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    EudraCT Number:2021-002639-48
    Sponsor's Protocol Code Number:54767414AMY2009
    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:2021-12-28
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2021-002639-48
    A.3Full title of the trial
    A Phase 2, Multicohort Study of Daratumumab-Based Therapies in Participants with Amyloid Light Chain (AL) Amyloidosis
    Estudio de fase 2, multicohorte, de tratamientos basados en daratumumab en participantes con amiloidosis de cadenas ligeras de amiloide (AL)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 2, Multicohort Study of Daratumumab-Based Therapies in Participants with Amyloid Light Chain (AL) Amyloidosis
    Estudio de fase 2, multicohorte, de tratamientos basados en daratumumab en participantes con amiloidosis de cadenas ligeras de amiloide (AL)
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code number54767414AMY2009
    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.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 CM
    B.5.4Telephone number+31715242166
    B.5.5Fax number+31715242110
    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. name DAZARLEX
    D. of the Marketing Authorisation holderJanssen-Cilag International NV
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/18/2020
    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 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 INNDaratumumab
    D.3.9.1CAS number 945721-28-8
    D.3.9.2Current sponsor codeJNJ-54767414
    D.3.9.3Other descriptive nameHuMax-CD38, 3003-005
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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. medicinal product typehuman 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
    Amyloid Light Chain Amyloidosis
    Amiloidosis de cadenas ligeras de amiloide
    E.1.1.1Medical condition in easily understood language
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.0
    E.1.2Level LLT
    E.1.2Classification code 10083938
    E.1.2Term Amyloid light-chain amyloidosis
    E.1.2System Organ Class 100000004870
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Cohort 1:
    - to characterize cardiac safety of different D-VCd treatment regimens in newly diagnosed systemic AL amyloidosis with cardiac involvement
    - to identify potential mitigation strategies for cardiac toxicity

    Cohort 2:
    - to characterize the PK of SC daratumumab, among racial and ethnic minorities with newly diagnosed systemic AL amyloidosis treated with D-VCd
    Cohorte 1:
    - caracterizar la seguridad cardíaca de diferentes regímenes de tratamiento con D-VCd en la amiloidosis AL sistémica de nuevo diagnóstico con afectación cardiaca
    - identificar posibles estrategias de mitigación de la toxicidad cardiaca

    Cohorte 2:
    - caracterizar la farmacocinética del daratumumab SC en distintas minorías raciales y étnicas con amiloidosis AL sistémica de nuevo diagnóstico tratada con DVCd
    E.2.2Secondary objectives of the trial
    - to evaluate efficacy measures
    - to assess the safety profile, including cardiac events
    - to characterize the PK of SC daratumumab
    - to assess the immunogenicity of SC daratumumab
    - to monitor the clinical signs and symptoms of cardiac AL amyloidosis to identify possible predictive factors for cardiac events
    - evaluar las medidas de la eficacia
    - evaluar el perfil de seguridad, incluidos los acontecimientos cardiacos
    - caracterizar la farmacocinética del daratumumab SC
    - evaluar la inmunogenia del daratumumab SC
    - estar atentos a los signos y síntomas clínicos de amiloidosis AL cardiaca para identificar posibles factores predictores de acontecimientos cardiacos
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - >/= 18 years of age.
    - New diagnosis of systemic AL amyloidosis based on both: (a) tissue deposition of amyloid in any organ other than bone marrow and (b) an underlying clonal plasma cell disorder as demonstrated by any one of the following:
    • Clonal plasma cells in the bone marrow
    • Monoclonal gammopathy in the serum or urine
    • Abnormal free light chain ratio
    - Measurable disease at screening defined by difference between iFLC and uninvolved FLC (dFLC) >/= 40mg/L per central laboratory
    - Cohort 1: Cardiac involvement (AL amyloidosis Mayo Cardiac Stage II and Stage IIIa; see Appendix 6) with or without other organ(s) involved
    - Cohort 2: One or more organs impacted by systemic AL amyloidosis according to consensus guidelines
    - Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1 or 2.
    - Pre-treatment clinical laboratory values meeting the following criteria during the Screening Phase:
    • Hemoglobin >/= 8.0 g/dL (>/= 5 mmol/L); red blood cell transfusion allowed until 7 days before randomization/enrollment
    • Platelets >/= 50×109/L; platelet transfusions are allowed until 7 days before randomization/enrollment
    • Absolute Neutrophil count >/= 1.0×109/L
    • Aspartate aminotransferase and alanine aminotransferase </= 2.5× ULN
    • Total bilirubin </= 1.5 × ULN; except in participants with congenital bilirubinemia, such as Gilbert syndrome (in which case direct bilirubin </= 2×ULN is required)
    • Estimated glomerular filtration rate >/= 20 mL/min/1.73 m2
    - A female participant of childbearing potential must have a negative serum or urine test at screening and within 72 hours of the first dose of study treatment and must agree to further serum or urine pregnancy tests during the study.
    - A female participant must be either of the following:
    a. Not of childbearing potential
    b. Of childbearing potential and practicing true abstinence or have a sole partner who is vasectomized or practicing at least 1 highly effective user independent method of contraception
    Contraception must begin 4 weeks prior to dosing and continue for 1 year after discontinuation of cyclophosphamide or 3 months after discontinuation of daratumumab, whichever is longer.
    - A male participant must wear a condom (with or without spermicidal foam/gel/film/cream/suppository) when engaging in any activity that allows for passage of ejaculate to another person during the study and for 6 months after discontinuation of cyclophosphamide or 3 months after discontinuation of daratumumab, whichever is longer. His female partner, if of childbearing potential, must also be practicing a highly effective method of contraception.
    If the male participant is vasectomized, he still must wear a condom (with or without spermicidal foam/gel/film/cream/suppository), but his female partner is not required to use contraception.
    - A female participant must agree not to donate eggs (ova, oocytes) or freeze for future use, for the purposes of assisted reproduction during the study and for a period of least 1 year after the last dose of cyclophosphamide or 3 months after discontinuation of daratumumab, whichever is longer.
    - A male participant must agree not to donate sperm for the purpose of reproduction during the study and for a minimum of 6 months after receiving the last dose of cyclophosphamide or 3 months after discontinuation of daratumumab, whichever is longer.
    - Signed an informed consent form (ICF).
    Cohort 2 only: self-identified racial and ethnic minorities, including Black or African American.
    - Edad >/= 18 años
    - Amiloidosis AL sistémica de nuevo diagnóstico, basado en : (a) depósitos tisulares de amiloide en cualquier órgano distinto de médula ósea, y (b) trastorno de plasmocitos clonales subyacente, demostrado por cualquiera de lo siguiente:
    • plasmocitos clonales en médula ósea
    • gammapatía monoclonal en suero u orina
    • cociente anormal de cadenas ligeras libres
    - enfermedad medible en la selección, que se define por la diferencia entre iFLC (cadenas ligeras libres involucradas) y FLC (cadenas ligeras libres no involucradas) (dFLC) >/= 40mg/L, según el laboratorio central
    - Cohorte 1: Afectación cardíaca (amiloidosis AL en estadios II y IIIa de la Clínica Mayo; véase el Apéndice 6), con o sin afectación de otro u otros órgano
    - Cohorte 2: Afectación de uno o más órganos por la amiloidosis AL sistémica según las normas del consenso
    - Puntuación del estado funcional del Eastern Cooperative Oncology Group (ECOG) de 0, 1 o 2.
    - Determinaciones de laboratorio antes del tratamiento que cumplen los siguientes criterios durante la Fase de Selección :
    • Hemoglobina >/= 8.0 g/dL (>/= 5 mmol/L); se permite la transfusión de hematíes hasta 7 días antes de la aleatorización/entrada en el estudio
    • Plaquetas >/= 50×109/L; se permite la transfusión de plaquetas hasta 7 días antes de la aleatorización/entrada en el estudio
    • Recuento absoluto de neutrófilos >/= 1.0×109/L
    • Aspartato aminotransferasq y alaninq aminotransferasq </= 2.5× límite superior de la normalidad (ULN)
    • Bilirrubina total </= 1.5 × ULN, excepto en los participantes con bilirrubinemia congénita, como síndrome de Gilbert (en cuyo caso se precisa una bilirrubina directa </= 2×ULN)
    • Tasa de filtración glomerular estimada >/= 20 mL/min/1.73 m2
    - Las mujeres participantes potencialmente fértiles deberán tener un resultado negativo de una prueba de embarazo (en suero u orina) en la selección y en el plazo de las 72 horas anteriores a la primera dosis del tratamiento del estudio; también deberán estar de acuerdo en que se les practiquen nuevas pruebas de embarazo (en suero u orina) durante el estudio.
    - Las mujeres participantes deben presentar una de las siguientes características:
    a. No ser potencialmente fértiles
    b. Si son potencialmente fértiles, deben practicar una abstinencia real o tener una sola pareja que está vasectomizada, o practicar como mínimo 1 método anticonceptivo altamente efectivo cuya eficacia no dependa de la usuaria
    Las medidas anticonceptivas deben iniciarse como mínimo 4 semanas antes del tratamiento y continuar hasta 1 año después de la suspensión de la ciclofosfamida o hasta 3 meses después de la suspensión del daratumumab, eligiéndose el mayor de estos plazos.
    - Los hombres participantes deben utilizar preservativos (con o sin espuma/gel/película/crema/ óvulo espermicidas) en toda actividad sexual que posibilite el paso del eyaculado a otra persona, durante el estudio y los 6 meses siguientes a la suspensión de la ciclofosfamida o los 3 meses de la suspensión del daratumumab, eligiéndose el mayor de estos plazos. También sus parejas femeninas, si son potencialmente fértiles, deben practicar un método anticonceptivo altamente efectivo.
    Aunque el varón participante esté vasectomizado, deberá seguir utilizando preservativos (con o sin espuma/gel/película/crema/óvulo espermicidas), pero no será necesario que su pareja femenina utilice un método anticonceptivo.
    - Las mujeres participantes deberán estar de acuerdo en no donar óvulos o congelarlos para su empleo futuro a fines de reproducción asistida, durante el estudio y durante un periodo de como mínimo 1 año después de la última dosis de ciclofosfamida o de 3 meses de la suspensión del daratumumab, eligiéndose el mayor de estos plazos .
    - Los varones participantes deberán estar de acuerdo en no donar semen a fines de reproducción, durante el estudio y durante un periodo de como mínimo 6 meses después de la última dosis de ciclofosfamida o de 3 meses después de la suspensión del daratumumab, eligiéndose el mayor de estos plazos.
    -Firma del documento de consentimiento informado (DCI).
    Solo en la Cohorte 2: minorías raciales y étnicas auto-identificadas, incluidos negros o afro-americanos.
    E.4Principal exclusion criteria
    - Prior therapy for systemic AL amyloidosis or multiple myeloma including medications that target CD38, with the exception of 160 mg dexamethasone or equivalent corticosteroid maximum exposure prior to randomization/enrollment.
    - Previous or current diagnosis of symptomatic multiple myeloma per International Myeloma Working Group (IMWG) Criteria.
    - Participant received any of the following therapies:
    a. treatment with an investigational drug or used an invasive investigational medical device within 14 days or at least 5 half-lives, whichever is less.
    b. vaccinated with an investigational vaccine (except for COVID-19, live attenuated or replicating viral vector vaccines within 4 weeks prior to randomization/enrollment.
    - Stem cell transplantation – Planned stem cell transplant during the first 9 cycles of protocol therapy are excluded. Stem cell collection during the first 9 cycles of protocol therapy is permitted.
    - Grade 2 sensory or Grade 1 painful peripheral neuropathy.
    - Evidence of significant cardiovascular conditions (as specified in protocol)
    - History of malignancy (other than AL amyloidosis) within 3 years before the date of randomization
    - Contraindications or life-threatening allergies, hypersensitivity, or intolerance to any study treatment or its excipients, including bortezomib, boron, mannitol, or cyclophosphamide or any of its metabolites
    - Known allergies, hypersensitivity, or intolerance to monoclonal antibodies, hyaluronidase, human proteins, or their excipients, or known sensitivity to mammalian-derived products
    - Pregnant or breastfeeding or planning to become pregnant while enrolled in this study or within 1 year after discontinuation of cyclophosphamide or 100 days after the last dose of daratumumab, whichever is longer
    - Plans to father a child while enrolled in this study or within 100 days after the last dose of study treatment
    - Chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) <50% of predicted normal
    - Moderate or severe persistent asthma within the past 2 years, or currently has uncontrolled asthma of any classification
    - Participant is known to be positive for human immunodeficiency virus (HIV), with 1 or more of the following:
    • Not receiving highly active antiretroviral therapy (ART)
    • Had a change in ART within 6 months of the start of screening
    • Receiving ART that may interfere with study treatment (consult Sponsor for review of medication prior to enrollment)
    • CD4 count <350 at screening
    • Acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within 6 months of start of screening
    • Not agreeing to start ART and be on ART >4 weeks plus having HIV viral load <400 copies/mL at end of 4-week period (to ensure ART is tolerated and HIV controlled)
    - Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HbsAg]). (Conditions for resolved infection are specified in protocol)
    - Known to be seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy).
    - Any serious underlying medical or psychiatric condition or disease, that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in this study, such as:
    • Evidence of serious active viral or bacterial infection, requiring systemic antimicrobial therapy, or uncontrolled systemic fungal infection.
    • Active autoimmune disease or a history of autoimmune disease within 2 years. EXCEPTION: Participants with vitiligo, type I diabetes, and prior autoimmune thyroiditis that is currently euthyroid based on clinical symptoms and laboratory testing are eligible regardless of when these conditions were diagnosed.
    • Disabling psychiatric conditions (eg, alcohol or drug abuse), severe dementia, or altered mental status.
    - Any other issue that would impair the ability of the participant to receive or tolerate the planned treatment at the study site, to understand informed consent or any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant or that could prevent, limit, or confound the protocol-specified assessments.
    - Major surgical procedure within 2 weeks before randomization/enrollment or has not fully recovered from an earlier surgical procedure, or has major surgical procedure planned during the time the participant is expected to participate in the study.
    - Any form of non-AL amyloidosis, including wild type or mutated (ATTR) amyloidosis.
    - Tratamiento previo de amiloidosis AL sistémica o de mieloma múltiple, lo que incluye medicamentos dirigidos frente a CD38, con la excepción de la recepción de como máximo 160 mg de dexametasona o la dosis equivalente de otro corticosteroide antes de la aleatorización/entrada en el estudio.
    - Diagnóstico previo o actual de mieloma múltiple sintomático según los criterios del IMWG
    - El participante ha recibido alguno de los siguientes:
    a. Tratamiento con un medicamento en fase de investigación o empleo de un producto sanitario invasivo en fase de investigación en el plazo de los 14 días anteriores o como mínimo 5 semividas del fármaco, eligiéndose el menor de estos .
    b. Vacunado con una vacuna experimental (excepto frente a la COVID-19, vacunas con vectores virales vivos atenuados o replicantes en el plazo de las 4 semanas anteriores a la aleatorización/entrada en el estudio
    -Trasplante de células madre – No podrán participar los sujetos que tengan programado un trasplante de células madre durante los 9 primeros ciclos del tratamiento del protocolo. Se permite la recogida de células madre durante los 9 primeros ciclos del protocolo.
    - Neuropatía periférica sensitiva de Grado 2 o dolorosa de Grado 1
    - Evidencia de enfermedades cardiovasculares importantes (de acuerdo a su especificación en el protocolo)
    - Antecedentes de neoplasia maligna (distinta de la amiloidosis AL) en el plazo de los 3 años anteriores a la fecha de la aleatorización
    - Contraindicaciones o alergias de riesgo vital, hipersensibilidad o intolerancia a cualquiera de los tratamientos del estudio o a sus excipientes, incluidos bortezomib, boro, manitol o ciclofosfamida o cualquiera de sus metabolitos
    - Conocimiento de alergias, hipersensibilidad o intolerancia a anticuerpos monoclonales, hialuronidasa, proteínas de origen humano o sus excipientes o conocimiento de hipersensibilidad a los productos derivados de mamíferos
    - Embarazo o lactancia o planificación de embarazo durante la participación en el estudio o en el plazo de 1 año después de la suspensión de la ciclofosfamida o dentro de los 100 días siguientes a la última dosis de daratumumab, eligiéndose el mayor de estos plazos
    - Planificación de engendrar un hijo por parte de un varón durante la participación este estudio o dentro de los 100 días siguientes a la última dosis del tratamiento del estudio
    -Enfermedad pulmonar obstructiva crónica (EPOC), con un volumen espiratorio forzado en 1 segundo (FEV1) <50% del teórico
    - Asma persistente moderado o severo en el curso de los 2 últimos años, o actualmente asma no controlado de cualquier clasificación
    - Conocimiento de positividad al virus de la inmunodeficiencia humana (VIH), con 1 o más de lo siguiente :
    • Sin tratamiento antirretroviral (TAR) altamente activo
    • El sujeto ha tenido un cambio en su TAR en el plazo de los 6 meses anteriores al inicio de la selección
    • En tratamiento con un TAR que puede interferir con el tratamiento del estudio (antes de la inclusión en el estudio, consúltese con el Promotor para la revisión de la medicación)
    • Recuento de CD4 <350 en la selección
    • Síndrome de inmunodeficiencia adquirida (sida) - definición de infección oportunista en el plazo de los 6 meses anteriores al inicio de la selección
    • No conformidad en iniciar TAR y seguir con TAR >4 semanas, más presentar una carga viral del VIH <400 Al término del periodo de 4 semanas (para comprobar la tolerancia del TAR y garantizar el control del VIH)
    - Seropositividad de hepatitis B (lo que se define como resultado positivo del antígeno de superficie de la hepatitis B [HbsAg]). (En el protocolo se especifican las condiciones para la definición de resolución de la infección)
    - Seropositividad de hepatitis C
    - Todo proceso o enfermedad médico o psiquiátrico grave que pudiera interferir con los procedimientos o los resultados del estudio o que, en opinión del investigador, suponga un riesgo para la participación en este estudio, como, por ejemplo:
    • Evidencia de infección bacteriana o vírica activa grave que precisa tratamiento o infección fúngica sistémica no controlada.
    • Enfermedad autoinmunitaria activa o antecedentes de enfermedad autoinmunitaria en los 2 años anteriores.
    • Trastornos psiquiátricos invalidantes (por ejemplo, alcoholismo o drogadicción), demencia severa o trastorno mental.
    - Cualquier otro problema que pueda afectar a la capacidad del participante para recibir o tolerar el tratamiento programado en el centro del estudio o para comprender el consentimiento informado
    - Procedimiento quirúrgico mayor en el plazo de las 2 semanas anteriores a la aleatorización/entrada en el estudio o sujeto que no se ha recuperado por completo de un procedimiento quirúrgico anterior o con programación de cirugía mayor durante su tiempo previsto de participación en el estudio
    - Cualquier forma de amiloidosis no Al, incluida la amiloidosis de tipo natural o mutada
    E.5 End points
    E.5.1Primary end point(s)
    Cohort 1:
    - incidence and severity of cardiac events

    Cohort 2:
    - C[trough]
    Cohorte 1:
    - Incidencia y severidad de los acontecimientos cardíacos

    Cohorte 2:
    - C[trough]
    E.5.1.1Timepoint(s) of evaluation of this end point
    Cohort 1: approximately 12-months after 120 participants have been randomized.

    Cohort 2: cycle 3 day 1 predose
    Cohorte 1: aproximadamente 12 meses después de la aleatorización de 120 participantes

    Cohorte 2: ciclo 3 día 1 antes de la dosis
    E.5.2Secondary end point(s)
    - Overall HemCR and HemCR rate at 6 months
    - Rate of VGPR or better
    - Time to HemCR (or VGPR or better)
    - Duration of response (HemCR and VGPR or better)
    - Organ response rate (OrRR) at 6 months and 12 months for kidney, heart, liver
    - Overall survival (OS)
    - Time to next treatment (TNT)
    - Incidence and severity of AEs
    - Pharmacokinetic profile of daratumumab
    - Immunogenicity of daratumumab and rHuPH20
    - Clinical signs and symptoms of cardiac AL amyloidosis
    - Tasas de Overall HemCR y de HemCR a los 6 meses
    - Tasa de VGPR o mejor
    - Tiempo hasta HemCR (o VGPR o mejor)
    - Duración de la respuesta (HemCR y VGPR o mejor)
    - Tasa de respuesta orgánica (Organ response rate, OrRR) a los 6 meses y 12 meses en riñón, corazón, hígado,
    - Supervivencia global (Overall survival, OS)
    - Tiempo hasta el siguiente tratamiento (Time to next treatment, TNT)
    - Incidencia y severidad de los acontecimientos adversos
    - Perfil farmacocinético del daratumumab
    - Inmunogenia de daratumumab y de rHuPH20
    - Signos y síntomas clínicos de amiloidosis AL cardiaca
    E.5.2.1Timepoint(s) of evaluation of this end point
    HemCR rate at 6 months
    OrRR at 6 and 12 months
    All other secondary end points during the conduct of the study.
    Tasa de HemCR a los 6 meses
    OrRR a los 6 y 12 meses
    Todos los demás criterios de valoración secundarios durante el desarrollo del 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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    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. trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 Yes
    E. trial design description
    Cohort 2 is not randomized
    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. description
    Cohort 1: different treatment schedule. VCd starting at cycle 1 day 1 or at cycle 4 day 1.
    E.8.2.4Number of treatment arms in the trial3
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA21
    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
    United Kingdom
    United States
    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
    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 months7
    E.8.9.1In the Member State concerned days12
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial days14
    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: 80
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 70
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 78
    F.4.2.2In the whole clinical trial 150
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Subjects will be instructed that study drug will not be available to them after they have completed/discontinued treatment and that they should return to their primary physician to determine standard of care (Prot Sect 6.7).Patients receiving daratumumab and who continue to benefit from the study treatment when study is over will have the option to continue on daratumumab treatment for a max of 2 year from the start of the study. Sponsor plans to provide study medication to these patients.
    Se informará a los sujetos de que no dispondrán del fármaco del estudio una vez que hayan completado el tratamiento, para su atención médica, deberán volver con su médico para determinar su tratamiento. Los pacientes que hayan recibido daratumumab y que continúen beneficiándose del tratamiento a la finalización del estudio, tendrán la opción de continuar con daratumumab un máximo de los 2 años siguientes al inicio del estudio. El promotor tiene previsto facilitarles la medicación del estudio.
    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 Decision2022-03-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-03-03
    P. End of Trial
    P.End of Trial StatusOngoing
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