- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01176266
Open-Label Study of Asfotase Alfa in Infants and Children ≤ 5 Years of Age With Hypophosphatasia (HPP)
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)
Study Overview
Detailed Description
Asfotase alfa was formerly referred to as ENB-0040
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 limited data available on the natural course of this disease over time, particularly in patients with the juvenile-onset form.
Study Type
Enrollment (Actual)
Phase
- Phase 2
- Phase 3
Contacts and Locations
Study Locations
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Queensland
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South Brisbane, Queensland, Australia, 4101
- Lady Cilento Children's Hospital
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Victoria
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Parkville, Victoria, Australia, 3052
- Royal Children's Hospital Melbourne
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Manitoba
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Winnipeg, Manitoba, Canada, R3A 1S1
- Health Sciences Centre Winnipeg, University of Manitoba
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Paris, France, 75743
- Necker Hospital
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Toulouse, France
- Chu de Toulouse
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Würzburg, Germany, 97080
- Universitätskinderklinikum Würzburg
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Genova, Italy, 16147
- Istituto Giannina Gaslini
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Roma, Italy, 00165
- Ospedale Pediatrico Bambino Gesù
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Saitama, Japan, 336-8522
- Saitama Municipal Hospital
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Fukuoka
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Koga, Fukuoka, Japan, 811-3195
- Fukuoka Higashi Medical Hospital
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Ishikawa
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Kanazawa, Ishikawa, Japan, 920-8530
- Ishikawa Prefectural Hospital
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Kanagawa
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Yokohama, Kanagawa, Japan, 241-0811
- St. Marianna University School of Medicine, Yokohayama City Seibu Hospital
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Tokyo
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Shinjuku, Tokyo, Japan, 160-0023
- Tokyo Medical University Hospital
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Moscow, Russian Federation, 117036
- Federal State Budgetary Institution
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Riyadh, Saudi Arabia, 11211
- King Faisal Specialist Hospital and Research Center
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Madrid, Spain, 28009
- Hospital Infantil Universitario Nino Jesus
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Bursa, Turkey, 16059
- Uludag University
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Birmingham, United Kingdom, B4 6NH
- Birmingham Children's Hospital
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Manchester, United Kingdom, M13 9WL
- Royal Manchester Children's Hospital
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Sheffield, United Kingdom, S10 2TH
- Sheffield Children's Hospital
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California
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Oakland, California, United States, 94609
- Children's Hospital & Research Center Oakland
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Ohio
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Cincinnati, Ohio, United States, 45229
- Cincinnati Children's Hospital Medical Center
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Pennsylvania
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Pittsburgh, Pennsylvania, United States, 15224
- Children's Hospital of Pittsburgh of UPMC
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
Patients must meet all of the following criteria for enrollment in this study:
- 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.
Documented diagnosis of HPP as indicated by:
- 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.
- 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.
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
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
- Onset of symptoms prior to 6 months of age
- Chronological age or adjusted age for premature infants born ≤ 37 weeks gestation of ≤ 5 years
- Otherwise medically stable in the opinion of the Investigator and/or Sponsor
Exclusion criteria:
Patients will be excluded from enrollment in this study if they meet any of the following exclusion criteria:
- Clinically significant disease that precludes study participation, in the opinion of the Investigator and/or Sponsor
- Serum calcium or phosphate levels below the normal range
- Current evidence of treatable form of rickets
- Prior treatment with bisphosphonates
- Treatment with an investigational drug within 1 month prior to the start of asfotase alfa treatment
- Current enrollment in any other study involving an investigational new drug, device or treatment for HPP (e.g., bone marrow transplantation)
- Intolerance to the investigational product (IP) or any of its excipients
- Previous participation in the same study
- Family relative of the Investigator
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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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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Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Effect of Asfotase Alfa Treatment on Skeletal Manifestations of Hypophosphatasia (HPP)
Time Frame: From Baseline to Week 24
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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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From Baseline to Week 24
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Safety and Tolerability of Repeated Subcutaneous (SC) Injections of Asfotase Alfa
Time Frame: 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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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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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 Measures
Outcome Measure |
Measure Description |
Time Frame |
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Effect of Asfotase Alfa Treatment on Skeletal Manifestations of Hypophosphatasia (HPP)
Time Frame: 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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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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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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Effect of Asfotase Alfa Treatment on Ventilator-free Survival (Week 312)
Time Frame: 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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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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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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Effect of Asfotase Alfa Treatment on Respiratory Function
Time Frame: 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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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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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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Effect of Asfotase Alfa Treatment on Physical Growth - Length/Height Z-scores Change From Baseline to Last Obtained Value
Time Frame: 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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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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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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Effect of Asfotase Alfa Treatment on Physical Growth - Weight Z-scores Change From Baseline to Last Obtained Value
Time Frame: 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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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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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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Effect of Asfotase Alfa on Biomarkers - Plasma Inorganic Pyrophosphate (PPi) Change From Baseline to Last Obtained Value
Time Frame: 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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Effect of asfotase alfa on PPi as measured by change from Baseline to last assessment for each patient
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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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Effect of Asfotase Alfa on Biomarkers - Plasma Pyridoxal-5' Phosphate (PLP) Change From Baseline to Last Obtained Value
Time Frame: 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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Effect of asfotase alfa on PLP as measured by change from Baseline to last assessment for each patient
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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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Effect of Asfotase Alfa on Serum Parathyroid Hormone (PTH) - Change From Baseline to Last Obtained Value
Time Frame: 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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Effect of asfotase alfa on serum PTH as measured by change from Baseline to last assessment for each patient
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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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Effect of Asfotase Alfa Treatment on Tooth Loss
Time Frame: 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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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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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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Pharmacokinetic (PK) Properties of Asfotase Alfa (Tlast)
Time Frame: 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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The PK properties (tlast) of asfotase alfa
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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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Pharmacokinetic (PK) Properties of Asfotase Alfa (Tmax)
Time Frame: 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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The PK properties (tmax) of asfotase alfa
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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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Pharmacokinetic (PK) Properties of Asfotase Alfa (Cmax)
Time Frame: 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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The PK properties (Cmax) of asfotase alfa
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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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Pharmacokinetic (PK) Properties of Asfotase Alfa (AUCt)
Time Frame: 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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The PK properties (AUCt) of asfotase alfa
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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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Collaborators and Investigators
Sponsor
Publications and helpful links
General 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.
- 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.
- 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.
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- ENB-010-10
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Hypophosphatasia
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AlexionEnrolling by invitationHypophosphatasia (HPP)France, Poland, United Kingdom, Germany, Spain, Saudi Arabia, United States, Canada, Russian Federation, Australia, Italy
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Hvidovre University HospitalOdense University HospitalActive, not recruitingHypophosphatasia (HPP)Denmark
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Alexion PharmaceuticalsCompletedHypophosphatasia (HPP)United States, Canada
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Alexion PharmaceuticalsCompletedHypophosphatasia (HPP)United States, Taiwan, United Kingdom, Australia, Canada, Germany, Spain
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Alexion PharmaceuticalsCompletedHypophosphatasia (HPP)United States, Canada
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Alexion PharmaceuticalsCompletedHypophosphatasia (HPP)United States, Canada
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Alexion PharmaceuticalsCompletedHypophosphatasia (HPP)United States, France, United Kingdom, Canada, Netherlands, Russian Federation, Turkey, Australia
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Alexion PharmaceuticalsCompletedHypophosphatasia (HPP)United States, Canada, United Arab Emirates, United Kingdom
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Alexion Pharmaceuticals, Inc.RecruitingHypophosphatasiaUnited States, Japan, Italy, Turkey, Australia, Germany, United Kingdom, Argentina, France, Canada, India
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Alexion Pharmaceuticals, Inc.Not yet recruiting
Clinical Trials on asfotase alfa
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Alexion PharmaceuticalsWithdrawn
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Alexion Pharmaceuticals, Inc.RecruitingHypophosphatasiaUnited States, Japan, Italy, Turkey, Australia, Germany, United Kingdom, Argentina, France, Canada, India
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AlexionRecruiting
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Alexion PharmaceuticalsCompletedHypophosphatasiaUnited States, Germany
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Alexion Pharmaceuticals, Inc.Xcenda, LLCActive, not recruitingHypophosphatasiaUnited States
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Alexion PharmaceuticalsCompleted
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Alexion PharmaceuticalsApproved for marketingHypophosphatasiaUnited States, France
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Alexion PharmaceuticalsCompletedHypophosphatasiaUnited States, United Arab Emirates, United Kingdom
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Translational Research Center for Medical Innovation...Osaka University Graduate School of MedicineCompleted
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Alexion PharmaceuticalsCompletedHypophosphatasia (HPP)United States, Canada, United Arab Emirates, United Kingdom