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Safety and Efficacy of Asfotase Alfa in Juvenile Patients With Hypophosphatasia (HPP)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Alexion Pharma GmbH
ClinicalTrials.gov Identifier:
NCT00952484
First received: August 3, 2009
Last updated: March 29, 2016
Last verified: March 2016
  Purpose
This clinical trial studied the safety and efficacy of asfotase alfa in children with HPP compared to a historical control group.

Condition Intervention Phase
Hypophosphatasia (HPP)
Biological: asfotase alfa
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomized, Open-Label, Multicenter, Multinational, Dose-Ranging, Historical Control Study of the Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of ENB-0040 (Human Recombinant Tissue Nonspecific Alkaline Phosphatase Fusion Protein) in Children With Hypophosphatasia (HPP)

Resource links provided by NLM:


Further study details as provided by Alexion Pharma GmbH:

Primary Outcome Measures:
  • Change in Rickets Severity on Skeletal Radiographs From Baseline to Week 24 as Measured by the Radiographic Global Impression of Change (RGI-C) Scale [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    A 7-point RGI-C (radiographic global impression of change) score was used to rate change in rickets severity. Only those patients with a minimum score of +2 indicating substantial healing of rickets) were considered responders. Three pediatric radiologists not affiliated with the conduct of the study performed the ratings.


Secondary Outcome Measures:
  • Change in Osteomalacia - Osteoid Thickness (as Measured by Trans-iliac Crest Bone Biopsy) [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    Change from Baseline to Week 24 in osteoid thickness.

  • Change in Osteomalacia - Osteoid Volume/Bone Volume (as Measured by Trans-iliac Crest Bone Biopsy) [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    Change from Baseline to Week 24 in osteoid volume/bone volume (%), calculated as the absolute difference of the Baseline and Week 24 percentages.

  • Change in Osteomalacia - Mineralization Lag Time (as Measured by Trans-iliac Crest Bone Biopsy) [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    Change from Baseline to Week 24 in mineralization lag time.

  • Change in Height (Z-scores) [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    Change from Baseline to Week 24 in Height Z-Score. Height Z-Scores assigned based on Centers for Disease Control (CDC) growth charts and methodology.

  • Change in Biomarkers of Asfotase Alfa Activity as Measured by Plasma Inorganic Pyrophosphate (PPi) [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    Change from Baseline to Week 24 in Plasma PPi

  • Change in Biomarkers of Asfotase Alfa Activity as Measured by Pyridoxal-5'-Phosphate (PLP) [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    Change from Baseline to Week 24 in Plasma PLP

  • Maximum Serum Concentration of Asfotase Alfa (Cmax). [ Time Frame: Study Week 1 (0 to 48 hours post-dose) ] [ Designated as safety issue: No ]
    Maximum serum concentration observed following single dose of asfotase alfa.

  • Time at Maximum Serum Concentration of Asfotase Alfa (Tmax) [ Time Frame: Study Week 1 (0 to 48 hours post-dose) ] [ Designated as safety issue: No ]
    Maximum serum concentration observed following single dose of asfotase alfa.

  • Area Under Serum Concentration-time Curve to Last Measurable Concentration of Asfotase Alfa (AUCt) [ Time Frame: Study Week 1 (0 to 48 hours post-dose) ] [ Designated as safety issue: No ]
    Area under serum concentration-time curve to last measurable concentration following single dose of asfotase alfa.

  • Maximum Serum Concentration of Asfotase Alfa (Cmax). [ Time Frame: Study Week 6 (0 to 48 hours post-dose) ] [ Designated as safety issue: No ]
    Maximum serum concentration observed following multiple doses of asfotase alfa.

  • Time at Maximum Serum Concentration of Asfotase Alfa (Tmax). [ Time Frame: Study Week 6 (0 to 48 hours post-dose) ] [ Designated as safety issue: No ]
    Time at maximum serum concentration observed following multiple doses of asfotase alfa.

  • Area Under Serum Concentration-time Curve to Last Measurable Concentration of Asfotase Alfa (AUCt) [ Time Frame: Study Week 6 (0 to 48 hours post-dose). ] [ Designated as safety issue: No ]
    Area under serum concentration-time curve to last measurable concentration following multiple doses of asfotase alfa.


Enrollment: 13
Study Start Date: September 2009
Study Completion Date: July 2010
Primary Completion Date: July 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 2 mg/kg
2 mg/kg subcutaneous injection three times per week.
Biological: asfotase alfa
2 mg/kg subcutaneous injection three times per week for 6 months.
Other Names:
  • Human Recombinant Tissue Nonspecific Alkaline Phosphatase Fusion Protein
  • sALP-Fc-D10
Active Comparator: 3 mg/kg
3 mg/kg subcutaneous injection three times per week.
Biological: asfotase alfa
3 mg/kg subcutaneous injection three times per week for 6 months.
Other Names:
  • Human Recombinant Tissue Nonspecific Alkaline Phosphatase Fusion Protein
  • sALP-Fc-D10

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 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.

Efficacy analyses were prospectively defined in the protocol with a comparison to historical controls. The historical control group came from patients whose characteristics matched as closely as possible the entry criteria for the trial. The control group included all patients who had x-rays within the age range defined by the inclusion criteria of this study (5 to 12 years of age, inclusive, with open growth plates).

The pre-specified plan for analysis was to combine the two asfotase alfa treated groups (asfotase alfa 2 mg/kg subcutaneous (SC) injection three times per week or 3 mg/kg subcutaneous (SC) injection three times per week) and compare them to historical controls.

  Eligibility

Ages Eligible for Study:   5 Years to 12 Years   (Child)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Written informed consent from parent or legal guardian prior to participation
  2. Patients > 5 and < 12 years of age with open growth plates at time of enrollment
  3. Tanner stage of 2 or less indicating pre-pubescence
  4. Documented history of HPP, as evidenced by:

    • Presence of HPP-related rickets on skeletal radiographs of the wrist and knee
    • Serum alkaline phosphatase (ALP) below age-adjusted normal range
    • Plasma PLP at least twice the upper limit of normal
  5. 25(OH) vitamin D level > 20 ng/mL
  6. Ability of patient and parent/guardian to comply with study requirements

Exclusion Criteria:

  1. Serum calcium or phosphorus below age-adjusted normal range
  2. History of sensitivity to any study drug constituent
  3. Medical condition, serious intercurrent illness, or other extenuating circumstance that, in the opinion of the Investigator, may significantly interfere with study compliance, including all prescribed evaluations and follow-up activities
  4. Treatment with an investigational drug within 1 month before start of study drug
  5. Current enrollment in any other study involving an investigational new drug, device, or treatment for HPP (e.g., bone marrow transplantation)
  6. Current evidence of a treatable form of rickets
  7. Prior treatment with bisphosphonates
  8. Bone fracture or orthopedic surgery within the past 12 months that, in the opinion of the Investigator would interfere with the ability of study patient to comply with study protocol
  9. Major congenital abnormality other than those associated with HPP
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00952484

Locations
United States, Missouri
Shriners Hospital for Children
St. Louis, Missouri, United States, 63131
Canada, Manitoba
The University of Manitoba Health Services Centre
Winnipeg, Manitoba, Canada, R3A 1S1
Sponsors and Collaborators
Alexion Pharma GmbH
  More Information

Additional Information:
Publications:
Responsible Party: Alexion Pharma GmbH
ClinicalTrials.gov Identifier: NCT00952484     History of Changes
Other Study ID Numbers: ENB-006-09 
Study First Received: August 3, 2009
Results First Received: May 14, 2011
Last Updated: March 29, 2016
Health Authority: United States: Food and Drug Administration
Canada: Health Canada

Keywords provided by Alexion Pharma GmbH:
Hypophosphatasia
HPP
Bone Disease
Soft Bones
Low Alkaline Phosphatase
genetic metabolic disorder
alkaline phosphatase
tissue non-specific alkaline phosphatase
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

ClinicalTrials.gov processed this record on September 28, 2016