Comparison of Aliskiren vs Negative Controls on Aortic Stiffness in Patients With MFS
Condition: Marfan Syndrome
MeSH terms: Marfan Syndrome; Arachnodactyly; Syndrome
Intervention: Aliskiren; Atenolol
Intervention MeSH terms: Atenolol
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Masking description: Open Label
Enrollment: 30.0
Sex: All
Minimum age: 14 Years
Maximum age: 55 Years
Healthy volunteers: No

Summary:

      Marfan syndrome (MFS) is an inherited disorder of connective tissue with morbidity and
      mortality from aortic dilatation and dissection. The current standard of care is beta-blocker
      (BB) treatment and therapeutic target is heart rate. The degree of aortic dilatation and
      response to BB vary in adults with MFS. However, aortic stiffness is often present, and can
      be a predictor of aortic dilatation and cardiovascular complications. Aortic stiffness is a
      logical therapeutic target in adults with MFS.

      Transforming growth factor beta(TGF-beta) mediates disease pathogenesis in MFS and
      contributes to aortic stiffness. Cross-talk between TGF-beta system and renin-angiotensin
      system (RAS) has been demonstrated. The angiotensin receptor blocker (ARB), losartan,
      inhibits TGF-beta activity and reverses aortic wall pathology in a Marfan mouse model. In a
      small cohort study, the use of ARB therapy (losartan or irbesartan) significantly slowed the
      rate of progressive aortic dilatation in patients with MFS, after BB therapy had failed to
      prevent aortic root dilatation. In another study, angiotensin converting enzyme inhibitor,
      perindopril, reduced both aortic stiffness and aortic root diameter in patients with MFS
      taking standard BB therapy. Renin inhibitor, aliskiren, has not been studied to reduce aortic
      stiffness and attenuate aortic dilatation in patients with MFS.

      This trial is a randomized, open-label trial of 32 patients with Marfan syndrome, treated
      with 6 months of aliskiren vs. negative controls in patients with MFS under atenolol
      treatment. MRI for aortic pulsed wave velocity (PWV) and distensibility, measurements of
      central BP (CBP) and augmentation index (AIx) will be performed at the beginning and end of
      treatment. A blood drawn for serum markers of TGF-beta, extracellular matrix turnover and
      inflammation will also be performed at 0 and 6 months. We plan to determine whether aliskiren
      decreases aortic stiffness significantly more than negative controls in patients with MFS
      under atenolol treatment.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Diagnosis of MFS by Ghent criteria and/or genetically proven Fibrillin-1 (FBN1)
             mutation

          2. Age between 14 and 55 years

          3. Beta-blocker treatment at least 3 months

          4. subjects must not have been receiving chronic RAS inhibitor therapy (i.e. ARBs, or ACE
             inhibitors)>= 90days prior to screening

          5. Written informed consent from the patients or authorized representatives must be
             obtained

        Exclusion Criteria:

          1. previous medical history of aortic surgery and/or dissection

          2. significant valve disease requiring surgery

          3. aortic root dimension > 5.5 cm

          4. renal dysfunction (creatinine > upper normal limit)

          5. pregnancy or planned pregnancy within 12 months of study entry or breast feeding women

          6. Known renal artery stenosis

          7. Hypersensitivity to the aliskiren or to any of the excipients

          8. Elevation of serum creatinine during follow-up (> 30% than baseline)

          9. Diarrhea, resulting severe dehydration

         10. Development of gout or ureter stone

         11. Symptomatic hypotension (SBP<90 with symptom)

         12. Hyperkalemia

         13. Concomitant use with ciclosporin A