Cardiovascular Structure and Function in the Mucopolysaccharidoses

Sponsor

Children's Hospital of Orange County (Other)

Overall Status

Recruiting

CT.gov ID

NCT05063435

Collaborator

Ultragenyx Pharmaceutical Inc (Industry)

Enrollment

Location

41.6

Anticipated Duration (Months)

0.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study's investigators previously demonstrated the potential utility of non-invasive carotid ultrasonography to calculate carotid intima media thickness (cIMT) and stiffness (as measured by the three parameters, carotid cross-sectional distensibility [cCSD], carotid cross-sectional compliance [cCSC], and carotid incremental elastic modulus [cIEM]) in people with mucopolysaccharidoses (MPS).

Investigators also studied arterial gene expression in animal models of MPS, and identified upregulation of a number of markers potentially tied to atherosclerosis and inflammation. These include the atherosclerotic marker known as Clusterin (CLU), Cathepsin S, Elastin, and the inflammatory cytokines interleukin 1-α, interleukin 1-β, interleukin 2, and interleukin 6. Other studies have identified elevation in circulating tumor necrosis factor-α correlating with pain and physical disability in certain mucopolysaccharidoses.

Since these studies are cross sectional, and not longitudinal, this study aims to annually measure these previously studied biomarkers (carotid measurements, circulating cytokines, cathepsin S, elastin, and CLU) in a large cohort of MPS patients. This study is a 3-year, prospective, anonymized, longitudinal assessment of cardiovascular structure, function, and circulating biomarkers in patients with mucopolysaccharidoses.

Condition or Disease	Intervention/Treatment	Phase
Mucopolysaccharidoses Carotid Disease Cardiac Disease Inflammation	Diagnostic Test: Carotid ultrasonography Diagnostic Test: Echocardiography, transthoracic Procedure: Venipuncture

Detailed Description

Specific Aims

Annually assess cardiac and carotid structure and function utilizing ultrasonography, in patients with mucopolysaccharidoses
Annually measure circulating levels of clusterin, elastin, cathepsin S, lipids, and cytokines in patients with mucopolysaccharidoses

Target enrollment 30 subjects at CHOC Children's Hospital

Study Protocol

Screening

Study Investigators will identify eligible patients to participate in the study from their current patient population and future referrals.
Eligible patients will be provided with study information on the study during their standard of care metabolic clinic visit.

Informed Consent

Informed consent will be obtained following the requirements set forth by 21 CFR 50.25.
Patients interested in the study will be provided the informed consent document. The document will be reviewed in a private quiet room and ample time for questions will be provided. The patient can keep a copy of the consent if they wish to discuss the study with friends and family. Consent will only be obtained once the patient has had time to ask questions and is aware that the study is completely voluntary.

Initial entry

Information regarding age, sex, MPS diagnosis (including genetic mutation and enzymatic levels, if possible) will be obtained
Height and weight will be obtained. If patient has had a recent (within 3 months) evaluation at CHOC Children's with height and weight, those parameters may be used
Medical records will be obtained specifically focusing upon
the genetic and/or enzymatic testing used to confirm the MPS diagnosis
the treatment status (treated or not) and duration of treatment (calculated by the difference between date of first carotid imaging and date of first treatment)
Carotid ultrasonography will be obtained
Study takes 10 - 15 minutes to complete
Subject will be asked to lay still and quietly during procedure
Blood pressure and heart rate will be obtained during the study
Results will be digitized and stored on CD
Echocardiography will be obtained
Study takes 15 - 20 minutes to complete
Subject will be asked to lay still and quietly during procedure
Results will be digitized and stored on CD
Venipuncture / phlebotomy
10 mL of blood total will be drawn (5 mL in a blue top citrate tube, 5 mL in a purple top EDTA tube). Measurements of cytokines, clusterin, lipidomics, cathepsin S protease, and elastin (previously identified potential biomarker candidates) will be performed.
Blood will preferably be drawn via venipuncture, but if patient has a port-a-cath already implanted and is having blood drawn via port-a-cath for clinically required reasons, then study-related blood draw via port-a-cath can take place concurrently with clinically required blood draws.

Annual studies Procedures 2), 4), 5), and 6) will be repeated on an annual basis for a total of three years

Study Design

Study Type:

Observational

Anticipated Enrollment :

30 participants

Observational Model:

Case-Only

Time Perspective:

Prospective

Official Title:

Cardiovascular Structure and Function in the Mucopolysaccharidoses

Actual Study Start Date :

Oct 13, 2021

Anticipated Primary Completion Date :

Oct 31, 2024

Anticipated Study Completion Date :

Mar 31, 2025

Outcome Measures

Primary Outcome Measures

Cardiovascular Event [3 years]
A cardiovascular event is defined by new onset of clinically significant aortic or mitral valve disease, aortic root dilatation, cardiomyopathy, reduction in cardiac contractile function, myocardial ischemia, myocardial infarction, or cerebrovascular accident

Secondary Outcome Measures

Age [3 years]
Change of age of subject (unit: years)
Height [3 years]
Change of height of subject (unit: meters)
Weight [3 years]
Change of weight of subject (unit: kilograms)
Blood pressure [3 years]
Change in systolic and diastolic blood pressure over the duration of the study (unit: millimeters of mercury)
Carotid structure [3 years]
Change in carotid intima media thickness over the duration of the study (mm).
Carotid stiffness [3 years]
Change in carotid cross-sectional distensibility over the duration of the study (unit: %). This metric is acquired in the carotid ultrasound, and measures the stiffness of the carotid artery via quantitation of the difference between end-systolic and end-diastolic carotid diameter.
Cardiac structure (left ventricle) [3 years]
Change in left ventricular mass index over the duration of the study (unit: grams / m2 body surface area). This metric is acquired in the echocardiogram, and quantitates the amount of myocardium in the left ventricle.
Cardiac structure (aortic root diameter) [3 years]
Change in aortic root measurement over the duration of the study (unit: mm). This metric is acquired in the echocardiogram, and quantitates the width of the aortic root.
Mitral valve function [3 years]
Assessment of changes in mitral valve function over the duration of the study (unit: 4 point Likert scale from 0 [none] to 4 [severe]). This metric is acquired during the echocardiogram, and assess the degree of mitral valve insufficiency.
Aortic valve function [3 years]
Assessment of changes in aortic valve function over the duration of the study (unit: 4 point Likert scale from 0 [none] to 4 [severe]). This metric is acquired during the echocardiogram, and assess the degree of aortic valve insufficiency.
Inflammatory biomarkers (Tumor Necrosis Factor - alpha) [3 years]
Change in plasma TNFa over the duration of the study.
Inflammatory biomarkers (Cathepsin S) [3 years]
Change in plasma Cathepsin S over the duration of the study. (Unit: mcg/L)
Inflammatory biomarkers (Elastin) [3 years]
Change in plasma Elastin levels over the duration of the study. (Unit: ng/mL)
Inflammatory biomarkers (Clusterin) [3 years]
Change in plasma clusterin levels over the duration of the study. (Unit: mcg/mL)
Inflammatory biomarkers (lipidomics) [3 years]
Change in plasma lipid levels over the duration of the study. (Unit: mcmol/L)

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Any patient with a molecularly confirmed diagnosis of mucopolysaccharidosis is eligible to enroll in this study
Parental / patient informed consent

Exclusion Criteria:

Any reason that the investigators would deem a patient unable to participate in this study
Inability to participate in the assessments required for this study