A Natural History Study in Children With a Type II Collagen Disorder With Short Stature

Study Overview
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Brief Summary
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There are relatively few data available on type II collagen disorders, and evidence is lacking on the disease course in relation to symptoms and development of complications, the level of actual disease burden over time as well as data to support identification of possible risk factors. This study aims to build a natural history data set through collection of a number of clinical, imaging, and laboratory assessments that may be specific predictors of type II collagen disorder progression and clinical outcome. Having a type II collagen disorder natural history data set can inform potential efficacy endpoints and biomarkers for future clinical trials. This natural history study will follow up to 60 individuals diagnosed with a type II collagen disorder for up to 3 years. Visits will be conducted every 3 months for the first year and then every 6 months, during which several assessments will be performed in order to learn about the natural course of the disease, including changes in clinical and functional outcomes, imaging and biofluid biomarkers. Some of the study activities include: a physical exam, height measurements, vision and breathing tests and x-ray. A blood sample will be collected once or twice each year. Most of the information collected, the tests done, and the schedule of visits in this study are the same as recommended for regular care of children with a type II collagen disorder.

Official Title
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An International Prospective Natural History Study in Children With a Type II Collagen Disorder With Short Stature

Conditions
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Kniest Dysplasia, SEDC, Hypochondrogenesis, Semd, Strudwick Type

Intervention / Treatment
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* Other: Natural History Study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of type II collagen disorder with short stature at birth (2 standard deviations (SD) or more below the mean) i.e., Hypochondrogenesis, Kniest, Spondyloepiphyseal dysplasia congenita (SEDc) Spondyloepimetaphyseal dysplasia (SEMD) Strudwick type, Spondyloperipheral dysplasia (SED). Children up to and including 12 years of age, up to the day before their 13th birthday, on the date of consent/assent. The patient is sufficiently able, in the opinion of the Investigator, to adhere to the study visit schedule and other protocol requirements. The patient's parent(s) or legal guardian(s) has signed written informed consent, according to the local regulations and after all relevant aspects of the study have been explained and discussed. The child (depending on local institutional review board/ethical committee requirements) has provided assent. Exclusion Criteria: Tanner stage 3 or more based on investigator assessment during physical examination The patient has a diagnosis of any short stature condition other than a type II collagen disorder. The investigator and/or clinical study advisory committee considers the patient has a type II collagen disorder which is not Hypochondrogenesis, SEDc, Kniest, SEMD or SED i.e., Stickler. The patient has any other medical condition that may impact growth or where the treatment is known to impact growth, such as but not limited to hypothyroidism or hyperthyroidism, insulin-requiring diabetes mellitus, autoimmune inflammatory disease, autonomic neuropathy or inflammatory bowel disease. Treatment in the previous 12 months prior to consent/assent with growth hormones, insulin-like growth factor 1, anabolic steroids, or any other drug expected to affect growth velocity. Brief (up to a few weeks) use of steroids is permitted. Participation in any interventional clinical trial or treatment for a type II collagenopathy. Has any condition or circumstance that in the view of the investigator places the child at high risk of poor compliance with the visit schedule or of not completing the study.

Ages Eligible for Study
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Maximum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Intervention/Treatment |
| --- |
|Other: Natural History Study|Longitudinal assessment of symptoms and development of complications in type II collagen disorders|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Collection of relevant medical data (retrospective and prospective) | Collection of demographic data, collagen type II-related medical complications, past medical and surgical history and current medication. | Up to 3 years | 
| Anthropometric measurements | Collection of consistent growth measurements (in centimeters). | Up to 3 years | 
| Change over time in motor function in children 2 years old and younger | Motor development will be assessed using the World Health Organisation (WHO) Motor Milestones. | Up to 2 years | 
| Change over time in motor function in children >2 years old | Timed 100-meter walk/run test (T100T). In the T100T, the participant is instructed to walk as fast as possible for a distance of 100 meters. Timed 10-meter walk/run test (T10T). Participants walk 10-meters at self-selected pace. Functional Mobility Scale (FMS) rates the walking ability in three different walking distances. | Up to 3 years | 
| Change over time in pulmonary function | Lung function measured through spirometry in all participants >4 years of age | Up to 3 years | 
| Change over time in ophthalmological assessment | Standard ophthalmological assessment. | Up to 3 years | 
| Change over time in skeletal abnormalities | Investigators should collect radiographs according standard of care to determine change in skeletal abnormalities and bone growth. | Up to 3 years | 
| Measurement of biomarkers for bone growth | Changes from baseline in serum collagen X fragments. | Up to 3 years | 
| Measurement of CNP/ProCNP | Changes from baseline in serum CNP/ProCNP | Up to 3 years | 
| Measurement of bone-specific alkaline phosphatase (BALP) | Changes from baseline in serum BALP | Up to 3 years | 
| Change in scores for the pediatric quality of life inventory parent report (PedsQL) | The PedsQL parent-proxy report has 23 items that investigate physical, emotional, and social QoL as well as school functioning. | Up to 3 years | 
| Change in PROMIS pediatric short form pain behaviors score | The PROMIS pediatric short form pain behaviors, parent-proxy report is an 8-item measure completed by parents that assesses pain behaviors displayed by their child in the past 7 days. Total scores are standardized to a T-score with a mean of 50 and a standard deviation of 10, where higher scores indicate increased behaviors due to pain. | Up to 3 years | 
| Change in fatigue | The PROMIS pediatric fatigue parent-proxy report is completed by parents to assess their child's ability to carry out daily activities. | Up to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Skeletal Dysplasia, Short Stature, Bone Disease