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Safety and Efficacy Study of Asfotase Alfa in Adolescents and Adults With Hypophosphatasia (HPP)

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ClinicalTrials.gov Identifier: NCT01163149
Recruitment Status : Completed
First Posted : July 15, 2010
Results First Posted : September 18, 2017
Last Update Posted : September 18, 2017
Sponsor:
Information provided by (Responsible Party):

June 24, 2010
July 15, 2010
June 27, 2017
September 18, 2017
September 18, 2017
June 2010
June 2016   (Final data collection date for primary outcome measure)
  • Change From Baseline to Week 24 for Plasma Pyridoxal-5' Phosphate (PLP) [ Time Frame: Baseline, Week 24 ]
    Blood samples were collected to evaluate the effect of asfotase alfa on reduction in plasma pyridoxal-5' phosphate (PLP)
  • Change From Baseline to Week 24 for Plasma Inorganic Pyrophosphate (PPi) [ Time Frame: Baseline, Week 24 ]
    Blood samples were collected to evaluate the effect of asfotase alfa on reduction in plasma inorganic pyrophosphate (PPi)
  • Safety and Tolerability of Asfotase Alfa [ Time Frame: Up to 288 weeks exposure to asfotase alfa ]
    The safety and tolerability of daily subcutaneous (SC) injections of asfotase alfa was assessed by routine monitoring of patients for treatment-emergent adverse events (TEAEs) and injection-associated reactions (IARs).
  • Effect of ENB-0040 on HPP-related osteomalacia [ Time Frame: Two bone biopsies will be performed - pre-treatment and 6 months post-treatment ]
    The effect of ENB-0040 on HPP-related osteomalacia will be measured using trans-iliac crest bone biopsy by comparing results from the two treatment cohorts to the concurrent control cohort
  • Safety and Tolerability of ENB-0040 [ Time Frame: Continuous monitoring for 6-month duration of study ]
    The safety and tolerability of daily subcutaneous (SC) injections of ENB-0040 will be assessed by routine monitoring of patients for adverse events (AEs) and injection-associated reactions (IARs) and monitoring changes from Baseline in physical examination findings, vital signs, clinical laboratory evaluations, renal ultrasound findings, funduscopic examinations, antibody evaluations, and results of pregnancy testing (in women of childbearing potential only).
Complete list of historical versions of study NCT01163149 on ClinicalTrials.gov Archive Site
  • Change From Baseline in Bone Mineral Content (BMC) as Measured by Dual-energy X-ray Absorptiometry (DXA) [ Time Frame: Baseline, every 24 weeks through Week 96, then every 48 weeks until Week 288. ]
    A DXA scan was performed to evaluate bone mineral content (BMC) of the spine, hip, and whole body during the primary (first 24 weeks) and extension treatment periods (up to 288 weeks).
  • Change From Baseline in Bone Mineral Density (BMD) as Measured by Dual-energy X-ray Absorptiometry (DXA) [ Time Frame: Baseline, every 24 weeks through Week 96, then every 48 weeks until Week 288. ]
    A DXA scan was performed to evaluate bone bone mineral density (BMD) of the spine, hip, and whole body during the primary (first 24 weeks) and extension treatment periods (up to 288 weeks).
  • Change in Walking Ability as Measured by the Six-Minute Walk Test (6MWT) [ Time Frame: Baseline, Week 24 (primary treatment period) and up to 288 weeks of asfotase alfa exposure ]
    The patient was instructed to walk the length of a pre-measured hallway for 6 minutes. The primary measurement was distance walked (in meters).
  • Change From Baseline in HPP-related Osteomalacia as Measured by Trans-iliac Crest Bone Biopsy: Osteoid Volume/Bone Volume [ Time Frame: Baseline, Week 24 (Control group), and Week 48 (Asfotase alfa groups). ]
    A trans-iliac crest bone biopsy was performed to quantify changes from Baseline in histomorphometric parameters relevant for evaluation of osteomalacia severity, including Osteoid Volume/Bone Volume (%). The difference in time under observation between asfotase alfa groups (Week 48) and control group (Week 24) resulted from study design, ie, control subjects transitioned to active treatment after the Week 24 visit.
  • Change From Baseline in HPP-related Osteomalacia as Measured by Trans-iliac Crest Bone Biopsy: Osteoid Thickness [ Time Frame: Baseline, Week 24 (Control group), and Week 48 (Asfotase alfa groups). ]
    A trans-iliac crest bone biopsy was performed to quantify changes from Baseline in histomorphometric parameters relevant for evaluation of osteomalacia severity, including Osteoid Thickness (um). The difference in time under observation between asfotase alfa groups (Week 48) and control group (Week 24) resulted from study design, ie, control subjects transitioned to active treatment after the Week 24 visit.
  • Change From Baseline in HPP-related Osteomalacia as Measured by Trans-iliac Crest Bone Biopsy: Mineralization Lag Time [ Time Frame: Baseline, Week 24 (Control group), and Week 48 (Asfotase alfa groups). ]
    A trans-iliac crest bone biopsy was performed to quantify changes from Baseline in histomorphometric parameters relevant for evaluation of osteomalacia severity, including Mineralization Lag Time (days). The difference in time under observation between asfotase alfa groups (Week 48) and control group (Week 24) resulted from study design, ie, control subjects transitioned to active treatment after the Week 24 visit.
  • Effect of ENB-0040 on walking ability [ Time Frame: Pre-treatment and 3 months and 6 months post-treatment ]
    Effect of ENB-0040 on walking ability as measured by the Six Minute Walk Test (6MWT)
  • Effect of ENB-0040 on gross motor function [ Time Frame: Pre-treatment and 3 months and 6 months post-treatment ]
    The effect of ENB-0040 on gross motor function as measured by a modified version of the Bruininks-Oseretsky Test of Motor Proficiency - Second Edition (BOT-2)
  • Effect of ENB-0040 on pain [ Time Frame: Pre-treatment and 3 months and 6 months post-treatment ]
    Change in self-reported pain as measured by a modified version of the Brief Pain Inventory - Short Form (BPI-SF)
  • Change in biomarkers of ENB-0040 activity [ Time Frame: Pre-treatment and 6 weeks, 3 months and 6 months post-treatment ]
    Change in biomarkers of ENB-0040 activity as measured by plasma inorganic pyrophosphate (PPi), plasma pyridoxal-5'-phosphate (PLP) and serum parathyroid hormone (PTH)
Not Provided
Not Provided
 
Safety and Efficacy Study of Asfotase Alfa in Adolescents and Adults With Hypophosphatasia (HPP)
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)
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.

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.

Interventional
Phase 2
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Hypophosphatasia
  • Drug: asfotase alfa
    Cohort 1: Daily SC injections of 0.3 mg/kg asfotase alfa (total of 2.1 mg/kg/week)
  • Drug: asfotase alfa
    Cohort 2: Daily SC injections of 0.5 mg/kg Asfotase Alfa (3.5 mg/kg/week total)
  • Experimental: Cohort 1
    Cohort 1: Daily SC injections of 0.3 mg/kg asfotase alfa (2.1 mg/kg/week total)
    Intervention: Drug: asfotase alfa
  • Experimental: Cohort 2
    Cohort 2: Daily SC injections of 0.5 mg/kg asfotase alfa (3.5 mg/kg/week total)
    Intervention: Drug: asfotase alfa
  • No Intervention: Concurrent Control
    Following completion of the Week 24 visit, all patients (including those randomized to the concurrent control cohort) may be eligible to participate in an open-label extension treatment period. In this extension period, all patients will be treated with daily SC injections of 0.5 mg/kg/day asfotase alfa (a total of 3.5 mg/kg/week) for approximately 24 weeks, then subjects will receive 1 mg/kg/day 6 days/week for an additional 48 weeks or until regulatory approval of the drug.
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
19
June 2016
June 2016   (Final data collection date for primary outcome measure)

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
Sexes Eligible for Study: All
13 Years to 65 Years   (Child, Adult)
No
Contact information is only displayed when the study is recruiting subjects
Canada,   United States
 
 
NCT01163149
ENB-009-10
Yes
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Not Provided
Alexion Pharma GmbH
Alexion Pharma GmbH
Not Provided
Not Provided
Alexion Pharma GmbH
August 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP