E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Multiple Myeloma |
mieloma múltiple |
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E.1.1.1 | Medical condition in easily understood language |
Multiple Myeloma |
mieloma múltiple |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10028228 |
E.1.2 | Term | Multiple myeloma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main 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 |
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E.2.2 | Secondary 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 |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full 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. |
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E.3 | Principal 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. |
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E.4 | Principal 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 |
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E.5 End points |
E.5.1 | Primary 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. |
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E.5.1.1 | Timepoint(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) |
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E.5.2 | Secondary 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) |
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E.5.2.1 | Timepoint(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) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 90 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
European Union |
Australia |
Canada |
Hong Kong |
Japan |
Korea, Republic of |
Malaysia |
New Zealand |
Russian Federation |
Singapore |
Switzerland |
Taiwan |
Turkey |
United States |
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E.8.7 | Trial 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
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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. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |