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

Marfan Syndrome Clinical Trial

— MaNeLo  

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.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00683124
• Other study ID #: FARM7KP2PX
• Secondary ID: EudraCT 2008-001
• Status: Recruiting
• Phase: Phase 3
• First received: May 21, 2008
• Last updated: July 20, 2011
• Start date: July 2008
• Est. completion date: July 2013

Study information

• Verified date: July 2011
• Source: IRCCS Policlinico S. Matteo
• Contact: Eloisa Arbustini, MD,FESC,FACC
• Phone: +390382501206
• Email: e.arbustini[@]smatteo.pv.it
• Is FDA regulated: No
• Health authority: Italy: Ethics CommitteeItaly: The Italian Medicines Agency
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 291
• Est. completion date: July 2013
• Est. primary completion date: July 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 12 Months to 55 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Marfan Syndrome

Intervention

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
• 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
• 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

Locations

Country	Name	City	State
Italy	IRCCS Foundation San Matteo Hospital	Pavia

Sponsors (3)

Lead Sponsor	Collaborator
IRCCS Policlinico S. Matteo	Menarini Group, Merck Sharp & Dohme Corp.

Country where clinical trial is conducted

Italy, 

References & Publications (14)

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( — View Citation

Border WA, Noble NA. Interactions of transforming growth factor-beta and angiotensin II in renal fibrosis. Hypertension. 1998 Jan;31(1 Pt 2):181-8. Review. — View Citation

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 aneu — View Citation

Hao J, Wang B, Jones SC, Jassal DS, Dixon IM. Interaction between angiotensin II and Smad proteins in fibroblasts in failing heart and in vitro. Am J Physiol Heart Circ Physiol. 2000 Dec;279(6):H3020-30. — View Citation

Ignarro LJ. Experimental evidences of nitric oxide-dependent vasodilatory activity of nebivolol, a third-generation beta-blocker. Blood Press Suppl. 2004 Oct;1:2-16. Review. — View Citation

Lim DS, Lutucuta S, Bachireddy P, Youker K, Evans A, Entman M, Roberts R, Marian AJ. Angiotensin II blockade reverses myocardial fibrosis in a transgenic mouse model of human hypertrophic cardiomyopathy. Circulation. 2001 Feb 13;103(6):789-91. — View Citation

Mangrella M, Rossi F, Fici F, Rossi F. Pharmacology of nebivolol. Pharmacol Res. 1998 Dec;38(6):419-31. Review. — View Citation

McEniery CM, Schmitt M, Qasem A, Webb DJ, Avolio AP, Wilkinson IB, Cockcroft JR. Nebivolol increases arterial distensibility in vivo. Hypertension. 2004 Sep;44(3):305-10. Epub 2004 Jul 19. — View Citation

Munger JS, Harpel JG, Gleizes PE, Mazzieri R, Nunes I, Rifkin DB. Latent transforming growth factor-beta: structural features and mechanisms of activation. Kidney Int. 1997 May;51(5):1376-82. Review. — View Citation

Pauwels PJ, Gommeren W, Van Lommen G, Janssen PA, Leysen JE. The receptor binding profile of the new antihypertensive agent nebivolol and its stereoisomers compared with various beta-adrenergic blockers. Mol Pharmacol. 1988 Dec;34(6):843-51. — View Citation

Roman MJ, Devereux RB, Kramer-Fox R, O'Loughlin J. Two-dimensional echocardiographic aortic root dimensions in normal children and adults. Am J Cardiol. 1989 Sep 1;64(8):507-12. — View Citation

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;1 — View Citation

Van Bortel LM, Bulpitt CJ, Fici F. Quality of life and antihypertensive effect with nebivolol and losartan. Am J Hypertens. 2005 Aug;18(8):1060-6. — View Citation

Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care. 1992 Jun;30(6):473-83. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	BSA and age-adjusted aortic root diameter (sinuses of Valsalva)		every 12 months	No
Secondary	The pharmacokinetics of the two drugs by age and dosages		every 12 months	No
Secondary	Comparative evaluation of the serum levels of total and active TGFb		every 12 months	No
Secondary	Quantitative assessment of the expression of the mutated gene (FBN1, both 5' and 3')		every 12 months	No
Secondary	Pharmacogenetic bases of drug responsiveness (Losartan: CYP2C9 gene) (Nebivolol: CYP2D6 gene)		every 12 months	No
Secondary	Aortic valve regurgitation severity		every 12 months	No
Secondary	Left ventricular end-diastolic diameter		every 12 months	No
Secondary	Left ventricular ejection fraction		every 12 months	No
Secondary	Spirometric lung volumes and flows		every 12 months	No
Secondary	QoL evaluation basing on SF-36 questionnaire		every 12 months	No
Secondary	Arterial stiffness (carotids)		every 12 months	No