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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Alexion Pharma International Sarl
ClinicalTrials.gov Identifier:
NCT01163149
First received: June 24, 2010
Last updated: January 24, 2013
Last verified: December 2011
  Purpose

This clinical trial is being 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 is to test the safety and efficacy of two doses of the study drug called Asfotase Alfa as compared to a control group to see what effects it has adolescents and adults with HPP.


Condition Intervention Phase
Hypophosphatasia
Drug: 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, Concurrent Control Study of the Safety, Efficacy, Pharmacokinetic of Asfotase Alfa (Human Recombinant Tissue Nonspecific Alkaline Phosphatase Fusion Protein) in Adolescents and Adults With Hypophosphatasia (HPP)

Resource links provided by NLM:


Further study details as provided by Alexion Pharma International Sarl:

Primary Outcome Measures:
  • Effect of Asfotase Alfa on reduction in plasma inorganic pyrophosphate (PPi) and plasma pyridoxal-5' phosphate (PLP) [ Time Frame: Month 6 ] [ Designated as safety issue: No ]
    Blood samples will be collected to evaluate the effect of Asfotase Alfa on reduction in plasma inorganic pyrophosphate (PPi) and plasma pyridoxal-5' phosphate (PLP)

  • Safety and Tolerability of Asfotase Alfa [ Time Frame: Month 6 ] [ Designated as safety issue: Yes ]
    The safety and tolerability of daily subcutaneous (SC) injections of Asfotase Alfa will be assessed by routine monitoring of patients for adverse events (AEs) and injection-associated reactions (IARs) and monitoring changes from Baseline in physical examination findings, vital signs, clinical laboratory evaluations, renal ultrasound findings, funduscopic examinations, antibody evaluations, and results of pregnancy testing (in women of childbearing potential only). Monitoring for changes in concomitant medications and therapies will also occur.


Secondary Outcome Measures:
  • Change in bone mineral content and density as measured by dual-energy X-ray absorptiometry (DXA) [ Time Frame: Month 6 ] [ Designated as safety issue: No ]
    A DXA scan will be performed to evaluate bone mineral content and density of the spine, hip, and whole body.

  • Change in walking ability as measured by the Six-Minute Walk Test (6MWT) [ Time Frame: Month 6 ] [ Designated as safety issue: No ]
    The effect of Asfotase Alfa on gross motor function as measured by a modified version of the Bruininks-Oseretsky Test of Motor Proficiency - Second Edition (BOT-2)

  • Change in HPP-related osteomalacia as measured by trans-iliac crest bone biopsy [ Time Frame: Month 6 ] [ Designated as safety issue: No ]
    A trans-iliac crest bone biopsy will be performed to quantify osteomalacia severity.

  • Change in biomarkers of Asfotase Alfa activity [ Time Frame: Month 6 ] [ Designated as safety issue: No ]
    Change in biomarkers of Asfotase Alfa activity as measured by plasma inorganic pyrophosphate (PPi), plasma pyridoxal-5'-phosphate (PLP) and serum parathyroid hormone (PTH)


Estimated Enrollment: 18
Study Start Date: June 2010
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 (tota1 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
Subjects randomized to this cohort will participate in all study assessments but will receive no treatment for the duration of the study. Upon successful completion of the study, all subjects will be eligible to continue to receive Asfotase Alfa treatment in an open-label extension period of this protocol. In the extension period, all patients will then be treated with daily SC injections of 0.5 mg/kg/day Asfotase Alfa (a total of 3.5 mg/kg/week) for approximately an additional 24 weeks.

Detailed Description:

Asfotase Alfa was formerly referred to as ENB-0040

Hypophosphatasia is rare inherited form of rickets and osteomalacia caused by inactivating mutations in the gene encoding the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). The prevalence of the disease is thought to be about 1:100,000. Inheritance can be autosomal recessive or dominant, and penetrance is variable resulting in a wide range of clinical expressivity. HPP differs from other forms of rickets and osteomalacia in that serum levels of calcium and phosphorus are generally normal or even elevated. Low circulating levels of alkaline phosphatase with elevated serum or urine levels of the TNSALP substrates, inorganic pyrophosphate (PPi), pyroxidal 5'-phosphate (PLP) and phosphoethanolamine (PEA), are the biochemical hallmarks of this inborn error of metabolism.

Disease severity is inversely related to the age at symptom presentation. The most severe cases occur in utero and almost invariably result in death, generally due to pulmonary compromise. Infants who present in the first six months of life have a mortality rate of approximately 50%. Children and adults have less severe disease but can have frequent fractures, bone pain, bowing of the long bones and muscle weakness. Morbidity is generally cumulative; some patients cannot ambulate independently and end up wheelchair-bound.

  Eligibility

Ages Eligible for Study:   13 Years to 65 Years
Genders Eligible for Study:   Both
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
Please refer to this study by its ClinicalTrials.gov identifier: NCT01163149

Locations
United States, Missouri
Shriner's Hospital for Children
St. 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 International Sarl
Investigators
Principal Investigator: Cheryl R Greenberg, MD Health Sciences Centre, Winnipeg, Manitoba Canada
Principal Investigator: Priya S Kishnani, MD Duke University Medical Center, Raleigh, NC USA
Principal Investigator: Michael Whyte, MD Shriner's Hospital for Children, St. Louis, MO USA
  More Information

Additional Information:
Publications:
Responsible Party: Alexion Pharma International Sarl
ClinicalTrials.gov Identifier: NCT01163149     History of Changes
Other Study ID Numbers: ENB-009-10
Study First Received: June 24, 2010
Last Updated: January 24, 2013
Health Authority: United States: Food and Drug Administration
Canada: Health Canada

Keywords provided by Alexion Pharma International Sarl:
genetic metabolic disorder
alkaline phosphatase
tissue-specific alkaline phosphatase (TNSALP)
osteomalacia

Additional relevant MeSH terms:
Hypophosphatasia
Metal Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases

ClinicalTrials.gov processed this record on April 17, 2014