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    Summary
    EudraCT Number:2010-019850-42
    Sponsor's Protocol Code Number:ENB-010-10
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-03-01
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2010-019850-42
    A.3Full title of the trial
    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)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    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)
    A.4.1Sponsor's protocol code numberENB-010-10
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAlexion Pharma International Sàrl
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAlexion Pharma International Sàrl
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAlexion Europe S.A.S
    B.5.2Functional name of contact pointEuropean Clinical Trial Information
    B.5.3 Address:
    B.5.3.1Street Address25 Boulevard de l'Amiral Bruix
    B.5.3.2Town/ cityParis
    B.5.3.3Post code75016
    B.5.3.4CountryFrance
    B.5.4Telephone number33153643848
    B.5.5Fax number33153643820
    B.5.6E-mailclinicaltrials.eu@alxn.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/08/594
    D.3 Description of the IMP
    D.3.1Product nameAsfotase alfa
    D.3.2Product code ENB-0040
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAsfotase alfa
    D.3.9.2Current sponsor codeENB-0040
    D.3.9.3Other descriptive nameHuman recombinant tissue non-specific alkaline phosphatase fusion protein
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/08/594
    D.3 Description of the IMP
    D.3.1Product nameAsfotase alfa
    D.3.2Product code ENB-0040
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAsfotase alfa
    D.3.9.2Current sponsor codeENB-0040
    D.3.9.3Other descriptive nameHuman recombinant tissue non-specific alkaline phosphatase fusion protein
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Hypophosphatasia
    E.1.1.1Medical condition in easily understood language
    Hypophosphatasia
    E.1.1.2Therapeutic area Body processes [G] - Genetic Phenomena [G05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 15.1
    E.1.2Level PT
    E.1.2Classification code 10049933
    E.1.2Term Hypophosphatasia
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the following:
    • Effect of asfotase alfa treatment on skeletal manifestations of HPP as measured by radiographs using a qualitative Radiographic Global Impression of Change (RGI-C) scale for all treated patients
    • Safety and tolerability of repeated subcutaneous (SC) injections of asfotase alfa for all treated patients
    E.2.2Secondary objectives of the trial
    To evaluate the following:
    - For patients who are not mechanically ventilated at the time of enrollment, the percentage who are alive and ventilator-free after receiving asfotase alfa as compared to an age-matched historical control group
    - Effect of asfotase alfa treatment on respiratoy function as measure by ventilator status, time on respiratory support (including time on ventilator or supplemental oxygen), ventilator rate or oxygen volume, ventilator pressures, and fraction of inspired oxygen (FiO2) for all treated patients
    - Effect of asfotase alfa treatment on physical growth as measured by body weight, length, arm span, head circumference, and chest circumference for all treated patients
    - Effect of asfotase alfa treatment on tooth loss for all treated patients
    - PK properties of asfotase alfa
    - Effect of asfotase alfa on plasma inorganic pyrophosphate (PPi) and plasma pyridoxal-5'-phosphate (PLP)
    - Effect of asfotase alfa on serum parathyroid hormone (PTH)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    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-related procedures. If the minor is in a position to comprehend the nature, significance, and implications of the clinical trial and to form a rational intention in the light of these facts, then he/she must provide his/her assent prior to any study procedures being performed.
    - Documented diagnosis of HPP as indicated by:
    o Total serum alkaline phosphatase (ALP) below the lower limit of normal for age
    o Plasma PLP above the upper limit of normal (unless patient is receiving pyridoxine for seizures)
    o Radiographic evidence of HPP, characterized by:
    * Flared and frayed metaphyses
    * Severe, generalized osteopenia
    * Widened growth plates
    * Areas of radiolucency or sclerosis
    o Two or more of the following HPP-related findings:
    * History or presence of:
    + Nontraumatic post-natal fracture
    + Delayed fracture healing
    * Nephrocalcinosis or history of elevated serum calcium
    * Functional craniosynostosis
    * Respiratory compromise or rachitic chest deformity
    * Vitamin B6-dependent seizures
    * Failure to thrive
    - Onset of symptoms prior to 6 months of age
    - Chronological age of ≤ 5 years or adjusted age for premature infants born ≤ 37 weeks gestation
    - Otherwise medically stable in the opinion of the Investigator and/or Sponsor
    E.4Principal exclusion criteria
    Patients will be excluded from enrollment in this study if they meet any of the following exclusion criteria:
    - Clinically significant disease, such as, but not limited to, hepatitis C virus (HCV) / human immunodeficiency virus (HIV) / hepatitis B virus (HBV), that precludes study participation, in the opinion of the Investigator and/or Sponsor
    - Serum calcium or phosphate levels below the normal range
    - Serum 25-hydroxy (25[OH]) vitamin D below 20 ng/mL
    - 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 study drug or any of its excipients
    - Previous participation in the same study
    - Close relation to the Investigator
    E.5 End points
    E.5.1Primary end point(s)
    • Effect of asfotase alfa treatment on skeletal manifestations of HPP as measured by radiographs using a qualitative Radiographic Global Impression of Change (RGI-C) scale for all treated patients
    • Safety and tolerability of repeated subcutaneous (SC) injections of asfotase alfa for all treated patients
    E.5.1.1Timepoint(s) of evaluation of this end point
    Efficacy endpoint: screening visit, month 3, month 6, month 9, month 12, month 18, month 24, month 30, month 36, month 42, month 48;
    Safety endpoint: continuous monitoring
    E.5.2Secondary end point(s)
    - For patients who are not mechanically ventilated at the time of enrollment, the percentage who are alive and ventilator-free after receiving asfotase alfa as compared to an age-matched historical control group
    - Effect of asfotase alfa treatment on respiratory function as measured by ventilator status, time on respiratory support (including time on ventilator or supplemental oxygen), ventilator rate or oxygen volume, ventilator pressures, and fraction of inspired oxygen (FiO2) for all treated patients
    - Effect of asfotase alfa treatment on physical growth as measured by body weight, length, arm span, head circumference, and chest circumference for all treated patients
    - Effect of asfotase alfa treatment on tooth loss for all treated patients
    - PK properties of asfotase alfa
    - Effect of asfotase alfa on plasma inorganic pyrophosphate (PPi) and plasma pyridoxal-5'-phosphate (PLP)
    - Effect of asfotase alfa on serum parathyroid hormone (PTH)
    E.5.2.1Timepoint(s) of evaluation of this end point
    week-4 to day -8, day -1, day 1, day 2, day 3, week 3, week 6 day 1, week 6 day 3, month 3, month 6, month 9, month 12, month 15, month 18, month 24, month 30, month 36, month 42, month 48.
    Not all secondary endpoints are measured on the same day.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA10
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Canada
    France
    Germany
    Italy
    Japan
    Saudi Arabia
    Spain
    Taiwan
    Turkey
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Last visit of last subject
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 60
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Yes
    F.1.1.2.1Number of subjects for this age range: 14
    F.1.1.3Newborns (0-27 days) Yes
    F.1.1.3.1Number of subjects for this age range: 14
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 14
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 18
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception Information not present in EudraCT
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    F.3.3.3Pregnant women Information not present in EudraCT
    F.3.3.4Nursing women Information not present in EudraCT
    F.3.3.5Emergency situation Information not present in EudraCT
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Infants and children <= 5 years of age
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 30
    F.4.2.2In the whole clinical trial 60
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Patients will receive treatment with asfotase alfa until the product is registered and available to treat patients diagnosed with HPP (in accordance with country specific regulations) or for a maximum of 48 months, whichever occurs first.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-05-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-03-13
    P. End of Trial
    P.End of Trial StatusCompleted
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