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

NCT01715207 | Completed Phase 3 Results

• 1 other identifier: 2009-10-025
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Marfan Syndrome

Outcome Measures

Primary Outcomes (1)

• Central Aortic Distensibility by MRI

  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.

  6 months

Secondary Outcomes (1)

• Central Aortic PWV(Pulsed Wave Velocity)

  6 months

Study Arms (2)

Atenolol & Aliskiren

EXPERIMENTAL

Atenolol tablet and Aliskiren 150mg or 300mg tablet by mouth per day for 6month

Drug: Aliskiren; Drug: Atenolol

Atenolol

OTHER

Atenolol tablet(Negative controls, Open-label)

Drug: Atenolol

Interventions

Aliskiren DRUG

Also known as: Rasilez

Atenolol & Aliskiren

Atenolol DRUG

Also known as: Tenormin

Atenolol; Atenolol & Aliskiren

Eligibility Criteria

• Age: 14 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Diagnosis of MFS by Ghent criteria and/or genetically proven Fibrillin-1 (FBN1) mutation
• Age between 14 and 55 years
• Beta-blocker treatment at least 3 months
• subjects must not have been receiving chronic RAS inhibitor therapy (i.e. ARBs, or ACE inhibitors)\>= 90days prior to screening
• Written informed consent from the patients or authorized representatives must be obtained

You may not qualify if:

• previous medical history of aortic surgery and/or dissection
• significant valve disease requiring surgery
• aortic root dimension \> 5.5 cm
• renal dysfunction (creatinine \> upper normal limit)
• pregnancy or planned pregnancy within 12 months of study entry or breast feeding women
• Known renal artery stenosis
• Hypersensitivity to the aliskiren or to any of the excipients
• Elevation of serum creatinine during follow-up (\> 30% than baseline)
• Diarrhea, resulting severe dehydration
• Development of gout or ureter stone
• Symptomatic hypotension (SBP\<90 with symptom)
• Hyperkalemia
• Concomitant use with ciclosporin A

Sponsors & Collaborators

• Samsung Medical Center: lead

Study Sites (1)

Samsung Medical Center

Seoul, 135-710, South Korea

Location

MeSH Terms

Conditions

Marfan Syndrome

Interventions

aliskiren; Atenolol

Condition Hierarchy (Ancestors)

Bone Diseases, Developmental; Bone Diseases; Musculoskeletal Diseases; Heart Defects, Congenital; Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn; Connective Tissue Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines

Results Point of Contact

• Title: Prof Duk-Kyung Kim
• Organization: SamsungMC

dukkyung.kim@samsung.com

01099333413

Study Officials

• Duk-Kyung Kim, PhD MD

  Samsung Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: Open Label
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: PhD, MD, Professor

Study Record Dates

• First Submitted: October 24, 2012
• First Posted: October 26, 2012
• Study Start: June 1, 2010
• Primary Completion: October 1, 2014
• Study Completion: December 1, 2014
• Last Updated: June 5, 2017
• Results First Posted: May 4, 2017

Record last verified: 2017-05

Data Sharing

• IPD Sharing: Will not share

Locations

KR (1)