ESPE Abstracts

Background: Hypophosphatasia (HPP) is a rare, inherited, metabolic disease caused by loss-of-function mutation(s) in the gene encoding tissue nonspecific alkaline phosphatase (TNSALP). Poor skeletal mineralisation, muscle weakness, pain, and accompanying complications characteristic of HPP result in impaired physical function, decreasing ability to perform daily activities, and quality of life. Improvement in physical function is a treatment target, yet established physical activity measures have not been validated in patients with HPP. The 6-Minute Walk Test (6MWT) is an accepted measure of physical activity reflective of daily functioning for children with other chronic diseases.

Objective/ Hypotheses: Determine concurrent validity and minimal clinically important difference (MCID) for the 6MWT for patients with HPP.

Methods: Data were from a Phase II trial of asfotase alfa, a replacement TNSALP, for children with HPP (ENB-006-09/ENB-008-10). MCID was estimated as per McDonald et al. 2013 using baseline/screening data, and standard error of measurement (SEM) and one-third standard deviation (1/3SD) distribution-based approaches. Clinical relevance was assessed via Pearson correlations between 6MWT and measures of skeletal disease (Radiographic Global Impression of Change [RGI-C] scale, Rickets Severity Scale [RSS]), and activities of daily living (parent-reported Childhood Health Assessment Questionnaire [CHAQ] Disability Index, Pediatric Outcomes Data Collection Instrument [PODCI]).

Results: MCID for patients with HPP was estimated at 20.2 meters (SEM) and 30.2 meters (1/3SD). Correlation analysis (127 datapoints) indicated significant (P<0.001), moderate-to-strong linear relationships between distance walked (percent predicted for age, gender, height) and RSS (r=−0.73), CHAQ Disability Index (r=−0.57), and PODCI subscales, including Global Function (r=0.76), Transfer/Basic Mobility (r=0.69), and Sports/Physical Functioning (r=0.78). Changes in 6MWT and RGI-C scores demonstrated weaker correlation (r=0.32; 68 datapoints; P<0.01).

Conclusions: The 6MWT is a valid, clinically relevant measure of disability and treatment outcomes for patients with HPP. A change of 20–30 meters represents a clinically meaningful difference in functional abilities in this population.