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    Summary
    EudraCT Number:2016-001205-16
    Sponsor's Protocol Code Number:54767414SMM3001
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-10-10
    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 number2016-001205-16
    A.3Full title of the trial
    A Phase 3 Randomized, Multicenter Study of Subcutaneous Daratumumab Versus Active Monitoring in Subjects with High-risk Smoldering Multiple Myeloma
    Estudio en Fase III, aleatorizado, multicéntrico con Daratumumab subcutáneo frente a monitorización activa en sujetos con Mieloma Múltiple Quiescente de alto riesgo.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study to compare the safety, effectiveness and pharmacokinetics (the way the body absorbs, distributes, and gets rid of a drug) of Daratumumab given through the subcutaneous route versus the active monitoring in patients with high risk smoldering multiple myeloma (precancerous form of blood cancer in the bone marrow)
    Un ensayo clínico para comparar la seguridad, eficacia y la farmacocinética (forma en la que el cuerpo absorbe, distribuye y elimina un medicamento) de
    daratumumab cuando se administra mediante una inyección bajo la piel en
    comparación con la monitorización activa en pacientes con mieloma múltiple quiescente de alto riesgo (forma precancerígena del cáncer hematológico en la médula ósea).
    A.4.1Sponsor's protocol code number54767414SMM3001
    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 SponsorJanssen-Cilag International N.V.
    B.1.3.4CountryBelgium
    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 supportJanssen Research & Development, LLC
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationJanssen-Cilag International N.V.
    B.5.2Functional name of contact pointClinical Registry group
    B.5.3 Address:
    B.5.3.1Street AddressArchimedesweg 29
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31715242166
    B.5.5Fax number+31715242110
    B.5.6E-mailClinicalTrialsEU@its.jnj.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 Yes
    D.2.5.1Orphan drug designation numberEU/3/13/1153
    D.3 Description of the IMP
    D.3.1Product nameDaratumumab co-formulated with recombinant human hyaluronidase (rHuPH20)
    D.3.2Product code JnJ 54767414
    D.3.4Pharmaceutical form 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 INNDARATUMUMAB
    D.3.9.1CAS number 945721-28-8
    D.3.9.2Current sponsor codeJnJ 54767414
    D.3.9.3Other descriptive nameHUMAX-CD38
    D.3.9.4EV Substance CodeSUB175772
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number120
    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
    Smoldering multiple myeloma
    Mieloma múltiple quiescente.
    E.1.1.1Medical condition in easily understood language
    Precancerous form of blood cancer in the bone marrow
    Forma precancerígena de cáncer hematológico en la médula ósea.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10028228
    E.1.2Term Multiple myeloma
    E.1.2System Organ Class 100000054086
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The main objective of this study is to determine whether treatment with daratumumab administered subcutaneously (SC) prolongs progression-free survival (PFS) compared with active monitoring in subjects with high-risk smoldering multiple myeloma (SMM).
    El objetivo principal es determinar si el tratamiento con daratumumab administrado por vía SC prolonga la supervivencia sin progresión (SSP) en comparación con la monitorización activa en pacientes con MMQ de alto riesgo.
    E.2.2Secondary objectives of the trial
    -To demonstrate additional clinical benefit (ORR, duration of response, OS, etc) for subjects
    with high-risk SMM treated with daratumumab compared with active monitoring
    - To assess the safety profile of daratumumab in subjects with high-risk SMM
    - To assess the clinical characteristics of symptomatic MM following progression of disease
    after therapy with daratumumab
    - To evaluate the PK and immunogenicity of daratumumab administered SC in subjects with
    high-risk SMM
    - To evaluate the immunogenicity of rHuPH20 when administered in combination with
    daratumumab SC in subjects with high-risk SMM
    - To evaluate the effect of treatment with daratumumab on health-related quality of life
    (HRQoL)
    • Demostrar otros efectos clínicos beneficiosos (TRG, duración de la respuesta, SG, etc.) en los pacientes con MMQ de alto riesgo tratados con daratumumab en comparación con la monitorización activa.
    • Evaluar el perfil de seguridad de daratumumab en pacientes con MMQ de alto riesgo.
    • Evaluar las características clínicas del MM sintomático después de la progresión de la enfermedad tras el tratamiento con daratumumab.
    • Evaluar la FC y la inmunogenicidad de daratumumab administrado por vía SC en pacientes con MMQ de alto riesgo.
    • Evaluar la inmunogenicidad de rHuPH20 cuando se administra en combinación con daratumumab SC en sujetos con MMQ de alto riesgo.
    • Evaluar el efecto del tratamiento con daratumumab en la calidad de vida relacionada con la salud (CdVRS).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Refer to protocol
    Each potential subject must satisfy all of the following criteria to be enrolled in the study:
    1. At least 18 years of age or at least the legal age of consent in the jurisdiction in which the study is taking place, whichever is the older age.
    2. Diagnosis of SMM for ≤5 years with measurable disease, defined as serum M protein ≥10 grams per litre (g/L) or urine M protein ≥200 milligrams (mg)/24 hours or involved serum free light chain (FLC) ≥100 milligrams per litre (mg/L) and abnormal serum FLC ratio.
    3. Bone marrow plasma cells (BMPCs) ≥10%; and
    At least 1 of the following;
    a. Serum M protein ≥30 g/L,
    b. Immunoglobulin A (IgA) SMM,
    c. Immunoparesis with reduction of 2 uninvolved immunoglobulin isotypes,
    d. Serum involved: uninvolved FLC ratio ≥8 and < 100, or
    e. Clonal BMPCs >50% to <60% with measurable disease.
    4. Eastern cooperative oncology group (ECOG) performance status score of 0 or 1.
    5. Pretreatment clinical laboratory values: refer to protocol
    6. Must sign an informed consent form (ICF) or their legally acceptable representative must sign indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study.
    7. Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for subjects participating in clinical studies. Women of childbearing potential must commit to either abstain continuously from heterosexual sexual intercourse or to use 1 method highly effective form of contraception (tubal ligation, intrauterine device, hormonal [birth control pills, injections, hormonal patches, vaginal rings or implants], or partner's vasectomy). Contraception must begin 4 weeks prior to dosing. Highly effective contraception is indicated even where there has been a history of infertility, unless due to hysterectomy.
    8. A woman of childbearing potential must have a negative serum or urine pregnancy test at screening within 14 days prior to randomization.
    9. During the study and for 3 months after receiving the last dose of daratumumab, a woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction.
    10. Willing and able to adhere to the prohibitions and restrictions specified in the protocol.
    Ver protocolo,
    Cada posible participante deberá cumplir todos los criterios siguientes para ser incluido en el estudio:
    1. Dieciocho años de edad como mínimo o la edad legal de consentimiento en la jurisdicción en la que tenga lugar el estudio, la que sea mayor.
    2. Diagnóstico de Mieloma Multiple Quiescente durante ≤ 5 años con enfermedad medible, definida como concentración sérica de proteína M≥ 10 g/l o proteína M en orina ≥ 200 mg/24 horas o cadenas ligeras sérica involucrada ≥ 100 mg/l y una proporción anormal de CLL en suero.
    3. CPMO ≥ 10%; y
    Al menos 1 de los siguientes:
    a. Proteína M sérica ≥ 30 g/l,
    b. MMQ de tipo IgA,
    c. Inmunoparesia con reducción de dos isotipos de inmunoglobulinas no involucradas,
    d. Cociente de CLL involucrada: no involucradas en suero ≥ 8 y < 100, o
    e. CPMO clonales > 50% a < 60% con enfermedad medible.
    4. Puntuación de capacidad funcional del ECOG de 0 o 1 (Anexo 1).
    5. Valores analíticos clínicos previos al tratamiento que cumplan los criterios siguientes durante la fase de selección:
    a. Recuento absoluto de neutrófilos ≥ 1,0 x 109/l (es decir, ≥ 1000/ µl).
    b Recuento de plaquetas ≥ 50 x 109/l (no se permite hacer transfusiones en las 2 semanas previas al recuento de plaquetas para alcanzar este nivel).
    c Aspartato aminotransferasa (AST) ≤ 2,5 veces el límite superior de la normalidad (LSN).
    d Alanina aminotransferasa (ALT) ≤ 2,5 x LSN.
    e Bilirrubina total ≤ 2,0 veces el LSN, excepto en sujetos con bilirrubinemia congénita, como síndrome de Gilbert (en cuyo caso se requiere una bilirrubina directa ≤ 2,0 veces el LSN).
    6. Firma del paciente o de su representante legal de un documento de consentimiento informado (DCI) en el que se declare que entiende el objetivo del estudio y los procedimientos que exige y que está dispuesto a participar en él.
    7. Uso de anticonceptivos tanto por varones como por mujeres que cumpla la normativa local aplicable al uso de métodos anticonceptivos para pacientes que participan en estudios clínicos.
    Las mujeres en edad fértil deberán comprometerse a abstenerse continuamente de mantener relaciones heterosexuales o a utilizar un método anticonceptivo muy eficaz (ligadura de trompas, dispositivo intrauterino, anticonceptivos hormonales [píldora, inyecciones, parches hormonales, anillos vaginales o implantes] o vasectomía de la pareja). La anticoncepción deberá comenzar 4 semanas antes de la administración. El uso de anticonceptivos muy eficaces está indicado incluso cuando existan antecedentes de infertilidad, a menos que se deban a una histerectomía.
    8. Las mujeres en edad fértil deberán obtener un resultado negativo en la prueba de embarazo en orina o en suero realizada en la selección en los 14 días previos a la aleatorización. Los requisitos durante la fase de tratamiento se pueden consultar en la sección 4.3.

    9. Durante el estudio y durante 3 meses después de recibir la última dosis de daratumumab, las mujeres deberán comprometerse a no donar óvulos (ovocitos) con fines de reproducción asistida.
    10. Pacientes dispuestos a respetar las prohibiciones y las restricciones especificadas en este protocolo y ser capaces de hacerlo.
    E.4Principal exclusion criteria
    Refer to protocol
    Any potential subject who meets any of the following criteria will be excluded from participating in the study:
    1. Multiple myeloma, requiring treatment, defined by any of the following:
    a. Bone lesions (one or more osteolytic lesions on low-dose whole body computed tomography [LDCT], positron-emission tomography with computed tomography [PET-CT] or computed tomography [CT])
    b. Hypercalcemia (serum calcium >0.25 mmol/L [>1 mg/dL] higher than ULN or >2.75 mmol/L [>11 mg/dL])
    c. Renal insufficiency, preferably determined by creatinine clearance <40 mL/min measured or estimated using the modification of diet in renal disease (MDRD), or serum creatinine >177 micro mole per litre (μmol/L)
    d. Anemia, defined as hemoglobin <10 gram per deci litre (g/dL) or >2 g/dL below lower limit of normal or both; transfusion support or concurrent treatment with erythropoietin stimulating agents is not permitted
    e. Clonal BMPC percentage ≥60%
    f. Serum FLC ratio (involved:uninvolved) ≥100 (The involved FLC must be ≥100 mg/L)
    g. More than 1 focal lesion ≥5 mm in diameter by magnetic resonance imaging (MRI)
    2. Primary systemic (immunoglobulin light chain) amyloidosis (AL)
    3. Exposure to any of the following
    a. Prior exposure to daratumumab or prior exposure to other anti-CD38 therapies
    b. Prior exposure to approved or investigational treatments for SMM or MM (including but not limited to conventional chemotherapies, immunomodulatory agent [IMiDs], or proteasome inhibitor [PIs]). Stable standard dosing of bisphosphonate as indicated for osteoporosis is acceptable.
    c. Exposure to investigational drug (including investigational vaccines) or invasive investigational medical device for any indication within 4 weeks or 5 half-lives, whichever is longer, before Cycle 1, Day 1
    d. Ongoing treatment with corticosteroids with a dose >10 mg prednisone or equivalent per day at the time of randomization; or >280 mg cumulative prednisone dose or equivalent for any 4-week period in the year prior to randomization
    4. Received treatment for a malignancy (other than SMM) within 3 years before the date of randomization (exceptions are squamous and basal cell carcinomas of the skin, carcinoma in situ of the cervix or breast, or other non-invasive lesion, which is considered cured with minimal risk of recurrence within 3 years.
    5. Either of the following:
    a. Known or suspected chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) <50% of predicted normal
    b. Moderate or severe persistent asthma within the past 2 years or currently has uncontrolled asthma of any classification (Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study)
    6. Any of the following:
    a. Known to be seropositive for human immunodeficiency virus (HIV)
    b. Known to be seropositive for hepatitis B (defined by a positive test for hepatitis B surface and antigen [HBsAg]) or with known prior hepatitis B infection without evidence of immunity (ie, subjects who are positive for antibodies to hepatitis B core antigen [anti-HBc] but negative for antibodies to hepatitis B surface antigen [anti-Hbs])
    c. Known to be seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at lease 12 weeks after completion of antiviral therapy)
    7. Medical or psychiatric condition or disease (eg, active systemic disease, uncontrolled diabetes) that is likely to interfere with the study procedures or results, or that in the opinion of the investigator, would constitute a hazard for participating in this study
    8. Clinically significant cardiac disease, including:
    a. Myocardial infarction within 6 months with left ventricular dysfunction or uncontrolled ischemic cardiac disease before Cycle 1 Day 1, or unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV)
    b. Uncontrolled cardiac arrhythmia (Grade 2 or higher by National Cancer
    Institute-Common Terminology Criteria for Adverse Events [NCI-CTCAE]
    Version 4.03) or clinically significant electrocardiogram (ECG) abnormalities
    c. Screening 12-lead ECG showing a baseline QT interval as corrected QT interval corrected for heart rate >470 msec
    The LDCT/PET-CT/CT performed for screening should be taken into consideration to determine if additional cardiac workup is required
    9. Known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies or human proteins, or their excipients, or known sensitivity to mammalian-derived products
    10. Vaccination with live attenuated vaccines within 4 weeks of first study agent administration
    11. Pregnant, breast-feeding, or planning to become pregnant while receiving study treatment or within 3 months after the last dose of daratumumab
    Ver protocolo,
    Se excluirá de participar en estudio a pacientes que cumplan alguno de criterios siguientes:
    1. Mieloma múltiple con necesidad de tratamiento,definido por cualquiera de los siguientes:
    a. Lesiones óseas(1 o más lesiones osteolíticas en TC de cuerpo entero en dosis bajas [TCDB],PET-TC o TC).
    b. Hipercalcemia(Ca sérico>0,25mmol/l[>1 mg/dlpor encima del LSN o >2,75mmol/l[>11mg/dl]).
    c. Insuficiencia renal,determinada preferiblemente por aclaramiento de creatinina<40ml/min medido o calculado mediante fórmula MDRD(Anexo2)o creatinina sérica>177µmol/l.
    d. Anemia,definida como una Hb<10g/dl o >2g/dl por debajo del límite inferior de normalidad o ambas;no se permite apoyo con transfusiones ni trat concomitante con fármacos estimuladores de eritropoyetina.
    e. Porcentaje de CPMO clonales ≥60%
    f. Cociente de CLL en suero(involucradas:no involucradas ≥100(valor de CLL involucradas debe ser ≥100mg/l).
    g. Más de 1 lesión focal≥5 mm de diámetro en la RM.
    2. Amiloidosis AL(cadenas ligeras de inmunoglobulinas)sistémica primaria.
    3. Exposición a cualquiera de los siguientes:
    a. Exposición previa a daratumumab o exposición prev a otros trat. anti-CD38.
    b. Exposición previa a trat. aprobados o en investigación para el MMQ o el MM(incluidos,entre otros,quimioterapias convencionales,IMiD o IP). Se acepta dosis habitual estable de bisfosfonatos cuando estén indicados para osteoporosis.
    c. Exposición al fármaco en investigación(incluidas vacunas experimentales) o a un producto sanitario en investigación invasivo para cualquier indicación en las 4semanas o el período equivalente a5 semividas,lo que suponga más tiempo,antes del día 1 del ciclo 1.
    d. Tratamiento en curso con corticosteroides con una dosis>10mg de prednisona o equivalente al día en el momento de la aleatorización;o dosis acumulada de prednisona>280 mg o equivalente durante cualquier período de 4semanas en el año prev a la aleatorización.
    4. Tratamiento para 1 neoplasia maligna(distinta del MMQ)en los 3 años prev a la fecha de la aleatorización(las excepciones son carcinomas espinocelulares y basocelulares de la piel,carcinoma in situ de cuello uterino o mama u otra lesión no invasiva,que se considera curada con 1 riesgo mínimo de recidiva en 3años.
    5. Cualquiera de los siguientes:
    a. Confirmación o sospecha de EPOC con un FEV1<50% del valor normal teórico.
    b. Asma persistente moderada o grave en los 2últimos años(véase el Anexo3)o asma no controlada de cualquier clasificación en actualidad.(Nota:se permite participación de pacientes que actualmente tengan asma intermitente controlada o asma persistente leve controlada).
    Se tendrá en cuenta la TCDB/PET-TC/TC realizada para selección para determinar si se precisa un estudio pulmonar adicional.
    6. Cualquiera de los siguientes:
    a. Seropositividad confirmada para el VIH.
    b. Seropositividad confirmada para la hepatitis B(definida por 1 prueba positiva para virus de superficie de hepB[HBsAg])o infección previa conocida por virus de hep B sin signos de inmunidad(es decir,sujetos con Ac contra el antígeno central del virus de la hepB[anti-HBc]pero sin anticuerpos contra el antígeno de superficie del virus de la hepB[anti-HBs]).
    c. Seropositividad confirmada para la hepatitisC (excepto en el contexto de una RVS), definida como la presencia de aviremia como mín 12semanas después de finalizar trat antiviral).
    7. Trastorno o enfermedad médica o psiquiátrica concurrente(p ej.,enf sistémica activa,diabetes no controlada)que probablemente interfiera con procedimientos o resultados del estudio o que,en opinión del invest.,supondría 1 peligro para la participación en estudio.
    8. Enf cardiaca de importancia clínica,p.ej:
    a. infarto de miocardio con disfunción ventricular izq o cardiopatía isquémica no controlada en 6meses previos al día 1 del ciclo 1 o enfermedad/proceso inestable o no controlado relacionado con o que afecta a la función cardíaca(p.ej.,angina inestable,insuf. cardíaca congestiva de clase III-IV de la NYHA)
    b. Arritmia cardíaca no controlada de grado2 o superior según CTCAE del NCI. versión 4.03 o anomalías electrocardiográficas clínicamente significativas.
    c. ECG de 12derivaciones en selección que muestra un intervalo QT basal corregido respecto a la frecuencia cardiaca>470 ms.
    Se tendrá en cuenta TCDB/PET-TC/TC realizada para selección para determinar si se precisa un estudio cardiaco adicional.
    9. El paciente presenta alergias,hipersensibilidad o intolerancia conocidas a los corticosteroides,a los Ac monoclonales o a las proteínas humanas, o a sus excipientes (véase el IB de daratumumab10)o hipersensibilidad conocida a productos derivados de mamíferos.
    10. Vacunación con vacunas de microbios vivos atenuados en las 4sem prev a la 1ª administración del fármaco del estudio
    11. Mujer embarazada,en periodo de lactancia o que planea quedarse embarazada durante tratamiento del estudio o en los 3meses siguientes a la última dosis de daratumumab.
    E.5 End points
    E.5.1Primary end point(s)
    Progression-free survival (PFS), defined as the time from the date of randomization to the date of initial documented progression to MM according to the international myeloma working group (IMWG) diagnostic criteria for MM or the date of death, whichever occurs first
    El criterio de valoración principal de este estudio es la SSP (que se define como el tiempo transcurrido desde la fecha de la aleatorización hasta la fecha inicial de la progresión documentada a MM según los criterios diagnósticos del IMWG para el MM o la fecha de la muerte, lo que antes ocurra).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Every 12 weeks until progressive disease
    Cada doce semanas hasta progresión de la enfermedad.
    E.5.2Secondary end point(s)
    1. Time to biochemical or diagnostic (SLiM-CRAB) progression defined as the earlier of time to the earlier of biochemical progression or diagnostic (SLiM-CRAB) progression
    2. Overall response rate (ORR), defined as, the proportion of subjects with a PR or better as defined by the IMWG response criteria
    3. Complete response (CR) rate, defined as, the proportion of subjects with a CR (or better) as defined by the IMWG response criteria
    4. Time to first-line treatment for MM, defined as, the time from the date of randomization to the date of the first-line treatment for MM
    5. Progression-free survival on first-line treatment for MM (PFS2), defined as, the time from the date of randomization to the date of documented progressive disease (PD) on the first-line treatment for MM or death, whichever comes first
    6. Overall survival (OS), defined as, the time from the date of randomization to the date of death
    7. Incidence of MM with adverse prognostic features, which include International Staging System Stage III (based on β2-microglobulin and albumin) and adverse cytogenetic characteristics
    8. Serum daratumumab PK concentrations and parameters including minimum observed concentration (Cmin) and maximum observed concentration (Cmax)
    9. Incidence of anti-daratumumab antibodies and anti-rHuPH20 antibodies
    10. Change from baseline in global health status and emotional functioning scales of the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)-C30, future perspective scale of the EORTC QLQ-MY20, and utility and visual analog scale of the European Quality of Life Five Dimensions Questionnaire (EQ-5D-5L)
    11. Duration of response, defined as date of onset of first response until date of disease progression or death
    12. Time to response, defined as the time from randomization until onset of first response
    Exploratory end point:
    13. Identification of novel biomarkers in relation to PFS/OS
    • Tiempo hasta la progresión bioquímica o diagnóstica (SLiM-CRAB), definido como el tiempo transcurrido hasta la progresión bioquímica o la progresión diagnóstica (slim-CRAB), lo que suceda antes (véase la sección 9.2.2 )
    • Tasa de respuesta global (TRG), definida como la proporción de sujetos con una RP o mejor, conforme a los criterios de respuesta del IMWG.
    • Tasa de respuesta completa (RC), definida como la proporción de sujetos con una RC (o mejor), conforme a los criterios de respuesta del IMWG.
    • Tiempo hasta el tratamiento de primera línea para el MM, definido como el tiempo transcurrido entre la fecha de aleatorización y la fecha del tratamiento de primera línea para el MM.
    • Supervivencia sin progresión con el tratamiento de primera línea para el MM (SSP2), definida como el tiempo transcurrido entre la fecha de aleatorización y la fecha de progresión documentada de la enfermedad (PE) durante el tratamiento de primera línea para el MM o la muerte, lo que ocurra antes
    • Supervivencia global (SG), definida como el tiempo transcurrido desde la fecha de la aleatorización hasta la fecha de la muerte.
    • Incidencia de MM con rasgos pronósticos adversos, que incluyen el estadio III (basado en la β2-microglobulina y la albúmina) del International Staging System y características citogenéticas adversas.
    • Concentraciones séricas y parámetros FC de daratumumab en suero, incluida la concentración mínima observada (Cmín) y la concentración máxima observada (Cmáx)
    • Incidencia de anticuerpos anti-daratumumab y anticuerpos anti-rhuph20.
    • Variación con respecto al valor basal del estado de salud general y las escalas de función emocional del cuestionario de calidad de vida (QLQ-C30) de la Organización Europea para la Investigación y el Tratamiento del Cáncer (EORTC), la escala de perspectiva futura del EORTC QLQ-MY20 y la escala de utilidad y la escala analógica visual del Cuestionario europeo de calidad de vida de cinco dimensiones (EQ-5D-5L).
    • Duración de la respuesta, definida como la fecha de inicio de la primera respuesta hasta la fecha de progresión de la enfermedad o la muerte.
    • Tiempo hasta la respuesta, definido como el tiempo transcurrido desde la aleatorización hasta el inicio de la primera respuesta.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1,2,3, 11 and 12. Every 12 weeks until progressive disease
    4&5. Every 6 months after PD duration until end of study
    6. Throughout study, and at least every 12 weeks until PD
    7. During screening and at the time of PD
    8. Pre dose on Cycle 1 Day 1, C3D1, C5D1, C7D1, C12D1, C24D1, and post dose C1D4, C3D4, and 28 (±3) days and 8 weeks after the last Daratumumab dose
    9. Pre dose on C1D1, C3D1, C5D1, C7D1, C12D1, C24D1, and 28 (±3) days and 8 weeks after the last Daratumumab dose
    10. C1D1, Week 12, 24, 60, then every year until the end of the the study or PD and then at Months 3, 6, 12, and 18 during post-PD follow-up
    13. At screening, 24, 48, and 96 weeks post randomization, end of treatment and during progressive disease
    1,2,3, 11 y 12. Cada 12semanas hasta progression de la enfermedad.
    4&5. Cada 6meses después de PE hasta el final del estudio.
    6. A lo largo del estudio y al menos cada doce semanas hasta PE.
    7. Durante la selección y en el momento de la PE.
    8. Predosis en Ciclo 1 Día 1, C3D1, C5D1, C7D1, C12D1, C24D1, y post-dosis en C1D4, C3D4, y 28 (±3) días y 8 semanas tras la última dosis de Daratumumab.
    9. Predosis en C1D1, C3D1, C5D1, C7D1, C12D1, C24D1, y 28 (±3) días y 8 semanas tras la última dosis de Daratumumab.
    10. C1D1, Semana 12, 24, 60, cada año hasta el final del estudio o PE y entonces en los meses 3,6,12 y 18 durante el seguimiento post-PE.
    13. En la selección, 24, 48, y 96 semanas post aleatorización, fin del tratamiento y durante PE.
    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 Yes
    E.6.13.1Other scope of the trial description
    Immunogenicity and Biomarker analyses
    Análisis de Inmunogenicidad y Biomarcadores.
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Monitorización Activa
    Active monitoring
    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 EEA68
    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
    Argentina
    Australia
    Belgium
    Brazil
    Canada
    China
    Czech Republic
    Denmark
    France
    Germany
    Greece
    Hungary
    Israel
    Italy
    Japan
    Mexico
    Netherlands
    Norway
    Poland
    Russian Federation
    Spain
    Sweden
    Turkey
    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 study is considered completed approximately 8 years after the first subject is randomized.
    El estudio será considerado completo aproximadamente 8 años después de que el primer sujeto sea aleatorizado.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years8
    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 years8
    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: 216
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 144
    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 state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 168
    F.4.2.2In the whole clinical trial 360
    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)
    At investigator treatment discretion
    Tratamiento a discreción del investigador.
    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 Decision2017-11-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-10-13
    P. End of Trial
    P.End of Trial StatusOngoing
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