Clinical trial NCT01176266: Open-Label Study of Asfotase Alfa in Infants and Children ≤ 5 Years of Age With Hypophosphatasia (HPP)
Official title: An Open-Label, Multicenter, Multinational Study of the Safety, Efficacy and Pharmacokinetics of Asfotase Alfa (Human Recombinant Tissue-nonspecific Alkaline Phosphatase Fusion Protein) in Infants and Children ≤ 5 Years of Age With Hypophosphatasia (HPP)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
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: 2010-08-05
Enrollment: 69
Sex: ALL
Minimum age (years): 1
Maximum age (years): 5
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
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 a study drug called asfotase alfa (human recombinant tissue non-specific alkaline phosphate fusion protein) to see what effects it has on patients 5 years of age or less 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 criteria for enrollment in this study:

1. Parent or legal guardian(s) must provide written informed consent prior to any study procedures being performed and must be willing to comply with all study-required procedures. Where appropriate and required by local regulations, patient assent should also be provided prior to any study procedures being performed.
2. Documented diagnosis of HPP as indicated by:

   1. Total serum alkaline phosphatase (ALP) below the lower limit of normal for age NOTE: Historical values for ALP may be used to determine patient eligibility.
   2. Plasma pyridoxal-5'-phosphate (PLP) above the upper limit of normal (unless patient is receiving pyridoxine for seizures) NOTE: Historical values for PLP may be used to determine patient eligibility.
   3. Radiographic evidence of HPP at screening, characterized by:

      * Flared and frayed metaphyses, and
      * Severe, generalized osteopenia, and
      * Widened growth plates, and
      * Areas of radiolucency or sclerosis
   4. Two or more of the following HPP-related findings:

      * History or presence of: i) Nontraumatic post-natal fracture or ii) Delayed fracture healing
      * Nephrocalcinosis or history of elevated serum calcium
      * Functional craniosynostosis
      * Respiratory compromise or rachitic chest deformity
      * Vitamin B6-responsive seizures
      * Failure to thrive
3. Onset of symptoms prior to 6 months of age
4. Chronological age or adjusted age for premature infants born ≤ 37 weeks gestation of ≤ 5 years
5. Otherwise medically stable in the opinion of the Investigator and/or Sponsor

Exclusion criteria:

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

1. Clinically significant disease that precludes study participation, in the opinion of the Investigator and/or Sponsor
2. Serum calcium or phosphate levels below the normal range
3. Current evidence of treatable form of rickets
4. Prior treatment with bisphosphonates
5. Treatment with an investigational drug within 1 month prior to the start of asfotase alfa treatment
6. Current enrollment in any other study involving an investigational new drug, device or treatment for HPP (e.g., bone marrow transplantation)
7. Intolerance to the investigational product (IP) or any of its excipients
8. Previous participation in the same study
9. Family relative of the Investigator

Primary outcomes:
measure: Effect of Asfotase Alfa Treatment on Skeletal Manifestations of Hypophosphatasia (HPP)
timeFrame: From Baseline to Week 24
measure: Safety and Tolerability of Repeated Subcutaneous (SC) Injections of Asfotase Alfa
timeFrame: Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).
Secondary outcomes:
measure: Effect of Asfotase Alfa Treatment on Skeletal Manifestations of Hypophosphatasia (HPP)
timeFrame: Up to 72 Months or regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).
measure: Effect of Asfotase Alfa Treatment on Ventilator-free Survival (Week 312)
timeFrame: Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).
measure: Effect of Asfotase Alfa Treatment on Respiratory Function
timeFrame: Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).
measure: Effect of Asfotase Alfa Treatment on Physical Growth - Length/Height Z-scores Change From Baseline to Last Obtained Value
timeFrame: Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).
measure: Effect of Asfotase Alfa Treatment on Physical Growth - Weight Z-scores Change From Baseline to Last Obtained Value
timeFrame: Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).
measure: Effect of Asfotase Alfa on Biomarkers - Plasma Inorganic Pyrophosphate (PPi) Change From Baseline to Last Obtained Value
timeFrame: Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).
measure: Effect of Asfotase Alfa on Biomarkers - Plasma Pyridoxal-5' Phosphate (PLP) Change From Baseline to Last Obtained Value
timeFrame: Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).
measure: Effect of Asfotase Alfa on Serum Parathyroid Hormone (PTH) - Change From Baseline to Last Obtained Value
timeFrame: Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).
measure: Effect of Asfotase Alfa Treatment on Tooth Loss
timeFrame: Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).
measure: Pharmacokinetic (PK) Properties of Asfotase Alfa (Tlast)
timeFrame: PK parameters were calculated using Week 6 study visit data. Week 6 study visit blood samples for PK testing were drawn pre-dose and 6, 12, 24, 32, and 48 hours post dose
measure: Pharmacokinetic (PK) Properties of Asfotase Alfa (Tmax)
timeFrame: PK parameters were calculated using Week 6 study visit data. Week 6 study visit blood samples for PK testing were drawn pre-dose and 6, 12, 24, 32, and 48 hours post dose
measure: Pharmacokinetic (PK) Properties of Asfotase Alfa (Cmax)
timeFrame: PK parameters were calculated using Week 6 study visit data. Week 6 study visit blood samples for PK testing were drawn pre-dose and 6, 12, 24, 32, and 48 hours post dose
measure: Pharmacokinetic (PK) Properties of Asfotase Alfa (AUCt)
timeFrame: PK parameters were calculated using Week 6 study visit data. Week 6 study visit blood samples for PK testing were drawn pre-dose and 6, 12, 24, 32, and 48 hours post dose
Other outcomes:
Locations:
city: Oakland
country: United States
facility: Children's Hospital & Research Center Oakland
state: California
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: South Brisbane
country: Australia
facility: Lady Cilento Children's Hospital
state: Queensland
city: Parkville
country: Australia
facility: Royal Children'S Hospital Melbourne
state: Victoria
city: Winnipeg
country: Canada
facility: Health Sciences Centre Winnipeg, University of Manitoba
state: Manitoba
city: Paris
country: France
facility: Necker Hospital
city: Toulouse
country: France
facility: Chu de Toulouse
city: Würzburg
country: Germany
facility: Universitätskinderklinikum Würzburg
city: Genova
country: Italy
facility: Istituto Giannina Gaslini
city: Roma
country: Italy
facility: Ospedale Pediatrico Bambino Gesù
city: Koga
country: Japan
facility: Fukuoka Higashi Medical Hospital
state: Fukuoka
city: Kanazawa
country: Japan
facility: Ishikawa Prefectural Hospital
state: Ishikawa
city: Yokohama
country: Japan
facility: St. Marianna University School of Medicine, Yokohayama City Seibu Hospital
state: Kanagawa
city: Shinjuku
country: Japan
facility: Tokyo Medical University Hospital
state: Tokyo
city: Saitama
country: Japan
facility: Saitama Municipal Hospital
city: Moscow
country: Russian Federation
facility: Federal State Budgetary Institution
city: Riyadh
country: Saudi Arabia
facility: King Faisal Specialist Hospital and Research Center
city: Madrid
country: Spain
facility: Hospital Infantil Universitario Nino Jesus
city: Bursa
country: Turkey
facility: Uludag University
city: Birmingham
country: United Kingdom
facility: Birmingham Children's Hospital
city: Manchester
country: United Kingdom
facility: Royal Manchester Children'S Hospital
city: Sheffield
country: United Kingdom
facility: Sheffield Children'S Hospital
Study officials:
References:
citation: Padidela R, Yates R, Benscoter D, McPhail G, Chan E, Nichani J, Mughal MZ, Myer C 4th, Narayan O, Nissenbaum C, Wilkinson S, Zhou S, Saal HM. Characterization of tracheobronchomalacia in infants with hypophosphatasia. Orphanet J Rare Dis. 2020 Aug 6;15(1):204. doi: 10.1186/s13023-020-01483-9.
citation: Hofmann CE, Harmatz P, Vockley J, Hogler W, Nakayama H, Bishop N, Martos-Moreno GA, Moseley S, Fujita KP, Liese J, Rockman-Greenberg C; ENB-010-10 Study Group. Efficacy and Safety of Asfotase Alfa in Infants and Young Children With Hypophosphatasia: A Phase 2 Open-Label Study. J Clin Endocrinol Metab. 2019 Jul 1;104(7):2735-2747. doi: 10.1210/jc.2018-02335.
citation: Whyte MP, Rockman-Greenberg C, Ozono K, Riese R, Moseley S, Melian A, Thompson DD, Bishop N, Hofmann C. Asfotase Alfa Treatment Improves Survival for Perinatal and Infantile Hypophosphatasia. J Clin Endocrinol Metab. 2016 Jan;101(1):334-42. doi: 10.1210/jc.2015-3462. Epub 2015 Nov 3.