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| ID | Type | Description | Link |
|---|---|---|---|
| EudraCT 2008-001462-81 |
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| Name | Class |
|---|---|
| Merck Sharp & Dohme LLC | INDUSTRY |
| Menarini Group | INDUSTRY |
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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).
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
|
| 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. |
|
| 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| BSA and age-adjusted aortic root diameter (sinuses of Valsalva) | every 12 months |
| Measure | Description | 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 | |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Eloisa Arbustini, MD,FESC,FACC | Contact | +390382501206 | e.arbustini@smatteo.pv.it | |
| Fabiana I Gambarin, MD | Contact | +390382501206 | f_gambarin@yahoo.it |
| Name | Affiliation | Role |
|---|---|---|
| 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 |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| IRCCS Foundation San Matteo Hospital | Recruiting | Pavia | 27100 | Italy |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 9150447 | Background | 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. | |
| 11087260 | 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. |
| Label | URL |
|---|---|
| home page of the Polyspecialistic Group for Marfan Syndrome diagnosis and management | View source |
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| ID | Term |
|---|---|
| D008382 | Marfan Syndrome |
| D003966 | Camurati-Engelmann Syndrome |
| ID | Term |
|---|---|
| D001848 | Bone Diseases, Developmental |
| D001847 | Bone Diseases |
| D009140 | Musculoskeletal Diseases |
| D006330 | Heart Defects, Congenital |
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| ID | Term |
|---|---|
| D019808 | Losartan |
| D000068577 | Nebivolol |
| ID | Term |
|---|---|
| D001713 | Biphenyl Compounds |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
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|
| 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 |
|
| 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 |
|
| 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 |
| 9453300 | 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. |
| 11171784 | 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. |
| 2462161 | 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. |
| 15587107 | 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. |
| 15262912 | 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. |
| 1593914 | 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. |
| 16296572 | 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. |
| 9990650 | 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. |
| 2773795 | 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. |
| 16601194 | Result | 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. |
| 17188619 | 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. |
| 17911499 | 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. |
|
| 19430350 | Derived | 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. |
| D018376 | Cardiovascular Abnormalities |
| D002318 | Cardiovascular Diseases |
| D006331 | Heart Diseases |
| D000015 | Abnormalities, Multiple |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D030342 | Genetic Diseases, Inborn |
| D003240 | Connective Tissue Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D010009 | Osteochondrodysplasias |
| D006838 |
| Hydrocarbons |
| D009930 | Organic Chemicals |
| D007093 | Imidazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D013777 | Tetrazoles |
| D004983 | Ethanolamines |
| D000605 | Amino Alcohols |
| D000438 | Alcohols |
| D000588 | Amines |
| D001578 | Benzopyrans |
| D011714 | Pyrans |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |