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

Phase 1

Completed

• Conditions: Hypophosphatasia (HPP)
• Interventions: Biological: asfotase alfa

• Registration Number: NCT00744042
• Lead Sponsor: Alexion Pharmaceuticals, Inc.

Brief Summary

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

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 Timeline

• Study First Submitted: 2008-08-27
• Study First Submitted QC: 2008-08-28
• Study First Posted: 2008-08-29
• Study Start: 2008-09
• Primary Completion: 2010-05
• Study Completion: 2010-05
• Results First Submitted: 2011-05-15
• Results First Submitted QC: 2011-08-24
• Results First Posted: 2011-09-30
• Status Verified: 2019-03
• Last Update Submitted: 2019-03-28
• Last Update Posted: 2019-04-01

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 11

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
asfotase alfa	asfotase alfa	asfotase alfa

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Area Under Serum Concentration-time Curve to Last Measurable Concentration of Asfotase Alfa (AUCt)	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 during intensive PK sampling interval.
Maximum Serum Concentration of Asfotase Alfa (Cmax)	Study Week 1 (0 to 168 hours post-dose). Study Week 2 and Study Week 3 (0 to 48 hours post-dose)	Maximum serum concentration observed during intensive PK sampling interval.
Time at Maximum Serum Concentration of Asfotase Alfa (Tmax)	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 observed during intensive PK sampling interval.

Trial Locations

Locations (10)

Vanderbilt Children's Hospital; 🇺🇸 Nashville, Tennessee, United States

Alfred I. duPont Hospital for Children; 🇺🇸 Wilmington, Delaware, United States

St. John's Hospital; 🇺🇸 Springfield, Missouri, United States

Royal Belfast Hospital for Sick Children; 🇬🇧 Belfast, Northern Ireland, United Kingdom

St. Vincent Hospital; 🇺🇸 Green Bay, Wisconsin, United States

Sheffield Children's Hospital; 🇬🇧 Sheffield, England, United Kingdom

The University of Manitoba Health Sciences Centre; 🇨🇦 Winnipeg, Manitoba, Canada

Arkansas Children's Hospital; 🇺🇸 Little Rock, Arkansas, United States

University of Nebraska Medical Center, Munroe-Meyer Institute; 🇺🇸 Omaha, Nebraska, United States

Tawam-John Hopkins Hospital; 🇦🇪 Al Ain, Abu-Dhabi, United Arab Emirates