Safety and Efficacy Study of Asfotase Alfa in Severely Affected Infants With Hypophosphatasia (HPP)
March 28, 2019 updated by: Alexion Pharmaceuticals
A Multicenter, Open-Label Study of the Safety, Tolerability and Pharmacology of Asfotase Alfa in up to 10 Severely Affected Patients With for the Treatment of Severely Affected Patients With Infantile Hypophosphatasia (HPP)
This clinical trial studies the safety and efficacy of asfotase alfa in infants and young children with infantile onset HPP.
Study Overview
Status
Completed
Conditions
Intervention / Treatment
Detailed Description
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 no approved disease-modifying treatments for patients with this disease.
There is also limited data available on the natural course of this disease over time, particularly in patients with the juvenile-onset form.
Study Type
Interventional
Enrollment (Actual)
11
Phase
- Phase 2
- Phase 1
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
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Manitoba
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Winnipeg, Manitoba, Canada, R3A 1S1
- The University of Manitoba Health Sciences Centre
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Abu-Dhabi
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Al Ain, Abu-Dhabi, United Arab Emirates
- Tawam-John Hopkins Hospital
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England
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Sheffield, England, United Kingdom, S10 2TH
- Sheffield Children's Hospital
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Northern Ireland
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Belfast, Northern Ireland, United Kingdom
- Royal Belfast Hospital for Sick Children
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Arkansas
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Little Rock, Arkansas, United States, 72202
- Arkansas Children's Hospital
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Delaware
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Wilmington, Delaware, United States, 19803
- Alfred I. DuPont Hospital for Children
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Missouri
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Springfield, Missouri, United States, 65804
- St. John's Hospital
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Nebraska
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Omaha, Nebraska, United States, 68114
- University of Nebraska Medical Center, Munroe-Meyer Institute
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Tennessee
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Nashville, Tennessee, United States, 37232
- Vanderbilt Children's Hospital
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Wisconsin
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Green Bay, Wisconsin, United States, 54301
- St. Vincent Hospital
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Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
No older than 3 years (Child)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
Inclusion Criteria:
- Legal guardian(s) must provide informed consent prior to any study procedures
Documented diagnosis of severe HPP as indicated by:
- Total serum alkaline phosphatase at least 3 standard deviations (SD) below the mean for age
- Plasma pyridoxal 5'-phosphate (PLP) at least 4 times the upper limit of normal
Radiographic evidence of HPP (hypophosphatasia), characterized by:
- Flared and frayed metaphyses
- Severe, generalized osteopenia
- Widened growth plates
One or more HPP-related findings:
History or presence of:
- Non-traumatic post-natal fracture
- Delayed fracture healing
- History of elevated serum calcium
- Functional craniosynostosis with decreased head circumference growth
- Nephrocalcinosis
- Respiratory compromise
- Rachitic chest deformity and/or vitamin B6 dependent seizures
- Failure to thrive
- Onset of symptoms prior to 6 months of age
- Age ≤ 36 months
- Otherwise medically stable (patient may be on ventilatory support)
- Legal guardian(s) must be willing to comply with the study
Exclusion Criteria:
- History of sensitivity to any of the constituents of the study drug
- Current or prior clinically significant cardiovascular, endocrinologic, hematologic, hepatic, immunologic, metabolic, infectious, urologic, pulmonary, neurologic, dermatologic, renal condition and/or other major disease which, in the opinion of the investigator, precludes study participation
- Treatment with an investigational drug within 1 month prior to the start of study drug administration
- Current enrollment in any other study involving an investigational new drug, device or treatment for HPP (e.g., bone marrow transplantation)
- Low serum calcium, phosphate or 25(OH) vitamin D
- Current evidence of a treatable form of rickets
- Prior treatment with bisphosphonate
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
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Other: asfotase alfa
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Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
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Change in Rickets Severity From Baseline to Week 24, Based on Assessment of Skeletal Radiographs Using Radiologic Global Impression of Change (RGI-C)
Time Frame: 24 weeks
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A 7-point RGI-C (Radiographic Global Impression of Change) score was used to rate change in rickets severity.
Scores ranged from -3 (severe worsening of rickets) to +3 (complete healing of rickets).
Only those patients with a minimum score of +2 indicating substantial healing of rickets) were considered "responders".
Three pediatric radiologists not affiliated with the conduct of the study performed the ratings.
Average scores were derived for each patient at each assessment.
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24 weeks
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
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Maximum Serum Concentration of Asfotase Alfa (Cmax)
Time Frame: Study Week 1 (0 to 168 hours post-dose). Study Week 2 and Study Week 3 (0 to 48 hours post-dose)
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Maximum serum concentration observed during intensive PK sampling interval.
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Study Week 1 (0 to 168 hours post-dose). Study Week 2 and Study Week 3 (0 to 48 hours post-dose)
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Time at Maximum Serum Concentration of Asfotase Alfa (Tmax)
Time Frame: Study Week 1 (0 to 168 hours post-dose). Study Week 2 and Study Week 3 (0 to 48 hours post-dose).
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Time at maximum serum concentration observed during intensive PK sampling interval.
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Study Week 1 (0 to 168 hours post-dose). Study Week 2 and Study Week 3 (0 to 48 hours post-dose).
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Area Under Serum Concentration-time Curve to Last Measurable Concentration of Asfotase Alfa (AUCt)
Time Frame: Study Week 1 (0 to 168 hours post-dose). Study Week 2 and Study Week 3 (0 to 48 hours post-dose).
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Area under serum concentration-time curve to last measurable concentration during intensive PK sampling interval.
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Study Week 1 (0 to 168 hours post-dose). Study Week 2 and Study Week 3 (0 to 48 hours post-dose).
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Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
General Publications
- Padidela R, Yates R, Benscoter D, McPhail G, Chan E, Nichani J, Mughal MZ, Myer C 4th, Narayan O, Nissenbaum C, Wilkinson S, Zhou S, Saal HM. Characterization of tracheobronchomalacia in infants with hypophosphatasia. Orphanet J Rare Dis. 2020 Aug 6;15(1):204. doi: 10.1186/s13023-020-01483-9.
- Whyte MP, Rockman-Greenberg C, Ozono K, Riese R, Moseley S, Melian A, Thompson DD, Bishop N, Hofmann C. Asfotase Alfa Treatment Improves Survival for Perinatal and Infantile Hypophosphatasia. J Clin Endocrinol Metab. 2016 Jan;101(1):334-42. doi: 10.1210/jc.2015-3462. Epub 2015 Nov 3.
- Millan JL, Narisawa S, Lemire I, Loisel TP, Boileau G, Leonard P, Gramatikova S, Terkeltaub R, Camacho NP, McKee MD, Crine P, Whyte MP. Enzyme replacement therapy for murine hypophosphatasia. J Bone Miner Res. 2008 Jun;23(6):777-87. doi: 10.1359/jbmr.071213.
- Drake MT, Khosla S. Bone-targeted replacement therapy for hypophosphatasia. J Bone Miner Res. 2008 Jun;23(6):775-6. doi: 10.1359/jbmr.080305. No abstract available.
- Whyte MP, Greenberg CR, Salman NJ, Bober MB, McAlister WH, Wenkert D, Van Sickle BJ, Simmons JH, Edgar TS, Bauer ML, Hamdan MA, Bishop N, Lutz RE, McGinn M, Craig S, Moore JN, Taylor JW, Cleveland RH, Cranley WR, Lim R, Thacher TD, Mayhew JE, Downs M, Millan JL, Skrinar AM, Crine P, Landy H. Enzyme-replacement therapy in life-threatening hypophosphatasia. N Engl J Med. 2012 Mar 8;366(10):904-13. doi: 10.1056/NEJMoa1106173.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start
September 1, 2008
Primary Completion (Actual)
May 1, 2010
Study Completion (Actual)
May 1, 2010
Study Registration Dates
First Submitted
August 27, 2008
First Submitted That Met QC Criteria
August 28, 2008
First Posted (Estimate)
August 29, 2008
Study Record Updates
Last Update Posted (Actual)
April 1, 2019
Last Update Submitted That Met QC Criteria
March 28, 2019
Last Verified
March 1, 2019
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- ENB-002-08
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.