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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 : March 13, 2019
Sponsor:
Information provided by (Responsible Party):
Alexion Pharmaceuticals

Tracking Information
First Submitted Date  ICMJE July 29, 2010
First Posted Date  ICMJE August 5, 2010
Results First Submitted Date  ICMJE October 3, 2017
Results First Posted Date  ICMJE February 26, 2018
Last Update Posted Date March 13, 2019
Study Start Date  ICMJE July 2010
Actual Primary Completion Date September 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 26, 2018)
  • 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).
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: August 4, 2010)
  • Effect of ENB-0040 treatment on skeletal manifestations of HPP [ Time Frame: Month 12 (Month 18 for participants < 9 months of age at enrollment) ]
    The effect of ENB-0040 on the skeletal manifestations of HPP after 6 months of ENB-0040 treatment will be measured by comparing Screening and Month 6 radiographs of the chest, upper and lower extremities using a qualitative Radiographic Global Impression of Change (RGI-C) scale
  • Safety and tolerability of repeated subcutaneous (SC) injections of ENB-0040 [ Time Frame: Month 12 (Month 18 for participants < 9 months of age at enrollment) ]
    The safety and tolerability of ENB-0040 will be assessed by monitoring adverse events and injection-associated reactions, as well as changes in physical examination findings, vital signs, clinical laboratory evaluations (including routine chemistry, hematology and urinalysis, 25(OH) vitamin D and urinary calcium:creatinine ratio), renal ultrasound and funduscopy findings and antibody evaluations. Changes in concomitant medications and therapies, calcium intake and caloric input will also be monitored.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 26, 2018)
  • 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).
  • 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
  • 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.
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
Original Secondary Outcome Measures  ICMJE
 (submitted: August 4, 2010)
  • Effect of ENB-0040 treatment on ventilator-free survival [ Time Frame: Month 12 (Month 18 for participants < 9 months of age at enrollment) ]
    For patients under 9 months of age who are not mechanically ventilated at the time of enrollment, the percentage who are alive and ventilator free at 18 months of age will be compared to an age-matched historical control group
  • Effect of ENB-0040 treatment on respiratory function [ Time Frame: Month 12 (Month 18 for participants < 9 months of age at enrollment) ]
    Effect of ENB-0040 treatment on respiratory function will be measured by monitoring ventilator status and settings (where applicable).
  • Effect of ENB-0040 treatment on physical growth [ Time Frame: Month 12 (Month 18 for participants < 9 months of age at enrollment) ]
    Effect of ENB-0040 treatment on physical growth will be measured by body weight, length, arm span, head circumference, and chest circumference
  • Effect of ENB-0040 treatment on tooth loss [ Time Frame: Month 12 (Month 18 for participants < 9 months of age at enrollment) ]
    Tooth loss will be evaluated by counting the number of teeth present at Baseline and the number of teeth gained and lost during the study
  • Pharmacokinetic (PK) properties of ENB-0040 [ Time Frame: Month 12 (Month 18 for participants < 9 months of age at enrollment) ]
    The PK properties of ENB-0040 will be evaluated by monitoring ENB-0040 activity in serum
  • Effect of ENB-0040 on biomarkers [ Time Frame: Month 12 (Month 18 for participants < 9 months of age at enrollment) ]
    Effect of ENB-0040 will be memasured on the following biomarkers (which are typically abnormal in HPP patients): plasma inorganic pyrophosphate (PPi), plasma pyridoxal-5' phosphate (PLP) and serum parathyroid hormone (PTH)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Open-Label Study of Asfotase Alfa in Infants and Children ≤ 5 Years of Age With Hypophosphatasia (HPP)
Official Title  ICMJE 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)
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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Hypophosphatasia
Intervention  ICMJE Drug: asfotase alfa
Other Name: ENB-0040
Study Arms  ICMJE 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)
Intervention: Drug: asfotase alfa
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 14, 2016)
69
Original Estimated Enrollment  ICMJE
 (submitted: August 4, 2010)
30
Actual Study Completion Date  ICMJE September 2016
Actual Primary Completion Date September 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 5 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Canada,   France,   Germany,   Italy,   Japan,   Russian Federation,   Saudi Arabia,   Spain,   Turkey,   United Kingdom,   United States
Removed Location Countries Taiwan
 
Administrative Information
NCT Number  ICMJE NCT01176266
Other Study ID Numbers  ICMJE ENB-010-10
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Alexion Pharmaceuticals
Study Sponsor  ICMJE Alexion Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Alexion Pharmaceuticals
Verification Date March 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP