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Safety and Efficacy Study of Asfotase Alfa in Adolescents and Adults With Hypophosphatasia (HPP)

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ClinicalTrials.gov Identifier: NCT01163149
Recruitment Status : Completed
First Posted : July 15, 2010
Results First Posted : September 18, 2017
Last Update Posted : September 18, 2017
Sponsor:
Information provided by (Responsible Party):
Alexion Pharma GmbH

Study Description
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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 two doses of the study drug called asfotase alfa as compared to a control group to see effects on adolescents and adults with HPP.

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

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 Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 19 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized, Open-Label, Multicenter, Multinational, Dose-Ranging, Concurrent Control Study of the Safety, Efficacy, Pharmacokinetic of ENB-0040 (Human Recombinant Tissue Nonspecific Alkaline Phosphatase Fusion Protein) in Adolescents and Adults With Hypophosphatasia (HPP)
Study Start Date : June 2010
Actual Primary Completion Date : June 2016
Actual Study Completion Date : June 2016

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arms and Interventions
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Arm Intervention/treatment
Experimental: Cohort 1
Cohort 1: Daily SC injections of 0.3 mg/kg asfotase alfa (2.1 mg/kg/week total)
 Drug: asfotase alfa
Cohort 1: Daily SC injections of 0.3 mg/kg asfotase alfa (total of 2.1 mg/kg/week)
Experimental: Cohort 2
Cohort 2: Daily SC injections of 0.5 mg/kg asfotase alfa (3.5 mg/kg/week total)
 Drug: asfotase alfa
Cohort 2: Daily SC injections of 0.5 mg/kg Asfotase Alfa (3.5 mg/kg/week total)
No Intervention: Concurrent Control
Following completion of the Week 24 visit, all patients (including those randomized to the concurrent control cohort) may be eligible to participate in an open-label extension treatment period. In this extension period, all patients will be treated with daily SC injections of 0.5 mg/kg/day asfotase alfa (a total of 3.5 mg/kg/week) for approximately 24 weeks, then subjects will receive 1 mg/kg/day 6 days/week for an additional 48 weeks or until regulatory approval of the drug.


Outcome Measures
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Primary Outcome Measures :
  1. Change From Baseline to Week 24 for Plasma Pyridoxal-5' Phosphate (PLP) [ Time Frame: Baseline, Week 24 ]
    Blood samples were collected to evaluate the effect of asfotase alfa on reduction in plasma pyridoxal-5' phosphate (PLP)

  2. Change From Baseline to Week 24 for Plasma Inorganic Pyrophosphate (PPi) [ Time Frame: Baseline, Week 24 ]
    Blood samples were collected to evaluate the effect of asfotase alfa on reduction in plasma inorganic pyrophosphate (PPi)

  3. Safety and Tolerability of Asfotase Alfa [ Time Frame: Up to 288 weeks exposure to asfotase alfa ]
    The safety and tolerability of daily subcutaneous (SC) injections of asfotase alfa was assessed by routine monitoring of patients for treatment-emergent adverse events (TEAEs) and injection-associated reactions (IARs).


Secondary Outcome Measures :
  1. Change From Baseline in Bone Mineral Content (BMC) as Measured by Dual-energy X-ray Absorptiometry (DXA) [ Time Frame: Baseline, every 24 weeks through Week 96, then every 48 weeks until Week 288. ]
    A DXA scan was performed to evaluate bone mineral content (BMC) of the spine, hip, and whole body during the primary (first 24 weeks) and extension treatment periods (up to 288 weeks).

  2. Change From Baseline in Bone Mineral Density (BMD) as Measured by Dual-energy X-ray Absorptiometry (DXA) [ Time Frame: Baseline, every 24 weeks through Week 96, then every 48 weeks until Week 288. ]
    A DXA scan was performed to evaluate bone bone mineral density (BMD) of the spine, hip, and whole body during the primary (first 24 weeks) and extension treatment periods (up to 288 weeks).

  3. Change in Walking Ability as Measured by the Six-Minute Walk Test (6MWT) [ Time Frame: Baseline, Week 24 (primary treatment period) and up to 288 weeks of asfotase alfa exposure ]
    The patient was instructed to walk the length of a pre-measured hallway for 6 minutes. The primary measurement was distance walked (in meters).

  4. Change From Baseline in HPP-related Osteomalacia as Measured by Trans-iliac Crest Bone Biopsy: Osteoid Volume/Bone Volume [ Time Frame: Baseline, Week 24 (Control group), and Week 48 (Asfotase alfa groups). ]
    A trans-iliac crest bone biopsy was performed to quantify changes from Baseline in histomorphometric parameters relevant for evaluation of osteomalacia severity, including Osteoid Volume/Bone Volume (%). The difference in time under observation between asfotase alfa groups (Week 48) and control group (Week 24) resulted from study design, ie, control subjects transitioned to active treatment after the Week 24 visit.

  5. Change From Baseline in HPP-related Osteomalacia as Measured by Trans-iliac Crest Bone Biopsy: Osteoid Thickness [ Time Frame: Baseline, Week 24 (Control group), and Week 48 (Asfotase alfa groups). ]
    A trans-iliac crest bone biopsy was performed to quantify changes from Baseline in histomorphometric parameters relevant for evaluation of osteomalacia severity, including Osteoid Thickness (um). The difference in time under observation between asfotase alfa groups (Week 48) and control group (Week 24) resulted from study design, ie, control subjects transitioned to active treatment after the Week 24 visit.

  6. Change From Baseline in HPP-related Osteomalacia as Measured by Trans-iliac Crest Bone Biopsy: Mineralization Lag Time [ Time Frame: Baseline, Week 24 (Control group), and Week 48 (Asfotase alfa groups). ]
    A trans-iliac crest bone biopsy was performed to quantify changes from Baseline in histomorphometric parameters relevant for evaluation of osteomalacia severity, including Mineralization Lag Time (days). The difference in time under observation between asfotase alfa groups (Week 48) and control group (Week 24) resulted from study design, ie, control subjects transitioned to active treatment after the Week 24 visit.


Eligibility Criteria
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Ages Eligible for Study:   13 Years to 65 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

Patients must meet all of the following inclusion criteria to be eligible for participation in this study:

  • Patients or their legal representative(s) must provide written informed consent prior to undergoing any study-related procedures
  • Patients must be ≥ 13 and ≤ 65 years of age at the time of study enrollment
  • Female patients of childbearing potential and sexually mature males must agree to use a medically acceptable form of birth control; for the purposes of this study, females are considered of non-childbearing potential if they are surgically sterile (i.e., have undergone a total hysterectomy, bilateral salpingo-oophorectomy or tubal ligation) or are post-menopausal, defined as having complete cessation of menstruation for at least 1 year after 45 years of age

  • Patients must have a pre-established clinical diagnosis of HPP as indicated by:

    • Serum alkaline phosphatase (ALP) below the age-adjusted normal range
    • Plasma PLP at least twice the upper limit of normal (no vitamin B6 administered for at least 1 week prior to determination)
    • Evidence of osteopenia or osteomalacia on skeletal radiographs
  • Patients must have osteomalacia on bone biopsy, characterized by an MLT z-score of +2 or more (results from ENB-001-08 may be used)
  • Patients must be willing to comply with study procedures and the visit schedule

Exclusion criteria:

Patients will be excluded from participation in this study if they meet any of the following exclusion criteria:

  • Women who are pregnant or lactating
  • History of sensitivity to tetracycline
  • Serum calcium or phosphate levels below the normal range
  • Serum 25(OH) vitamin D below 20 ng/mL
  • Serum creatinine or parathyroid hormone (PTH) levels above the upper limit of normal
  • 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
  • Orthopedic surgery within 12 months prior to study entry that may interfere with the ability to perform functional assessments for the study
  • Prior treatment with bisphosphonates within 2 years of study entry for any length of time or for more than 2 years at any time point; for patients with prior bisphosphonate use that is allowed, the bone resorption markers serum C-telopeptide and urine N-telopeptide or urine deoxypyridinoline must also be within the normal range or elevated to be eligible for study participation
  • Treatment with PTH within 6 months prior to the start of asfotase alfa administration
  • Participation in an interventional or investigational drug study within 30 days prior to study participation
Contacts and Locations
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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

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): NCT01163149


Locations
United States, Missouri
Shriner's Hospital for Children
Saint Louis, Missouri, United States, 63131
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
Canada, Manitoba
Health Sciences Centre Winnipeg, University of Manitoba
Winnipeg, Manitoba, Canada, R3A 1S1
Sponsors and Collaborators
Alexion Pharma GmbH
More Information
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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Additional Information:
Hypophosphatasie Europe  This link exits the ClinicalTrials.gov site
HPP support group  This link exits the ClinicalTrials.gov site
US Hypophosphatasia Group (Soft Bones)  This link exits the ClinicalTrials.gov site
Hypophosphatasia Website  This link exits the ClinicalTrials.gov site
Hypophosphatasia Website for Healthcare Providers  This link exits the ClinicalTrials.gov site

Publications:

Responsible Party: Alexion Pharma GmbH
ClinicalTrials.gov Identifier: NCT01163149     History of Changes
Other Study ID Numbers: ENB-009-10
First Posted: July 15, 2010    Key Record Dates
Results First Posted: September 18, 2017
Last Update Posted: September 18, 2017
Last Verified: August 2017

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