Safety Study of Human Recombinant Tissue Non-Specific Alkaline Phosphatase Fusion Protein Asfotase Alfa in Adults With Hypophosphatasia (HPP)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Alexion Pharma International Sarl
ClinicalTrials.gov Identifier:
NCT00739505
First received: August 19, 2008
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 of Asfotase Alfa and see what effects it has on humans and HPP. The study will also look at differences in injecting the drug into a vein with a needle (intravenously) and injecting it under the surface of the skin (subcutaneously).


Condition Intervention Phase
Hypophosphatasia
Biological: Asfotase Alfa
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Multicenter, Open-Label, Dose Escalating Study of the Safety, Tolerability and Pharmacology of Human Recombinant Tissue Non-Specific Alkaline Phosphatase Fusion Protein Asfotase Alfa in Adults With Hypophosphatasia (HPP)

Resource links provided by NLM:


Further study details as provided by Alexion Pharma International Sarl:

Primary Outcome Measures:
  • To determine the safety and tolerability of Asfotase Alfa given intravenously and given subcutaneously. [ Time Frame: Within the first 2 months (8 weeks). ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • To assess the pharmacokinetics (PK) of Asfotase Alfa given intravenously and subcutaneously [ Time Frame: Within the first 2 months (8 weeks) ] [ Designated as safety issue: No ]
  • To assess the bioavailability of the subcutaneous Asfotase Alfa [ Time Frame: Within the first 2 months (8 weeks) ] [ Designated as safety issue: No ]

Enrollment: 6
Study Start Date: August 2008
Study Completion Date: February 2009
Primary Completion Date: January 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort 1
3 HPP patients are to be enrolled in Cohort 1 and receive a single IV dose and three weekly SC doses of Asfotase Alfa . End of Study for patients in Cohort 1 is at 8 weeks.
Biological: Asfotase Alfa

The initial IV dose to be administered to patients was set at one-tenth the no adverse effect level (NOAEL) as determined by one month toxicology studies in animals in which Asfotase Alfa was administered as a single weekly IV dose. The SC doses to be administered are lower than the IV doses and are thought to be near or at the anticipated daily efficacious dose. Dosing will be as follows:

Cohort 1: In Week 1, patients will receive an IV infusion of Asfotase Alfa at a dose of 3 mg/kg. In Weeks 2, 3 and 4, patients will receive weekly SC injections of Asfotase Alfa at a dose of 1 mg/kg SC.

Experimental: Cohort 2
Cohort 2 will begin when the safety and PK data for Cohort 1 weeks 1-4 has been reviewed by the DSMB. Cohort 2 will enroll 3 HPP patients and will receive a higher dose level than Cohort 1. Cohort 2 patients will have a single IV dose and three weekly SC doses of Asfotase Alfa . End of Study for patients in Cohort 2 is at 8 weeks.
Biological: Asfotase Alfa
Cohort 2: In Week 1, patients will receive an IV infusion of Asfotase Alfa at a dose of 7 mg/kg. In Weeks 2, 3 and 4, patients will receive weekly SC injections of Asfotase Alfa at a dose of 1.5 mg/kg SC.

Detailed Description:

Asfotase Alfa was formerly referred to as ENB-0040

Hypophosphatasia (HPP) is a 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 although it is markedly higher in a small Canadian Mennonite population (Fraser 1957, Chodirker 1990). 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 (Whyte 2002). Low circulating levels of alkaline phosphatase with elevated serum or urine levels of the TNSALP substrates inorganic pyrophosphate (PPi), pyridoxal 5'-phosphate (PLP) and phosphoethanolamine (PEA) are the biochemical hallmarks of this inborn error of metabolism.

Disease severity in HPP 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 about 50% mortality. Children and adults have less severe disease but can have frequent fractures, bone pain, bowing of the long bones and muscle weakness, and morbidity is generally cumulative. Some patients cannot ambulate independently and end up wheelchair-bound.

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

In order to qualify for participation, patients must meet all of the following criteria:

  • Patients must provide written informed consent, including privacy authorization, prior to participation.
  • Women of childbearing potential must sign the Women of Childbearing Potential Addendum and must be using an acceptable method of birth control. Women considered not of childbearing potential must be surgically sterile (total hysterectomy, bilateral salpingo-oophorectomy, or tubal ligation) or post-menopausal, which is defined as a complete cessation of menstruation for at least one year after the age of 45 years. All women must have a serum pregnancy test conducted at Screening prior to enrollment and the results must be negative.
  • Be between 18 and 80 years of age at the time of consent
  • Patients must be medically stable in the opinion of the Investigator.
  • Patients must be willing to comply with study procedures and the visit schedule.
  • Pre-established clinical diagnosis of HPP as indicated by:

    • a. Serum alkaline phosphatase at least 3 SD below the mean for age
    • b. Radiologic evidence of osteopenia or osteomalacia
    • c. Two or more HPP-related findings:

      • i. Plasma pyridoxal 5'-phosphate at least 2.5 SD above the mean (no vitamin B6 administered for at least 1 week prior to determination
      • ii. History of rickets
      • iii. History of premature loss of deciduous teeth
      • iv. Bone deformity consistent with osteomalacia or past history of rickets
      • v. History of any one of the following:

        • 1. Non-traumatic fracture
        • 2. Pseudofracture
        • 3. Non-healing fracture

Exclusion Criteria:

In order to qualify for participation, patients must not meet any of the following criteria:

  • Women who are pregnant or lactating.
  • History of sensitivity to any of the constituents of the study drug.
  • Low levels of serum calcium, magnesium or phosphate.
  • Serum 25(OH) vitamin D level below 9.2 ng/mL.
  • Elevated serum creatinine or parathyroid hormone level.
  • Known cause of hypophosphatasemia other than HPP.
  • Current or prior clinically significant cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal condition and/or other major disease which, in the opinion of the investigator, precludes study participation.
  • Treatment with a bisphosphonate or parathyroid hormone (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: NCT00739505

Locations
United States, Missouri
Barnes Jewish Hospital- Washington University School of Medicine
St. Louis, Missouri, United States, 63110
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
Canada, Manitoba
Department of Pediatrics & Child Health, Health Sciences Centre Winnipeg, University of Manitoba
Winnipeg, Manitoba, Canada, R3A 1S1
Sponsors and Collaborators
Alexion Pharma International Sarl
Investigators
Principal Investigator: Cheryl Rockman-Greenberg, MD Department of Pediatrics, University of Manitoba, 840 Sherbrooke Street, Winnipeg, Canada R3A 1S1
  More Information

Additional Information:
Publications:
Responsible Party: Alexion Pharma International Sarl
ClinicalTrials.gov Identifier: NCT00739505     History of Changes
Other Study ID Numbers: ENB-001-08
Study First Received: August 19, 2008
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 non-specific alkaline phosphatase
rickets
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