Nebivolol Versus Losartan Versus Nebivolol+Losartan Against Aortic Root Dilation in Genotyped Marfan Patients (MaNeLo)
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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 3 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Investigator, Outcomes Assessor) Primary Purpose: Treatment |
| 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. |
- BSA and age-adjusted aortic root diameter (sinuses of Valsalva) [ Time Frame: every 12 months ] [ Designated as safety issue: No ]
- 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 2013 |
| Estimated Primary Completion Date: | July 2013 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
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 |
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.
Eligibility| Ages Eligible for Study: | 12 Months to 55 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
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.
Contacts and Locations| Contact: Eloisa Arbustini, MD,FESC,FACC | +390382501206 | e.arbustini@smatteo.pv.it |
| Contact: Fabiana I Gambarin, MD | +390382501206 | f_gambarin@yahoo.it |
| 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: Mario Regazzi, MD | |
| Sub-Investigator: Catherine Klersy, MD | |
| 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
Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | Doctor Eloisa Arbustini, MD, FESC, FACC, IRCCS Foundation San Matteo Hospital |
| ClinicalTrials.gov Identifier: | NCT00683124 History of Changes |
| Other Study ID Numbers: | FARM7KP2PX, EudraCT 2008−001462−81 |
| Study First Received: | May 21, 2008 |
| Last Updated: | July 20, 2011 |
| 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 |
Additional relevant MeSH terms:
|
Marfan Syndrome Arachnodactyly Dilatation, Pathologic Bone Diseases, Developmental Bone Diseases Musculoskeletal Diseases Heart Defects, Congenital Cardiovascular Abnormalities Cardiovascular Diseases Heart Diseases Abnormalities, Multiple Congenital Abnormalities Genetic Diseases, Inborn Connective Tissue Diseases Limb Deformities, Congenital |
Musculoskeletal Abnormalities Pathological Conditions, Anatomical Nebivolol Losartan Antihypertensive Agents Cardiovascular Agents Therapeutic Uses Pharmacologic Actions Vasodilator Agents Adrenergic beta-1 Receptor Antagonists Adrenergic beta-Antagonists Adrenergic Antagonists Adrenergic Agents Neurotransmitter Agents Molecular Mechanisms of Pharmacological Action |
ClinicalTrials.gov processed this record on May 22, 2013