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

Primary Purpose

Marfan Syndrome

Status
Unknown status
Phase
Phase 3
Locations
Italy
Study Type
Interventional
Intervention
Losartan and nebivolol
Losartan
Nebivolol
Sponsored by
IRCCS Policlinico S. Matteo
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Marfan Syndrome focused on measuring Marfan Syndrome, Losartan, Nebivolol, Transforming Growth Factor Beta, Aortic Root Dilation

Eligibility Criteria

12 Months - 55 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • IRCCS Foundation San Matteo HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Losartan

Nebivolol

Losartan+Nebivolol

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

The pharmacokinetics of the two drugs by age and dosages
Comparative evaluation of the serum levels of total and active TGFb
Quantitative assessment of the expression of the mutated gene (FBN1, both 5' and 3')
Pharmacogenetic bases of drug responsiveness (Losartan: CYP2C9 gene) (Nebivolol: CYP2D6 gene)
Aortic valve regurgitation severity
Left ventricular end-diastolic diameter
Left ventricular ejection fraction
Spirometric lung volumes and flows
QoL evaluation basing on SF-36 questionnaire
Arterial stiffness (carotids)

Full Information

First Posted
May 21, 2008
Last Updated
July 20, 2011
Sponsor
IRCCS Policlinico S. Matteo
Collaborators
Merck Sharp & Dohme LLC, Menarini Group
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1. Study Identification

Unique Protocol Identification Number
NCT00683124
Brief Title
Nebivolol Versus Losartan Versus Nebivolol+Losartan Against Aortic Root Dilation in Genotyped Marfan Patients
Acronym
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.
Study Type
Interventional

2. Study Status

Record Verification Date
July 2011
Overall Recruitment Status
Unknown status
Study Start Date
July 2008 (undefined)
Primary Completion Date
July 2013 (Anticipated)
Study Completion Date
July 2013 (Anticipated)

3. Sponsor/Collaborators

Name of the Sponsor
IRCCS Policlinico S. Matteo
Collaborators
Merck Sharp & Dohme LLC, Menarini Group

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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).
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Marfan Syndrome
Keywords
Marfan Syndrome, Losartan, Nebivolol, Transforming Growth Factor Beta, Aortic Root Dilation

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
InvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
291 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Losartan
Arm Type
Experimental
Arm Description
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.
Arm Title
Nebivolol
Arm Type
Experimental
Arm Description
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.
Arm Title
Losartan+Nebivolol
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Losartan and nebivolol
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Losartan
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Nebivolol
Intervention Description
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
Primary Outcome Measure Information:
Title
BSA and age-adjusted aortic root diameter (sinuses of Valsalva)
Time Frame
every 12 months
Secondary Outcome Measure Information:
Title
The pharmacokinetics of the two drugs by age and dosages
Time Frame
every 12 months
Title
Comparative evaluation of the serum levels of total and active TGFb
Time Frame
every 12 months
Title
Quantitative assessment of the expression of the mutated gene (FBN1, both 5' and 3')
Time Frame
every 12 months
Title
Pharmacogenetic bases of drug responsiveness (Losartan: CYP2C9 gene) (Nebivolol: CYP2D6 gene)
Time Frame
every 12 months
Title
Aortic valve regurgitation severity
Time Frame
every 12 months
Title
Left ventricular end-diastolic diameter
Time Frame
every 12 months
Title
Left ventricular ejection fraction
Time Frame
every 12 months
Title
Spirometric lung volumes and flows
Time Frame
every 12 months
Title
QoL evaluation basing on SF-36 questionnaire
Time Frame
every 12 months
Title
Arterial stiffness (carotids)
Time Frame
every 12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Months
Maximum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
No
Eligibility 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 = 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Eloisa Arbustini, MD,FESC,FACC
Phone
+390382501206
Email
e.arbustini@smatteo.pv.it
First Name & Middle Initial & Last Name or Official Title & Degree
Fabiana I Gambarin, MD
Phone
+390382501206
Email
f_gambarin@yahoo.it
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Eloisa Arbustini, MD,FESC,FACC
Organizational Affiliation
IRCCS Foundation San Matteo Hospital, Pavia
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Luigi Tavazzi, MD,FESC,FACC
Organizational Affiliation
IRCCS Foundation San Matteo Hospital, Pavia
Official's Role
Study Chair
Facility Information:
Facility Name
IRCCS Foundation San Matteo Hospital
City
Pavia
ZIP/Postal Code
27100
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Eloisa Arbustini, MD,FESC,FACC
Phone
+390382501206
Email
e.arbustini@smatteo.pv.it
First Name & Middle Initial & Last Name & Degree
Fabiana I Gambarin, MD
Phone
+390382501206
Email
f.gambarin@smatteo.pv.it
First Name & Middle Initial & Last Name & Degree
Eloisa Arbustini, MD,FESC,FACC
First Name & Middle Initial & Last Name & Degree
Fabiana I Gambarin, MD
First Name & Middle Initial & Last Name & Degree
Valentina Favalli, Engineer
First Name & Middle Initial & Last Name & Degree
Alessandra Serio, MD
First Name & Middle Initial & Last Name & Degree
Mario Regazzi, MD
First Name & Middle Initial & Last Name & Degree
Catherine Klersy, MD

12. IPD Sharing Statement

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

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