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Open-Label Study of Asfotase Alfa in Infants and Children ≤ 5 Years of Age With Hypophosphatasia (HPP)

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ClinicalTrials.gov Identifier: NCT01176266
Recruitment Status : Completed
First Posted : August 5, 2010
Results First Posted : February 26, 2018
Last Update Posted : February 26, 2018
Sponsor:
Information provided by (Responsible Party):
Alexion Pharma GmbH

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.

Condition or disease Intervention/treatment Phase
Hypophosphatasia Drug: asfotase alfa Phase 2 Phase 3

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 : Interventional  (Clinical Trial)
Actual Enrollment : 69 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official 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)
Study Start Date : July 2010
Actual Primary Completion Date : September 2016
Actual Study Completion Date : September 2016

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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)
Drug: asfotase alfa
Other Name: ENB-0040




Primary Outcome Measures :
  1. Effect of Asfotase Alfa Treatment on Skeletal Manifestations of Hypophosphatasia (HPP) [ Time Frame: From Baseline to Week 24 ]
    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).

  2. 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). ]
    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.


Secondary Outcome Measures :
  1. 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). ]
    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).

  2. 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). ]
    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

  3. 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). ]
    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.

  4. 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). ]
    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

  5. 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). ]
    Effect of asfotase alfa treatment on physical growth as measured by change from Baseline to last assessment for each patient in weight Z-scores

  6. 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). ]
    Effect of asfotase alfa on PPi as measured by change from Baseline to last assessment for each patient

  7. 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). ]
    Effect of asfotase alfa on PLP as measured by change from Baseline to last assessment for each patient

  8. 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). ]
    Effect of asfotase alfa on serum PTH as measured by change from Baseline to last assessment for each patient

  9. 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). ]
    Effect of asfotase alfa treatment on tooth loss assessed by the proportion of patients who experienced tooth loss during the study

  10. 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 ]
    The PK properties (tlast) of asfotase alfa

  11. 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 ]
    The PK properties (tmax) of asfotase alfa

  12. 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 ]
    The PK properties (Cmax) of asfotase alfa

  13. 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 ]
    The PK properties (AUCt) of asfotase alfa



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 5 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

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

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): NCT01176266


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Sponsors and Collaborators
Alexion Pharma GmbH

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Alexion Pharma GmbH
ClinicalTrials.gov Identifier: NCT01176266     History of Changes
Other Study ID Numbers: ENB-010-10
First Posted: August 5, 2010    Key Record Dates
Results First Posted: February 26, 2018
Last Update Posted: February 26, 2018
Last Verified: January 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Alexion Pharma GmbH:
Hypophosphatasia
HPP
Bone Disease
Soft Bones
Low Alkaline Phosphatase
Genetic metabolic disorder
Alkaline phosphatase
Tissue-specific alkaline phosphatase (TNSALP)
Rickets
Osteomalacia

Additional relevant MeSH terms:
Hypophosphatasia
Metal Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases
Immunoglobulin G
Immunologic Factors
Physiological Effects of Drugs