Open-Label Study of Asfotase Alfa (ENB-0040) in Infants and Children ≤ 5 Years of Age With Hypophosphatasia (HPP)
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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 (ENB-0040) to see what effects it has on patients ≤ 5 years of age or less with HPP.
| Condition | Intervention | Phase |
|---|---|---|
|
Hypophosphatasia |
Biological: 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 (ENB-0040) in Infants and Children ≤ 5 Years of Age With Hypophosphatasia (HPP) |
- 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
- 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: | 30 |
| 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) |
-
Biological: asfotase alfa
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 |
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 ENB-0040 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 (OH) vitamin D levels are eligible for study participation after correction of levels with vitamin D supplementation.
Contacts and Locations| United States, California | |
| Children's Hospital & Research Center Oakland | Recruiting |
| Oakland, California, United States, 94609 | |
| Contact: Paul R. Harmatz, MD 510-428-3058 pharmatz@chori.org | |
| Contact: Jacqueline Madden, PNP 510-428-3885 jmadden@chori.org | |
| United States, Pennsylvania | |
| Children's Hospital of Pittsburgh of UPMC | Recruiting |
| Pittsburgh, Pennsylvania, United States, 15224 | |
| Contact: Stephanie DeWard, MS, CGC 412-692-5232 Stephanie.DeWard@chp.edu | |
| Principal Investigator: Gerard Vockley, MD | |
| Canada, Manitoba | |
| Health Sciences Centre Winnipeg, University of Manitoba | Recruiting |
| Winnipeg, Manitoba, Canada, R3A 1S1 | |
| Contact: Amy Yakimoski 204-789-3779 ayakimoski@mich.ca | |
| Sub-Investigator: Aizeddin (Aziz) Mhanni, MD | |
| Principal Investigator: Cheryl Greenberg, MD | |
| Sub-Investigator: Edward Leung, MD | |
| Germany | |
| Universitat Medizin der Johannes Gutenberg-Universität Mainz Villa Metabolica AG Lysosomale | Recruiting |
| Mainz, Germany, 55131 | |
| Contact: Seyfullah Gokce, MD, MD +49 (0) 6131 17-5754 goekce@kinder.klinik.uni-mainz.de | |
| Principal Investigator: Michael Beck, MD | |
| Universitats-Kinderklinik Wurzburg | Recruiting |
| Würzburg, Germany, 97080 | |
| Contact: Christine Beck, MD, MD +49- 931 - 201 27728 Beck_C@kinderklinik.uni-wuerzburg.de | |
| Principal Investigator: Johannes G. Liese, Prof., MD | |
| Principal Investigator: | Cheryl R Greenberg, MD | Health Sciences Centre, Winnipeg, Manitoba Canada |
| Principal Investigator: | Gerard Vockley, MD | Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania United States |
| Principal Investigator: | Johannes G Liese, MD | Universitat Qurzburg, Wurzburg Germany |
More Information
Additional Information:
No publications provided
| Responsible Party: | Alexion International Sàrl |
| ClinicalTrials.gov Identifier: | NCT01176266 History of Changes |
| Other Study ID Numbers: | ENB-010-10 |
| Study First Received: | July 29, 2010 |
| Last Updated: | July 3, 2012 |
| Health Authority: | United States: Food and Drug Administration Canada: Health Canada Germany: Ministry of Health |
Keywords provided by Alexion International Sàrl:
|
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 May 23, 2013