Hypophosphatasia (HPP)
Conditions
Keywords
Hypophosphatasia, HPP, bone disease, Soft Bones, low Alkaline Phosphatase, genetic metabolic disorder, alkaline phosphatase, tissue non-specific alkaline phosphatase, rickets, osteomalacia
Brief summary
The purpose of this study is to characterize the natural history of HPP in patients with Juvenile-onset HPP.
Detailed description
Hypophosphatasia (HPP) is a life-threatening, genetic, and ultra-rare metabolic disease characterized by defective bone mineralization and impaired phosphate and calcium regulation that can lead to progressive damage to multiple vital organs, including destruction and deformity of bones, profound muscle weakness, seizures, impaired renal function, and respiratory failure. There are no approved disease-modifying treatments for patients with this disease. There is also limited data available on the natural course of this disease over time, particularly in patients with the juvenile-onset form.
Interventions
None listed
Sponsors
Alexion Pharmaceuticals, Inc.
Study design
Observational model
OTHER
Time perspective
RETROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
5 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Documented informed consent unless patient is deceased * Patients with Juvenile-onset HPP, defined as documented onset of first signs/symptoms at ≥ 6 months to ˂18 years * Documented diagnosis of HPP as indicated by skeletal manifestations and low alkaline phosphatase or genotyping
Exclusion criteria
* Received treatment with asfotase alfa in the ENB-006-09 study and/or currently enrolled in the ENB-008-10 study * Received other treatment and/or intervention to treat HPP up to 15 years old * Other clinically significant disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Radiographic Global Impression of Change - RGI-C | Between Baseline (earliest available, complete, and readable x-ray set) and all available, readable post-Baseline x-ray sets during the period of patients' aged 5 to 15 years, inclusive. | The RGI-C scale is a 7-point ordinal scale that is used to evaluate musculoskeletal characteristics of HPP (eg, metaphyseal fraying, demineralization of distal metaphyses). The scores range from -3 (severe worsening) to +3 (complete or near-complete healing). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Height Z-score From Baseline to Last Assessment | Any available growth data during the period of patients' aged 5 to 15 years, inclusive. Baseline is the earliest available assessment while post baselines are time points after Baseline during the defined age period. | Height measurements were assigned to Z-scores which were calculated using the Centers for Disease Control and Prevention (CDC) 2000 growth charts and methodology. The Z-score indicates the number of standard deviations away from the mean. A Z-score of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. Higher Z-scores indicate a better outcome. |
| Change in Weight Z-score From Baseline to Last Assessment | Any available growth data during the period of patients' aged 5 to 15 years, inclusive. Baseline is the earliest available assessment while Post baselines are time points after Baseline during the defined age period. | Weight measurements were assigned a Z-score which was calculated using the Centers for Disease Control and Prevention (CDC) 2000 growth charts and methodology. The Z-score indicates the number of standard deviations away from the mean. A Z-score of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. Higher Z-scores indicate a better outcome. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Rickets Severity Sale - RSS | Any available data during the period of patients' aged 5 to 15 years, inclusive. Baseline is the earliest available assessment value during the period. | The RSS is a 10-point scale, developed for nutritional rickets, that evaluates the degree of metaphyseal cupping and fraying and the proportion of growth plate affected (10 points = severe cupping/fraying, 0 points = absence of cupping/fraying). |
Countries
Australia, Canada, France, Netherlands, Russia, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
Patients were enrolled between March 2014 and September 2014. Fifty-four patients were screened and 32 patients were enrolled at 15 centers across the United States, Canada, Australia, Turkey, The Netherlands, and the United Kingdom.
Participants by arm
| Arm | Count |
|---|---|
| Patients Diagnosed With Juvenile-onset HPP Patients diagnosed with juvenile-onset HPP (ie, documented onset of first signs/symptoms of HPP at ≥ 6 months to \< 18 years of age). | 32 |
| Total | 32 |
Baseline characteristics
| Characteristic | Patients Diagnosed With Juvenile-onset HPP |
|---|---|
| Age, Customized | 47 months STANDARD_DEVIATION 32.21 |
| Growth Measured by Height Z-score | -0.86 Z-score |
| Growth Measured by Weight Z-score | -0.86 Z-score |
| Race/Ethnicity, Customized Unknown or Not Reported | 1 participants |
| Race/Ethnicity, Customized White | 31 participants |
| Region of Enrollment Australia | 2 participants |
| Region of Enrollment Europe | 5 participants |
| Region of Enrollment North America | 25 participants |
| Rickets Severity Scale - RSS | 1.00 units on a scale |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 |
Outcome results
Primary
Radiographic Global Impression of Change - RGI-C
The RGI-C scale is a 7-point ordinal scale that is used to evaluate musculoskeletal characteristics of HPP (eg, metaphyseal fraying, demineralization of distal metaphyses). The scores range from -3 (severe worsening) to +3 (complete or near-complete healing).
Time frame: Between Baseline (earliest available, complete, and readable x-ray set) and all available, readable post-Baseline x-ray sets during the period of patients' aged 5 to 15 years, inclusive.
Population: Patients diagnosed with juvenile-onset HPP.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Patients Diagnosed With Juvenile-onset HPP | Radiographic Global Impression of Change - RGI-C | 0.33 units on a scale |
Comparison: Pairs of radiographs were centrally evaluated by 3 independent, blinded pediatric radiologists trained in the assessment of the skeletal manifestations of HPP. The mean RGI-C score across the 3 radiologists was calculated and served as the patient's RGI-C score for a specific time pointp-value: 0.0755Sign test
Secondary
Change in Height Z-score From Baseline to Last Assessment
Height measurements were assigned to Z-scores which were calculated using the Centers for Disease Control and Prevention (CDC) 2000 growth charts and methodology. The Z-score indicates the number of standard deviations away from the mean. A Z-score of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. Higher Z-scores indicate a better outcome.
Time frame: Any available growth data during the period of patients' aged 5 to 15 years, inclusive. Baseline is the earliest available assessment while post baselines are time points after Baseline during the defined age period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Patients Diagnosed With Juvenile-onset HPP | Change in Height Z-score From Baseline to Last Assessment | -0.05 Z-score |
Comparison: The earliest documented height measurement that was abstracted within the period from 5 to 15 years of age, inclusive, was defined as the baseline height. Height measurements were assigned to Z-scores calculated using Centers for Disease Control and Prevention 2000 growth charts and methodology. Changes in height Z-score from Baseline were computed by subtracting baseline height Z-score from post baseline height Z-scores. The post baseline time points were grouped by time intervals.p-value: 0.6344Sign test
Secondary
Change in Weight Z-score From Baseline to Last Assessment
Weight measurements were assigned a Z-score which was calculated using the Centers for Disease Control and Prevention (CDC) 2000 growth charts and methodology. The Z-score indicates the number of standard deviations away from the mean. A Z-score of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. Higher Z-scores indicate a better outcome.
Time frame: Any available growth data during the period of patients' aged 5 to 15 years, inclusive. Baseline is the earliest available assessment while Post baselines are time points after Baseline during the defined age period.
Population: All patients who met all of the inclusion and none of the exclusion criteria were defined as the enrolled population, which was also the analysis population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Patients Diagnosed With Juvenile-onset HPP | Change in Weight Z-score From Baseline to Last Assessment | 0.12 Z-score |
Comparison: The earliest documented weight measurement that was abstracted within the period from 5 to 15 years of age, inclusive, was defined as the baseline weight. Weight measurements were assigned to Z-scores calculated using Centers for Disease Control and Prevention 2000 growth charts and methodology. Changes in weight Z-score from Baseline were computed by subtracting baseline weight Z-score from post baseline weight Z-scores. The post baseline time points were grouped by time intervals.p-value: 0.452Sign test
Other Pre-specified
Rickets Severity Sale - RSS
The RSS is a 10-point scale, developed for nutritional rickets, that evaluates the degree of metaphyseal cupping and fraying and the proportion of growth plate affected (10 points = severe cupping/fraying, 0 points = absence of cupping/fraying).
Time frame: Any available data during the period of patients' aged 5 to 15 years, inclusive. Baseline is the earliest available assessment value during the period.
Population: All patients who met all of the inclusion and none of the exclusion criteria were defined as the enrolled population, which was also the analysis population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Patients Diagnosed With Juvenile-onset HPP | Rickets Severity Sale - RSS | 0.00 units on a scale |
Comparison: The Baseline x-ray set defined for RGI-C, which was compared with its subsequent x-ray sets, was also used as the Baseline x-ray set for the RSS reading. Changes from Baseline were computed based on this baseline RSS score, and postbaseline time points were grouped by intervals of time from Baseline.p-value: 0.4545Sign test