ClinicalTrials.gov
ClinicalTrials.gov Menu

Longitudinal Study of Bone Disease in Children With Mucopolysaccharidoses (MPS) I, II, and VI

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01521429
Recruitment Status : Active, not recruiting
First Posted : January 30, 2012
Last Update Posted : August 7, 2018
Sponsor:
Collaborators:
Rare Diseases Clinical Research Network
National Institute of Neurological Disorders and Stroke (NINDS)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Children's Hospital & Research Center Oakland
National Center for Advancing Translational Science (NCATS)
Information provided by (Responsible Party):
Los Angeles Biomedical Research Institute

Brief Summary:
Approximately 85% of individuals with Mucopolysaccharidosis (MPS) type I, II, or VI report weekly pain and 50-60% have significant limitations in their activities of daily living due to MPS related musculoskeletal disease despite treatment with enzyme replacement therapy (ERT). Thus there is a critical need to identify additional therapies to alleviate the burden of musculoskeletal disease in order to improve the health and quality of life of individuals with MPS. However, disease progression needs to be quantified to be able to determine efficacy of new therapies. This study is a multi-institutional, 5-year, longitudinal study of musculoskeletal disease in MPS. The objective is to quantitatively describe the progression of skeletal disease and identify biomarkers that either predict disease severity or could be used as therapeutic targets in individuals with MPS I, II, and VI. A database of standardized measurements of musculoskeletal disease in MPS will allow the field to efficiently move forward with therapeutic clinical trials in patients with MPS.

Condition or disease
Mucopolysaccharidoses

  Hide Detailed Description

Detailed Description:

Although children with MPS I, II, and VI who are treated with hematopoietic cell transplantation (HCT) and/or enzyme replacement therapy (ERT) are now living into adulthood with good cognitive development, their quality of life is significantly impacted by their skeletal abnormalities (i.e., kyphosis, scoliosis, genu valgum), joint contractures, pain, and severe short stature. Additional therapies (e.g., post-HCT supplemental ERT, anti-TNFα drugs, stop codon suppression drugs, gene therapy) to decrease the burden of skeletal disease and improve growth are needed. However, prior to these therapeutic studies, control data quantifying the progression of skeletal disease in individuals with MPS I, II and VI treated with ERT and/or HCT are needed, along with biomarkers to be used as early predictors of response to treatment.

Osteoporosis has been described in animal models of MPS. It is unknown whether abnormalities seen in animal models of MPS can be extrapolated to osteoporosis or increased risk of fracture in children and adults affected with MPS. Preliminary data suggest that children and adolescents with MPS I, II and VI have low bone mineral density (BMD) after adjustment for short stature and abnormal bone geometry and that markers of bone remodeling are cross-sectionally associated with BMD. It is unknown whether this decreased BMD during childhood will result in osteoporosis and increased fracture risk in adulthood. Determining the risk for osteoporosis in MPS I, II and VI has become particularly important as these individuals are now healthier and more mobile with new and improved treatments and thus have a greater opportunity for fracture.

Glycosaminoglycan (GAG) deposition has been identified in bone and cartilage in animal models of MPS. GAG deposition in cartilage has specifically been shown to induce inflammation (e.g. increased tumor necrosis-alpha [TNF- α ] levels in serum and synovial fluid), chondrocyte apoptosis, and hyperplasia of the synovial membranes. We have found that serum TNF-α is elevated in children and adolescents with MPS I, II and VI and is associated with bodily pain and poor physical function.

Our long-term goal is to identify and test new therapies for musculoskeletal disease in MPS. The objective of this proposed longitudinal observational study is to document the progression of skeletal disease and identify biomarkers that either predict disease severity or could be used as therapeutic targets in individuals with MPS I, II, and VI. The rationale for this project is to obtain baseline data for future therapeutic clinical trials and to identify potential therapeutic targets. Our central hypothesis is that skeletal disease will progress over time and that biomarkers of inflammation, and bone and cartilage turnover, will predict the severity of skeletal disease over time. Therefore, this study has the following specific aims (SA):

SA1: To characterize the progression of skeletal disease from childhood into young adulthood for individuals with MPS I, II and VI. Our hypothesis is that there will be a progressive decrease in bone health as this population matures into young adulthood due to decreasing mobility, chronic inflammation, and intrinsic MPS related bone disease.

SA2: To identify prognostic biomarkers of inflammation, bone remodeling, and cartilage turnover that can predict the progression of skeletal disease and impaired physical function in MPS I, II and VI. Our hypothesis is that biomarkers of inflammation, bone remodeling, and cartilage turnover, will be predictive of change in physical function, BMD, range of motion, hip dysplasia, kyphoscoliosis, quality of life, and height over 5 years.

At the completion of this study we expect to quantify the progression of skeletal disease in MPS I, II and VI treated with ERT and/or HCT to be used in future therapeutic clinical trials. In addition, we will obtain biomarkers of skeletal disease progression that could identify early treatment efficacy. Finally, we will gain further insight into the mechanism of persistent skeletal disease in MPS that will provide potential therapeutic targets.


Study Type : Observational
Actual Enrollment : 55 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Longitudinal Study of Bone and Endocrine Disease in Children With MPS I, II, and VI: A Multicenter Study of the Lysosomal Disease Network.
Study Start Date : August 2009
Estimated Primary Completion Date : September 2019
Estimated Study Completion Date : September 2019


Group/Cohort
MPS I
Mucopolysaccharidosis I (Hurler, Scheie, Hurler-Scheie)
MPS II
Mucopolysaccharidosis II (Hunter)
MPS VI
Mucopolysaccharidosis VI (Maroteaux-Lamy)



Primary Outcome Measures :
  1. Annual change in dual energy x-ray absorptiometry (DXA) [ Time Frame: baseline, year 1, year 2, year 3 ]
    Measurement of bone density and body composition


Secondary Outcome Measures :
  1. Annual change in Peripheral quantitative computer tomography (pQCT) [ Time Frame: baseline, year 1, year 2, year 3 ]
    Measurement of volumetric bone density, bone geometry, bone strength, and muscle fat

  2. Annual change in Biomarkers of bone remodeling [ Time Frame: baseline, year 1, year 2, year 3 ]
    Measurements of bone turnover

  3. Annual change in Biodex [ Time Frame: baseline, year 1, year 2, year 3 ]
    Measurement of muscle strength

  4. Annual change in Endocrine function tests [ Time Frame: baseline, year 1, year 2, year 3 ]
    Thyroid function, growth factor levels, pubertal hormones, vitamin D

  5. Annual change in growth measurements [ Time Frame: baseline, year 1, year 2, year 3 ]
    sitting and standing heights, arm and tibial length


Biospecimen Retention:   Samples With DNA
Serum, plasma, white cells for DNA extraction, and urine will be retained.


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   5 Years to 35 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
community sample
Criteria

Inclusion Criteria:

  • Diagnosis of MPS I, II, or VI
  • Ability to travel to study center for evaluations.
  • Age ≥ 5 years and < 35 years: age at entry into study must be ≥5 years and ≤33 years to ensure a minimum of 2 study visits.

Exclusion Criteria:

  • Pregnancy (will be determined at each study visit)
  • Participation in any other study within the past 12 months which would result in increasing the child's radiation exposure above 500 mrem for the calendar year.
  • Participants who cannot comply with study procedures or have other factors that would inhibit their participation as determined by the PI's discretion.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01521429


Locations
United States, California
Children's Hospital & Research Center Oakland
Oakland, California, United States, 94609
Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
Torrance, California, United States, 90502
United States, Minnesota
University of Minnesota
Minneapolis, Minnesota, United States, 55454
Sponsors and Collaborators
Los Angeles Biomedical Research Institute
Rare Diseases Clinical Research Network
National Institute of Neurological Disorders and Stroke (NINDS)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Children's Hospital & Research Center Oakland
National Center for Advancing Translational Science (NCATS)
Investigators
Principal Investigator: Lynda E Polgreen, MD, MS Los Angeles Biomedical Research Institute

Responsible Party: Los Angeles Biomedical Research Institute
ClinicalTrials.gov Identifier: NCT01521429     History of Changes
Other Study ID Numbers: 0906M68810
U54NS065768 ( U.S. NIH Grant/Contract )
First Posted: January 30, 2012    Key Record Dates
Last Update Posted: August 7, 2018
Last Verified: August 2018

Additional relevant MeSH terms:
Mucopolysaccharidoses
Carbohydrate Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Lysosomal Storage Diseases
Mucinoses
Connective Tissue Diseases
Metabolic Diseases