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

Hypophosphatasia (HPP) Clinical Trial

Official title:

A Randomized, Open-Label, Multicenter, Multinational, Dose-Ranging, Historical Control Study of the Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of ENB-0040 (Human Recombinant Tissue Nonspecific Alkaline Phosphatase Fusion Protein) in Children With Hypophosphatasia (HPP)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00952484
• Other study ID #: ENB-006-09
• Status: Completed
• Phase: Phase 2
• Start date: September 2009
• Est. completion date: July 2010

Study information

• Verified date: March 2019
• Source: Alexion Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 13
• Est. completion date: July 2010
• Est. primary completion date: July 2010
• Accepts healthy volunteers: No
• Gender: All
• Age group: 5 Years to 12 Years

Eligibility

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

Related Conditions & MeSH terms

• Hypophosphatasia
• Hypophosphatasia (HPP)

Intervention

Biological:
• asfotase alfa
2 mg/kg subcutaneous injection three times per week for 6 months.
• asfotase alfa
3 mg/kg subcutaneous injection three times per week for 6 months.

Locations

Country	Name	City	State
Canada	The University of Manitoba Health Services Centre	Winnipeg	Manitoba
United States	Shriners Hospital for Children	Saint Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
Alexion Pharmaceuticals

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (1)

Millán 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Rickets Severity on Skeletal Radiographs From Baseline to Week 24 as Measured by the Radiographic Global Impression of Change (RGI-C) Scale	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.	Baseline and Week 24
Secondary	Change in Osteomalacia - Osteoid Thickness (as Measured by Trans-iliac Crest Bone Biopsy)	Change from Baseline to Week 24 in osteoid thickness.	Baseline and Week 24
Secondary	Change in Osteomalacia - Osteoid Volume/Bone Volume (as Measured by Trans-iliac Crest Bone Biopsy)	Change from Baseline to Week 24 in osteoid volume/bone volume (%), calculated as the absolute difference of the Baseline and Week 24 percentages.	Baseline and Week 24
Secondary	Change in Osteomalacia - Mineralization Lag Time (as Measured by Trans-iliac Crest Bone Biopsy)	Change from Baseline to Week 24 in mineralization lag time.	Baseline and Week 24
Secondary	Change in Height (Z-scores)	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.	Baseline and Week 24
Secondary	Change in Biomarkers of Asfotase Alfa Activity as Measured by Plasma Inorganic Pyrophosphate (PPi)	Change from Baseline to Week 24 in Plasma PPi	Baseline and Week 24
Secondary	Change in Biomarkers of Asfotase Alfa Activity as Measured by Pyridoxal-5'-Phosphate (PLP)	Change from Baseline to Week 24 in Plasma PLP	Baseline and Week 24
Secondary	Maximum Serum Concentration of Asfotase Alfa (Cmax).	Maximum serum concentration observed following single dose of asfotase alfa.	Study Week 1 (0 to 48 hours post-dose)
Secondary	Time at Maximum Serum Concentration of Asfotase Alfa (Tmax)	Maximum serum concentration observed following single dose of asfotase alfa.	Study Week 1 (0 to 48 hours post-dose)
Secondary	Area Under Serum Concentration-time Curve to Last Measurable Concentration of Asfotase Alfa (AUCt)	Area under serum concentration-time curve to last measurable concentration following single dose of asfotase alfa.	Study Week 1 (0 to 48 hours post-dose)
Secondary	Maximum Serum Concentration of Asfotase Alfa (Cmax).	Maximum serum concentration observed following multiple doses of asfotase alfa.	Study Week 6 (0 to 48 hours post-dose)
Secondary	Time at Maximum Serum Concentration of Asfotase Alfa (Tmax).	Time at maximum serum concentration observed following multiple doses of asfotase alfa.	Study Week 6 (0 to 48 hours post-dose)
Secondary	Area Under Serum Concentration-time Curve to Last Measurable Concentration of Asfotase Alfa (AUCt)	Area under serum concentration-time curve to last measurable concentration following multiple doses of asfotase alfa.	Study Week 6 (0 to 48 hours post-dose).

External Links

•   HPP support group
•   Hypophosphatasia Website
•   Hypophosphatasia Website for Healthcare Providers
•   Hypophosphatasie Europe
•   US Hypophosphatasia Group (Soft Bones)
•   Yahoo health group for HPP with an international list serve where patients can correspond and post questions to the group