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.
试验速览
- 阶段
- 3 期
- 发起方
- 入组人数
- 291
- 试验地点
- 1
- 主要终点
- BSA and age-adjusted aortic root diameter (sinuses of Valsalva)
研究概览
简要总结
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).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 12 Months 至 55 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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.
干预措施: Losartan (Drug)
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.
干预措施: Nebivolol (Drug)
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.
干预措施: Losartan and nebivolol (Drug)
结局指标
主要结局
BSA and age-adjusted aortic root diameter (sinuses of Valsalva)
时间窗: every 12 months
次要结局
- Quantitative assessment of the expression of the mutated gene (FBN1, both 5' and 3')(every 12 months)
- 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)
- 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)