Open-Label Study of Asfotase Alfa in Infants and Children ≤ 5 Years of Age With Hypophosphatasia (HPP)

NCT01176266 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: ENB-010-10
• Study Type: interventional
• Target: 69
• Locations: 12 countries
• Sites: 23

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.

Conditions

Hypophosphatasia

Keywords

Hypophosphatasia; HPP; Bone Disease; Soft Bones; Low Alkaline Phosphatase; Genetic metabolic disorder; Alkaline phosphatase; Tissue-specific alkaline phosphatase (TNSALP); Rickets; Osteomalacia

Outcome Measures

Primary Outcomes (2)

• Effect of Asfotase Alfa Treatment on Skeletal Manifestations of Hypophosphatasia (HPP)

  The effect of asfotase alfa treatment on skeletal manifestations of HPP (i.e., change in rickets severity) was measured by radiographs using a qualitative Radiographic Global Impression of Change (RGI-C) scale. Skeletal radiographs obtained at Week 24 were compared with skeletal radiographs obtained before initiation of treatment. The RGI-C is a 7-point rating scale that ranges from -3 (indicative of severe worsening of HPP-associated rickets) to +3 (indicative of complete or near complete healing of HPP-associated rickets).

  From Baseline to Week 24

• Safety and Tolerability of Repeated Subcutaneous (SC) Injections of Asfotase Alfa

  Safety and tolerability of repeated subcutaneous (SC) injections of asfotase alfa for all treated patients was assessed by the number of patients with 1 or more treatment-emergent adverse event.

  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 (13)

• Effect of Asfotase Alfa Treatment on Skeletal Manifestations of Hypophosphatasia (HPP)

  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).

• Effect of Asfotase Alfa Treatment on Ventilator-free Survival (Week 312)

  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).

• Effect of Asfotase Alfa Treatment on Respiratory Function

  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).

• Effect of Asfotase Alfa Treatment on Physical Growth - Length/Height Z-scores Change From Baseline to Last Obtained Value

  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).

• Effect of Asfotase Alfa Treatment on Physical Growth - Weight Z-scores Change From Baseline to Last Obtained Value

  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).

Study Arms (1)

Asfotase alfa

EXPERIMENTAL

A total of 6 mg/kg/week of asfotase alfa administered by SC injection (either 1 mg/kg asfotase alfa 6 times per week, or 2 mg/kg asfotase alfa 3 times per week)

Drug: asfotase alfa

Interventions

asfotase alfa DRUG

Also known as: ENB-0040

Asfotase alfa

Eligibility Criteria

• Age: 1 Minute - 5 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Patients must meet all of the following criteria for enrollment in this study:
• 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.
• Documented diagnosis of HPP as indicated by:
• 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.
• 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.
• 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
• 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

You may not qualify if:

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

Sponsors & Collaborators

• Alexion Pharmaceuticals, Inc.: lead

Study Sites (23)

Children's Hospital & Research Center Oakland

Oakland, California, 94609, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, 15224, United States

Location

Lady Cilento Children's Hospital

South Brisbane, Queensland, 4101, Australia

Location

Royal Children'S Hospital Melbourne

Parkville, Victoria, 3052, Australia

Location

Health Sciences Centre Winnipeg, University of Manitoba

Winnipeg, Manitoba, R3A 1S1, Canada

Location

Necker Hospital

Paris, 75743, France

Location

Chu de Toulouse

Toulouse, France

Location

Universitätskinderklinikum Würzburg

Würzburg, 97080, Germany

Location

Istituto Giannina Gaslini

Genova, 16147, Italy

Location

Ospedale Pediatrico Bambino Gesù

Roma, 00165, Italy

Location

Fukuoka Higashi Medical Hospital

Koga, Fukuoka, 811-3195, Japan

Location

Ishikawa Prefectural Hospital

Kanazawa, Ishikawa-ken, 920-8530, Japan

Location

St. Marianna University School of Medicine, Yokohayama City Seibu Hospital

Yokohama, Kanagawa, 241-0811, Japan

Location

Tokyo Medical University Hospital

Shinjuku, Tokyo, 160-0023, Japan

Location

Saitama Municipal Hospital

Saitama, 336-8522, Japan

Location

Federal State Budgetary Institution

Moscow, 117036, Russia

Location

King Faisal Specialist Hospital and Research Center

Riyadh, 11211, Saudi Arabia

Location

Hospital Infantil Universitario Nino Jesus

Madrid, 28009, Spain

Location

Uludag University

Bursa, 16059, Turkey (Türkiye)

Location

Birmingham Children's Hospital

Birmingham, B4 6NH, United Kingdom

Location

Royal Manchester Children'S Hospital

Manchester, M13 9WL, United Kingdom

Location

Sheffield Children'S Hospital

Sheffield, S10 2TH, United Kingdom

Location

Related Publications (3)

• 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.

  PMID: 32762706 DERIVED

• 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.

  PMID: 30811537 DERIVED

• 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.

  PMID: 26529632 DERIVED

Related Links

• HPP support group
• US Hypophosphatasia Group (Soft Bones)
• Hypophosphatasia Website
• Hypophosphatasia Website for Healthcare Providers

MeSH Terms

Conditions

Hypophosphatasia; Bone Diseases; Rickets; Osteomalacia

Interventions

asfotase alfa

Condition Hierarchy (Ancestors)

Metal Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases; Musculoskeletal Diseases; Bone Diseases, Metabolic; Calcium Metabolism Disorders; Vitamin D Deficiency; Avitaminosis; Deficiency Diseases; Malnutrition; Nutrition Disorders

Results Point of Contact

• Title: Director of Clinical Trials
• Organization: Alexion Pharmaceuticals, Inc.

ClinicalTrials@alexion.com

475-230-2596

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 29, 2010
• First Posted: August 5, 2010
• Study Start: July 1, 2010
• Primary Completion: September 1, 2016
• Study Completion: September 1, 2016
• Last Updated: March 13, 2019
• Results First Posted: February 26, 2018

Record last verified: 2019-03

Locations

SA (1); RU (1); FR (2); DE (1); GB (3); IT (2); CA (1); AU (2); ES (1); JP (5); US (3); TU (1)