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    Summary
    EudraCT Number:2016-003083-39
    Sponsor's Protocol Code Number:20140444
    Clinical Trial Type:Outside EU/EEA
    Date on which this record was first entered in the EudraCT database:2017-12-18
    Trial 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
    H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED
    Expand All   Collapse All
    A. Protocol Information
    A.2EudraCT number2016-003083-39
    A.3Full title of the trial
    A Phase 3 Randomized, Double-blind, Placebo-controlled, Parallel-group Study to Evaluate the Safety and Efficacy of Denosumab in Pediatric Subjects With Glucocorticoid-induced Osteoporosis
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to assess the safety and efficacy of denosumab vs. placebo in children with glucocorticoid-induced osteoporosis
    A.4.1Sponsor's protocol code number20140444
    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 States
    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 States
    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
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Glucocorticoid-induced Osteoporosis
    E.1.1.1Medical condition in easily understood language
    Osteoporosis caused by taking glucocorticoids
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10031287
    E.1.2Term Osteoporosis steroid-induced
    E.1.2System Organ Class 100000004859
    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 as assessed by dual-energy X-ray absorptiometry (DXA) at 12 months in
    children 5 to 17 years of age with glucocorticoid (GC)-induced osteoporosis (GiOP).
    E.2.2Secondary objectives of the trial
    To evaluate the effect of denosumab in children 5 to 17 years of age with GiOP with respect to:
    • Change in lumbar spine BMD Z-score as assessed by DXA from baseline to 6, 18, 24, and 36 months
    • Change in proximal femur BMD Z-score as assessed by DXA from baseline to 6, 12, 18, 24, and 36 months
    • Incidence of X-ray confirmed long-bone fractures and new and worsening vertebral fractures from pretreatment to posttreatment at 12, 24, and 36 months
    • Incidence of improving vertebral fractures from pretreatment to posttreatment at 12, 24, and 36 months (overall, among subjects with clinical fracture reduction, and among subjects with clinical fracture increase)
    • Incidence of pretreatment compared with posttreatment vertebral and nonvertebral fractures at 12, 24, and 36 months
    • Change in Childhood Health Questionnaire – Parent Form-50 (CHQ-PF-50) Physical Summary Score at 12, 24, and 36 months

    [For complete list of secondary objectives, 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 100 subjects
    to
    - determine serum concentration of denosumab at day 30 and month 3
    - evaluate changes observed in bone turnover markers (bone-specific alkaline phosphatase [BSAP], serum type I collagen C-telopeptide [sCTX]) at day 30 and month 3
    E.3Principal inclusion criteria
    • Male or female subjects, age 5 to 17 years, inclusive, at the time of informed consent
    • Clinical diagnosis of GiOP as defined by the following (and consistent with the International Society for Clinical Densitometry definition of osteoporosis in children and adolescents)
    − A confirmed diagnosis of non-malignant condition(s) requiring treatment with systemic GC (including, but not limited to, chronic rheumatologic, gastrointestinal, neurologic, respiratory, and/or nephrological conditions)
    o Subjects who are on systemic GC only as replacement therapy for adrenal insufficiency are not eligible for the study
    − Treatment with systemic GC (intravenous or oral) of any duration for the underlying non-malignant condition(s) within the 12 months prior to screening
    − Evidence of at least 1 vertebral compression fracture of Genant Grade 1 or higher, as assessed by the central imaging vendor on lateral spine X-rays performed at screening or within 2 months prior to screening; OR, in the absence of vertebral compression fractures, presence of both clinically significant fracture history (ie, ≥ 2 long-bone fractures by age 10 years or ≥ 3 long-bone fractures at any age up to 17 years) and lumbar spine BMD Z-score ≤ -2.0, as assessed by the central imaging vendor
    E.4Principal exclusion criteria
    • Current hyperthyroidism (unless well controlled on stable antithyroid therapy)
    • Current clinical hypothyroidism (unless well controlled on stable thyroid replacement therapy)
    • History of hyperparathyroidism
    • Current hypoparathyroidism
    • Duchenne muscular dystrophy with symptomatic cardiac abnormality
    • Current malabsorption
    • Active infection or history of infections
    • History of malignancy
    • History of any solid organ or bone marrow transplant
    • Evidence of untreated oral cavities or oral infections
    • Recent or planned invasive dental procedure
    • Surgical tooth extraction which has not healed by screening
    • Currently unhealed fracture or osteotomy, as defined by orthopedic opinion
    • Osteotomy within 5 months prior to screening
    • Spinal fusion surgery within 5 months prior to screening or not yet healed (per orthopedic
    surgeon)
    • Rodding surgery within 5 months prior to screening or not yet healed (per orthopedic
    surgeon)
    • Serum albumin-corrected calcium < lower limit of normal (LLN) or > 10% upper limit of normal
    (ULN) at screening
    • Serum vitamin D < 20 ng/mL at screening (rescreening for vitamin D level < 20 ng/mL will be
    allowed, after adequate supplementation)
    • Serum phosphorus < LLN at screening
    • Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5 x ULN (or
    > 5 x ULN in subjects with dystrophinopathies) at screening
    • Serum total bilirubin (TBL) > 1.5 x ULN at screening (subjects with Gilbert syndrome are
    eligible)
    • Positive blood screen for human immunodeficiency virus (HIV)-1 or -2 antibody
    • Positive blood screen for hepatitis B surface antigen or hepatitis C antibody
    • Estimated glomerular filtration rate < 60 mL/min/1.73 m2 at screening (calculated by the
    bedside Schwartz equation)
    • Less than 2 evaluable vertebrae by DXA evaluation in the region of interest L1-L4, as
    confirmed by the central imaging laboratory
    • Prior treatment for bone disease with any of the following at any time:
    − Denosumab, strontium, fluoride
    − Bisphosphonates (BP), according to the following guidelines
    o Zoledronic acid within 6 months prior to screening
    o Oral BP or intravenous BP other than zoledronic acid, if the first dose of investigational product would be before their next scheduled BP dose would have been given
    • Administration of any of the following treatment within 3 months prior to screening:
    − Growth hormone (unless on stable dose for at least 3 months prior to screening)
    − Calcitonin
    − Cathepsin K inhibitor
    − Other bone active drugs including anti-convulsants (except gabapentin and benzodiazepines) and heparin
    − Chronic systemic ketoconazole, androgens (except subjects who have received testosterone therapy for physiologic replacement in the setting of documented hormonal deficiency), cinacalcet, aluminum, lithium, protease inhibitors, gonadotropin releasing
    hormone agonists
    • Initiation of any of the following biologic agents within 4 weeks prior to screening:
    − Anti-alpha 4 integrin antibody (eg, natalizumab)
    − Anti-CD4/CD8 T-cells (eg, alefacept)
    − Anti-IL-12/IL-23 (eg, ustekinumab)
    − CTLA4 inhibitor (eg, abatacept)
    − IL1 receptor antagonist (eg, anakinra)
    − IL6 inhibitor (eg, tocilizumab)
    − Monoclonal antibody to CD20 (eg, rituximab)
    − Tumor necrosis factor antagonist (eg, adalimumab, certolizumab, golimumab, etanercept,
    infliximab)
    • Currently pregnant or planning a pregnancy during the study and for an additional 5 months after the last dose of investigational product
    • Currently breastfeeding or planning on breastfeeding during the study and for an additional 5 months after the last dose of investigational product
    • 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 investigational product
    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
    • Subject incidence of X-ray confirmed long-bone fractures and new and worsening
    vertebral fractures at 12, 24, and 36 months compared to pre-treatment
    • Subject incidence of improving vertebral fractures at 12, 24, and 36 months compared to
    pretreatment (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 pretreatment
    • 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 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 12, 24 and 36 months
    • Serum concentration of denosumab at 1, 10, and 30 days, and 3, 6, 12, and 18 months
    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 Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    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 Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 Will this trial be conducted at a single site globally? No
    E.8.4 Will this trial be conducted at multiple sites globally? Yes
    E.8.6 Trial involving sites outside the EEA
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3Specify the countries outside of the EEA in which trial sites are planned
    Canada
    Colombia
    India
    Korea, Republic of
    Russian Federation
    Turkey
    Ukraine
    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
    End of study: last subject last visit date
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    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: 81
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 69
    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 Yes
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.2 For a multinational trial
    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
    H.4 Third Country in which the Trial was first authorised
    H.4.1Third Country in which the trial was first authorised: Russian Federation
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