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

NCT00683124 | Unknown Phase 3 DMC

• 2 other identifiers: FARM7KP2PXEudraCT 2008-001462-81
• Study Type: interventional
• Target: 291
• Locations: 1 country
• Sites: 1

Brief 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).

Conditions

Marfan Syndrome

Keywords

Marfan Syndrome; Losartan; Nebivolol; Transforming Growth Factor Beta; Aortic Root Dilation

Outcome Measures

Primary Outcomes (1)

• BSA and age-adjusted aortic root diameter (sinuses of Valsalva)

  every 12 months

Secondary Outcomes (10)

• 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

Study Arms (3)

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

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

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

Interventions

Losartan and nebivolol DRUG

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+Nebivolol

Losartan DRUG

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

Nebivolol DRUG

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

Nebivolol

Eligibility Criteria

• Age: 12 Months - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Fondazione IRCCS Policlinico San Matteo di Pavia: lead
• Merck Sharp & Dohme LLC: collaborator
• Menarini Group: collaborator

Study Sites (1)

IRCCS Foundation San Matteo Hospital

Pavia, 27100, Italy

RECRUITING

Related Publications (15)

• 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. doi: 10.1038/ki.1997.188.

  PMID: 9150447 BACKGROUND

• 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. doi: 10.1152/ajpheart.2000.279.6.H3020.

  PMID: 11087260 BACKGROUND

• 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. doi: 10.1161/01.hyp.31.1.181.

  PMID: 9453300 BACKGROUND

• 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. doi: 10.1161/01.cir.103.6.789.

  PMID: 11171784 BACKGROUND

• 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.

  PMID: 2462161 BACKGROUND

• 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.

  PMID: 15587107 BACKGROUND

• 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. doi: 10.1161/01.HYP.0000137983.45556.6e. Epub 2004 Jul 19.

  PMID: 15262912 BACKGROUND

• 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.

  PMID: 1593914 BACKGROUND

• 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. doi: 10.1016/j.amjhyper.2005.03.733.

  PMID: 16296572 BACKGROUND

• Mangrella M, Rossi F, Fici F, Rossi F. Pharmacology of nebivolol. Pharmacol Res. 1998 Dec;38(6):419-31. doi: 10.1006/phrs.1998.0387.

  PMID: 9990650 BACKGROUND

• 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. doi: 10.1016/0002-9149(89)90430-x.

  PMID: 2773795 BACKGROUND

• 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.

  PMID: 16601194 RESULT

• 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.

  PMID: 17188619 RESULT

• 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.

  PMID: 17911499 RESULT

• 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.

  PMID: 19430350 DERIVED

Related Links

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

MeSH Terms

Conditions

Marfan Syndrome; Camurati-Engelmann Syndrome

Interventions

Losartan; Nebivolol

Condition Hierarchy (Ancestors)

Bone Diseases, Developmental; Bone Diseases; Musculoskeletal Diseases; Heart Defects, Congenital; Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Osteochondrodysplasias

Intervention Hierarchy (Ancestors)

Biphenyl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Tetrazoles; Ethanolamines; Amino Alcohols; Alcohols; Amines; Benzopyrans; Pyrans; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Eloisa Arbustini, MD,FESC,FACC

  IRCCS Foundation San Matteo Hospital, Pavia

  PRINCIPAL INVESTIGATOR

• Luigi Tavazzi, MD,FESC,FACC

  IRCCS Foundation San Matteo Hospital, Pavia

  STUDY CHAIR

Central Study Contacts

Eloisa Arbustini, MD,FESC,FACC

CONTACT

+390382501206; e.arbustini@smatteo.pv.it

Fabiana I Gambarin, MD

CONTACT

+390382501206; f_gambarin@yahoo.it

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: May 21, 2008
• First Posted: May 23, 2008
• Study Start: July 1, 2008
• Primary Completion: July 1, 2013
• Study Completion: July 1, 2013
• Last Updated: July 22, 2011

Record last verified: 2011-07

Locations

IT (1)