Clinical trial NCT00952484: Safety and Efficacy of Asfotase Alfa in Juvenile Patients With Hypophosphatasia (HPP)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hypophosphatasia (HPP)
Keywords: Hypophosphatasia
HPP
Bone Disease
Soft Bones
Low Alkaline Phosphatase
genetic metabolic disorder
alkaline phosphatase
tissue non-specific alkaline phosphatase
rickets
osteomalacia
Lead sponsor: Alexion Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2009-08-06
Enrollment: 13
Sex: ALL
Minimum age (years): 5
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in Rickets Severity on Skeletal Radiographs From Baseline to Week 24 as Measured by the Radiographic Global Impression of Change (RGI-C) Scale
timeFrame: Baseline and Week 24
Secondary outcomes:
measure: Change in Osteomalacia - Osteoid Thickness (as Measured by Trans-iliac Crest Bone Biopsy)
timeFrame: Baseline and Week 24
measure: Change in Osteomalacia - Osteoid Volume/Bone Volume (as Measured by Trans-iliac Crest Bone Biopsy)
timeFrame: Baseline and Week 24
measure: Change in Osteomalacia - Mineralization Lag Time (as Measured by Trans-iliac Crest Bone Biopsy)
timeFrame: Baseline and Week 24
measure: Change in Height (Z-scores)
timeFrame: Baseline and Week 24
measure: Change in Biomarkers of Asfotase Alfa Activity as Measured by Plasma Inorganic Pyrophosphate (PPi)
timeFrame: Baseline and Week 24
measure: Change in Biomarkers of Asfotase Alfa Activity as Measured by Pyridoxal-5'-Phosphate (PLP)
timeFrame: Baseline and Week 24
measure: Maximum Serum Concentration of Asfotase Alfa (Cmax).
timeFrame: Study Week 1 (0 to 48 hours post-dose)
measure: Time at Maximum Serum Concentration of Asfotase Alfa (Tmax)
timeFrame: Study Week 1 (0 to 48 hours post-dose)
measure: Area Under Serum Concentration-time Curve to Last Measurable Concentration of Asfotase Alfa (AUCt)
timeFrame: Study Week 1 (0 to 48 hours post-dose)
measure: Maximum Serum Concentration of Asfotase Alfa (Cmax).
timeFrame: Study Week 6 (0 to 48 hours post-dose)
measure: Time at Maximum Serum Concentration of Asfotase Alfa (Tmax).
timeFrame: Study Week 6 (0 to 48 hours post-dose)
measure: Area Under Serum Concentration-time Curve to Last Measurable Concentration of Asfotase Alfa (AUCt)
timeFrame: Study Week 6 (0 to 48 hours post-dose).
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Shriners Hospital for Children
state: Missouri
city: Winnipeg
country: Canada
facility: The University of Manitoba Health Services Centre
state: Manitoba
Study officials:
References:
citation: 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.
citation: Simmons JH, Rush ET, Petryk A, Zhou S, Martos-Moreno GA. Dual X-ray absorptiometry has limited utility in detecting bone pathology in children with hypophosphatasia: A pooled post hoc analysis of asfotase alfa clinical trial data. Bone. 2020 Aug;137:115413. doi: 10.1016/j.bone.2020.115413. Epub 2020 May 14.
citation: Whyte MP, Madson KL, Phillips D, Reeves AL, McAlister WH, Yakimoski A, Mack KE, Hamilton K, Kagan K, Fujita KP, Thompson DD, Moseley S, Odrljin T, Rockman-Greenberg C. Asfotase alfa therapy for children with hypophosphatasia. JCI Insight. 2016 Jun 16;1(9):e85971. doi: 10.1172/jci.insight.85971.