Clinical trial NCT05063435: Cardiovascular Structure and Function in the Mucopolysaccharidoses
Official title: Cardiovascular Structure and Function in the Mucopolysaccharidoses
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Mucopolysaccharidoses
Carotid Disease
Cardiac Disease
Inflammation
Keywords: mucopolysaccharidosis
carotid
cardiac
cardiovascular
biomarker
longitudinal
observational
Lead sponsor: Children's Hospital of Orange County
Sponsor class: OTHER
Collaborators: name: Ultragenyx Pharmaceutical Inc
First posted: 2021-10-01
Enrollment: 30
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Any patient with a diagnosis of mucopolysaccharidosis who provides informed consent is eligible for this study. Mucopolysaccharidoses are a group of inherited metabolic disorders involving abnormal degradation of glycosaminoglycans. There are 11 different genes which, when altered, can give rise to a mucopolysaccharidosis. People with this diagnosis can develop significant cardiovascular disease (left ventricular hypertrophy, valvular dysfunction, aortic root dilatation, arterial wall thickening and stiffness).

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.

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

   1. the genetic and/or enzymatic testing used to confirm the MPS diagnosis
   2. 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)
4. Carotid ultrasonography will be obtained

   1. Study takes 10 - 15 minutes to complete
   2. Subject will be asked to lay still and quietly during procedure
   3. Blood pressure and heart rate will be obtained during the study
   4. Results will be digitized and stored on CD
5. Echocardiography will be obtained

   1. Study takes 15 - 20 minutes to complete
   2. Subject will be asked to lay still and quietly during procedure
   3. Results will be digitized and stored on CD
6. Venipuncture / phlebotomy

   1. 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.
   2. 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

Eligibility criteria: 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

Primary outcomes:
measure: Cardiovascular Event
timeFrame: 3 years
Secondary outcomes:
measure: Age
timeFrame: 3 years
measure: Height
timeFrame: 3 years
measure: Weight
timeFrame: 3 years
measure: Blood pressure
timeFrame: 3 years
measure: Carotid structure
timeFrame: 3 years
measure: Carotid stiffness
timeFrame: 3 years
measure: Cardiac structure (left ventricle)
timeFrame: 3 years
measure: Cardiac structure (aortic root diameter)
timeFrame: 3 years
measure: Mitral valve function
timeFrame: 3 years
measure: Aortic valve function
timeFrame: 3 years
measure: Inflammatory biomarkers (Tumor Necrosis Factor - alpha)
timeFrame: 3 years
measure: Inflammatory biomarkers (Cathepsin S)
timeFrame: 3 years
measure: Inflammatory biomarkers (Elastin)
timeFrame: 3 years
measure: Inflammatory biomarkers (Clusterin)
timeFrame: 3 years
measure: Inflammatory biomarkers (lipidomics)
timeFrame: 3 years
Other outcomes:
Locations:
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
Study officials:
affiliation: CHOC Children's Hospital
name: Raymond Wang, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Wang RY, Covault KK, Halcrow EM, Gardner AJ, Cao X, Newcomb RL, Dauben RD, Chang AC. Carotid intima-media thickness is increased in patients with mucopolysaccharidoses. Mol Genet Metab. 2011 Dec;104(4):592-6. doi: 10.1016/j.ymgme.2011.09.004. Epub 2011 Sep 10.
citation: Wang RY, Braunlin EA, Rudser KD, Dengel DR, Metzig AM, Covault KK, Polgreen LE, Shapiro E, Steinberger J, Kelly AS. Carotid intima-media thickness is increased in patients with treated mucopolysaccharidosis types I and II, and correlates with arterial stiffness. Mol Genet Metab. 2014 Feb;111(2):128-32. doi: 10.1016/j.ymgme.2013.11.001. Epub 2013 Nov 12.
citation: Wang RY, Rudser KD, Dengel DR, Braunlin EA, Steinberger J, Jacobs DR, Sinaiko AR, Kelly AS. The Carotid Intima-Media Thickness and Arterial Stiffness of Pediatric Mucopolysaccharidosis Patients Are Increased Compared to Both Pediatric and Adult Controls. Int J Mol Sci. 2017 Mar 15;18(3):637. doi: 10.3390/ijms18030637.
citation: Wang RY, Rudser KD, Dengel DR, Evanoff N, Steinberger J, Movsesyan N, Garrett R, Christensen K, Boylan D, Braddock SR, Shinawi M, Gan Q, Montano AM. Abnormally increased carotid intima media-thickness and elasticity in patients with Morquio A disease. Orphanet J Rare Dis. 2020 Mar 17;15(1):73. doi: 10.1186/s13023-020-1331-y.