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Comparison of Aliskiren vs Negative Controls on Aortic Stiffness in Patients With MFS

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Duk-Kyung Kim, Samsung Medical Center
ClinicalTrials.gov Identifier:
NCT01715207
First received: October 24, 2012
Last updated: May 3, 2017
Last verified: May 2017
  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
Intervention Model: Parallel Assignment
Masking: No masking
Masking Description:
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 Duk-Kyung Kim, Samsung Medical Center:

Primary Outcome Measures:
  • Central Aortic Distensibility by MRI [ Time Frame: 6 months ]
    Analyses of the MRIs were performed using commercial software (Argus version 4.02, Siemens Medical Systems, Germany) by experienced observers who were blinded to patient information. To measure central aortic distensibility, the systolic and diastolic cross-sectional areas were measured by manual contouring of the aorta through the cardiac cycle on the cine image. Distensibility at the four regions was calculated as the mean of values obtained from the following equation: Distensibility = (Amax - Amin)/[Amin × (Pmax - Pmin)](10-3mm/Hg), where Amax is the maximal (systolic) aortic area, Amin is the minimal (diastolic) aortic area, Pmax is the systolic blood pressure (SBP), and Pmin is the diastolic blood pressure (DBP). Central aortic blood pressure measured non-invasively by SphygmoCor was used for systolic and diastolic blood pressure.


Secondary Outcome Measures:
  • Central Aortic PWV(Pulsed Wave Velocity) [ Time Frame: 6 months ]
    Aortic PWV was measured according to the well-validated method using MRI 19. From the velocity-encoded MRIs, aortic contours were automatically detected and manually adjusted in each slice area throughout the cardiac cycle. The transit time between the flow curves of each region of the aorta was determined from the midpoint of the systolic up-slope on the flow versus time curve 26-28. The up-slopes were identified by drawing a line between the points of 40% and 60% maximum velocity on the waveform. The distance between each aortic level was measured on black blood images using a curved line along the center of the aorta. Based on these data, the regional PWV was calculated as the ratio of the distance between levels and the time differences between the arrival of the pulse wave at each level. The PWV was measured at two regions: the proximal aorta (proximal PWV between level 1 and level 2) and the entire aorta (PWV-total between level 1 and level 4).


Enrollment: 30
Study Start Date: June 2010
Study Completion Date: December 2014
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

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   14 Years to 55 Years   (Child, Adult)
Sexes Eligible for Study:   All
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
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: NCT01715207

Locations
Korea, Republic of
Samsung Medical Center
Seoul, Korea, Republic of, 135-710
Sponsors and Collaborators
Samsung Medical Center
Investigators
Principal Investigator: Duk-Kyung Kim, PhD MD Samsung Medical Center
  More Information

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
Results First Received: November 21, 2016
Last Updated: May 3, 2017
Individual Participant Data  
Plan to Share IPD: No
Plan Description: to contact the principal investigator

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
Atenolol
Anti-Arrhythmia Agents
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 June 22, 2017