Safety and Efficacy Study of Asfotase Alfa in Severely Affected Infants With Hypophosphatasia (HPP)

Study Overview
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Brief Summary
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This clinical trial studies the safety and efficacy of asfotase alfa in infants and young children with infantile onset HPP.

Detailed Description
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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.

Official Title
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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)

Conditions
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Hypophosphatasia (HPP)

Intervention / Treatment
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* Biological: asfotase alfa


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 36 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: asfotase alfa<br>asfotase alfa | Biological: asfotase alfa<br> <br> * Other names: Human Recombinant Tissue Nonspecific Alkaline Phosphatase Fusion Protein;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Rickets Severity From Baseline to Week 24, Based on Assessment of Skeletal Radiographs Using Radiologic Global Impression of Change (RGI-C) | 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. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Serum Concentration of Asfotase Alfa (Cmax) | Maximum serum concentration observed during intensive PK sampling interval. | Study Week 1 (0 to 168 hours post-dose). Study Week 2 and Study Week 3 (0 to 48 hours post-dose) | 
| Time at Maximum Serum Concentration of Asfotase Alfa (Tmax) | Time at maximum serum concentration observed during intensive PK sampling interval. | Study Week 1 (0 to 168 hours post-dose). Study Week 2 and Study Week 3 (0 to 48 hours post-dose). | 
| Area Under Serum Concentration-time Curve to Last Measurable Concentration of Asfotase Alfa (AUCt) | Area under serum concentration-time curve to last measurable concentration during intensive PK sampling interval. | Study Week 1 (0 to 168 hours post-dose). Study Week 2 and Study Week 3 (0 to 48 hours post-dose). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypophosphatasia, HPP, Bone Disease, Soft Bones, Low Alkaline Phosphatase, genetic metabolic disorder, alkaline phosphatase, tissue non-specific alkaline phosphatase, rickets, osteomalacia