MD,FESC,FACC

Lead Sponsor: IRCCS Policlinico S. Matteo

Collaborator:

More information:https://clinicaltrials.gov/show/NCT00683124

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Habashi JP, Judge DP, Holm TM, Cohn RD, Loeys BL, Cooper TK, Myers L, Klein EC, Liu G, Calvi C, Podowski M, Neptune ER, Halushka MK, Bedja D, Gabrielson K, Rifkin DB, Carta L, Ramirez F, Huso DL, Dietz HC. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science. 2006 Apr 7;312(5770):117-21.

Selamet Tierney ES, Feingold B, Printz BF, Park SC, Graham D, Kleinman CS, Mahnke CB, Timchak DM, Neches WH, Gersony WM. Beta-blocker therapy does not alter the rate of aortic root dilation in pediatric patients with Marfan syndrome. J Pediatr. 2007 Jan;150(1):77-82.

Ahimastos AA, Aggarwal A, D'Orsa KM, Formosa MF, White AJ, Savarirayan R, Dart AM, Kingwell BA. Effect of perindopril on large artery stiffness and aortic root diameter in patients with Marfan syndrome: a randomized controlled trial. JAMA. 2007 Oct 3;298(13):1539-47. Retraction in: JAMA. 2015 Dec 22-29;314(24):2692-3.

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