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    Summary
    EudraCT Number:2014-000184-40
    Sponsor's Protocol Code Number:20130173
    National Competent Authority:Hungary - National Institute of Pharmacy
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-08-29
    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 ConcernedHungary - National Institute of Pharmacy
    A.2EudraCT number2014-000184-40
    A.3Full title of the trial
    Prospective, Multicenter, Single-arm Study to Evaluate Efficacy, Safety, and Pharmacokinetics of Denosumab in Children With Osteogenesis Imperfecta
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to Evaluate Efficacy, Safety, and Pharmacokinetics of Denosumab in Children With Osteogenesis Imperfecta
    A.4.1Sponsor's protocol code number20130173
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/058/2016
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAmgen, Inc.
    B.1.3.4CountryUnited Kingdom
    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 supportAmgen Inc
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAmgen (Europe) GmbH
    B.5.2Functional name of contact pointIHQ-Medical Info - Clinical Trials
    B.5.3 Address:
    B.5.3.1Street AddressDammstrasse 23, P.O Box 1557
    B.5.3.2Town/ cityZug
    B.5.3.3Post codeCH-6300
    B.5.3.4CountrySwitzerland
    B.5.6E-mailMedinfoInternational@amgen.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 Yes
    D.2.1.1.1Trade name XGEVA
    D.2.1.1.2Name of the Marketing Authorisation holderAmgen Europe B.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameDenosumab
    D.3.2Product code AMG 162
    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 INNDenosumab
    D.3.9.1CAS number 615258-40-7
    D.3.9.2Current sponsor codeAMG 162
    D.3.9.3Other descriptive nameDenosumab - Immunoglobulin G2 Human Monoclonal Antibody to RANK Ligand
    D.3.9.4EV Substance CodeSUB29173
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number70
    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
    Osteogenesis Imperfecta
    E.1.1.1Medical condition in easily understood language
    Osteogenesis Imperfecta
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level PT
    E.1.2Classification code 10031243
    E.1.2Term Osteogenesis imperfecta
    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 evaluate the effect of denosumab on lumbar spine bone mineral density (BMD) Z-score at 12 months, as assessed by dual-energy X-ray absorptiometry (DXA), in children 2 to 17 years of age with osteogenesis imperfecta (OI).
    E.2.2Secondary objectives of the trial
    To evaluate denosumab in children 2 to 17 years of age with OI with respect to:
    - Change in lumbar spine BMD Z-score, as assessed by DXA, at 6, 18, 24, and 36 months
    - Change in proximal femur BMD Z-score, as assessed by DXA, at 6, 12, 18, 24, and 36 months (in subjects 5 years of age and older)
    - Incidence of x-ray confirmed long bone and new and worsening vertebral fractures from pre-treatment to post-treatment at 12, 24, and 36 months
    - Incidence of improving vertebral fractures from pre-treatment to post-treatment at 12, 24, and 36 months (overall, among subjects with clinical fracture reduction, and among subjects with clinical fracture increase)
    - Incidence of pre-treatment compared with post-treatment vertebral and nonvertebral fractures at 12, 24, and 36 months
    + Exploratory and Safety objectives
    For complete list, please refer to the protocol
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    PK/bone turnover markers (BTM) substudy of approximately 50 subjects to
    - determine serum concentration of denosumab at 1 and 10 days and 6, 12, 18, 24, 30, and 36 months in all subjects
    - evaluate changes observed in bone turnover markers (bone-specific alkaline phosphatase [BSAP], serum type I collagen C-telopeptide [sCTX])
    E.3Principal inclusion criteria
    - Informed consent (to be provided by parent or legal guardian) and informed assent (to be provided by subjects when age-appropriate).
    - Children aged 2 to 17 years inclusive at screening
    - Clinical diagnosis of OI defined as a clinical history consistent with type I-IV OI as determined by presence of expected phenotype (examples include: facial shape, voice, blue sclera, dentinogenesis imperfecta, typical radiographic features, fracture pattern) and lack of additional features unrelated to type I-IV OI (eg, blindness, mental retardation, neuropathy, craniosynostosis; premature exfoliation of deciduous teeth)
    * If familial, also must be autosomal dominant
    - Clinical severity of OI as defined by
    o 2 or more prevalent vertebral compression fractures; OR
    o 1 prevalent vertebral compression fracture and 1 or more nonvertebral fractures within the previous 2 years; OR
    o 3 or more fractures within the previous 2 years
    E.4Principal exclusion criteria
    Subjects meeting any of the following criteria at screening are not eligible for enrollment:
    - Inability or unwillingness to comply with the requirements for frequent calcium and phosphorus monitoring for 14 days after the first dose of denosumab (only applies to the first 5 subjects age 11 to17 enrolled in the study and the first 5 subjects of any age meeting the criteria for increased bone turnover (see Section 2.3.2.1)
    - Currently unhealed fracture or osteotomy as defined by orthopedic opinion
    - Osteotomy within 5 months of screening
    - Evidence of untreated oral cavities or oral infections
    - Recent or planned invasive dental procedure
    - Surgical tooth extraction which has not healed by screening
    - History of an electrophoresis pattern inconsistent with type I to IV OI
    - History of known mutation in a gene other than COL1A1/COL1A2 causing OI or metabolic bone disease
    - Abnormalities of the following per central laboratory reference ranges at screening:
    o Serum albumin corrected calcium < lower limit of normal (LLN)
    o Serum vitamin D < 20 ng/mL; re-screening for Vitamin D level < 20 ng/mL will be allowed, after adequate supplementation
    o Aspartate aminotransferase (AST), alanine aminotransferase (ALT) > 1.5 x upper limit of normal (ULN)
    o Total bilirubin (TBL) > 1.5 x ULN (subjects with Gilbert syndrome are eligible)
    o Serum phosphorus < LLN
    o Serum alkaline phosphatase > 20% above the ULN or > 20% below the LLN
    - Estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 (calculated by the Schwartz equation at screening)
    - Evidence of any of the following:
    o Current hyperthyroidism (unless well-controlled on stable antithyroid therapy)
    o Current clinical hypothyroidism (unless well-controlled on stable thyroid replacement therapy)
    o History of hyperparathyroidism
    o Current hypoparathyroidism
    o Current, uncontrolled hypercalcemia (albumin-corrected serum Ca >10% ULN)
    o History of osteomalacia or rickets (chart review)
    o Other bone diseases that affect bone metabolism (eg, osteoporosis pseudoglioma syndrome, idiopathic juvenile osteoporosis, osteopetrosis, hypophosphatasia)
    o History of autoimmune disease
    o History of malabsorption (in children with serum albumin < LLN, malabsorption should be clinically ruled out by the PI to confirm eligibility)
    o History of rare hereditary problems of fructose intolerance
    o History of long QT syndrome
    o History of non-healing osteotomy
    o History of malignancy
    o History of alcohol or drug abuse
    o History of any solid organ or bone marrow transplant
    o Contraindicated or poorly tolerant of denosumab therapy
    - Positive blood screen for human immunodeficiency virus -1 or -2
    antibody
    - Positive blood screen for hepatitis B surface antigen or hepatitis C antibody
    - Currently pregnant or planning a pregnancy during the study and for an additional 5 months after the last dose of denosumab
    - For sexually active girls: refusal to use highly effective methods of contraception and to continue this practice for 5 months after the last injection of denosumab
    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline in lumbar spine BMD Z-score, as assessed by DXA, at 12 months.
    E.5.1.1Timepoint(s) of evaluation of this end point
    at 12 months
    E.5.2Secondary end point(s)
    - Change from baseline in lumbar spine BMD Z-score, as assessed by DXA, at 6, 18, 24, and 36 months
    - Change from baseline in proximal femur BMD Z-score, as assessed by DXA, at 6, 12, 18, 24, and 36 months (in subjects 5 years of age and older)
    - Subject incidence of x-ray confirmed long bone and new and worsening vertebral fractures at 12, 24, and 36 months compared to pre-treatment
    - Subject incidence of improved vertebral fractures at 12, 24, and 36 months compared to pre-treatment (overall, among subjects with clinical fracture reduction and among subjects with clinical fracture increase)
    - Subject incidence of vertebral and nonvertebral fractures at 12, 24, and 36 months compared to pre-treatment
    - Change from baseline in CHQ-PF-50 Physical Summary score at 12, 24, and 36 months
    - Change from baseline in CHQ-PF-50 Psychological Summary score at 12, 24, and 36 months
    - Change from baseline in CHAQ Disability Index score at 12, 24, and 36 months
    - Change from baseline in WBFPRS at 12, 24, and 36 months
    - Change from baseline in growth velocity (determined by calculating age-adjusted Z-scores for height, weight and BMI) at 36 months
    - Serum concentration of denosumab at 1 and 10 days, and 6, 12, 18, 24, 30, and 36 months
    - Serum concentration of denosumab at 1, 10, and 30 days, and 3, 6, 12, 18, 24, 30, and 36 months (PK/BTM substudy only)
    E.5.2.1Timepoint(s) of evaluation of this end point
    see list above
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 concerned1
    E.8.5The trial involves multiple Member States No
    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
    Australia
    Bulgaria
    Canada
    Czech Republic
    France
    Germany
    Hungary
    Poland
    Spain
    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
    the end of the trial is defined as the date when the last subject is last assessed for evaluation in the study, which corresponds to the month 36 visit.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    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 years6
    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: 150
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 80
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 70
    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 No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Subjects under age incapable of giving consent personally.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 94
    F.4.2.2In the whole clinical trial 150
    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)
    None
    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 Decision2014-10-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-10-14
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-03-28
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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