Safety and Efficacy of Asfotase Alfa in Juvenile Patients With Hypophosphatasia (HPP)

Phase 2

Completed

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

• Registration Number: NCT00952484
• Lead Sponsor: Alexion Pharmaceuticals, Inc.

Brief Summary

This clinical trial studied the safety and efficacy of asfotase alfa in children with HPP compared to a historical control group.

Detailed Description

Asfotase Alfa was formerly referred to as ENB-0040

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.

Efficacy analyses were prospectively defined in the protocol with a comparison to historical controls. The historical control group came from patients whose characteristics matched as closely as possible the entry criteria for the trial. The control group included all patients who had x-rays within the age range defined by the inclusion criteria of this study (5 to 12 years of age, inclusive, with open growth plates).

The pre-specified plan for analysis was to combine the two asfotase alfa treated groups (asfotase alfa 2 mg/kg subcutaneous (SC) injection three times per week or 3 mg/kg subcutaneous (SC) injection three times per week) and compare them to historical controls.

Study Timeline

• Study First Submitted: 2009-08-03
• Study First Submitted QC: 2009-08-05
• Study First Posted: 2009-08-06
• Study Start: 2009-09
• Primary Completion: 2010-07
• Study Completion: 2010-07
• Results First Submitted: 2011-05-14
• Results First Submitted QC: 2011-06-28
• Results First Posted: 2011-07-26
• Status Verified: 2019-03
• Last Update Submitted: 2019-03-28
• Last Update Posted: 2019-04-01

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 13

Inclusion Criteria

1. Written informed consent from parent or legal guardian prior to participation

2. Patients > 5 and < 12 years of age with open growth plates at time of enrollment

3. Tanner stage of 2 or less indicating pre-pubescence

4. Documented history of HPP, as evidenced by:

   • Presence of HPP-related rickets on skeletal radiographs of the wrist and knee
   • Serum alkaline phosphatase (ALP) below age-adjusted normal range
   • Plasma PLP at least twice the upper limit of normal

5. 25(OH) vitamin D level > 20 ng/mL

6. Ability of patient and parent/guardian to comply with study requirements

Exclusion Criteria

1. Serum calcium or phosphorus below age-adjusted normal range
2. History of sensitivity to any study drug constituent
3. Medical condition, serious intercurrent illness, or other extenuating circumstance that, in the opinion of the Investigator, may significantly interfere with study compliance, including all prescribed evaluations and follow-up activities
4. Treatment with an investigational drug within 1 month before start of study drug
5. Current enrollment in any other study involving an investigational new drug, device, or treatment for HPP (e.g., bone marrow transplantation)
6. Current evidence of a treatable form of rickets
7. Prior treatment with bisphosphonates
8. Bone fracture or orthopedic surgery within the past 12 months that, in the opinion of the Investigator would interfere with the ability of study patient to comply with study protocol
9. Major congenital abnormality other than those associated with HPP

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
2 mg/kg	asfotase alfa	2 mg/kg subcutaneous injection three times per week.
3 mg/kg	asfotase alfa	3 mg/kg subcutaneous injection three times per week.

Primary Outcome Measures

Name	Time	Method
Change in Rickets Severity on Skeletal Radiographs From Baseline to Week 24 as Measured by the Radiographic Global Impression of Change (RGI-C) Scale	Baseline and Week 24	A 7-point RGI-C (radiographic global impression of change) score was used to rate change in rickets severity. 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.

Secondary Outcome Measures

Name	Time	Method
Change in Osteomalacia - Osteoid Volume/Bone Volume (as Measured by Trans-iliac Crest Bone Biopsy)	Baseline and Week 24	Change from Baseline to Week 24 in osteoid volume/bone volume (%), calculated as the absolute difference of the Baseline and Week 24 percentages.
Change in Osteomalacia - Mineralization Lag Time (as Measured by Trans-iliac Crest Bone Biopsy)	Baseline and Week 24	Change from Baseline to Week 24 in mineralization lag time.
Change in Biomarkers of Asfotase Alfa Activity as Measured by Plasma Inorganic Pyrophosphate (PPi)	Baseline and Week 24	Change from Baseline to Week 24 in Plasma PPi
Change in Height (Z-scores)	Baseline and Week 24	Change from Baseline to Week 24 in Height Z-Score. Height Z-Scores assigned based on Centers for Disease Control (CDC) growth charts and methodology.
Change in Biomarkers of Asfotase Alfa Activity as Measured by Pyridoxal-5'-Phosphate (PLP)	Baseline and Week 24	Change from Baseline to Week 24 in Plasma PLP
Time at Maximum Serum Concentration of Asfotase Alfa (Tmax).	Study Week 6 (0 to 48 hours post-dose)	Time at maximum serum concentration observed following multiple doses of asfotase alfa.
Change in Osteomalacia - Osteoid Thickness (as Measured by Trans-iliac Crest Bone Biopsy)	Baseline and Week 24	Change from Baseline to Week 24 in osteoid thickness.
Maximum Serum Concentration of Asfotase Alfa (Cmax).	Study Week 6 (0 to 48 hours post-dose)	Maximum serum concentration observed following multiple doses of asfotase alfa.
Time at Maximum Serum Concentration of Asfotase Alfa (Tmax)	Study Week 1 (0 to 48 hours post-dose)	Maximum serum concentration observed following single dose of asfotase alfa.
Area Under Serum Concentration-time Curve to Last Measurable Concentration of Asfotase Alfa (AUCt)	Study Week 6 (0 to 48 hours post-dose).	Area under serum concentration-time curve to last measurable concentration following multiple doses of asfotase alfa.

Trial Locations

Locations (2)

Shriners Hospital for Children; 🇺🇸 Saint Louis, Missouri, United States

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