Clinical trial NCT01163149: Safety and Efficacy Study of Asfotase Alfa in Adolescents and Adults With Hypophosphatasia (HPP)
Official title: A Randomized, Open-Label, Multicenter, Multinational, Dose-Ranging, Concurrent Control Study of the Safety, Efficacy, Pharmacokinetic of ENB-0040 (Human Recombinant Tissue Nonspecific Alkaline Phosphatase Fusion Protein) in Adolescents and Adults With Hypophosphatasia (HPP)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hypophosphatasia
Keywords: Hypophosphatasia
HPP
Bone Disease
Soft Bones
Low Alkaline Phosphatase
genetic metabolic disorder
alkaline phosphatase
tissue-specific alkaline phosphatase (TNSALP)
rickets
osteomalacia
Lead sponsor: Alexion Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2010-07-15
Enrollment: 19
Sex: ALL
Minimum age (years): 13
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This clinical trial was conducted to study hypophosphatasia (HPP), a bone disorder caused by gene mutations or changes. These gene mutations cause low levels of an enzyme needed to harden bone. The purpose of this study was to test the safety and efficacy of two doses of the study drug called asfotase alfa as compared to a control group to see effects on adolescents and adults with HPP.

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 limited data available on the natural course of this disease over time, particularly in patients with the juvenile-onset form.

Eligibility criteria: Inclusion criteria:

Patients must meet all of the following inclusion criteria to be eligible for participation in this study:

* Patients or their legal representative(s) must provide written informed consent prior to undergoing any study-related procedures
* Patients must be ≥ 13 and ≤ 65 years of age at the time of study enrollment
* Female patients of childbearing potential and sexually mature males must agree to use a medically acceptable form of birth control; for the purposes of this study, females are considered of non-childbearing potential if they are surgically sterile (i.e., have undergone a total hysterectomy, bilateral salpingo-oophorectomy or tubal ligation) or are post-menopausal, defined as having complete cessation of menstruation for at least 1 year after 45 years of age
* Patients must have a pre-established clinical diagnosis of HPP as indicated by:

  * Serum alkaline phosphatase (ALP) below the age-adjusted normal range
  * Plasma PLP at least twice the upper limit of normal (no vitamin B6 administered for at least 1 week prior to determination)
  * Evidence of osteopenia or osteomalacia on skeletal radiographs
* Patients must have osteomalacia on bone biopsy, characterized by an MLT z-score of +2 or more (results from ENB-001-08 may be used)
* Patients must be willing to comply with study procedures and the visit schedule

Exclusion criteria:

Patients will be excluded from participation in this study if they meet any of the following exclusion criteria:

* Women who are pregnant or lactating
* History of sensitivity to tetracycline
* Serum calcium or phosphate levels below the normal range
* Serum 25(OH) vitamin D below 20 ng/mL
* Serum creatinine or parathyroid hormone (PTH) levels above the upper limit of normal
* 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
* Orthopedic surgery within 12 months prior to study entry that may interfere with the ability to perform functional assessments for the study
* Prior treatment with bisphosphonates within 2 years of study entry for any length of time or for more than 2 years at any time point; for patients with prior bisphosphonate use that is allowed, the bone resorption markers serum C-telopeptide and urine N-telopeptide or urine deoxypyridinoline must also be within the normal range or elevated to be eligible for study participation
* Treatment with PTH within 6 months prior to the start of asfotase alfa administration
* Participation in an interventional or investigational drug study within 30 days prior to study participation

Primary outcomes:
measure: Change From Baseline to Week 24 for Plasma Pyridoxal-5' Phosphate (PLP)
timeFrame: Baseline, Week 24
measure: Change From Baseline to Week 24 for Plasma Inorganic Pyrophosphate (PPi)
timeFrame: Baseline, Week 24
measure: Safety and Tolerability of Asfotase Alfa
timeFrame: Up to 288 weeks exposure to asfotase alfa
Secondary outcomes:
measure: Change From Baseline in Bone Mineral Content (BMC) as Measured by Dual-energy X-ray Absorptiometry (DXA)
timeFrame: Baseline, every 24 weeks through Week 96, then every 48 weeks until Week 288.
measure: Change From Baseline in Bone Mineral Density (BMD) as Measured by Dual-energy X-ray Absorptiometry (DXA)
timeFrame: Baseline, every 24 weeks through Week 96, then every 48 weeks until Week 288.
measure: Change in Walking Ability as Measured by the Six-Minute Walk Test (6MWT)
timeFrame: Baseline, Week 24 (primary treatment period) and up to 288 weeks of asfotase alfa exposure
measure: Change From Baseline in HPP-related Osteomalacia as Measured by Trans-iliac Crest Bone Biopsy: Osteoid Volume/Bone Volume
timeFrame: Baseline, Week 24 (Control group), and Week 48 (Asfotase alfa groups).
measure: Change From Baseline in HPP-related Osteomalacia as Measured by Trans-iliac Crest Bone Biopsy: Osteoid Thickness
timeFrame: Baseline, Week 24 (Control group), and Week 48 (Asfotase alfa groups).
measure: Change From Baseline in HPP-related Osteomalacia as Measured by Trans-iliac Crest Bone Biopsy: Mineralization Lag Time
timeFrame: Baseline, Week 24 (Control group), and Week 48 (Asfotase alfa groups).
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Shriner's Hospital for Children
state: Missouri
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Winnipeg
country: Canada
facility: Health Sciences Centre Winnipeg, University of Manitoba
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: Gospe SM 3rd, Santiago-Turla C, DeArmey SM, Cummings TJ, Kishnani PS, Bhatti MT. Ectopic Ocular Surface Calcification in Patients With Hypophosphatasia Treated With Asfotase Alfa. Cornea. 2019 Jul;38(7):896-900. doi: 10.1097/ICO.0000000000001947.