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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/study/NCT01176266
Registration number
NCT01176266
Ethics application status
Date submitted
29/07/2010
Date registered
5/08/2010
Date last updated
13/03/2019
Titles & IDs
Public title
Open-Label Study of Asfotase Alfa in Infants and Children = 5 Years of Age With Hypophosphatasia (HPP)
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Scientific title
An Open-Label, Multicenter, Multinational Study of the Safety, Efficacy and Pharmacokinetics of Asfotase Alfa (Human Recombinant Tissue-nonspecific Alkaline Phosphatase Fusion Protein) in Infants and Children = 5 Years of Age With Hypophosphatasia (HPP)
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Secondary ID [1]
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ENB-010-10
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Hypophosphatasia
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Condition category
Condition code
Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Experimental: Asfotase alfa - A total of 6 mg/kg/week of asfotase alfa administered by SC injection (either 1 mg/kg asfotase alfa 6 times per week, or 2 mg/kg asfotase alfa 3 times per week)
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Effect of Asfotase Alfa Treatment on Skeletal Manifestations of Hypophosphatasia (HPP)
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Assessment method [1]
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The effect of asfotase alfa treatment on skeletal manifestations of HPP (i.e., change in rickets severity) was measured by radiographs using a qualitative Radiographic Global Impression of Change (RGI-C) scale. Skeletal radiographs obtained at Week 24 were compared with skeletal radiographs obtained before initiation of treatment. The RGI-C is a 7-point rating scale that ranges from -3 (indicative of severe worsening of HPP-associated rickets) to +3 (indicative of complete or near complete healing of HPP-associated rickets).
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Timepoint [1]
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From Baseline to Week 24
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Primary outcome [2]
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Safety and Tolerability of Repeated Subcutaneous (SC) Injections of Asfotase Alfa
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Assessment method [2]
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Safety and tolerability of repeated subcutaneous (SC) injections of asfotase alfa for all treated patients was assessed by the number of patients with 1 or more treatment-emergent adverse event.
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Timepoint [2]
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Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).
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Secondary outcome [1]
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Effect of Asfotase Alfa Treatment on Skeletal Manifestations of Hypophosphatasia (HPP)
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Assessment method [1]
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The effect of asfotase alfa treatment on skeletal manifestations of HPP (i.e., change in rickets severity) was measured by radiographs using a qualitative Radiographic Global Impression of Change (RGI-C) scale. Skeletal radiographs obtained at the patient's last assessment were compared with skeletal radiographs obtained before initiation of treatment. The RGI-C is a 7-point rating scale that ranges from -3 (indicative of severe worsening of HPP-associated rickets) to +3 (indicative of complete or near complete healing of HPP-associated rickets).
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Timepoint [1]
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Up to 72 Months or regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).
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Secondary outcome [2]
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Effect of Asfotase Alfa Treatment on Ventilator-free Survival (Week 312)
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Assessment method [2]
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For patients who were not on respiratory support at the time of enrollment, the Kaplan-Meier estimate of ventilator-free survival at the end of the study
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Timepoint [2]
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Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).
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Secondary outcome [3]
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Effect of Asfotase Alfa Treatment on Respiratory Function
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Assessment method [3]
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Effect of asfotase alfa treatment on respiratory function as measured by the shift in proportion of patients requiring respiratory support at their last assessment compared with Baseline.
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Timepoint [3]
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Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).
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Secondary outcome [4]
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Effect of Asfotase Alfa Treatment on Physical Growth - Length/Height Z-scores Change From Baseline to Last Obtained Value
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Assessment method [4]
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Effect of asfotase alfa treatment on physical growth as measured by change from Baseline to last assessment for each patient in length/height Z-scores
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Timepoint [4]
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Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).
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Secondary outcome [5]
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Effect of Asfotase Alfa Treatment on Physical Growth - Weight Z-scores Change From Baseline to Last Obtained Value
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Assessment method [5]
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Effect of asfotase alfa treatment on physical growth as measured by change from Baseline to last assessment for each patient in weight Z-scores
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Timepoint [5]
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Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).
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Secondary outcome [6]
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Effect of Asfotase Alfa on Biomarkers - Plasma Inorganic Pyrophosphate (PPi) Change From Baseline to Last Obtained Value
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Assessment method [6]
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Effect of asfotase alfa on PPi as measured by change from Baseline to last assessment for each patient
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Timepoint [6]
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Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).
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Secondary outcome [7]
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Effect of Asfotase Alfa on Biomarkers - Plasma Pyridoxal-5' Phosphate (PLP) Change From Baseline to Last Obtained Value
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Assessment method [7]
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Effect of asfotase alfa on PLP as measured by change from Baseline to last assessment for each patient
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Timepoint [7]
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Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).
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Secondary outcome [8]
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Effect of Asfotase Alfa on Serum Parathyroid Hormone (PTH) - Change From Baseline to Last Obtained Value
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Assessment method [8]
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Effect of asfotase alfa on serum PTH as measured by change from Baseline to last assessment for each patient
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Timepoint [8]
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Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).
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Secondary outcome [9]
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Effect of Asfotase Alfa Treatment on Tooth Loss
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Assessment method [9]
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Effect of asfotase alfa treatment on tooth loss assessed by the proportion of patients who experienced tooth loss during the study
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Timepoint [9]
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Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).
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Secondary outcome [10]
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Pharmacokinetic (PK) Properties of Asfotase Alfa (Tlast)
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Assessment method [10]
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The PK properties (tlast) of asfotase alfa
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Timepoint [10]
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PK parameters were calculated using Week 6 study visit data. Week 6 study visit blood samples for PK testing were drawn pre-dose and 6, 12, 24, 32, and 48 hours post dose
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Secondary outcome [11]
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Pharmacokinetic (PK) Properties of Asfotase Alfa (Tmax)
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Assessment method [11]
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The PK properties (tmax) of asfotase alfa
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Timepoint [11]
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PK parameters were calculated using Week 6 study visit data. Week 6 study visit blood samples for PK testing were drawn pre-dose and 6, 12, 24, 32, and 48 hours post dose
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Secondary outcome [12]
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Pharmacokinetic (PK) Properties of Asfotase Alfa (Cmax)
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Assessment method [12]
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The PK properties (Cmax) of asfotase alfa
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Timepoint [12]
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PK parameters were calculated using Week 6 study visit data. Week 6 study visit blood samples for PK testing were drawn pre-dose and 6, 12, 24, 32, and 48 hours post dose
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Secondary outcome [13]
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Pharmacokinetic (PK) Properties of Asfotase Alfa (AUCt)
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Assessment method [13]
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The PK properties (AUCt) of asfotase alfa
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Timepoint [13]
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PK parameters were calculated using Week 6 study visit data. Week 6 study visit blood samples for PK testing were drawn pre-dose and 6, 12, 24, 32, and 48 hours post dose
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Eligibility
Key inclusion criteria
Patients must meet all of the following criteria for enrollment in this study:
1. Parent or legal guardian(s) must provide written informed consent prior to any study procedures being performed and must be willing to comply with all study-required procedures. Where appropriate and required by local regulations, patient assent should also be provided prior to any study procedures being performed.
2. Documented diagnosis of HPP as indicated by:
1. Total serum alkaline phosphatase (ALP) below the lower limit of normal for age NOTE: Historical values for ALP may be used to determine patient eligibility.
2. Plasma pyridoxal-5'-phosphate (PLP) above the upper limit of normal (unless patient is receiving pyridoxine for seizures) NOTE: Historical values for PLP may be used to determine patient eligibility.
3. Radiographic evidence of HPP at screening, characterized by:
* Flared and frayed metaphyses, and
* Severe, generalized osteopenia, and
* Widened growth plates, and
* Areas of radiolucency or sclerosis
4. Two or more of the following HPP-related findings:
* History or presence of: i) Nontraumatic post-natal fracture or ii) Delayed fracture healing
* Nephrocalcinosis or history of elevated serum calcium
* Functional craniosynostosis
* Respiratory compromise or rachitic chest deformity
* Vitamin B6-responsive seizures
* Failure to thrive
3. Onset of symptoms prior to 6 months of age
4. Chronological age or adjusted age for premature infants born = 37 weeks gestation of = 5 years
5. Otherwise medically stable in the opinion of the Investigator and/or Sponsor
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Minimum age
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Maximum age
5
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
Exclusion criteria:
Patients will be excluded from enrollment in this study if they meet any of the following exclusion criteria:
1. Clinically significant disease that precludes study participation, in the opinion of the Investigator and/or Sponsor
2. Serum calcium or phosphate levels below the normal range
3. Current evidence of treatable form of rickets
4. Prior treatment with bisphosphonates
5. Treatment with an investigational drug within 1 month prior to the start of asfotase alfa treatment
6. Current enrollment in any other study involving an investigational new drug, device or treatment for HPP (e.g., bone marrow transplantation)
7. Intolerance to the investigational product (IP) or any of its excipients
8. Previous participation in the same study
9. Family relative of the Investigator
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Study design
Purpose of the study
Treatment
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Allocation to intervention
NA
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Single group
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Other design features
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Phase
Phase 2
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
1/07/2010
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
1/09/2016
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Sample size
Target
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Accrual to date
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Final
69
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Recruitment in Australia
Recruitment state(s)
QLD,VIC
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Recruitment hospital [1]
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Lady Cilento Children's Hospital - South Brisbane
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Recruitment hospital [2]
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Royal Children'S Hospital Melbourne - Parkville
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Recruitment postcode(s) [1]
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4101 - South Brisbane
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Recruitment postcode(s) [2]
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3052 - Parkville
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Recruitment outside Australia
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United States of America
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California
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United States of America
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Ohio
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United States of America
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Pennsylvania
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Canada
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Manitoba
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France
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Paris
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France
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Toulouse
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Germany
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Würzburg
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Italy
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Genova
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Italy
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Roma
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Japan
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Fukuoka
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Japan
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Ishikawa
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Japan
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Kanagawa
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Japan
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Tokyo
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Japan
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Saitama
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Russian Federation
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Moscow
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Saudi Arabia
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Riyadh
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Spain
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Madrid
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Turkey
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Bursa
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United Kingdom
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Birmingham
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United Kingdom
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Manchester
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United Kingdom
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Sheffield
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Funding & Sponsors
Primary sponsor type
Commercial sector/industry
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Name
Alexion Pharmaceuticals, Inc.
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Address
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Ethics approval
Ethics application status
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Summary
Brief summary
This clinical trial was conducted to study hypophosphatasia (HPP), a bone disorder caused by gene mutations or changes. These gene mutations cause low levels of an enzyme needed to harden bone. The purpose of this study was to test the safety and efficacy of a study drug called asfotase alfa (human recombinant tissue non-specific alkaline phosphate fusion protein) to see what effects it has on patients 5 years of age or less with HPP.
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Trial website
https://clinicaltrials.gov/study/NCT01176266
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Trial related presentations / publications
Padidela R, Yates R, Benscoter D, McPhail G, Chan E, Nichani J, Mughal MZ, Myer C 4th, Narayan O, Nissenbaum C, Wilkinson S, Zhou S, Saal HM. Characterization of tracheobronchomalacia in infants with hypophosphatasia. Orphanet J Rare Dis. 2020 Aug 6;15(1):204. doi: 10.1186/s13023-020-01483-9. Hofmann CE, Harmatz P, Vockley J, Hogler W, Nakayama H, Bishop N, Martos-Moreno GA, Moseley S, Fujita KP, Liese J, Rockman-Greenberg C; ENB-010-10 Study Group. Efficacy and Safety of Asfotase Alfa in Infants and Young Children With Hypophosphatasia: A Phase 2 Open-Label Study. J Clin Endocrinol Metab. 2019 Jul 1;104(7):2735-2747. doi: 10.1210/jc.2018-02335. Whyte MP, Rockman-Greenberg C, Ozono K, Riese R, Moseley S, Melian A, Thompson DD, Bishop N, Hofmann C. Asfotase Alfa Treatment Improves Survival for Perinatal and Infantile Hypophosphatasia. J Clin Endocrinol Metab. 2016 Jan;101(1):334-42. doi: 10.1210/jc.2015-3462. Epub 2015 Nov 3.
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Public notes
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Contacts
Principal investigator
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Contact person for public queries
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Contact person for scientific queries
No information has been provided regarding IPD availability
What supporting documents are/will be available?
No Supporting Document Provided
Results publications and other study-related documents
No documents have been uploaded by study researchers.
Results are available at
https://clinicaltrials.gov/study/NCT01176266
Download to PDF