Carotid Structure and Function in MPS Syndromes: A Multicenter Study of the Lysosomal Disease Network

• Sponsor: University of Minnesota (Other)
• Overall Status: Completed
• CT.gov ID: NCT01586871
• Collaborator: Rare Diseases Clinical Research Network (Other), National Center for Advancing Translational Science (NCATS) (NIH), National Institute of Neurological Disorders and Stroke (NINDS) (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
• Enrollment: 1,147
• Locations: 2
• Duration (Months): 63
• Patients Per Site: 573.5
• Patients Per Site Per Month: 9.1

Study Details

Study Description

Brief Summary

Mucopolysaccharidosis (MPS) syndromes are disorders characterized by enzyme deficiencies, and they have been linked to heart health complications. However, there are currently no proven markers of heart and artery health for this population. The main purpose of this observational study is to evaluate the ease and convenience of a non-invasive measurement of artery function in MPS I, MPS II and MPS VI patients compared to healthy control subjects. An observational study is a research design meaning that there is no treatment in this study.

The research questions are:

1. Is the artery health of MPS I, II and VI patients different than healthy controls?

2. Is the artery health of MPS VI patients different than MPS I and II patients?

It is hypothesized that MPS patients will have poorer outcomes of artery health compared to healthy controls.

Condition or Disease	Intervention/Treatment	Phase
Mucopolysaccharidoses

Detailed Description

Mucopolysaccharidosis (MPS) syndromes are disorders characterized by enzyme deficiencies. As a result of the enzyme deficiency, glycosaminoglycans that are normally recycled in a healthy individual cannot be degraded in the MPS patient. MPS syndromes have been linked to heart health complications. Complications related to coronary artery stenosis (narrowing) are recognized as potentially fatal sequelae of untreated and treated MPS. Presently, national guidelines are largely silent on coronary artery disease risk in this population. There are currently no validated markers of cardiovascular or coronary artery disease in the MPS population. The main purpose of this observational study is to evaluate the ease and convenience of a non-invasive measurement of artery function in MPS I, MPS II and MPS VI patients compared to healthy control subjects. Exploring the validity and usefulness of this non-invasive measurement is the first step towards developing validated markers of cardiovascular or coronary artery disease in the MPS population.

Specific Aim #1: Compare carotid artery intima-media thickness and carotid stiffness in individuals with MPS I, II, and VI (treated and non-treated) vs. healthy age-and gender-matched controls. It is hypothesized that MPS patients will have increased carotid artery thickness and reduced carotid compliance and distensibility compared to healthy controls.

Specific Aim #2: Compare carotid artery intima-media thickness and carotid stiffness in individuals with MPS VI vs. I and II and between MPS I patients clinically treated with HSCT vs. ERT. It is hypothesized that MPS VI will have decreased carotid thickness and increased carotid compliance and distensibility compared to MPS I and II and that MPS I patients treated with ERT will have increased carotid thickness and reduced carotid compliance and distensibility compared to MPS I patients treated with HSCT.

Study Design

• Study Type: Observational
• Actual Enrollment: 1147 participants
• Observational Model: Case-Control
• Time Perspective: Retrospective
• Official Title: Carotid Structure and Function in MPS Syndromes: A Multicenter Study of the Lysosomal Disease Network
• Study Start Date: Mar 1, 2012
• Actual Primary Completion Date: Aug 1, 2016
• Actual Study Completion Date: Jun 1, 2017

Outcome Measures

Primary Outcome Measures

1. Carotid Intima-media Thickness, Measured in Millimeters [Baseline]

   The carotid intima-media thickness test (CIMT) is a measure used to diagnose the extent of carotid atherosclerotic vascular disease. The test measures the thickness of the inner two layers of the carotid artery-the intima and media-and alerts physicians to any thickening when patients are still asymptomatic. CIMT was measured from the far wall of the left common carotid.

Secondary Outcome Measures

1. Carotid Cross-sectional Distensibility [Baseline]

   Carotid distensibility is a measure of carotid artery elasticity that has been introduced as a risk factor for cardiovascular disease. It is defined by the percent change in carotid lumen area from diastole to systole, has the unit of % and is defined by the equation (sD^2 - dD^2/dD^2)*100 where sD is the maximum systolic carotid diameter, dD is the minimum diastolic carotid diameter. Increasing carotid distensibility reflects high carotid distensibility and low stiffness, and vice versa.

2. Carotid Cross-sectional Compliance [Baseline]

   This is defined by the relative change in carotid lumen area from diastole to systole for a given change in blood pressure, has the unit mm^2/mmHg and is defined by the equation ¶(sD^2-dD^2)/4*PP where PP is pulse pressure (or systolic blood pressure-diastolic blood pressure). Increasing carotid cross sectional compliance reflects high carotid distensibility and low stiffness, and vice versa.

3. Carotid Incremental Elastic Modulus [Baseline]

   A way of measuring the elasticity constant of the carotid vessel, has the unit mmHg and is defined by the equation 3(1+sD^2/dD^2)/cross sectional compliance value. In contrast to carotid cross sectional compliance and carotid cross sectional distensibility, increasing carotid incremental elastic modus reflects low carotid distensibility and high thickness.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 3 Years to 18 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Be between the ages of 3 and 18 years old

• Be diagnosed with MPS I, MPS II or MPS VI

Exclusion Criteria:

• None

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital of Orange County	Orange	California	United States	92868
2	University of Minnesota	Minneapolis	Minnesota	United States	55455

Sponsors and Collaborators

• University of Minnesota
• Rare Diseases Clinical Research Network
• National Center for Advancing Translational Science (NCATS)
• National Institute of Neurological Disorders and Stroke (NINDS)
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Principal Investigator: Aaron S Kelly, Ph.D., University of Minnesota

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Rare Disease Clinical Research Network

Publications

None provided.

• Responsible Party: University of Minnesota
• ClinicalTrials.gov Identifier: NCT01586871
• Other Study ID Numbers: 1202M09721; U54NS065768
• First Posted: Apr 27, 2012
• Last Update Posted: Feb 24, 2021
• Last Verified: Feb 1, 2021

• Keywords provided by University of Minnesota: MPS I; MPS II; MPS IIIA; MPS VI
• Additional relevant MeSH terms: Mucopolysaccharidoses

Study Results

Participant Flow

Recruitment Details

This was a dual-center, cross-sectional assessment of carotid imaging data obtained from 33 patients with biochemically and/or molecularly confirmed MPS Types I, II, III and VI; 560 healthy pediatric control patients; and 554 adult control patients. The pediatric and adult controls were obtained from prior studies of insulin resistance and cardiovascular risk at the University of Minnesota. Clinical data from MPS patients were obtained from chart review.

Arm/Group Title	Pediatric Control Patients	Adult Controls	MPS Patients
Arm/Group Description	The pediatric control patients were obtained from prior studies of insulin resistance and cardiovascular risk at the University of Minnesota.	The adult controls were obtained from prior studies of insulin resistance and cardiovascular risk at the University of Minnesota.	Clinical data (demographic information, anthropometrics, ethnicity, confirmation of diagnosis, and treatment status) from MPS patients were obtained from chart review. For this project, data from MPS I, MPS II, MPS IIIa and MPS VI was available.
Period Title: Overall Study
STARTED	560	554	33
COMPLETED	560	554	33
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Pediatric Control	Adult Control	Mucopolysaccharidosis (MPS ) Subjects	Total
Arm/Group Description	Healthy pediatric control subjects	Healthy adult control subjects	Mucopolysaccharidosis subjects type I, II, IIIA and VI.	Total of all reporting groups
Overall Participants	560	554	33	1147
Age (years) [Median (Standard Deviation) ]
Median (Standard Deviation) [years]	13.14 (4.01)	39.16 (2.24)	12.47 (4.66)	21.59 (3.63)
Sex: Female, Male (Count of Participants)
Female	259 46.3%	285 51.4%	10 30.3%	554 48.3%
Male	301 53.8%	269 48.6%	23 69.7%	593 51.7%
Height (centimeters) [Median (Standard Deviation) ]
Median (Standard Deviation) [centimeters]	155 (18.3)	171 (12.8)	132 (16.59)	152.66 (15.89)
Weight (kilograms) [Median (Standard Deviation) ]
Median (Standard Deviation) [kilograms]	53.8 (23.54)	86.39 (23.33)	36.66 (16.74)	58.95 (21.20)
Body Mass Index (Kg/m^2) [Median (Standard Deviation) ]
Median (Standard Deviation) [Kg/m^2]	21.44 (5.84)	29.46 (7.47)	20.03 (4.50)	23.64 (5.93)
Systolic blood pressure (mm Hg) [Median (Standard Deviation) ]
Median (Standard Deviation) [mm Hg]	106 (10.42)	125 (15.59)	106 (10.98)	112.33 (12.33)
Diastolic blood pressure (mm Hg) [Median (Standard Deviation) ]
Median (Standard Deviation) [mm Hg]	58 (7.78)	71.97 (10.39)	55 (13.73)	61.65 (10.63)

Outcome Measures

1. Primary Outcome

Title	Carotid Intima-media Thickness, Measured in Millimeters
Description	The carotid intima-media thickness test (CIMT) is a measure used to diagnose the extent of carotid atherosclerotic vascular disease. The test measures the thickness of the inner two layers of the carotid artery-the intima and media-and alerts physicians to any thickening when patients are still asymptomatic. CIMT was measured from the far wall of the left common carotid.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pediatric Control	Adult Control	Mucopolysaccharidosis (MPS ) Subjects
Arm/Group Description	Healthy pediatric control subjects	Healthy adult control subjects	Mucopolysaccharidosis subjects type I, II, IIIA and VI.
Measure Participants	560	554	33
Median (Standard Deviation) [mm]	0.44 (0.04)	0.52 (0.09)	0.56 (0.05)

2. Secondary Outcome

Title	Carotid Cross-sectional Distensibility
Description	Carotid distensibility is a measure of carotid artery elasticity that has been introduced as a risk factor for cardiovascular disease. It is defined by the percent change in carotid lumen area from diastole to systole, has the unit of % and is defined by the equation (sD^2 - dD^2/dD^2)*100 where sD is the maximum systolic carotid diameter, dD is the minimum diastolic carotid diameter. Increasing carotid distensibility reflects high carotid distensibility and low stiffness, and vice versa.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pediatric Control	Adult Control	Mucopolysaccharidosis (MPS ) Subjects
Arm/Group Description	Healthy pediatric control subjects	Healthy adult control subjects	Mucopolysaccharidosis subjects type I, II, IIIA and VI.
Measure Participants	560	554	33
Mean (Standard Deviation) [percentage of change]	32.03 (8.35)	16.33 (4.73)	28.36 (15.70)

3. Secondary Outcome

Title	Carotid Cross-sectional Compliance
Description	This is defined by the relative change in carotid lumen area from diastole to systole for a given change in blood pressure, has the unit mm^2/mmHg and is defined by the equation ¶(sD^2-dD^2)/4*PP where PP is pulse pressure (or systolic blood pressure-diastolic blood pressure). Increasing carotid cross sectional compliance reflects high carotid distensibility and low stiffness, and vice versa.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pediatric Control	Adult Control	Mucopolysaccharidosis (MPS ) Subjects
Arm/Group Description	Healthy pediatric control subjects	Healthy adult control subjects	Mucopolysaccharidosis subjects type I, II, IIIA and VI.
Measure Participants	560	554	33
Mean (Standard Deviation) [mm^2*mm Hg-1]	0.16 (0.05)	0.11 (0.04)	0.14 (0.08)

4. Secondary Outcome

Title	Carotid Incremental Elastic Modulus
Description	A way of measuring the elasticity constant of the carotid vessel, has the unit mmHg and is defined by the equation 3(1+sD^2/dD^2)/cross sectional compliance value. In contrast to carotid cross sectional compliance and carotid cross sectional distensibility, increasing carotid incremental elastic modus reflects low carotid distensibility and high thickness.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pediatric Control	Adult Control	Mucopolysaccharidosis (MPS ) Subjects
Arm/Group Description	Healthy pediatric control subjects	Healthy adult control subjects	Mucopolysaccharidosis subjects type I, II, IIIA and VI.
Measure Participants	560	554	33
Median (Standard Deviation) [mm Hg]	951 (379.84)	1859 (755.3)	1341 (817.06)

Adverse Events

Time Frame	This is a chart review study that collected data at only one timepoint.
Adverse Event Reporting Description	There were no adverse events to be reported as this is a chart review study.
Arm/Group Title	MPS Patients		Pediatric Controls		Adult Controls
Arm/Group Description	Individuals with MPS disease (17 MPS I, 9 MPS II, 4 MPS IIIA , 3 MPS VI)		Healthy pediatric control subjects		Healthy adult control subjects
All Cause Mortality
	MPS Patients		Pediatric Controls		Adult Controls
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/33 (0%)		0/560 (0%)		0/554 (0%)
Serious Adverse Events
	MPS Patients		Pediatric Controls		Adult Controls
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/33 (0%)		0/560 (0%)		0/554 (0%)
Other (Not Including Serious) Adverse Events
	MPS Patients		Pediatric Controls		Adult Controls
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/33 (0%)		0/560 (0%)		0/554 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.