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

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).

Study Overview

• Status: Unknown
• Conditions: Marfan Syndrome
• Intervention / Treatment: Drug: Losartan; Drug: Nebivolol; Drug: Losartan and nebivolol

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.

• Study Type: Interventional
• Enrollment (Anticipated): 291
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Eloisa Arbustini, MD,FESC,FACC; Phone Number: +390382501206; Email: e.arbustini@smatteo.pv.it
• Study Contact Backup: Name: Fabiana I Gambarin, MD; Phone Number: +390382501206; Email: f_gambarin@yahoo.it

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 months to 53 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Losartan; 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; 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
Experimental: Nebivolol; 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; 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
Experimental: Losartan+Nebivolol; 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; 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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: IRCCS Policlinico S. Matteo
• Collaborators: Merck Sharp & Dohme LLC; Menarini Group
• Investigators: Principal Investigator: Eloisa Arbustini, MD,FESC,FACC, IRCCS Foundation San Matteo Hospital, Pavia; Study Chair: Luigi Tavazzi, MD,FESC,FACC, IRCCS Foundation San Matteo Hospital, Pavia

Publications and helpful links

General Publications

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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. doi: 10.1126/science.1124287.
• 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. doi: 10.1016/j.jpeds.2006.09.003.
• 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. doi: 10.1001/jama.298.13.1539.
• Gambarin FI, Favalli V, Serio A, Regazzi M, Pasotti M, Klersy C, Dore R, Mannarino S, Vigano M, Odero A, Amato S, Tavazzi L, Arbustini E. Rationale and design of a trial evaluating the effects of losartan vs. nebivolol vs. the association of both on the progression of aortic root dilation in Marfan syndrome with FBN1 gene mutations. J Cardiovasc Med (Hagerstown). 2009 Apr;10(4):354-62. doi: 10.2459/JCM.0b013e3283232a45.

Study record dates

Study Major Dates

• Study Start: July 1, 2008
• Primary Completion (Anticipated): July 1, 2013
• Study Completion (Anticipated): July 1, 2013

Study Registration Dates

• First Submitted: May 21, 2008
• First Submitted That Met QC Criteria: May 22, 2008
• First Posted (Estimate): May 23, 2008

Study Record Updates

• Last Update Posted (Estimate): July 22, 2011
• Last Update Submitted That Met QC Criteria: July 20, 2011
• Last Verified: July 1, 2011

More Information

Terms related to this study

• Keywords: Nebivolol; Losartan; Marfan Syndrome; Transforming Growth Factor Beta; Aortic Root Dilation
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Disease; Congenital Abnormalities; Genetic Diseases, Inborn; Musculoskeletal Diseases; Connective Tissue Diseases; Pathological Conditions, Anatomical; Bone Diseases; Heart Defects, Congenital; Cardiovascular Abnormalities; Musculoskeletal Abnormalities; Abnormalities, Multiple; Bone Diseases, Developmental; Limb Deformities, Congenital; Syndrome; Marfan Syndrome; Arachnodactyly; Dilatation, Pathologic; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents; Adrenergic Agonists; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Adrenergic beta-Agonists; Adrenergic beta-1 Receptor Agonists; Losartan; Nebivolol
• Other Study ID Numbers: FARM7KP2PX; EudraCT 2008-001462-81