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)
30
Enrollment
1
Location
40.9
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 DiseaseIntervention/TreatmentPhase
  • Diagnostic Test: Carotid ultrasonography
  • Diagnostic Test: Echocardiography, transthoracic
  • Procedure: Venipuncture

Detailed Description

Specific Aims

  1. Annually assess cardiac and carotid structure and function utilizing ultrasonography, in patients with mucopolysaccharidoses

  2. 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

  1. Study Investigators will identify eligible patients to participate in the study from their current patient population and future referrals.

  2. Eligible patients will be provided with study information on the study during their standard of care metabolic clinic visit.

Informed Consent

  1. Informed consent will be obtained following the requirements set forth by 21 CFR 50.25.

  2. 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

  1. Information regarding age, sex, MPS diagnosis (including genetic mutation and enzymatic levels, if possible) will be obtained

  2. 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

  3. Medical records will be obtained specifically focusing upon

  4. the genetic and/or enzymatic testing used to confirm the MPS diagnosis

  5. 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)

  6. Carotid ultrasonography will be obtained

  7. Study takes 10 - 15 minutes to complete

  8. Subject will be asked to lay still and quietly during procedure

  9. Blood pressure and heart rate will be obtained during the study

  10. Results will be digitized and stored on CD

  11. Echocardiography will be obtained

  12. Study takes 15 - 20 minutes to complete

  13. Subject will be asked to lay still and quietly during procedure

  14. Results will be digitized and stored on CD

  15. Venipuncture / phlebotomy

  16. 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.

  17. 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
Anticipated Study Start Date :
Nov 1, 2021
Anticipated Primary Completion Date :
Oct 31, 2024
Anticipated Study Completion Date :
Mar 31, 2025

Outcome Measures

Primary Outcome Measures

  1. 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

  1. Age [3 years]

    Change of age of subject (unit: years)

  2. Height [3 years]

    Change of height of subject (unit: meters)

  3. Weight [3 years]

    Change of weight of subject (unit: kilograms)

  4. Blood pressure [3 years]

    Change in systolic and diastolic blood pressure over the duration of the study (unit: millimeters of mercury)

  5. Carotid structure [3 years]

    Change in carotid intima media thickness over the duration of the study (mm).

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. Inflammatory biomarkers (Tumor Necrosis Factor - alpha) [3 years]

    Change in plasma TNFa over the duration of the study.

  12. Inflammatory biomarkers (Cathepsin S) [3 years]

    Change in plasma Cathepsin S over the duration of the study. (Unit: mcg/L)

  13. Inflammatory biomarkers (Elastin) [3 years]

    Change in plasma Elastin levels over the duration of the study. (Unit: ng/mL)

  14. Inflammatory biomarkers (Clusterin) [3 years]

    Change in plasma clusterin levels over the duration of the study. (Unit: mcg/mL)

  15. 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:
No
Inclusion Criteria:
  1. Any patient with a molecularly confirmed diagnosis of mucopolysaccharidosis is eligible to enroll in this study

  2. Parental / patient informed consent

Exclusion Criteria:
  1. Any reason that the investigators would deem a patient unable to participate in this study

  2. Inability to participate in the assessments required for this study

Contacts and Locations

Locations

SiteCityStateCountryPostal Code
1Children's Hospital of Orange CountyOrangeCaliforniaUnited States92868

Sponsors and Collaborators

  • Children's Hospital of Orange County
  • Ultragenyx Pharmaceutical Inc

Investigators

  • Principal Investigator: Raymond Wang, M.D., CHOC Children's Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

Responsible Party:
Children's Hospital of Orange County
ClinicalTrials.gov Identifier:
NCT05063435
Other Study ID Numbers:
  • 200107
First Posted:
Oct 1, 2021
Last Update Posted:
Oct 1, 2021
Last Verified:
Sep 1, 2021
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
No
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Children's Hospital of Orange County
Additional relevant MeSH terms:

Study Results

No Results Posted as of Oct 1, 2021