Nebivolol Versus Losartan Versus Nebivolol+Losartan Against Aortic Root Dilation in Genotyped Marfan Patients - Full Text View

Sponsors and Collaborators:	IRCCS Policlinico S. Matteo Merck Sharp & Dohme Menarini Group
Information provided by:	IRCCS Policlinico S. Matteo
ClinicalTrials.gov Identifier:	NCT00683124

Purpose

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).

Condition	Intervention	Phase
Marfan Syndrome	Drug: Losartan and nebivolol Drug: Losartan Drug: Nebivolol	Phase III

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Investigator, Outcomes Assessor), Active Control, Parallel Assignment, Efficacy Study
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.

Resource links provided by NLM:

Genetics Home Reference related topics: Marfan syndrome

MedlinePlus related topics: Marfan Syndrome

Drug Information available for: Nebivolol Losartan Losartan potassium

U.S. FDA Resources

Further study details as provided by IRCCS Policlinico S. Matteo:

Primary Outcome Measures:

BSA and age-adjusted aortic root diameter (sinuses of Valsalva) [ Time Frame: every 12 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

The pharmacokinetics of the two drugs by age and dosages [ Time Frame: every 12 months ] [ Designated as safety issue: No ]
Comparative evaluation of the serum levels of total and active TGFb [ Time Frame: every 12 months ] [ Designated as safety issue: No ]
Quantitative assessment of the expression of the mutated gene (FBN1, both 5' and 3') [ Time Frame: every 12 months ] [ Designated as safety issue: No ]
Pharmacogenetic bases of drug responsiveness (Losartan: CYP2C9 gene) (Nebivolol: CYP2D6 gene) [ Time Frame: every 12 months ] [ Designated as safety issue: No ]
Aortic valve regurgitation severity [ Time Frame: every 12 months ] [ Designated as safety issue: No ]
Left ventricular end-diastolic diameter [ Time Frame: every 12 months ] [ Designated as safety issue: No ]
Left ventricular ejection fraction [ Time Frame: every 12 months ] [ Designated as safety issue: No ]
Spirometric lung volumes and flows [ Time Frame: every 12 months ] [ Designated as safety issue: No ]
QoL evaluation basing on SF-36 questionnaire [ Time Frame: every 12 months ] [ Designated as safety issue: No ]
Arterial stiffness (carotids) [ Time Frame: every 12 months ] [ Designated as safety issue: No ]

Estimated Enrollment:	291
Study Start Date:	July 2008
Estimated Study Completion Date:	July 2012
Estimated Primary Completion Date:	July 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Losartan: Experimental 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
Nebivolol: Experimental 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
Losartan+Nebivolol: Experimental 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

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.

Eligibility

Ages Eligible for Study:	12 Months to 55 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00683124

Contacts

Contact: Eloisa Arbustini, MD,FESC,FACC	+390382501206	e.arbustini@smatteo.pv.it
Contact: Fabiana I Gambarin, MD	+390382501206	f.gambarin@smatteo.pv.it

Locations

Italy
IRCCS Foundation San Matteo Hospital	Recruiting
Pavia, Italy, 27100
Contact: Eloisa Arbustini, MD,FESC,FACC +390382501206 e.arbustini@smatteo.pv.it
Contact: Fabiana I Gambarin, MD +390382501206 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: Michele Pasotti, MD
Sub-Investigator: Mario Regazzi, MD
Sub-Investigator: Catherine Klersy, MD
Sub-Investigator: Savina Mannarino, MD

Sponsors and Collaborators

IRCCS Policlinico S. Matteo

Merck Sharp & Dohme

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

More Information

Additional Information:

home page of the Polyspecialistic Group for Marfan Syndrome diagnosis and management This link exits the ClinicalTrials.gov site

Publications:

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

Additional publications automatically indexed to this study by National Clinical Trials Identifier (NCT ID):

Gambarin FI, Favalli V, Serio A, Regazzi M, Pasotti M, Klersy C, Dore R, Mannarino S, Viganò 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.

Responsible Party:	IRCCS Foundation San Matteo Hospital ( Doctor Eloisa Arbustini, MD, FESC, FACC )
Study ID Numbers:	FARM7KP2PX, EudraCT 2008−001462−81
Study First Received:	May 21, 2008
Last Updated:	August 27, 2009
ClinicalTrials.gov Identifier:	NCT00683124 History of Changes
Health Authority:	Italy: Ethics Committee; Italy: The Italian Medicines Agency

Keywords provided by IRCCS Policlinico S. Matteo:

Marfan Syndrome
Losartan
Nebivolol
Transforming Growth Factor Beta
Aortic Root Dilation

Study placed in the following topic categories:

Vasodilator Agents
Neurotransmitter Agents
Dilatation, Pathologic
Adrenergic Agents
Disease Progression
Bone Diseases
Musculoskeletal Abnormalities
Musculoskeletal Diseases
Abnormalities, Multiple
Bone Diseases, Developmental
Connective Tissue Diseases
Mitogens
Adrenergic beta-Antagonists
Anti-Arrhythmia Agents

Congenital Abnormalities
Losartan
Heart Diseases
Cardiovascular Abnormalities
Nebivolol
Cardiovascular Agents
Angiotensin II
Marfan Syndrome
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Genetic Diseases, Inborn
Adrenergic Antagonists
Heart Defects, Congenital
Arachnodactyly

Additional relevant MeSH terms:

Neurotransmitter Agents
Vasodilator Agents
Molecular Mechanisms of Pharmacological Action
Adrenergic Agents
Physiological Effects of Drugs
Bone Diseases
Musculoskeletal Abnormalities
Limb Deformities, Congenital
Pathologic Processes
Musculoskeletal Diseases
Syndrome
Therapeutic Uses
Abnormalities, Multiple
Bone Diseases, Developmental
Connective Tissue Diseases

Adrenergic beta-Antagonists
Cardiovascular Diseases
Anti-Arrhythmia Agents
Congenital Abnormalities
Losartan
Heart Diseases
Disease
Cardiovascular Abnormalities
Nebivolol
Cardiovascular Agents
Marfan Syndrome
Antihypertensive Agents
Pharmacologic Actions
Angiotensin II Type 1 Receptor Blockers
Genetic Diseases, Inborn

ClinicalTrials.gov processed this record on September 10, 2009