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Characterisation of Adult-Onset Hypophosphatasia

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ClinicalTrials.gov Identifier: NCT02796885
Recruitment Status : Recruiting
First Posted : June 13, 2016
Last Update Posted : June 4, 2019
Sponsor:
Collaborators:
National Institute for Health Research, United Kingdom
Alexion Pharmaceuticals
Information provided by (Responsible Party):
Sheffield Teaching Hospitals NHS Foundation Trust

Brief Summary:

Hypophosphatasia (HPP) is an inherited condition which causes a defect in bone calcification, leading to weak bones. Early childhood forms are severe and easily recognised, and there is now a drug treatment which is very effective in children.

Adult forms are milder, often missed by doctors or confused with osteoporosis. This is important because the usual osteoporosis treatments may be harmful in HPP, and increase the risk of broken bones. One of the reasons it is missed is a lack of research describing the typical features of HPP, so doctors don't recognise the signs, and don't know when or how to test for it.

The aim of this study is to establish clear criteria (from clinical history, examination and blood tests) to identify people with HPP. The results will also determine if there should be a trial of drug treatment for adults with HPP.


Condition or disease Intervention/treatment
Hypophosphatasia Other: no intervention - observational study

Detailed Description:

Hypophosphatasia (HPP) is a genetic disorder caused by mutation in the tissue-non-specific alkaline phosphatase gene (TNSALP). It causes impaired bone mineralisation, fractures, tooth loss, muscle weakness and possibly other adverse health outcomes.

The infantile-onset forms are severe, and were often fatal until the recent availability of a treatment (Asfotase Alfa, Alexion Pharma). The childhood-onset forms are less severe, and the adult-onset form is mild, and often unrecognised or misdiagnosed as osteoporosis.

The less severe forms of the disease are not well described, and because there has been no available treatment there has not been much research in adults. However, now that treatment is available there is a possibility of a clinical trial in adults.

Additionally, patients with hypophosphatasia are often not recognised, and are misdiagnosed as having osteoporosis. This is important because patients with hypophosphatasia are at risk of developing atypical femoral fractures if they are treated with usual osteoporosis medication (bisphosphonates).

A major contributor to the under-recognition of adult HPP is the lack of phenotypic description and biomarker definitions. The aim of this project is to identify the clinical and biochemical characteristics that identify HPP.

In preparation for this study reference ranges for the commonly used HPP biomarkers (ALP and PLP) have been established, and used to screen 2000 patients presenting to metabolic bone services in Sheffield and Oxford.

For this study, patients who have biochemistry suggestive of HPP (low ALP and high PLP), will undergo a detailed clinical assessment, with medical history, physical examination, bone biochemistry, targeted musculoskeletal imaging and HPP gene testing. Their results will be compared with a control group of metabolic bone clinic patients with normal ALP and PLP, and a group of patients with known gene-proven and clinically manifest HPP.

The results will establish clinical phenotype and biomarker criteria for HPP diagnosis, which could be incorporated into future pathways for patients presenting to metabolic bone clinics. This will improve the identification of HPP and prevent harm from incorrect treatment with bisphosphonates.


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Study Type : Observational
Estimated Enrollment : 250 participants
Observational Model: Case-Control
Time Perspective: Cross-Sectional
Official Title: Characterisation of Adult-Onset Hypophosphatasia
Study Start Date : November 2016
Estimated Primary Completion Date : December 31, 2019
Estimated Study Completion Date : December 31, 2019

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
Possible hypophosphatasia
Patients attending metabolic bone services, not previously know to have HPP, with biochemistry suggestive of HPP Will have TNSALP gene test, clinical assessment for possible features of HPP, bone turnover marker profile.
Other: no intervention - observational study
Normal
Patients attending metabolic bone services, not previously know to have HPP, with normal HPP biochemistry Will have TNSALP gene test, clinical assessment for possible features of HPP, bone turnover marker profile.
Other: no intervention - observational study
Known hypophosphatasia
Patients attending metabolic bone services or registered with RUDY database, known to have HPP Will have TNSALP gene test, clinical assessment for possible features of HPP, bone turnover marker profile.
Other: no intervention - observational study



Primary Outcome Measures :
  1. ALP and PLP [ Time Frame: baseline cross-sectional ]
    predictive value of low ALP with high PLP for TNSALP mutation (ROC curve)


Secondary Outcome Measures :
  1. ALP:PINP ratio [ Time Frame: baseline cross-sectional ]
    predictive value of ALP:PINP ratio for TNSALP mutation (ROC curve)PP

  2. prevalence of imaging-confirmed musculoskeletal pathology in patients with HPP [ Time Frame: baseline cross-sectional ]

    History and clinical examination will be obtained to identify possible musculoskeletal pathology. Imaging (x-ray, ultrasound or MRI) will be obtained to determine the nature of the pathology. Will include arthritis, enthesopathy, tendonitis.

    Prevalence of musculoskeletal pathology in people with biochemistry suggestive of HPP and positive gene test will be compared with normal controls.


  3. short physical function battery score [ Time Frame: baseline cross-sectional ]
    physical function battery score in people with biochemistry suggestive of HPP and positive gene test (compared with normal controls)


Biospecimen Retention:   Samples With DNA
Serum, plasma, urine, whole blood for DNA


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Ages Eligible for Study:   16 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
Patients attending metabolic bone services in Sheffield and Oxford, UK Patients with hypophosphatasia registered on the RUDY database.
Criteria

Inclusion Criteria:

  • As the groups described above
  • Able and willing to participate in the study and provide written informed consent

Exclusion Criteria:

  • Other conditions known to affect serum ALP and PLP (Coeliac disease, B12 deficiency, untreated hypothyroidism, Wilson's disease)
  • Taking nutritional supplements containing vitamin B6
  • Pregnant

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): NCT02796885


Contacts
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Contact: Richard Eastell 01142714705 r.eastell@sheffield.ac.uk
Contact: Jennifer S Walsh 01142714705 j.walsh@sheffield.ac.uk

Locations
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United Kingdom
Nuffield Orthopaedic Research Not yet recruiting
Oxford, United Kingdom, OX3 7HE
Contact: Kassim Javaid    01865737871    kassim.javaid@ndorms.ox.ac.uk   
University of Sheffield Recruiting
Sheffield, United Kingdom, S10 2TN
Contact: Jennifer S Walsh, MBChB PhD    +44 0114 2714705    j.walsh@sheffield.ac.uk   
Contact: Richard Eastell, MB MD    +44 0114 2714705    r.eastell@sheffield.ac.uk   
Sponsors and Collaborators
Sheffield Teaching Hospitals NHS Foundation Trust
National Institute for Health Research, United Kingdom
Alexion Pharmaceuticals
Investigators
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Principal Investigator: Richard Eastell University of Sheffield

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Responsible Party: Sheffield Teaching Hospitals NHS Foundation Trust
ClinicalTrials.gov Identifier: NCT02796885     History of Changes
Other Study ID Numbers: STH18683
16/NW/0385 ( Other Identifier: UK HRA REC )
202179 ( Other Identifier: UK HRA IRAS )
First Posted: June 13, 2016    Key Record Dates
Last Update Posted: June 4, 2019
Last Verified: June 2019

Additional relevant MeSH terms:
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Hypophosphatasia
Metal Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases