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

The recruitment status of this study is unknown because the information has not been verified recently.
Verified July 2011 by IRCCS Policlinico S. Matteo.
Recruitment status was  Recruiting
Sponsor:
Collaborators:
Merck Sharp & Dohme Corp.
Menarini Group
Information provided by:
IRCCS Policlinico S. Matteo
ClinicalTrials.gov Identifier:
NCT00683124
First received: May 21, 2008
Last updated: July 20, 2011
Last verified: July 2011
  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.

Resource links provided by NLM:


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 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
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

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@yahoo.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: Mario Regazzi, MD         
Sub-Investigator: Catherine Klersy, MD         
Sponsors and Collaborators
IRCCS Policlinico S. Matteo
Merck Sharp & Dohme Corp.
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

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:
Syndrome
Marfan Syndrome
Arachnodactyly
Disease
Pathologic Processes
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
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

ClinicalTrials.gov processed this record on September 30, 2014