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    Summary
    EudraCT Number:2010-020454-34
    Sponsor's Protocol Code Number:20090482
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-05-11
    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
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2010-020454-34
    A.3Full title of the trial
    A Randomized, Double-Blind, Multicenter Study of Denosumab Compared With Zoledronic Acid (Zometa) in the Treatment of Bone Disease in Subjects with Newly Diagnosed Multiple Myeloma
    Estudio multicéntrico, aleatorizado y doble ciego de denosumab en comparación con ácido zoledrónico (Zometa®) para el tratamiento de enfermedad ósea en sujetos con mieloma múltiple de nuevo diagnostico
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Denosumab Compared to Zoledronic Acid in the Treatment of Bone Disease in Subjects With Multiple Myeloma
    Denosumab en comparación con ácido zoledrónico para el tratamiento de enfermedad ósea en sujetos con mieloma múltiple
    A.4.1Sponsor's protocol code number20090482
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01345019
    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 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 code(CH-)6300
    B.5.3.4CountrySwitzerland
    B.5.4Telephone numberNANANANA
    B.5.5Fax numberNANANANA
    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 nameImmunoglobulin G2 Human Monoclonal Antibody to RANK Ligand
    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.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 Zometa
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm Limited
    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 nameZoledronic acid
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNZoledronic acid
    D.3.9.1CAS number 118072-93-8
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.8
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 No
    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
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboConcentrate for solution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Multiple Myeloma
    mieloma múltiple
    E.1.1.1Medical condition in easily understood language
    Multiple Myeloma
    mieloma múltiple
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10028228
    E.1.2Term Multiple myeloma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine if denosumab is non-inferior to zoledronic acid with respect to the first on-study occurrence of a skeletal related event (SRE) in subjects with multiple myeloma
    Determinar la no inferioridad de denosumab frente al ácido zoledrónico respecto a la primera aparición de un evento relacionado con el esqueleto (ERE) durante el estudio en sujetos con mieloma múltiple
    E.2.2Secondary objectives of the trial
    - To determine if denosumab is superior to zoledronic acid with respect to the first on-study SRE;
    - To determine if denosumab is superior to zoledronic acid with respect to the first and subsequent on-study SRE (multiple event analysis);
    - To assess the treatment effects of denosumab and zoledronic acid on progression-free survival and overall survival;
    - To assess the safety and tolerability of denosumab compared with zoledronic acid.
    - Determinar si denosumab es superior frente al ácido zoledrónico respecto a la primera aparición de un ERE durante el estudio
    - Determinar si denosumab es superior frente al ácido zoledrónico respecto a la primera y las siguientes apariciones de ERE durante el estudio (análisis de varios eventos)
    - Evaluar los efectos del tratamiento con denosumab y con ácido zoledrónico sobre la supervivencia libre de progresión y la supervivencia global
    - Evaluar la seguridad y la tolerabilidad de denosumab en comparación con el ácido zoledrónico
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Pharmacokinetic sub-study, 18 August 2011: Samples for measurement of serum denosumab concentration levels will be obtained on a subset of approximately 150 subjects prior to administration of the investigational products on study day 1, then weeks 5, 9, 13, 25, 49, and the end of treatment phase visit. The centers that will participate in this part of the study will be determined at the time of site selection, on the basis of center interest, site ability to obtain and process serum denosumab concentration samples, and recruitment capacity.
    The purpose of this sub-study is to evaluate the pharmacokinetic profile of denosumab when given at a dose of 120 mg every 4 weeks (Q4W) to newly diagnosed subjects with multiple myeloma.
    Subestudio de farmacocinética, 18 de agosto de 2011: Las muestras para determinar las concentraciones séricas de denosumab se obtendrán de un subconjunto de aproximadamente 150 sujetos al inicio del estudio, tal como se indica en el esquema de evaluaciones - día 1 del estudio y luego semanas 5, 9, 13, 25, 49 y visita de fin de la fase de tratamiento. Los centros que participarán en esta parte del estudio se determinarán en el momento de la selección de los centros, en función del interés del centro, de su capacidad para obtener y procesar muestras para determinar la concentración de denosumab, y de su capacidad para incluir sujetos.
    El propósito de este subestudio es evaluar el perfil farmacocinético de denosumab administrado a una dosis de 120 mg cada 4 semanas (Q4W) a los sujetos recién diagnosticados con mieloma múltiple.
    E.3Principal inclusion criteria
    - Adults with newly diagnosed multiple myeloma;
    - Radiographic evidence of at least 1 bone lesion;
    - Plan to receive primary frontline anti-myeloma therapies;
    - Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2;
    - Adequate organ function;
    - Written informed consent.
    - Adultos con mieloma múltiple de nuevo diagnostico;
    - Evidencia radiológica de al menos una lesión lítica ósea;
    - Plan para recibir un tratamiento antimieloma principal de primera línea;
    - Estado funcional del Eastern Cooperative Oncology Group (ECOG) de 0, 1 ó 2;
    - Función orgánica adecuada;
    - Consentimiento informado por escrito.
    E.4Principal exclusion criteria
    - Nonsecretory multiple myeloma (unless baseline serum free light chain level is elevated);
    - Plasma cell leukemia;
    - Polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (POEMS) syndrome;
    - Previous treatment with anti-myeloma therapy (does not include radiotherapy or a single short course of steroid [ie, less than or equal to the equivalent of dexamethasone 40 mg/day for 4 days]). Anti-myeloma therapy (excluding bisphosphonates) may be started before randomization if the subject has signed informed consent and screening blood samples have been collected for central analysis.
    - Planned radiation therapy or surgery to bone (does not include procedures;
    performed before randomization)
    - Prior administration of denosumab;
    - Prior or current IV bisphosphonate administration;
    - Use of oral bisphosphonates within the past 1 year;
    - Prior history or current evidence of osteonecrosis/ osteomyelitis of the jaw.
    - Mieloma múltiple no secretor (a menos que los niveles de cadenas ligeras libres basales estén elevados)
    - Leucemia de células plasmáticas
    - Polineuropatía, organomegalia, endocrinopatía, proteínas monoclonales y cambios en la piel (síndrome POEMS)
    - Tratamiento previo con un tratamiento antimieloma (no incluye radioterapia o un ciclo corto único de esteroides [es decir, inferior o igual al equivalente a dexametasona 40 mg/día durante 4 días]). El tratamiento antimieloma (con excepción de los bifosfonatos) puede iniciarse antes de la aleatorización si el sujeto ha firmado el consentimiento informado y se han recogido las muestras de sangre de selección para el análisis central
    - Radioterapia o cirugía ósea programadas (no incluye los procedimientos realizados antes de la aleatorización)
    - Administración previa de denosumab
    - Administración previa o en curso de bisfosfonatos IV
    - Uso de bisfosfonatos orales en el último año
    - Antecedentes o evidencia actual de osteonecrosis/osteomielitis mandibular
    E.5 End points
    E.5.1Primary end point(s)
    Time to the first on-study SRE (non-inferiority)
    SRE is an aggregate endpoint that includes pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression.
    Tiempo hasta el primer ERE durante el estudio (no inferioridad). Los ERE representan una variable agrupada que incluye las fracturas patológicas (vertebrales o no vertebrales), la radioterapia ósea (incluido el uso de radioisótopos), la cirugía ósea o la compresión de la médula espinal.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Primary analysis cut-off date is event-driven (i.e. when approximately 800 subjects have experienced at least one on-study SRE)
    Fecha de corte de los datos del análisis principal está dirigida por eventos (es decir cuando el sujeto número 800 presentará al menos un ERE durante el estudio)
    E.5.2Secondary end point(s)
    - Time to the first on-study SRE (superiority);
    - Time to the first-and-subsequent on-study SRE (superiority, using multiple event analysis);
    Additional Secondary Endpoints:
    - Progression-free survival (PFS);
    - Overall survival (OS);
    Safety Endpoints:
    - Subject incidence of treatment emergent adverse events;
    - Changes in laboratory values;
    - Incidence of anti-denosumab antibody (binding and neutralizing) formation.
    - tiempo hasta el primer ERE durante el estudio (superioridad)
    - tiempo hasta el primer y los siguientes ERE durante el estudio (superioridad, empleando un análisis de varios acontecimientos)
    Otras Variables Secundarias:
    - supervivencia libre de progresión (PFS)
    - supervivencia globval (OS)
    Variables de seguridad:
    - incidencia de sujetos con acontecimientos adversos relacionados con el tratamiento
    - cambios en los valores de laboratorio
    - incidencia de formación de anticuerpos antidenosumab (de unión y neutralizantes)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Primary analysis cut-off date is event-driven (i.e. when approximately 800 subjects have experienced at least one on-study SRE)
    Fecha de corte de los datos del análisis principal está dirigida por eventos (es decir cuando el sujeto número 800 presentará al menos un ERE durante el estudio)
    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 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) 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 concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA90
    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
    Canada
    European Union
    Hong Kong
    Japan
    Korea, Republic of
    Malaysia
    New Zealand
    Russian Federation
    Singapore
    Switzerland
    Taiwan
    Turkey
    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
    If denosumab is determined to have a positive benefit/risk profile compared with zoledronic acid, the end of the study is defined as approximately 4 weeks after the last dose of denosumab in the open-label treatment phase. If the benefit/risk profile is not positive, the end of the clinical study is defined as approximately 4 weeks after the last subject?s follow-up assessment, or withdrawal from study, in the survival follow-up phase.
    Si se determina que denosumab tiene un perfil beneficio/riesgo positivo en comparación con el ácido zoledrónico, el final del estudio se define como aproximadamente 4 semanas después de la última dosis de denosumab en la fase de tratamiento abierto. Si el perfil beneficio/riesgo no es positivo, el final del estudio clínico se define como aproximadamente 4 semanas después de la evaluación de seguimiento o de la retirada en la fase de seguimiento de la supervivencia del último sujeto del estudio.
    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 months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years6
    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: 560
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 960
    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.4.1In the member state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 600
    F.4.2.2In the whole clinical trial 1520
    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)
    For subjects ending participation in the blinded treatment phase before the open-label treatment phase, or if the benefit:risk profile is not positive, follow-up survival information will be collected by clinic visit or telephone contact every 12 weeks (+- 14 days) for 2 years after the last dose of IMP. Additionally, a serum sample to evaluate for the presence of anti-denosumab antibodies is to be obtained 24 weeks (approximately 6 months) after the last dose of investigational product.
    Para los sujetos que finalicen su participación en el estudio en la fase de tratamiento o si el perfil beneficio/riesgo no es positivo, se recogerán datos de seguimiento de la supervivencia mediante visitas a la clínica o contacto telef. cada12 semanas (+-14 días) durante2 años a partir de la última dosis del producto en investigación. Además, se obtendrán muestras de suero para evaluar la presencia de anticuerpos antidenosumab 24 semanas después de la última dosis del producto en investigación.
    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 Decision2012-06-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-06-14
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-03-29
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