Comparison Study of the Effect of Aliskiren Versus Negative Controls on Aortic Stiffness in Patients With Marfan Syndrome Under Treatment With Atenolol

This study is currently recruiting participants.
Verified October 2012 by Samsung Medical Center
Sponsor:
Information provided by (Responsible Party):
Duk-Kyung Kim, Samsung Medical Center
ClinicalTrials.gov Identifier:
NCT01715207
First received: October 24, 2012
Last updated: October 29, 2012
Last verified: October 2012
  Purpose

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.


Condition Intervention Phase
Marfan Syndrome
Drug: Aliskiren
Drug: Atenolol
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Comparison Study of the Effect of Aliskiren Versus Negative Controls on Aortic Stiffness in Patients With Marfan Syndrome Under Treatment With Atenolol

Resource links provided by NLM:


Further study details as provided by Samsung Medical Center:

Primary Outcome Measures:
  • Central aortic PWV(pulsed wave velocity) [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Central aortic distensibility by MRI at week 24 [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Estimated Enrollment: 32
Study Start Date: June 2010
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Atenolol & Aliskiren
Atenolol tablet and Aliskiren 150mg or 300mg tablet by mouth per day for 6month
Drug: Aliskiren
Other Name: Rasilez
Drug: Atenolol
Other Name: Tenormin
Atenolol
Atenolol tablet(Negative controls, Open-label)
Drug: Atenolol
Other Name: Tenormin

  Eligibility

Ages Eligible for Study:   14 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01715207

Contacts
Contact: Duk-Kyung Kim, PhD MD 82-2-3410-3419 dukkyung.kim@samsung.com
Contact: Sung-A Chang, PhD MD 82-2-3410-3419 elisabet.chang@gmail.com

Locations
Korea, Republic of
Samsung Medical Center Recruiting
Seoul, Korea, Republic of, 135-710
Contact: Duk-Kyung Kim, PhD MD    82-2-3410-3419    dukkyung.kim@samsung.com   
Contact: Sung-A Chang, PhD MD    82-2-3410-3419    elisabet.chang@gmail.com   
Principal Investigator: Duk-Kyung Kim, PhD MD         
Sub-Investigator: Sung-A Chang, PhD MD         
Sponsors and Collaborators
Samsung Medical Center
Investigators
Principal Investigator: Duk-Kyung Kim, PhD MD Samsung Medical Center
  More Information

No publications provided

Responsible Party: Duk-Kyung Kim, PhD, MD, Professor, Samsung Medical Center
ClinicalTrials.gov Identifier: NCT01715207     History of Changes
Other Study ID Numbers: 2009-10-025
Study First Received: October 24, 2012
Last Updated: October 29, 2012
Health Authority: South Korea: Institutional Review Board

Additional relevant MeSH terms:
Marfan Syndrome
Arachnodactyly
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
Atenolol
Anti-Arrhythmia Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Antihypertensive Agents
Sympatholytics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Adrenergic beta-1 Receptor Antagonists
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents

ClinicalTrials.gov processed this record on April 23, 2014