Open-Label Study of Asfotase Alfa in Infants and Children ≤ 5 Years of Age With Hypophosphatasia (HPP)

This study is currently recruiting participants.
Verified December 2013 by Alexion Pharma International Sarl
Sponsor:
Information provided by (Responsible Party):
Alexion Pharma International Sarl
ClinicalTrials.gov Identifier:
NCT01176266
First received: July 29, 2010
Last updated: December 20, 2013
Last verified: December 2013
  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 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.


Condition Intervention Phase
Hypophosphatasia
Drug: asfotase alfa
Phase 2
Phase 3

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open-Label, Multicenter, Multinational Study of the Safety, Efficacy and Pharmacokinetics of Asfotase Alfa Formerly (ENB-0040) in Infants and Children ≤ 5 Years of Age 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 treatment on skeletal manifestations of HPP [ Time Frame: Up to 48 months ] [ Designated as safety issue: No ]
    Effect of asfotase alfa treatment on skeletal manifestations of HPP as measured by radiographs using a qualitative Radiographic Global Impression of Change (RGI-C) scale for all treated patients

  • Safety and tolerability of repeated subcutaneous (SC) injections of asfotase alfa [ Time Frame: Up to 48 months ] [ Designated as safety issue: Yes ]
    Safety and tolerability of repeated subcutaneous (SC) injections of asfotase alfa for all treated patients


Secondary Outcome Measures:
  • Effect of asfotase alfa treatment on ventilator-free survival [ Time Frame: Up to 48 months ] [ Designated as safety issue: No ]
    For patients who are not mechanically ventilated at the time of enrollment, the percentage who are alive and ventilator-free after receiving asfotase alfa as compared to an age-matched historical control group

  • Effect of asfotase alfa treatment on respiratory function [ Time Frame: Up to 48 months ] [ Designated as safety issue: No ]
    Effect of asfotase alfa treatment on respiratory function as measured by ventilator status, time on respiratory support (including time on ventilator or supplemental oxygen), ventilator rate or oxygen volume, ventilator pressures, and fraction of inspired oxygen (FiO2) for all treated patients

  • Effect of asfotase alfa treatment on physical growth [ Time Frame: Up to 48 months ] [ Designated as safety issue: No ]
    Effect of asfotase alfa treatment on physical growth as measured by body weight, length, arm span, head circumference, and chest circumference for all treated patients

  • Effect of asfotase alfa treatment on tooth loss [ Time Frame: Up to 48 months ] [ Designated as safety issue: No ]
    Effect of asfotase alfa treatment on tooth loss for all treated patients

  • Pharmacokinetic (PK) properties of asfotase alfa [ Time Frame: Up to 48 months ] [ Designated as safety issue: No ]
    The PK properties of asfotase alfa

  • Effect of asfotase alfa on biomarkers [ Time Frame: Up to 48 months ] [ Designated as safety issue: No ]
    Effect of asfotase alfa on plasma inorganic pyrophosphate (PPi) and plasma pyridoxal-5' phosphate (PLP)

  • Effect of asfotase alfa on serum parathyroid hormone (PTH) [ Time Frame: Up to 48 months ] [ Designated as safety issue: No ]
    Effect of asfotase alfa on serum parathyroid hormone (PTH)


Estimated Enrollment: 60
Study Start Date: July 2010
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Single arm Drug: asfotase alfa

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 may have less severe disease but can have frequent fractures, bone pain, bowing of the long bones and muscle weakness. Morbidity is generally cumulative.

  Eligibility

Ages Eligible for Study:   up to 5 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Patients must meet all of the following criteria for enrollment in this study:

  • 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
  • Documented diagnosis of HPP as indicated by:

    • Total serum alkaline phosphatase below the lower limit of normal for age
    • Plasma PLP above the upper limit of normal (unless patient is receiving pyridoxine for seizures)
    • Radiographic evidence of HPP, characterized by:

      • Flared and frayed metaphyses
      • Severe, generalized osteopenia
      • Widened growth plates
      • Areas of radiolucency or sclerosis
    • Two or more of the following HPP-related findings:

      • History or presence of:

        • Nontraumatic post-natal fracture
        • Delayed fracture healing
      • Nephrocalcinosis or history of elevated serum calcium
      • Functional craniosynostosis
      • Respiratory compromise or rachitic chest deformity
      • Vitamin B6 dependent seizures
      • Failure to thrive
  • Onset of symptoms prior to 6 months of age
  • Chronological age or adjusted age for premature infants born ≤ 37 weeks gestation of ≤ 5 years
  • Otherwise medically stable in the opinion of the Investigator and/or Enobia

Exclusion criteria:

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

  • Clinically significant disease that precludes study participation, in the opinion of the Investigator and/or Enobia
  • Serum calcium or phosphate levels below the normal range
  • Serum 25 hydroxy (25 [OH]) vitamin D below 20 ng/mL
  • Current evidence of treatable form of rickets
  • Prior treatment with bisphosphonates
  • Treatment with an investigational drug within 1 month prior to the start of Asfotase Alfa treatment
  • Current enrollment in any other study involving an investigational new drug, device or treatment for HPP (e.g., bone marrow transplantation)

NOTE: Historical values for PLP may be used to determine patient eligibility. Patients with low 25(OH) vitamin D levels are eligible for study participation after correction of levels with vitamin D supplementation.

  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01176266

Contacts
Contact: Alexion Pharma International Sàrl (Sponsor) clinicaltrials@alxn.com

Locations
United States, California
Children's Hospital & Research Center Oakland Recruiting
Oakland, California, United States, 94609
Contact: Alexion Pharma International Sàrl (sponsor)       clinicaltrials@alxn.com   
United States, Ohio
Cincinnati Children's Hospital Medical Center Recruiting
Cincinnati, Ohio, United States, 45229
Contact: Alexion Pharma International Sàrl (sponsor)       clinicaltrials@alxn.com   
United States, Pennsylvania
Children's Hospital of Pittsburgh of UPMC Recruiting
Pittsburgh, Pennsylvania, United States, 15224
Contact: Alexion Pharma International Sàrl (sponsor)       clinicaltrials@alxn.com   
Canada, Manitoba
Health Sciences Centre Winnipeg, University of Manitoba Recruiting
Winnipeg, Manitoba, Canada, R3A 1S1
Contact: Alexion Pharma International Sàrl (Sponsor)       clinicaltrials@alxn.com   
Germany
Universitätskinderklinik Würzburg Recruiting
Würzburg, Germany, D-97080
Contact: Alexion Pharma International Sàrl (sponsor)       clinicaltrials@alxn.com   
Italy
Istituto Giannina Gaslini Recruiting
Genova, Italy, 16147
Contact: Alexion Pharma International Sàrl (Sponsor)       clinicaltrials@alxn.com   
Ospedale Pediatrico Bambino Gesù Recruiting
Roma, Italy, 00165
Contact: Alexion Pharma International Sàrl (sponsor)       clinicaltrials@alxn.com   
Japan
Fukuoka Higashi Medical Hospital Recruiting
Koga-city, Fukuoka, Japan, 811-3195
Contact: Alexion Pharma International Sàrl (Sponsor)       clinicaltrials@alxn.com   
Ishikawa Prefectural Hospital Recruiting
Kanazawa-city, Ishikawa, Japan, 920-8530
Contact: Alexion Pharma International Sàrl (sponsor)       clinicaltrials@alxn.com   
Saitama Municipal Hospital Recruiting
Saitama-city, Saitama, Japan, 336-8522
Contact: Alexion Pharma International Sàrl (Sponsor)       clinicaltrials@alxn.com   
Tokyo Medical University Hospital Recruiting
Shinjuku-ku, Tokyo, Japan, 160-0023
Contact: Alexion Pharma International Sàrl (Sponsor)       clinicaltrials@alxn.com   
St. Marianna University School of Medicine, Yokohayama City Seibu Hospital Recruiting
Yokohama-city, Kanagawa, Yokohama-city, Japan, 241-0811
Contact: Alexion Pharma International Sàrl (sponsor)       clinicaltrials@alxn.com   
Spain
Hospital Infantil Universitario Nino Jesus Recruiting
Madrid, Spain, 28009
Contact: Alexion Pharma International Sàrl (Sponsor)       clinicaltrials@alxn.com   
Taiwan
National Taiwan University Hospital Recruiting
Taipei, Taiwan, 10041
Contact: Alexion Pharma International Sàrl (sponsor)       clinicaltrials@alxn.com   
Turkey
Uludag Universitesi Hastanesi Recruiting
Nilüfer, Bursa, Turkey, 16059
Contact: Alexion Pharma International Sàrl (sponsor)       clinicaltrials@alxn.com   
United Kingdom
Birmingham Children's Hospital Recruiting
Birmingham, United Kingdom, B4 6NH
Contact: Alexion Pharma International Sàrl (Sponsor)       clinicaltrials@alxn.com   
Royal Manchester Children'S Hospital Recruiting
Manchester, United Kingdom, M13 9WL
Contact: Alexion Pharma International Sàrl (sponsor)       clinicaltrials@alxn.com   
Sheffield Children'S Hospital Recruiting
Sheffield, United Kingdom, S10 2TH
Contact: Alexion Pharma International Sàrl (sponsor)       clinicaltrials@alxn.com   
Sponsors and Collaborators
Alexion Pharma International Sarl
  More Information

Additional Information:
No publications provided

Responsible Party: Alexion Pharma International Sarl
ClinicalTrials.gov Identifier: NCT01176266     History of Changes
Other Study ID Numbers: ENB-010-10
Study First Received: July 29, 2010
Last Updated: December 20, 2013
Health Authority: United States: Food and Drug Administration
Canada: Health Canada
Germany: Ministry of Health
Taiwan : Food and Drug Administration
Japan: Pharmaceuticals and Medical Devices Agency
Turkey: Ministry of Health
Italy: The Italian Medicines Agency
Spain: Agencia Española de Medicamentos y Productos Sanitarios
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Alexion Pharma International Sarl:
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

ClinicalTrials.gov processed this record on April 23, 2014