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    Summary
    EudraCT Number:2018-003523-11
    Sponsor's Protocol Code Number:CGP24112301
    National Competent Authority:Bulgarian Drug Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2019-05-09
    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 ConcernedBulgarian Drug Agency
    A.2EudraCT number2018-003523-11
    A.3Full title of the trial
    A randomized, double-blind, multicenter integrated phase I/III study in postmenopausal women with osteoporosis to compare the pharmacokinetics, pharmacodynamics, efficacy, safety and immunogenicity of GP2411 (proposed biosimilar denosumab) and Prolia® (EU-authorized)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The study is investigating the use of an investigational medication (GP2411, a proposed biosimilar medicine to Prolia®) for postmenopausal women with osteoporosis. The aim of study is to understand the efficacy and safety of the medication as well as how the medication is processed by the body and the effect it has on the body and/or the disease.
    A.3.2Name or abbreviated title of the trial where available
    ROSALIA
    A.4.1Sponsor's protocol code numberCGP24112301
    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 SponsorHexal AG
    B.1.3.4CountryGermany
    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 supportHexal AG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationHexal AG
    B.5.2Functional name of contact pointClinical Trial Information Desk
    B.5.3 Address:
    B.5.3.1Street AddressIndustriestr. 25
    B.5.3.2Town/ cityHolzkirchen
    B.5.3.3Post code83607
    B.5.3.4CountryGermany
    B.5.6E-mailbiosimilar.clinicaltrials@sandoz.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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameDenosumab
    D.3.2Product code GP2411
    D.3.4Pharmaceutical form Solution for injection in pre-filled syringe
    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 codeGP2411
    D.3.9.3Other descriptive nameDENOSUMAB
    D.3.9.4EV Substance CodeSUB29173
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    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 Yes
    D.3.11.13.1Other medicinal product typehuman IgG2 type monoclonal antibody
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    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 Prolia
    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 nameProlia
    D.3.4Pharmaceutical form Solution for injection in pre-filled syringe
    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.3.9.3Other descriptive nameDENOSUMAB
    D.3.9.4EV Substance CodeSUB29173
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    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 Yes
    D.3.11.13.1Other medicinal product typeHuman IgG2 type monoclonal antibody
    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
    Osteoporosis is defined as a progressive, systemic skeletal disorder characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Osteoporosis is estimated to affect 200 million women worldwide, approximately one-tenth of women aged 60, one-fifth of women aged 70, and two-fifths of women aged 80 (Johnell and Kanis 2006).
    E.1.1.1Medical condition in easily understood language
    Osteoporosis is defined as a progressive, systemic skeletal disorder characterized by low bone mass and microarchitectural deterioration of bone tissue.
    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 PT
    E.1.2Classification code 10031282
    E.1.2Term Osteoporosis
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10031285
    E.1.2Term Osteoporosis postmenopausal
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    - To demonstrate similar efficacy between GP2411 and EU-authorized Prolia, in terms of bone mineral density (EMA, FDA and PMDA)
    - To demonstrate similar PD between GP2411 and EU-authorized Prolia, in terms of the bone resorption marker CTX (EMA)
    - To demonstrate similar PK between GP2411 and EU-authorized Prolia (PMDA)
    E.2.2Secondary objectives of the trial
    - To demonstrate similar PD between GP2411 and EU-authorized Prolia, in terms of the bone resorption marker CTX (FDA and PMDA).
    - To compare GP2411 and EU-authorized Prolia in terms of PK, PD, efficacy, safety and immunogenicity.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients eligible for inclusion in this study must meet all of the following criteria:
    1. Signed informed consent must be obtained prior to participation in the study.
    2. Postmenopausal women, diagnosed with osteoporosis. Postmenopausal status is defined as at least 12 consecutive months of amenorrhea prior to date of screening, for which there is no other obvious pathological or physiological cause.
    3. Aged ≥ 55 and ≤ 80 years at screening
    4. Body weight ≥ 50 kg and ≤ 90 kg at screening
    5. Absolute bone mineral density consistent with T-score ≤ -2.5 and ≥ -4.0 at the lumbar spine as measured by DXA during the Screening Period
    6. At least two vertebrae in the L1-L4 region (wertebrae to be assessed by central reading of lateral spine X-ray during the Screening Period) and at least one hip joint are evaluable by DXA
    E.4Principal exclusion criteria
    Patients meeting any of the following criteria are not eligible for inclusion in this study.
    1. Use of other investigational drugs within 5 half-lives of the drug or until the expected pharmacodynamic effect of the drug has returned to baseline, whichever is longer, or longer if required by local regulations
    2. Previous exposure to denosumab (Prolia, Xgeva, or biosimilar denosumab)
    3. History of hypersensitivity to any recombinant protein drugs or any of the excipients used in GP2411 or Prolia (excipients detailed in Table 6-1)
    4. History and/or presence of one severe or more than two moderate vertebral fractures (as determined by central reading of lateral spine X-ray during the Screening Period)
    5. History and/or presence of hip fracture
    6. Presence of active healing fracture according to assessment of investigators
    7. History and/or presence of bone metastases (see also exclusion criterion #25), bone disease, metabolic disease (except osteoporosis) that may interfere with the interpretation of the results, e.g. Paget's disease, rheumatoid arthritis, ankylosing spondylitis, osteomalacia, osteogenesis imperfecta, osteopetrosis, Cushing's disease, hyperprolactinemia or malabsorption syndrome
    8. Ongoing use of any osteoporosis treatment (other than calcium and vitamin D supplements). Following rules for wash-out periods for osteoporosis treatments have to be adhered to:
    - Drugs being investigated for osteoporosis, e.g. romosozumab: dose received at any time
    - Strontium or fluoride (for osteoporosis): dose received at any time
    - Intravenous bisphosphonates: dose received within 5 years prior to screening
    - Oral bisphosphonates
     - > 3 years of cumulative use prior to screening
     - any dose received within 12 months prior to screening
    - Teriparatide or any PTH analogs: dose received within 12 months prior to screening
    - Tibolone, oral or transdermal estrogen, selective estrogen receptor modulators: dose received within 12 months prior to screening
    - Calcitonin: dose received within 6 months prior to screening
    - Cinacalcet: dose received within 3 months prior to screening
    9. Systemic glucocorticosteroids (≥ 5 mg prednisone equivalent per day for ≥ 10 days or a total cumulative dose of ≥ 50 mg) within the past 3 months before screening
    10. Other bone active drugs including heparin, anti-convulsives (with the exception of benzodiazepines), systemic ketoconazole, adrenocorticotropic hormone, lithium, gonadotropin releasing hormone agonists, anabolic steroids, within the past 3 months
    before screening
    11. Oral or dental conditions:
    - osteomyelitis or history and/or presence of osteonecrosis of the jaw (ONJ)
    - presence of risk factors for ONJ (e.g. periodontal disease, poorly fitting dentures, invasive dental procedures such as tooth extractions in 6 months before screening)
    - active dental or jaw condition which requires oral surgery
    - planned invasive dental procedure
    12. Current uncontrolled status of hypothyroidism or hyperthyroidism
    13. History and/or current hypoparathyroidism or hyperparathyroidism, irrespective of current controlled or uncontrolled status
    14. Vitamin D deficiency (25 [OH] vitamin D serum level <50 nmol/L
    [<20 ng/mL]). An Appropriate vitamin D dose in addition to vitamin D
    supplementation is permitted at the investigator's discretion and
    patients will be retested during the screening period or may be
    rescreened .
    15. Current hypocalcemia, defined as calcium <2.10 mmol/L
    [<8.42mg/dL] or hypercalcemia, defined as calcium >2.62 mmol/L
    [>10.50 mg/dL]; patients must have normal albumin values (32-55 g/L[3.2-5.5 g/dL]) according to
    central laboratory normal range.
    16. Known intolerance to, or malabsorption of calcium or vitamin D supplements
    17. History and / or presence of a severe allergic reaction (e.g. anaphylaxis)
    18. History and/or presence of significant cardiac disease as per investigator's discretion, including but not restricted to:
    - ECG abnormalities at screening indicating significant risk of safety for patients participating in the study
    - history and/or presence of myocardial infarction within 6 months before screening
    - history and/or presence of NYHA class III or IV heart failure
    19. Patients having at screening any of the following hematology values:
    - Hemoglobin < 10.0 g/dL [<100 g/L]
    - White blood cell (WBC) count < 3,500/μL [< 3.5 x 109 /L], or neutrophil count < 2,000/μL [< 2.0 x 109 /L, or platelet count < 125,000/μL [< 125 x 109 /L
    20. Renal impairment manifesting with an estimated glomerular filtration rate (eGFR) < 45 ml/min

    Other protocol-defined exclusion criteria may apply (please see protocol section 5.2 for full exclusion list)
    E.5 End points
    E.5.1Primary end point(s)
    - Percent change from baseline (%CfB) in lumbar spine BMD (LS-BMD)
    - Area under the effective curve (AUEC) of %CfB in serum CTX (only EMA)
    - Serum PK parameters AUCinf and Cmax
    E.5.1.1Timepoint(s) of evaluation of this end point
    - %CfB in LS-BMD at week 52 (FDA, EMA, PMDA)
    - AUEC after first dose (until week 26) of %CfB in sCTX
    - Serum PK parameters AUCinf and Cmax after first dose (until week 26)
    E.5.2Secondary end point(s)
    - AUEC of %CfB in sCTX (FDA, PMDA)
    - %CfB in BMD at lumber spine, femoral neck and total hip (LS-BMD, FN-BMD, TH-BMD)
    - PD markers: CTX and procollagen 1 N-terminal propeptide (P1NP) serum concentrations#
    - Safety : Fractures, vital signs , laboratory safety assessments , injection site reactions, electrocardiogram, (ECG), occurrence of adverse events (AE's) and serious AE's
    - Immunogenicity: Development of binding and neutralizing anti-drug antibodies (ADAs)
    - Serum PK parameters AUCinf and Cmax after first dose (only EMA)
    - Denosumab serum concentrations
    E.5.2.1Timepoint(s) of evaluation of this end point
    - AUEC after first dose (until week 26) of %CfB in sCTX (FDA, PMDA)
    - %CfB in LS-BMD, FN-BMD and TH-BMD at week 26, week 52 and week 78
    - PD markers: CTX and procollagen 1 N-terminal propeptide (P1NP) serum concentrations as per visit schedule from week 52 to week 78
    - Safety : Fractures, vital signs , laboratory safety assessments , injection site reactions, electrocardiogram, (ECG), occurrence of adverse events (AE's) and serious AE's from week 52 to week 78
    - Immunogenicity: Development of binding and neutralizing anti-drug antibodies (ADAs) from week 52 to week 78
    - Serum PK parameters AUCinf and Cmax after first dose (up until week 26, only EMA)
    - Denosumab serum concentrations as per visit schedule from week 52 to week 78
    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 Yes
    E.6.8Bioequivalence Yes
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Immunogenicity
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans Yes
    E.7.1.2Bioequivalence study Yes
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA34
    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
    Japan
    United States
    Bulgaria
    Poland
    Spain
    Czechia
    E.8.7Trial has a data monitoring committee No
    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
    Study completion is defined as the date when the last patient finishes the End of Study Visit/Early Termination Visit, or the date at which the last data point from the last patient is received, whichever is later.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    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 No
    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) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 147
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 345
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state160
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 356
    F.4.2.2In the whole clinical trial 492
    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)
    The investigator is advised to provide appropriate follow-up antiresorptive osteoporosis treatment for all patients completed the study, especially for those with high risk of fractures.
    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 Decision2019-08-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-07-18
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-04-22
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